PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T1	0-9	Sentence	denotes	COVID-19:
T2	10-63	Sentence	denotes	Is there a role for immunonutrition in obese patient?
T3	65-73	Sentence	denotes	Abstract
T4	74-231	Sentence	denotes	On December 12, 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19).
T5	232-370	Sentence	denotes	Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19.
T6	371-483	Sentence	denotes	In this context, immunonutrition can play a pivotal role in improving immune responses against viral infections.
T7	484-572	Sentence	denotes	Immunonutrition has been based on the concept that malnutrition impairs immune function.
T8	573-846	Sentence	denotes	Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patient outcomes.
T9	847-1037	Sentence	denotes	In literature, significant evidences indicate that obesity, a malnutrition state, negatively impacts on immune system functionality and on host defense, impairing protection from infections.
T10	1038-1151	Sentence	denotes	Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function.
T11	1152-1308	Sentence	denotes	Immune system dysfunction is considered to increase the risk of viral infections, such as SARS-CoV-2, and was observed in different pathological situations.
T12	1309-1506	Sentence	denotes	Obese patients develop severe COVID-19 sequelae, due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity.
T13	1507-1635	Sentence	denotes	Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response.
T14	1636-1825	Sentence	denotes	Additionally, gut microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system, as well as contributing to develop obese phenotype.
T15	1826-1969	Sentence	denotes	The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”.
T16	1970-2196	Sentence	denotes	This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this in turn can affect the gut microbiota.
T17	2197-2328	Sentence	denotes	Therefore, the modulation of gut microbiota in obese COVID-19 patients can play a key role in immunonutrition therapeutic strategy.
T18	2329-2515	Sentence	denotes	This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.
T19	2517-2527	Sentence	denotes	Background
T20	2528-2685	Sentence	denotes	On December 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19) [1].
T21	2686-2824	Sentence	denotes	Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19.
T22	2825-2956	Sentence	denotes	At the beginning of this pandemic, it was difficult to identify COVID-19 risk factors, that can be targeted for disease prevention.
T23	2957-3034	Sentence	denotes	Working on risk factors can, in fact, prevent infection and improve outcomes.
T24	3035-3157	Sentence	denotes	Now it is well known that obesity represents a significant risk factor both for COVID-19 susceptibility and prognosis [2].
T25	3158-3307	Sentence	denotes	Applying immunonutrition to obese patients can also prevent hospitalization, representing an additional risk factor for worsening COVID-19 prognosis.
T26	3308-3489	Sentence	denotes	Moreover, immunonutrition in obese patients may be a relevant strategy to lower the burden of COVID-19 disease [3], given that obesity affects almost 13% of people in the world [4].
T27	3490-3763	Sentence	denotes	The present umbrella review seeks to answer the question of whether a nutritional approach could be used to enhance the immune system’s response to obesity in patients affected by COVID-19, focusing on the interplay between immunonutrition, inflammation and gut microbiota.
T28	3765-3805	Sentence	denotes	Immune system, inflammation and COVID-19
T29	3806-3930	Sentence	denotes	The immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5].
T30	3931-4012	Sentence	denotes	A self-tolerance system prevents the immune response from damaging human tissues.
T31	4013-4075	Sentence	denotes	The immune system is always active, carrying out surveillance.
T32	4076-4326	Sentence	denotes	The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6].
T33	4327-4552	Sentence	denotes	The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors.
T34	4553-4827	Sentence	denotes	The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium.
T35	4828-5102	Sentence	denotes	Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system.
T36	5103-5163	Sentence	denotes	Both innate and adaptive immunity is mediated by leukocytes.
T37	5164-5385	Sentence	denotes	Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT).
T38	5386-5620	Sentence	denotes	From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells.
T39	5621-5732	Sentence	denotes	T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells.
T40	5733-5917	Sentence	denotes	The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig).
T41	5918-6000	Sentence	denotes	TCR is capable of binding the antigen processed by antigen-presenting cells (APC).
T42	6001-6223	Sentence	denotes	Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].
T43	6224-6368	Sentence	denotes	Following the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].
T44	6369-6527	Sentence	denotes	The activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2.
T45	6528-6930	Sentence	denotes	Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9].
T46	6931-7000	Sentence	denotes	Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).
T47	7001-7237	Sentence	denotes	The binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT).
T48	7238-7327	Sentence	denotes	Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription.
T49	7328-7823	Sentence	denotes	Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11].
T50	7824-7917	Sentence	denotes	IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis.
T51	7918-8089	Sentence	denotes	In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB).
T52	8090-8457	Sentence	denotes	NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation.
T53	8458-8565	Sentence	denotes	The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12].
T54	8566-8668	Sentence	denotes	PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated.
T55	8669-8804	Sentence	denotes	PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA.
T56	8805-8918	Sentence	denotes	TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes.
T57	8919-9042	Sentence	denotes	In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13].
T58	9043-9201	Sentence	denotes	Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14].
T59	9202-9419	Sentence	denotes	Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15].
T60	9420-9484	Sentence	denotes	The processes involved in antiviral immunity is shown in Fig. 1.
T61	9485-9558	Sentence	denotes	Fig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity.
T62	9559-9561	Sentence	denotes	B:
T63	9562-9823	Sentence	denotes	B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR:
T64	9824-9871	Sentence	denotes	Toll-like receptor; TNF: tumour necrosis factor
T65	9872-10100	Sentence	denotes	Normal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.).
T66	10101-10234	Sentence	denotes	Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.
T67	10235-10524	Sentence	denotes	Dysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].
T68	10525-10780	Sentence	denotes	SARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].
T69	10781-10936	Sentence	denotes	The access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18].
T70	10937-11100	Sentence	denotes	SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney.
T71	11101-11164	Sentence	denotes	SARS-CoV-2 enters the cell for endocytosis and membrane fusion.
T72	11165-11368	Sentence	denotes	Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19].
T73	11369-11522	Sentence	denotes	The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19.
T74	11523-11704	Sentence	denotes	Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20].
T75	11705-11974	Sentence	denotes	Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression.
T76	11975-12085	Sentence	denotes	The antiviral system functions well in the presence of general good health and an adequate genetic background.
T77	12086-12405	Sentence	denotes	However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21].
T78	12406-12762	Sentence	denotes	As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK).
T79	12763-13046	Sentence	denotes	BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor.
T80	13047-13161	Sentence	denotes	BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].
T81	13162-13333	Sentence	denotes	Interestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis.
T82	13334-13539	Sentence	denotes	BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].
T83	13540-13730	Sentence	denotes	During the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27].
T84	13731-13927	Sentence	denotes	Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients.
T85	13928-14033	Sentence	denotes	In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.
T86	14034-14276	Sentence	denotes	Inflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions.
T87	14277-14575	Sentence	denotes	In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts.
T88	14576-14715	Sentence	denotes	The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28].
T89	14716-14856	Sentence	denotes	As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30].
T90	14857-14948	Sentence	denotes	Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma.
T91	14949-15241	Sentence	denotes	Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20].
T92	15242-15507	Sentence	denotes	Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated.
T93	15508-15651	Sentence	denotes	The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.
T94	15652-15880	Sentence	denotes	Patients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32].
T95	15881-16014	Sentence	denotes	Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].
T96	16015-16201	Sentence	denotes	This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.
T97	16202-16339	Sentence	denotes	Immunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses.
T98	16340-16481	Sentence	denotes	This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses.
T99	16482-16595	Sentence	denotes	Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function.
T100	16596-16919	Sentence	denotes	Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].
T101	16920-17091	Sentence	denotes	Personalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients.
T102	17092-17184	Sentence	denotes	That therapeutic strategy could be effective in case of other potential epidemic infections.
T103	17185-17292	Sentence	denotes	It would also allow a reduction of the enormous medical care cost supported by the National Health Service.
T104	17294-17321	Sentence	denotes	Immunonutrition and obesity
T105	17322-17601	Sentence	denotes	According to the World Health Organization (WHO), obesity is defined as a condition in which percentage of body fat (PBF) is increased to an extent in which health and well-being are impaired, and, due to the alarming prevalence increase, declared it as a “global epidemic” [35].
T106	17602-17747	Sentence	denotes	It is characterized by a state of low-grade, chronic inflammation, in addition to altered levels of circulating nutrients and metabolic hormones.
T107	17748-17937	Sentence	denotes	The condition of obesity is a multifactorial pathology that can be related to an altered nutritional behaviour or secondary to genetic, hypothalamic, iatrogenic or endocrine disorders [36].
T108	17938-18039	Sentence	denotes	Underlining the importance of nutritional behaviour, it depends directly on food nutritional quality.
T109	18040-18125	Sentence	denotes	Obesity is considered as a malnutritional status due to the poor quality of the diet.
T110	18126-18207	Sentence	denotes	The chance to get healthy foods is largely determined by one’s own profitability.
T111	18208-18349	Sentence	denotes	Nowadays, the most vulnerable communities fight disadvantage conditions because of socioeconomic, educational, and environmental disparities.
T112	18350-18455	Sentence	denotes	People, who follow a poor quality of diet combined with economic disparity, are at major risk of obesity.
T113	18456-18577	Sentence	denotes	The expansion of fat mass, in turn, is linked to various chronic diseases, including cardiovascular disease and diabetes.
T114	18578-18756	Sentence	denotes	In the context of Covid-19 pandemic, these conditions affect severe outcomes from SARS-CoV-2 infection, as well as contribute to increasing the risk of mortality in general [37].
T115	18757-18834	Sentence	denotes	Adiposopathy, also known as “sick fat”, is at the basis of obesity condition.
T116	18835-18933	Sentence	denotes	It is defined as pathological dysfunction of both anatomical and functional within adipose tissue.
T117	18934-19072	Sentence	denotes	It is promoted by an excess of caloric energy intake and a sedentary lifestyle in genetically and environmentally susceptible individuals.
T118	19073-19164	Sentence	denotes	This latter may cause or worsen metabolic disease in adverse endocrine and immune response.
T119	19165-19334	Sentence	denotes	Modifiable lifestyle choices play a role in fat function and dysfunction, but the strong genetic component has a real chance on predisposition to dysfunctional fat [38].
T120	19335-19651	Sentence	denotes	The disruption of adipose tissue processes, as occurs in adipocyte hypertrophy and visceral fat accumulation, results in the production of pro-inflammatory components (like the plethora of cytokines) and adipocyte factors dysregulation, which may be both genesis and/or main contributors to metabolic disorders [39].
T121	19652-19747	Sentence	denotes	Adipose tissue is not only part of the endocrine system, but it is an active immune organ [40].
T122	19748-20024	Sentence	denotes	As an organ suitable to manage the adaptive and innate immune responses, in healthy lean individuals, its immune cells have the main role in the formation of extracellular matrix modelling, insulin sensitivity, adipogenesis, angiogenesis and clearance of apoptotic adipocytes.
T123	20025-20192	Sentence	denotes	On the contrary, during the expansion of adipose tissue like in obesity, inflammation results in adipocyte hypertrophy, cell death, fibrosis and metabolic dysfunction.
T124	20193-20320	Sentence	denotes	The inflammatory process, involving both innate and adaptive immune cells, plays an important role in adipose immunometabolism.
T125	20321-20453	Sentence	denotes	Among those, macrophages are fundamental for adipose tissue homeostasis and are most thoroughly studied in response to obesity [41].
T126	20454-20575	Sentence	denotes	As a result of the augmentation of the PBF in obesity, there is the proportional increment of adipose tissue macrophages.
T127	20576-20861	Sentence	denotes	Consequently, the system undergoes to a massive pro-inflammatory response resulting by adipose tissue secretion of pro-inflammatory factors, the adipocytes stimulation of inflammation-inducing factors in other tissues and the reduction of anti-inflammatory and protective factors [42].
T128	20862-21256	Sentence	denotes	Understanding the relationship between the adipose tissue, classified as an endocrine organ, and its immune function, the development of new therapeutic and immunonutritional strategies for obesity in COVID-19, may have important implications especially because it may act as a reservoir for more severe viral spread, with increased shedding, immune activation, and cytokine amplification [43].
T129	21257-21370	Sentence	denotes	In the cytokine storm milieu in obesity and COVID-19, over 50 adipokines with diverse roles have been identified.
T130	21371-21516	Sentence	denotes	Leptin, adiponectin, IL-6 and TNF-α mainly act in adipocyte metabolism, insulin sensitivity and metabolic disorders associated with obesity [44].
T131	21517-21692	Sentence	denotes	Leptin is an adipocyte-derived hormone with an important role in the central control of energy metabolism and with many pleiotropic effects in different physiological systems.
T132	21693-21832	Sentence	denotes	One of these is the regulatory role between energy metabolism and the immune system, being a pillar in the new concept of immunometabolism.
T133	21833-21943	Sentence	denotes	Leptin receptor, expressed overall in the immune system, acts in both innate and adaptive immune system cells.
T134	21944-22033	Sentence	denotes	As an adipokine, leptin is responsible for the inflammatory state found in overnutrition.
T135	22034-22130	Sentence	denotes	Moreover, in undernutrition status, it plays as crucial mediator of the immunosuppressive state.
T136	22131-22328	Sentence	denotes	New research frontiers for immunometabolic pathophysiology are considering leptin and leptin receptor as markers of inflammation and immune activation in the context of innate-adaptive system [45].
T137	22329-22436	Sentence	denotes	In the light of above mentioned, leptin represents a connection between metabolism and the immune response.
T138	22437-22548	Sentence	denotes	Its dysregulatory activity would have serious consequences during an eventual infection, such as COVID-19 [46].
T139	22549-22719	Sentence	denotes	By altering the metabolic setting, hyperleptinemia and insulin resistance in obesity disrupt T-cell function, resulting in a suppressed T-cell response to infection [47].
T140	22720-22909	Sentence	denotes	This metabolic condition compromises the immune response and leads patients to morbidity and mortality from SARS-CoV-2 infection, coupled with the lack of containing viral replication [46].
T141	22910-23038	Sentence	denotes	The pivotal role of IL-6 in mediating the acute phase response seems to interest the strategical treatment in COVID-19 patients.
T142	23039-23289	Sentence	denotes	Researches are still in progress and it would be intriguing to investigate whether people with obesity and higher circulating IL-6 levels, compared with lean controls, respond more favourably to IL-6 inhibition strategies in SARS-CoV-2 pandemic [43].
T143	23290-23394	Sentence	denotes	TNF-α is a pyrogen cytokine released in the acute phase of inflammation by macrophages and immune cells.
T144	23395-23516	Sentence	denotes	It is well known that during influenzae and viral infections, the expression of TNF-α in lung epithelial cells is higher.
T145	23517-23632	Sentence	denotes	In patients with COVID-19 and obesity, the IL-6 and TNF-α high serum levels are negatively associated with T-cells.
T146	23633-23727	Sentence	denotes	On the contrary, T cell levels are restored by reducing concentrations of both IL-6 and TNF-α.
T147	23728-23840	Sentence	denotes	These findings suggested that these cytokines could represent important targets of anti-COVID-19 therapies [48].
T148	23841-23937	Sentence	denotes	Infectious diseases, like COVID-19, are characterized by an increased production of adiponectin.
T149	23938-24239	Sentence	denotes	In fact, it seems that adiponectin can reduce innate and adaptive immune cell proliferation and polarization on two fronts: acting on the production blockage of pro-inflammatory cytokines such as TNF-α, IL-2, and IL-6, and enhancing the secretion of anti-inflammatory cytokines such as IL-10 [49, 50].
T150	24240-24340	Sentence	denotes	It seems interesting the possibility to improve the action of adiponectin through diet intervention.
T151	24341-24479	Sentence	denotes	A healthy lifestyle and a Mediterranean diet seem to ameliorate adiponectin levels in human, working on omega-3 biochemical pathways [51].
T152	24480-24608	Sentence	denotes	Finally, in light of the above, a possible COVID-19 therapy would combine drug therapy with a personalized immunonutrition [48].
T153	24609-24790	Sentence	denotes	Whereas healthy adipose tissue is essential to achieve a metabolic health status, sick inflamed fat leads to metabolic pathways dysregulation and different chronic pathologies [52].
T154	24791-25147	Sentence	denotes	According to what mentioned above and considering the endocrine and inflammatory role of the adipose tissue, it is necessary to classify obesity on the basis of body fat composition and distribution [53], rather than simply anthropometric measurements, e.g. Body Mass Index (BMI) classification, that could lead to a large error and misclassification [54].
T155	25148-25429	Sentence	denotes	As different phenotypes of obesity can be diagnosed according to percentage of total bodyfat mass (PBF), associated with an early inflammatory status, and high oxidative stress level [55], to identify obese subjects at risk of COVID-19 it is necessary to evaluate body composition.
T156	25430-25576	Sentence	denotes	Moreover, obesity and adiposopathy contribute to the pathways related to appetite regulation, fat storage and alteration of intestinal microbiota.
T157	25577-25683	Sentence	denotes	Dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases [56].
T158	25684-25785	Sentence	denotes	The impact of these metabolic abnormalities has undergone intense investigation over the past decade.
T159	25786-25944	Sentence	denotes	Although that, it is still not clear how the immune system and host defense are influenced by the pro-inflammatory and excess energy milieu of the obese [57].
T160	25945-26119	Sentence	denotes	There is strong evidence in literature indicating that abundant adiposity negatively impacts on immune system functionality and host defense in individuals with obesity [57].
T161	26120-26254	Sentence	denotes	In people with obesity, the caloric balance surplus is not directly proportional to the high nutritional food components quality [53].
T162	26255-26431	Sentence	denotes	Hence, the overfed malnourished patient may be compared to the underfed malnourishment, because malnutrition is considered the primary cause of immunodeficiency worldwide [58].
T163	26432-26529	Sentence	denotes	Chronic diseases, such as obesity, have been recognized as virulence factors for severe COVID-19.
T164	26530-26655	Sentence	denotes	These morbidities are usually coupled to protein-energy malnutrition, which is demonstrated to impair immune cell activation.
T165	26656-26756	Sentence	denotes	This process allows longer viral persistence and increased dealing of pro-inflammatory factors [59].
T166	26757-26867	Sentence	denotes	This will allow you to make a personalized emergency intervention, in all the subjects suffering from obesity.
T167	26868-27000	Sentence	denotes	In the onset of COVID-19 era, the nutritional approach might be managed in two different strategies, considering the disease status.
T168	27001-27232	Sentence	denotes	In a severe phase of COVID-19 in a patient with obesity, immunonutrition would be fundamental to support the immune response and protein synthesis, and, at the same time, to reduce inflammation caused by the pathological condition.
T169	27233-27388	Sentence	denotes	The organism fights both the acute inflammatory state triggered by COVID-19 and, in addition, the latent chronic inflammation due to the obesity condition.
T170	27389-27593	Sentence	denotes	This latter is employed in the case of malnourished surgical patients, where immunonutrition significantly reduced the risk of acquired infections, wound complications, and length of stay at the hospital.
T171	27594-27737	Sentence	denotes	In this context, immunomodulating diets (IMDs) have been demonstrated to improve immune system response and modulate inflammation cascade [60].
T172	27738-27966	Sentence	denotes	Furthermore, the nutritional approach should be firstly preventive to reduce the large number of complications linked to obesity condition; and, secondly, could be predictive to act on the etiopathogenesis of SARS-CoV-2 disease.
T173	27967-28080	Sentence	denotes	In the current pandemic panorama, the connection between nutrition science and virology takes a predictable turn.
T174	28081-28180	Sentence	denotes	It is worth that nutritional innovation must correlate all the previously treated clinical aspects.
T175	28181-28472	Sentence	denotes	By referring to WHO guidelines, it is fundamental to follow healthy eating habits and lifestyle to achieve an optimal health status supporting immune cells system, and to switch from an unhealthy condition of dysbiosis to a healthy condition of eubiosis and modulating systemic inflammation.
T176	28473-28592	Sentence	denotes	This is essentially possible pursuing a balanced diet based on the Mediterranean concept and staying physically active.
T177	28594-28656	Sentence	denotes	Immunonutrition: the role of specific nutrients and microbiota
T178	28657-28802	Sentence	denotes	An optimal nutritional status guarantees the main modulating processes of inflammatory and oxidative stress, both connected to the immune system.
T179	28803-28908	Sentence	denotes	The metabolic system applied for biosynthesis and energy request needs many different dietary components.
T180	28909-29117	Sentence	denotes	In fact, some nutrients and their metabolites are direct regulators of gene expression of the immune compartment and play a key role in the maturation, differentiation and responsiveness of immune cells [61].
T181	29118-29250	Sentence	denotes	It is easy to understand that an adequate and balanced supply of these nutrients is essential to set an appropriate immune response.
T182	29251-29385	Sentence	denotes	Basically, good nutrition creates a setting in which the immune system can respond appropriately to challenge, whatever this might be.
T183	29386-29497	Sentence	denotes	On the contrary, poor nutrition produces an environment in which the immune system cannot respond well [62–64].
T184	29498-29644	Sentence	denotes	Furthermore, nutritional status, the role of diet and lifestyle may play an important part in different severe infections, especially in COVID-19.
T185	29645-29823	Sentence	denotes	The importance of nutrition as a mitigation strategy to support immune function, is reachable identifying food groups and key nutrients as defense against respiratory infections.
T186	29824-30045	Sentence	denotes	A balanced diet, rich in some foods, is associated with anti-inflammatory and immunomodulatory compounds, including vitamins (C, D, and E) and minerals (zinc and selenium), and may influence human nutritional status [16].
T187	30046-30132	Sentence	denotes	During this COVID-19 pandemic many myths surfaced on how strengthen the immune system.
T188	30133-30266	Sentence	denotes	Several research publications have focused on the role of diet and specific nutrients, some focusing on respiratory viral infections.
T189	30267-30394	Sentence	denotes	The most of micronutrients have been identified as the main responsible for maintenance the complex needs of the immune system.
T190	30395-30488	Sentence	denotes	Below we will focus on the main nutrients with specific reference to respiratory health [65].
T191	30490-30509	Sentence	denotes	Omega 3 fatty acids
T192	30510-30658	Sentence	denotes	Reactive oxygen species create a pro-oxidant environment against which the body needs protection through vitamins, enzymes and antioxidant feedings.
T193	30659-30871	Sentence	denotes	Particularly, omega-3 fatty acids are known to exert anti-inflammatory and antioxidant properties [66, 67], and to support the immune system, specifically by helping to resolve the inflammatory response [63, 68].
T194	30872-31057	Sentence	denotes	The intake of omega-3 fatty acids from fish and seafood has been shown to trigger anti-inflammatory reactions via oxygenated metabolites (oxylipins), including resolvins and protectins.
T195	31058-31297	Sentence	denotes	Omega-3 fatty acids include linolenic acid (ALA) consumed from various plant sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumed especially from fish and seafood sources, such as salmon, mackerel, and tuna [69].
T196	31298-31509	Sentence	denotes	Notably, the omega-3 fatty acids EPA and DHA involved in the inflammation process, are enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins [66, 67].
T197	31510-31673	Sentence	denotes	These molecules, alongside with others, function together to orchestrate the resolution of inflammation and to support healing, including in the respiratory tract.
T198	31674-31796	Sentence	denotes	Deficiencies of omega-3 fatty acids EPA and DHA are accountable for delayed or suboptimal resolution of inflammation [70].
T199	31797-31959	Sentence	denotes	This could be very important in the context of severe COVID-19, which manifests as uncontrolled inflammation, the so-called cytokine storm, linked with ARDS [71].
T200	31961-31979	Sentence	denotes	Oleoylethanolamide
T201	31980-32143	Sentence	denotes	Oleoylethanolamide (OEA), synthesized in the gastrointestinal tract, is a bioactive lipid mediator derived from the omega-9 monounsaturated fatty acid, oleic acid.
T202	32144-32335	Sentence	denotes	Based on previous evidences, OEA showed anti-inflammatory activities, a role in modulation of immune response, anti-oxidant effects and stimulation of lipolysis and fatty acid oxidation [72].
T203	32336-32543	Sentence	denotes	In this context OEA is considered an endocannabinoid-like lipid, which interacts with the peroxisome proliferator-activated receptor-alpha (PPAR-α) and intervenes during the anti-inflammatory processes [73].
T204	32544-32762	Sentence	denotes	Scientific researchers recently showed that endocannabinoid system is involved in the management of infectious agents such as viruses, bacteria, and some protozoa, also reducing inflammation and pain in the lungs [74].
T205	32763-33074	Sentence	denotes	In view of the fact that SARS-CoV-2 infection leads to increase the pro-inflammatory cytokines, including IL-6 and IL-1β in COVID-19 patients via binding to the TLRs, an important components of the innate immune system, it is assumed that OEA inhibits this pathway through its anti-inflammatory properties [75].
T206	33075-33292	Sentence	denotes	OEA binds with high affinity to PPAR-α receptors and increases the expression level of anti-inflammatory cytokine such as IL-10, then initiates a cascade of events, which can attenuate the inflammatory responses [73].
T207	33293-33450	Sentence	denotes	Furthermore, OEA attenuates the inflammatory responses modulating the expression of TLR-4, and interfering with the ERK1/2/AP-1/STAT3 signaling cascade [73].
T208	33451-33598	Sentence	denotes	OEA may modulate cross-talk between PPAR-α and TLRs and regulates the inflammatory responses with beneficial synergistic effect against SARS-CoV-2.
T209	33599-33934	Sentence	denotes	Nowadays, discovering therapeutic options from currently available agents appears to be essential for the treatment and prophylaxis of this pandemic, especially in obese patients with comorbidities [76] and this bioactive lipid mediator can be considered as a novel potential pharmacological alternative for the management of COVID-19.
T210	33936-33945	Sentence	denotes	Vitamin A
T211	33946-34078	Sentence	denotes	The role of vitamin A and its metabolites in the immune system and host susceptibility is discussed in a series of reviews [77, 78].
T212	34079-34398	Sentence	denotes	This nutrient is involved in normal differentiation of epithelial tissue, furthermore retinoic acid is essential for imprinting T and B cells with gut-homing specificity and T array cells and IgA cells in intestinal tissues [79], thus enhancing the intestinal immune response and supporting the intestinal barrier [80].
T213	34399-34624	Sentence	denotes	Carotenoids (both provitamin A and non-provitamin A carotenoids) have immunoregulatory actions including the reduction of the toxic effects of ROS and the regulation of membrane fluidity and gap-junctional communication [81].
T214	34625-34753	Sentence	denotes	Vitamin A deficiency impairs barrier function, impairs immune responses and increases susceptibility to a variety of infections.
T215	34754-34859	Sentence	denotes	Furthermore, many aspects of innate immunity, in addition to barrier function, are affected by vitamin A.
T216	34860-35084	Sentence	denotes	For example, vitamin A regulates the number and function of NK cells [82], contributes to the phagocytic and oxidative activity of the macrophage burst [79] and controls the maturation of neutrophils and its deficiency [83].
T217	35085-35167	Sentence	denotes	The activity of natural killer cells is therefore reduced by vitamin A deficiency.
T218	35168-35320	Sentence	denotes	The impact of vitamin A on acquired immunity is however clear since it is involved in the development and differentiation of Th1 and Th2 cells [62, 79].
T219	35321-35508	Sentence	denotes	Moreover there is evidence that vitamin A deficiency alters the balance of Th1 and Th2 cells, decreasing the Th2 response, without affecting or, in some cases, enhancing the Th1 response.
T220	35509-35586	Sentence	denotes	This suggests that vitamin A increases the Th1 cell average in immunity [84].
T221	35587-35920	Sentence	denotes	However, studies in several experimental models have shown how the retinoic acid metabolite of vitamin A reduces the responses of Th1-type cells (cytokines, cytokine receptors and the transcription factor T-bet, which promotes Th1), improving responses to Th2-type cells (cytokines and Th2-favoring transcription factor GATA-3) [62].
T222	35921-36063	Sentence	denotes	Indeed, it maintains the normal Th2 response mediated by antibodies by suppressing the production of IL-12, TNF-α and IFN-γ by Th1 cells [85].
T223	36064-36259	Sentence	denotes	Vitamin A appears to be important in the differentiation of regulatory T lymphocytes by suppressing Th17 differentiation, which have implications for the control of adverse immune reactions [86].
T224	36260-36439	Sentence	denotes	It helps regulate the production of IL-2 and the pro-inflammatory TNF-γ, which activates the phagocytic and oxidative action of the macrophages activated during inflammation [79].
T225	36440-36563	Sentence	denotes	It ensures the normal functioning of B lymphocytes, necessary for the generation of antibody responses to the antigen [85].
T226	36564-36750	Sentence	denotes	Retinoic acid appears to promote the movement of T cells to gut-associated lymphoid tissue and, interestingly, some gut-associated immune cells are able to synthesize retinoic acid [87].
T227	36751-36927	Sentence	denotes	Vitamin A deficiency is associated with increased morbidity and mortality in children and appears to predispose to respiratory infections, diarrhea and severe measles [88, 89].
T228	36928-37058	Sentence	denotes	Moreover, supplementing vitamin A in deficient children improves recovery from infectious diseases and reduces mortality [78, 90].
T229	37059-37152	Sentence	denotes	The Recommended Dietary Allowance (RDA) for vitamin A reports a range of 900–700 µg/day [91].
T230	37154-37163	Sentence	denotes	Vitamin C
T231	37164-37274	Sentence	denotes	The role of vitamin C in immunity and in host susceptibility to infection has been scientifically proven [92].
T232	37275-37435	Sentence	denotes	Vitamin C, in fact, is necessary for the biosynthesis of collagen and is essential for maintaining epithelial integrity and protecting against oxidative stress.
T233	37436-37683	Sentence	denotes	It protects cell membranes from damage caused by free radicals, so as to support the integrity of the epithelial barriers [79], also improves keratinocytic differentiation and lipid synthesis as well as fibroblast proliferation and migration [92].
T234	37684-38099	Sentence	denotes	It plays a role in various aspects of immunity, in fact it is involved in the proliferation, function and movement of neutrophils, monocytes and phagocytes [82] and the migration of leukocytes to sites of infection, phagocytosis and bacterial killing, in the activity of natural killer cells and in the function of T lymphocytes (especially CD8 cytotoxic T lymphocytes) and in the production of antibodies [79, 82].
T235	38100-38323	Sentence	denotes	Vitamin C is also involved in apoptosis and elimination of depleted neutrophils from macrophage infection sites [92] and attenuates the formation of extracellular trap (NET), thus reducing the associated tissue damage [92].
T236	38324-38457	Sentence	denotes	Infections have a significant impact on vitamin C levels, due to the increased energy needs required by the body during inflammation.
T237	38458-38597	Sentence	denotes	This nutrient, in fact, promotes the proliferation of lymphocytes, with a consequent increase in the generation of antibodies [79, 85, 92].
T238	38598-38868	Sentence	denotes	It is well known that infections increase oxidative stress and usually activate phagocytes that release ROS, so vitamin C is a well-known antioxidant that can counteract these effects by increasing phagocytosis and ROS generation and improving microbial killing [92–94].
T239	38869-38994	Sentence	denotes	Furthermore, supplementation with vitamin C appears to be able to prevent and treat respiratory and systemic infections [92].
T240	38995-39172	Sentence	denotes	High levels of this nutrient can enhance antimicrobial effects and increase serum levels of complement proteins, also playing an important role in IFN-γ production [85, 92, 95].
T241	39173-39296	Sentence	denotes	Low levels of vitamin C are responsible for an increased susceptibility to severe respiratory infections such as pneumonia.
T242	39297-39487	Sentence	denotes	Indeed, a meta-analysis reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with a low dietary intake of this nutrient [96].
T243	39488-39699	Sentence	denotes	Vitamin C supplementation has also been demonstrated to reduce the duration and severity of upper respiratory tract infections, such as the common cold, especially in people under increased physical stress [96].
T244	39700-39804	Sentence	denotes	Currently, there are limited recommendations for taking vitamin C supplementation against COVID-19 [97].
T245	39805-39974	Sentence	denotes	Nevertheless, there is sufficient evidence to conduct several clinical trials to assess vitamin C efficacy in COVID-19 prevention and treatment (www.clinicaltrials.gov).
T246	39975-40064	Sentence	denotes	Previously, doses of 1–2 g/day were effective in preventing upper respiratory infections.
T247	40065-40209	Sentence	denotes	As those levels are not attainable through dietary sources, supplementation may be advised for those at a higher risk of respiratory infections.
T248	40210-40284	Sentence	denotes	Doses above 200 mg/day may not be beneficial for healthy individuals [98].
T249	40286-40295	Sentence	denotes	Vitamin D
T250	40296-40418	Sentence	denotes	Many reviews discuss the role of vitamin D and its metabolites in host immunity and susceptibility to infections [99–101].
T251	40419-40645	Sentence	denotes	Vitamin D receptors have been identified in most immune cells, of which some can also synthesize the active form of vitamin D from its precursor, therefore suggesting that might have important immunoregulatory properties [99].
T252	40646-40812	Sentence	denotes	Vitamin D is synthesized at skin level in the presence of UV-light from cholesterol and it is also taken up from the diet (fish, eggs, fortified milk, and mushrooms).
T253	40813-41120	Sentence	denotes	The active form of vitamin D, calcitriol (1,25-dihydroxy vitamin D3), formed following kidney and liver hydroxylation, is most renowned for its regulating role in calcium homeostasis and bone health status, but it has also been shown to regulate the immune system, mainly in the functioning of T-cell [102].
T254	41121-41395	Sentence	denotes	Among the main functions of vitamin D, its ability to improve the integrity of the epithelium has mainly been observed as well as the ability to induce the synthesis of an antimicrobial peptide in epithelial cells and macrophages, thus directly improving host defense [103].
T255	41396-41605	Sentence	denotes	Vitamin D also promotes the differentiation of monocytes from macrophages [95], promotes the movement and phagocyability of macrophages [79], superoxide production and bacterial killing by innate immune cells.
T256	41606-41689	Sentence	denotes	Hence, it promotes the processing of antigen presentation by dendritic cells [104].
T257	41690-41837	Sentence	denotes	Calcitriol regulates the expression of antimicrobial proteins (cathelicidin and defensin), which directly kill pathogens, especially bacteria [99].
T258	41838-42017	Sentence	denotes	It inhibits the production of IFN-γ [71] and reduces the expression of pro-inflammatory cytokines by increasing the expression of anti-inflammatory cytokines by macrophages [105].
T259	42018-42225	Sentence	denotes	Calcitriol modulates antimicrobial proteins (cathelicidin and β-defensin), responsible for modifying the intestinal microbiota, favoring a healthy composition and supporting the intestinal barrier [80, 106].
T260	42226-42478	Sentence	denotes	It also helps protect the lungs against infection, increases the expression of the tight junction protein, E-cadherin and connexion 43 in the intestine, maintains renal-epithelial barrier function and improves corneal epithelial barrier function [104].
T261	42479-42662	Sentence	denotes	The 1,25-dihydroxyvitamin D3 can bind to a specific nuclear receptor (vitamin D receptor, VDR) and its role for both the innate and adaptive immune systems has been highlighted [107].
T262	42663-42767	Sentence	denotes	Moreover, vitamin D has been controversially discussed for its role in influenza prevention and therapy.
T263	42768-42910	Sentence	denotes	As shown in literature, 1,25-dihydroxyvitamin D3 undoubtedly plays a strong role as an immunomodulating agent in adaptive and innate immunity.
T264	42911-43058	Sentence	denotes	Different reviews have also reported that individuals with low vitamin D status have a higher risk of viral respiratory tract infections [99, 108].
T265	43059-43389	Sentence	denotes	Several systematic reviews show that levels of this vitamin are inversely related to respiratory tract infection [109, 110] and underlines that individuals with low vitamin D levels show an increased risk of viral tract infections, concluding that its supplementation can reduce the risk of respiratory tract infections [82, 111].
T266	43390-43580	Sentence	denotes	Some studies on the influenza prevention provide a negative correlation between the enhanced post-immunization vaccine and obese patients, because obesity involves a deficiency of vitamin D.
T267	43581-43768	Sentence	denotes	According to most authors, more randomized controlled trials with large populations are needed to explore the preventive effect of vitamin D supplementation on viral flu infections [107].
T268	43770-43779	Sentence	denotes	Vitamin E
T269	43780-43953	Sentence	denotes	Vitamin E exists mainly in the form of tocopherols present in high amounts in nuts and vegetable oils, whereas tocotrienols are found predominantly in some seeds and grains.
T270	43954-44034	Sentence	denotes	This vitamin is involved in immunity and host susceptibility to infection [112].
T271	44035-44271	Sentence	denotes	A positive association was demonstrated between plasma vitamin E and cell-mediated immune responses, while a negative association was observed among plasma vitamin E and the risk of infections in healthy adults over 60 years of age [8].
T272	44272-44390	Sentence	denotes	It protects cell membranes from damage caused by free radicals and supports the integrity of epithelial barriers [79].
T273	44391-44551	Sentence	denotes	Vitamin E has also been shown to regulate the maturation and functions of dendritic cells, which are important for the innate and adaptive immune systems [112].
T274	44552-45049	Sentence	denotes	The immune response mechanisms in which vitamin E is involved are as follows: (i) maintains or improves the cytotoxic activity of NK cells [82] and reduces prostaglandin E2 (PGE2) production by the inhibition of cyclooxygenase-2 (COX-2) activity, mediated through decreasing of nitric oxide production [64, 112, 113]; (ii) the improvement of immune synapse formation in naive T cells, increasing the percentage of memory experienced with the antigen [112]; (iii) the modulation of Th1/Th2 balance.
T275	45050-45196	Sentence	denotes	Indeed it improves lymphocyte proliferation and T cell mediated functions, optimizes and improves the Th1 response and suppress Th2 response [95].
T276	45197-45347	Sentence	denotes	The role of this vitamin in the prevention of infections such as influenza has been discussed, but more controlled studies in humans are needed [114].
T277	45348-45538	Sentence	denotes	Notably, it is accepted that vitamin E may exert its immune-enhancing effects by scavenging oxygen species to reduce oxidative stress [112] and it may induce anti-inflammatory effects [113].
T278	45539-45723	Sentence	denotes	In particular, it appears to be an important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain breaking effect) and protects cells from them [95].
T279	45725-45729	Sentence	denotes	Zinc
T280	45730-45987	Sentence	denotes	Zinc is considered a “guardian” for the body, as it plays an essential role in the functioning of the immune system [115], plays a central role in cell growth and differentiation of the immune system cells that have rapid differentiation and turnover [116].
T281	45988-46276	Sentence	denotes	Most of the studies have recently reported a very interesting evaluation of the function of zinc in antiviral immunity, suggesting how it can play a role in host defense against RNA viruses, inhibiting the RNA polymerase required by RNA viruses (such as coronaviruses) to replicate [117].
T282	46277-46363	Sentence	denotes	The zinc-binding metallothionein seems to play an important role in antiviral defense.
T283	46364-46579	Sentence	denotes	Zinc deficiency has a marked impact on bone marrow, decreasing the number of immune precursor cells, with reduced output of naive B lymphocytes, and causes thymic atrophy, reducing the output of naive T lymphocytes.
T284	46580-46741	Sentence	denotes	Therefore, zinc is essential for cell growth and differentiation of immune cells, helping to modulate the cytokine release and trigger CD8+ T cell proliferation.
T285	46742-47022	Sentence	denotes	Among the main activities of zinc in immune function there are: maintaining skin and mucosal integrity (e.g., cofactor for metalloenzymes required for cell membrane repair) [118]; improving the cytotoxic activity of NK cells [79, 82] and the phagocytic capacity of monocytes [64].
T286	47023-47279	Sentence	denotes	It is involved in the complement activity and in the production of IFN-γ [92, 95]; it is an important anti-inflammatory agent [119] and helps modulate the release of cytokines [95] by attenuating the development of pro-inflammatory Th17 and Th9 cells [64].
T287	47280-47452	Sentence	denotes	Furthermore, by influencing the generation of cytokines such as IL-2, IL-6 and TNF, it has antioxidant effects that protect against ROS and reactive nitrogen species [120].
T288	47453-47606	Sentence	denotes	Zinc also induces the proliferation of cytotoxic T cells [62] and is involved in the production of Th1 cytokines and thus supports the Th1 response [95].
T289	47607-47880	Sentence	denotes	It is essential for the intracellular binding of tyrosine kinase to T cell receptors, which is required for T cell development, differentiation and activation [118] and induces the development of Treg cells and is therefore important for maintaining immune tolerance [120].
T290	47881-48045	Sentence	denotes	Finally, zinc is involved in the production of antibodies [79, 121] and it is important to maintain immune tolerance in recognizing the “self” from “non-self” [64].
T291	48046-48167	Sentence	denotes	Low zinc status impairs many aspects of innate immunity, including phagocytosis, respiratory burst and NK cells activity.
T292	48168-48262	Sentence	denotes	Zinc also supports the release of neutrophil extracellular traps, that capture microbes [122].
T293	48263-48393	Sentence	denotes	Zinc malabsorption also displays severe immune impairments and increased susceptibility to bacterial, viral and fungal infections.
T294	48394-48562	Sentence	denotes	It has widely been suggested that increasing zinc intakes may be useful against COVID-19 infections, by reducing viral replication and lower respiratory symptoms [123].
T295	48563-48774	Sentence	denotes	Recent systematic reviews report a shorter duration of the common cold in adults with a good level of zinc and a reduced incidence of mortality when it is supplemented to adults with severe pneumonia [124, 125].
T296	48775-48855	Sentence	denotes	Further research will be necessary to support a zinc supplementation in advices.
T297	48856-49120	Sentence	denotes	The RDA of zinc, according to the Dietary Recommendation Intake (DRI), is 8–11 mg/day for adults (tolerable upper intake level 40 mg/day), suggesting that a zinc intake of 30–50 mg/day might aid in the RNA viruses control, such as influenza and coronaviruses [98].
T298	49122-49130	Sentence	denotes	Selenium
T299	49131-49259	Sentence	denotes	Selenium is an essential micronutrient that plays a significant role in many physiological processes including immune responses.
T300	49260-49412	Sentence	denotes	The immune system needs an adequate intake of this nutrient mostly through its incorporation into selenoproteins to exerts its biological effects [126].
T301	49413-49586	Sentence	denotes	In fact, it has an important antioxidant role to quench ROS, influencing leukocyte and NK cell function and consequently modulating the host antioxidant defense system [85].
T302	49587-49734	Sentence	denotes	In fact, selenoproteins act as redox regulators and cellular antioxidants, potentially counteracting the ROS produced during oxidative stress [82].
T303	49735-49861	Sentence	denotes	Selenium is involved in T-lymphocyte proliferation and the humoral system [85], especially in immunoglobulin production [127].
T304	49862-49976	Sentence	denotes	It helps improve Th cell counts and maintain antibody levels [85] and also increases the production of IFN-γ [95].
T305	49977-50177	Sentence	denotes	Selenium deficiencies have been associated with viral infections such as influenza, determining adaptive and innate immunity responses and leading to a high level of virus-related pathogenicity [128].
T306	50178-50314	Sentence	denotes	Low concentrations of selenium in humans have been linked to the reduced activity of NK cells and the increase in mycobacterial disease.
T307	50315-50464	Sentence	denotes	Moreover, selenium deficiency has been shown to allow mutations of coxsackievirus, poliovirus and murine influenza virus, increasing their virulence.
T308	50465-50587	Sentence	denotes	Dietary selenium supplementations were suggested as adjuvant therapies of influenza, supporting the immune response [129].
T309	50588-50801	Sentence	denotes	The beneficial effects of a higher selenium status have been supported for some viral infections, although there are some studies that do not conclusively demonstrate effective improvements in anti-viral immunity.
T310	50802-50941	Sentence	denotes	On the contrary, the antioxidant properties of some selenoproteins have been suggested to contribute to boosting anti-viral immunity [129].
T311	50942-51187	Sentence	denotes	Currently, the recommended amounts of adequate selenium intake for adults range between 25 and 100 μg/die [130], with an average of 60 μg/die for men and 53 μg/die for women [131]; the tolerable upper intake level is set at 300–450 μg/die [132].
T312	51188-51292	Sentence	denotes	More research is needed to improve knowledge of selenium metabolism and requirements for optimal health.
T313	51293-51446	Sentence	denotes	The relationships between selenium dietary intake and health status, or risk of disease, are complex and require elucidation to inform clinical practice.
T314	51448-51452	Sentence	denotes	Iron
T315	51453-51551	Sentence	denotes	The role of iron in immunonutrition has been widely discussed and confirmed by many studies [133].
T316	51552-51752	Sentence	denotes	Iron is required for a number of different cellular functions and there is a constant balance between iron uptake, transport, storage, and utilization required to maintain iron homeostasis [134, 135].
T317	51753-51885	Sentence	denotes	As the body lacks a defined mechanism for the active excretion of iron, iron balance is mainly regulated at the point of absorption.
T318	51886-51998	Sentence	denotes	Iron deficiency induces thymus atrophy and has multiple effects on immune function in human subjects [133, 136].
T319	51999-52232	Sentence	denotes	The effects of this micronutrient in modulating the immune system include the regulation of T cell differentiation and proliferation [85], also helping to regulate the interplay between helper T cells and cytotoxic T cells [95, 137].
T320	52233-52405	Sentence	denotes	It also play a role in IFN-γ production and participates in the production of cytokines, in fact it is involved in the regulation of the production and action of cytokines.
T321	52406-52639	Sentence	denotes	It forms highly toxic hydroxyl radicals, involved in the killing of bacteria by neutrophils and it is a component of enzymes critical for the functioning of immune cells (e.g. ribonucleotide reductase involved in DNA synthesis) [95].
T322	52640-52766	Sentence	denotes	The iron-rich state promotes the M2-like macrophage phenotype and negatively regulates the M1 pro-inflammatory response [138].
T323	52767-52890	Sentence	denotes	This nutrient is necessary for the generation of ROS, that kill pathogens (by neutrophils) during the oxidative burst [85].
T324	52891-52988	Sentence	denotes	Finally, it appears to be essential for the differentiation and growth of epithelial tissue [95].
T325	52989-53128	Sentence	denotes	Iron at doses above the upper threshold has been associated with increased risk of malaria and other infections, including pneumonia [139].
T326	53129-53259	Sentence	denotes	Obviously it should be noted that treatment for anemia in a malarious area must be preceded by an effective anti-malarial therapy.
T327	53260-53383	Sentence	denotes	Notably, iron rich status promotes M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response [65].
T328	53384-53460	Sentence	denotes	On the other hand, iron overload causes impairment of immune function [140].
T329	53461-53613	Sentence	denotes	Iron excess increases the harmfulness of inflammation and the microorganisms themselves require iron as it can contribute to the growth of the pathogen.
T330	53614-53664	Sentence	denotes	RDA for iron reports a range of 8–18 mg/day [138].
T331	53666-53675	Sentence	denotes	Glutamine
T332	53676-53822	Sentence	denotes	The consumption of high biological value proteins is an essential component for a healthy diet and for the optimal production of antibodies [141].
T333	53823-53946	Sentence	denotes	Proteins, or amino acids, deficiency is known to impair immune function and increase susceptibility to infectious diseases.
T334	53947-54025	Sentence	denotes	In fact, some amino acids modulate both metabolism and immune functions [142].
T335	54026-54265	Sentence	denotes	Most reviews indicate an important role for amino acids in the immunity by regulating the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; cellular redox state, gene expression and lymphocyte proliferation.
T336	54266-54458	Sentence	denotes	Evidence shows that the dietary integration of specific amino acids in humans with malnutrition and infectious diseases improves the immune status, thus reducing morbidity and mortality [141].
T337	54459-54652	Sentence	denotes	Glutamine is the most abundant and versatile amino acid present in the body and its level in the immune cells is similar to, or even greater than, glucose in both health and disease conditions.
T338	54653-54840	Sentence	denotes	The biological activities of this nutrient are also associated with the reduced cellular potential of oxygen, which mainly depends on the ratio between reduced/oxidized glutathione [143].
T339	54841-55028	Sentence	denotes	In addition, glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytes plus secretory activities and bacterial killing of neutrophils.
T340	55029-55255	Sentence	denotes	In immune cells, glucose is mainly converted into lactate (glycolysis), while glutamine is converted into glutamate, aspartate and alanine undergoing a partial oxidation in carbon dioxide, in a process of glutaminolysis [142].
T341	55256-55341	Sentence	denotes	This unique conversion plays a crucial role in the effective functioning of immunity.
T342	55342-55680	Sentence	denotes	Glutamine is necessary for the expression of a variety of immune system genes [144], in particular through the activation of proteins, such as the ERK and JNK kinases which are involved in the activation of transcription factors, including JNK and AP-1, finally promoting the transcription of genes that participate in cell proliferation.
T343	55681-55870	Sentence	denotes	Besides, a sufficient level of glutamine is important to express the key markers of the cell surface of the lymphocytes and also various cytokines, for example, IL-6, IFN and TNF [143–145].
T344	55871-56197	Sentence	denotes	In healthy subjects with a balanced diet, glutamine supplementation does not increase the effectiveness of immune surveillance or prevent disease episodes, as reported by some reviews, but in some catabolic situations or in a low glutamine intake obtained from the diet, the amino acid supplementation could be required [142].
T345	56199-56207	Sentence	denotes	Arginine
T346	56208-56367	Sentence	denotes	The modulation of metabolism and immune functions, essential in the interaction and susceptibility to infectious diseases, is also regulated by arginine [146].
T347	56368-56497	Sentence	denotes	Arginine is a precursor for the synthesis of proteins, nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine.
T348	56498-56861	Sentence	denotes	The role and relationships between the pathways of arginine synthesis and catabolism are complex, due to the compartmentalized expression of various enzymes in different organs (e.g. liver, small intestine and kidney) and subcellular compartments (cytosol and mitochondria), as well as changes in gene expression in response to diet, hormones and cytokines [147].
T349	56862-57134	Sentence	denotes	As reported by several studies, arginine is the precursor of macrophages and it is now clear that arginine metabolism of immune cells is particularly involved in cancer, inflammation, infections, fibrotic diseases, pregnancy and the regulation of immune system [148, 149].
T350	57135-57251	Sentence	denotes	Macrophage arginine metabolism influences the outcome of immune responses in which innate immune cells are involved.
T351	57252-57412	Sentence	denotes	Arginine supplementation is reported to increase T lymphocyte response and Th cell numbers, suggesting a possible role in prolonged or repeated infection [150].
T352	57413-57672	Sentence	denotes	The importance of arginine metabolism as a new field of investigation includes that its depletion delays the growth of some types of tumours, while others report that its integration improves anticancer effects, probably by ameliorating immune function [150].
T353	57673-57817	Sentence	denotes	As discussed, vitamins E, C, D, zinc and selenium are important examples of nutrients that play a key role in supporting the immune system [65].
T354	57818-57859	Sentence	denotes	They can work individually or in synergy.
T355	57860-57981	Sentence	denotes	Furthermore, other dietary components are likely to play a role in modulating immunity, but have not yet been identified.
T356	57982-58058	Sentence	denotes	It is clear how nutritional deficiencies can compromise the immune response.
T357	58059-58235	Sentence	denotes	In addition, inflammation related to unhealthy eating habits has reached alarming proportions, particularly concerning chronic non-communicable diseases [100] (Tables 1 and 2).
T358	58236-58298	Sentence	denotes	Table 1 Dietary sources and immune function roles of nutrients
T359	58299-58350	Sentence	denotes	Nutrient Good dietary sources Immune function roles
T360	58351-58775	Sentence	denotes	Vitamin A Milk and cheese, eggs, liver, oily fish, fortified cereals, dark orange or green vegetables (e.g., carrots, sweet potatoes, pumpkin, squash, kale, spinach, broccoli), orange fruits (e.g., apricots, peaches, papaya, mango, cantaloupe melon), tomato juice Normal differentiation of epithelial tissue; retinoic acid ↑ T and B cells with gut-homing specificity and array T cells and IgA + cells into intestinal tissues
T361	58776-58941	Sentence	denotes	Supporting the gut barrier; carotenoids; ↑immunoregulatory actions including ↓ toxic effects of ROS and regulating membrane fluidity and gap-junctional communication
T362	58942-59043	Sentence	denotes	Regulates number and function of NK cells,↑ to phagocytic and oxidative burst activity of macrophages
T363	59044-59072	Sentence	denotes	Downregulates IFN production
T364	59073-59277	Sentence	denotes	Helps to regulate the production of IL-2 and the pro-inflammatory TNF-γ, ↑ microbial action of macrophages; involved in phagocytic and oxidative burst activity of macrophages activated during inflammation
T365	59278-59477	Sentence	denotes	Development and differentiation of Th1 and Th2 cells; ↑ TGF- β-dependent conversion of naïve T cells into regulatory T cells; plays a role in acquisition of mucosal-homing properties by T and B cells
T366	59478-59643	Sentence	denotes	Development and differentiation of Th 1 and Th2 cells; maintains normal antibody-mediated Th2 response by suppressing IL-12, TNF-α, and IFN-γ production of Th1 cells
T367	59644-59846	Sentence	denotes	Normal functioning of B cells, necessary for generation of antibody responses to antigen; required for B cell-mediated IgA antibody responses to bacterial polysaccharide antigens [62, 79–82, 85, 92, 95]
T368	59847-60155	Sentence	denotes	Vitamin C Oranges and orange juice, red and green peppers, strawberries, blackcurrants, kiwi, broccoli, brussels sprouts, potatoes ↑ collagen synthesis and protects cell membranes from damage caused by free radicals; ↑ keratinocyte differentiation; ↑ lipid synthesis; ↑ fibroblast proliferation and migration
T369	60156-60271	Sentence	denotes	Proliferation, function, and movement of neutrophils, monocytes and phagocytes; ↑ NK cell activities and chemotaxis
T370	60272-60326	Sentence	denotes	↑ Phagocytosis and ROS generation; ↑ microbial killing
T371	60327-60412	Sentence	denotes	↑ Apoptosis and clearance of spent neutrophils from sites of infection by macrophages
T372	60413-60466	Sentence	denotes	↓ Extracellular trap (NET) formation, ↓ tissue damage
T373	60467-60529	Sentence	denotes	↑ Antimicrobial effects; ↑ serum levels of complement proteins
T374	60530-60780	Sentence	denotes	Maintains redox homeostasis within cells and protects against ROS and RNS during oxidative burst; regenerates other important antioxidants, such as glutathione and vitamin E, to their active state; modulates cytokine production and ↓ histamine levels
T375	60781-60961	Sentence	denotes	Roles in production, differentiation, and proliferation of T cells, particularly cytotoxic T cells; ↑ proliferation of lymphocytes, ↑ generation of antibodies [79, 85, 92, 95, 120]
T376	60962-61406	Sentence	denotes	Vitamin D Oily fish, liver, eggs, fortified foods (spreads and some breakfast cereals) Regulates antimicrobial proteins (cathelicidin and β-defensin), modifying intestinal microbiota to a healthier composition and supporting the gut, as well as protecting the lungs against infection; ↑ tight junction protein expression, E-cadherin and connexion 43 in the gut; maintains renal epithelial barrier function; ↑ corneal epithelial barrier function
T377	61407-61581	Sentence	denotes	Vitamin D receptor found in, e.g., monocytes, macrophages, and DCs; ↑ differentiation of monocytes to macrophages; calcitriol ↑ movement and phagocytic ability of macrophages
T378	61582-61724	Sentence	denotes	Regulates antimicrobial protein expression (cathelicidin and defensin), which directly kill pathogens, especially bacteria; ↓ IFN-γ production
T379	61725-61932	Sentence	denotes	↑ The oxidative burst potential of macrophages; increases superoxide synthesis; reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages
T380	61933-62317	Sentence	denotes	Homing of T cells to the skin; ↓ T-cell proliferation; inhibitory effects mainly in adaptive immunity (e.g., Th1-cell activity); stimulatory effects in innate immunity; ↓ the effector functions of T helper cells and cytotoxic T cells; ↑ the production of Tregs; inhibitory effect on the differentiation and maturation of the antigen-presenting DCs, and helps program DCs for tolerance
T381	62318-62350	Sentence	denotes	↓ Antibody production by B cells
T382	62351-62457	Sentence	denotes	↑ Antigen processing; role in the down-regulation of MHC-II) [64, 71, 79–81, 85, 95, 99, 104–106, 151–153]
T383	62458-62637	Sentence	denotes	Vitamin E Many vegetable oils, nuts and seeds, wheat germ (e.g., in cereals) Protects cell membranes from damage caused by free radicals and ↑ the integrity of epithelial barriers
T384	62638-62745	Sentence	denotes	↑ NK cell cytotoxic activity; ↓ PGE2 production by macrophages (thus indirectly protecting T-cell function)
T385	62746-62973	Sentence	denotes	Important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain-breaking effect) and protects cells against them; ↑ IL-2 production; ↓ production of PGE2 (indirectly protecting T-cell function)
T386	62974-63191	Sentence	denotes	↑ Lymphocyte proliferation and T-cell-mediated functions; ↑ Th1 response; ↓ Th2 response; helps to form effective immune synapses between Th cells; ↑ proportion of antigen-experienced memory [64, 79, 82, 95, 112, 113]
T387	63192-63405	Sentence	denotes	Zinc Shellfish, meat, cheese, some grains and seeds, cereals, seeded or whole grain breads Helps maintain integrity of skin and mucosal membrane (e.g., cofactor for metalloenzymesrequired for cell membrane repair)
T388	63406-63586	Sentence	denotes	↑ NK cell cytotoxic activity; central role in cellular growth and differentiation of immune cells that have a rapid differentiation and turnover; ↑ phagocytic capacity of monocytes
T389	63587-63644	Sentence	denotes	Involved in complement activity; role in IFN-γ production
T390	63645-63969	Sentence	denotes	Anti-inflammatory agent; helps to modulate cytokine release by dampening the development of pro-inflammatory Th17 and Th9 cells and influencing the generation of cytokines such as IL-2, IL-6, and TNF; has antioxidant effects that protect against ROS and reactive nitrogen species; influences activity of antioxidant proteins
T391	63970-64299	Sentence	denotes	↑ Proliferation of cytotoxic T cells; involved in Th1 cytokine production and thus supports Th1 response; essential for intracellular binding of tyrosine kinase to T cell receptors, required for T cell development, differentiation, and activation; ↑ development of Treg cells and is thus important in maintaining immune tolerance
T392	64300-64506	Sentence	denotes	Involved in antibody production, particularly IgG; involved in antibody response; important in maintaining immune tolerance (i.e., the ability to recognize “self” from “non-self”) [64, 82, 95, 116, 118–121]
T393	64507-64595	Sentence	denotes	Selenium Fish, shellfish, meat, eggs, some nuts especially brazil nuts ↑ IFN-γproduction
T394	64596-64698	Sentence	denotes	Selenoproteins important for antioxidant host defense system, affecting leukocyte and NK cell function
T395	64699-64858	Sentence	denotes	Essential for function of selenoproteins that act as redox regulators and cellular antioxidants, potentially counteracting ROS produced during oxidative stress
T396	64859-64912	Sentence	denotes	Roles in differentiation and proliferation of T cells
T397	64913-64978	Sentence	denotes	↑ Th cell counts and to maintain antibody levels [82, 85, 92, 95]
T398	64979-65201	Sentence	denotes	Iron Meat, liver, beans, nuts, dried fruit (e.g., apricots), wholegrains (e.g., brown rice), fortified cereals, most dark green leafy vegetables (spinach, kale) Essential for differentiation and growth of epithelial tissue
T399	65202-65557	Sentence	denotes	Forms highly-toxic hydroxyl radicals, thus involved in killing of bacteria by neutrophils; component of enzymes critical for functioning of immune cells (e.g., ribonucleotide reductase involved in DNA synthesis); involved in regulation of cytokine production and action; ↑ M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response
T400	65558-65582	Sentence	denotes	Role in IFN-γ production
T401	65583-65726	Sentence	denotes	Involved in regulation of cytokine production and action; required for generation of pathogen-killing ROS by neutrophils during oxidative burst
T402	65727-65868	Sentence	denotes	Important in differentiation and proliferation of T cells; helps to regulate ratio between T helper cells and cytotoxic T cells [85, 95, 138]
T403	65869-66087	Sentence	denotes	Long chain omega-3 fatty acids (EPA and DHA) Oilyfish Anti-inflammatory and antioxidant properties when enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins
T404	66088-66165	Sentence	denotes	↑ Immune system, by helping to resolve the inflammatory response [63, 66, 67]
T405	66166-66247	Sentence	denotes	Table 2 Nutrient’s supplementation suggested in support of respiratory infections
T406	66248-66331	Sentence	denotes	Nutrient Recommended supplementation suggested in support of respiratory infections
T407	66332-66366	Sentence	denotes	Omega 3 fatty acids 2–4 g/day [68]
T408	66367-66399	Sentence	denotes	Vitamin D 20,000–50,000 IU [154]
T409	66400-66426	Sentence	denotes	Vitamin E 135 mg/day [114]
T410	66427-66449	Sentence	denotes	Zinc 30–50 mg/day [98]
T411	66450-66478	Sentence	denotes	Selenium 25–100 μg/day [130]
T412	66479-66524	Sentence	denotes	Arginine and glutamine 25–35 g/day [142, 146]
T413	66525-66549	Sentence	denotes	Vitamin C 1–2 g/day [98]
T414	66550-66579	Sentence	denotes	Vitamin A 900–700 µg/day [91]
T415	66580-66602	Sentence	denotes	Iron 8–18 mg/day [138]
T416	66604-66658	Sentence	denotes	The role of gut microbiota in COVID-19 immunonutrition
T417	66659-66741	Sentence	denotes	The human intestine hosts a complex bacterial community called the gut microbiota.
T418	66742-66861	Sentence	denotes	The microbiota is specific to each individual despite the existence of several bacterial species shared by most adults.
T419	66862-66931	Sentence	denotes	Scientific studies reveal its influence on human health and diseases.
T420	66932-67136	Sentence	denotes	In particular they have shown that the intestinal microbiota can play a causal role in the development of obesity and associated metabolic disorders, leading to the identification of different mechanisms.
T421	67137-67369	Sentence	denotes	In humans, differences are observed in the composition of the microbiota, in the functional genes and in the metabolic activities between obese and lean individuals, that suggest a contribution of the microbiota to these phenotypes.
T422	67370-67584	Sentence	denotes	Finally, the evidence linking intestinal bacteria to host metabolism could allow the development of new therapeutic strategies based on the modulation of the intestinal microbiota to treat or prevent obesity [155].
T423	67585-67710	Sentence	denotes	Microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system [156].
T424	67711-67854	Sentence	denotes	The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”.
T425	67855-68083	Sentence	denotes	This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this, in turn, can affect the gut microbiota.
T426	68084-68206	Sentence	denotes	The immunological health of the gut, primarily mediated by the microbiota, influences lung health via the “gut-lung axis”.
T427	68207-68380	Sentence	denotes	In addition, microbial communities inhabiting the mucosal surfaces of the respiratory tract also contribute towards host defense against viral respiratory infections (VRIs).
T428	68381-68511	Sentence	denotes	Acute VRIs are associated with microbial dysbiosis in these communities, thus acting the optimal functioning of the immune system.
T429	68512-68752	Sentence	denotes	Alterations in the microbiota during influenza virus infection contributes to the pathogenesis of secondary bacterial infections, thus increasing the severity of the clinical course in the absence of appropriate immune responses [157, 158].
T430	68753-68967	Sentence	denotes	It is also known that alterations of the immune functions associated with chronic inflammation and related metabolic dysfunctions lead to a compromise of innate and acquired immune functions in the host [159, 160].
T431	68968-69150	Sentence	denotes	Moreover, chronic inflammation and the use of antibiotics are known to accompany disorders in the gut microbiota, resulting in dysbiosis and aggravation of immune dysfunctions [161].
T432	69151-69433	Sentence	denotes	In addition, the prevalence of comorbid conditions (including chronic lung disease, diabetes, hypertension and cardiovascular diseases) and old age predispose to infection, the development of ARDS and pneumonia, factors already observed for other infections such as influenza [162].
T433	69434-69549	Sentence	denotes	This point raises an interesting possibility that the new SARS-Cov-2 may also have an impact on the gut microbiota.
T434	69550-69683	Sentence	denotes	Indeed, several studies have shown that respiratory infections are associated with a change in the composition of the gut microbiota.
T435	69684-69833	Sentence	denotes	Numerous experimental and clinical observations have suggested that the gut microbiota plays a key role in the pathogenesis of sepsis and ARDS [163].
T436	69834-70057	Sentence	denotes	Moreover, it is known that the signals derived from the intestinal microbiota tune the cells of the immune system for pro and anti-inflammatory responses which thus influence the susceptibility to various diseases (Fig. 2).
T437	70058-70163	Sentence	denotes	Fig. 2 Graphical representation of immune homeostasis disequilibrium during SARS-Coronavirus 2 infection.
T438	70164-70290	Sentence	denotes	ARDS: acute respiratory distress syndrome; T lymphocyte; IL: interleukin; Th: helper T lymphocyte; TNF: tumour necrosis factor
T439	70291-70384	Sentence	denotes	It is also known that respiratory virus infection causes perturbations in the gut microbiota.
T440	70385-70510	Sentence	denotes	Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity [164].
T441	70511-70616	Sentence	denotes	There is growing evidence that supports the roles of the gut microbiota and diet to shape immunity [165].
T442	70617-70787	Sentence	denotes	Modulating the composition and metabolic capacity of the microbiome for specific dietary components is a promising strategy for influencing immune responses against VRIs.
T443	70788-71008	Sentence	denotes	Functional food components including probiotics, prebiotics and other bioactive ingredients of plant origin have been associated with immune benefits, mainly via microbiota modulation and impact on oxidative stress [65].
T444	71009-71235	Sentence	denotes	Several papers, regarding body composition, evaluated the correlation between fat mass and disease risk and then identified a new frontier of gut microbiota composition in the bodyweight decrease and anti-inflammatory effects.
T445	71236-71587	Sentence	denotes	As shown, the prevention of cardiometabolic diseases, considering the relationship with obesity, may be possible reducing the inflammatory state, acting on the gut-microbiota and on the intestinal permeability improving the health of the intestinal flora, with 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols [166].
T446	71588-71772	Sentence	denotes	Prebiotic from fruits and vegetables is well-established to modulate the gut microbiota and numerous benefits have been reported in chronic inflammatory and metabolic conditions [167].
T447	71773-71951	Sentence	denotes	In fact, dietary fibers are a good source of accessible carbohydrates for microbiota then prebiotics have been studied in the context of modification of the human gut microbiota.
T448	71952-72123	Sentence	denotes	The compounds such as inulin, polydextrose, maize fiber have been shown to improve the immunity, gut diversity, digestion in humans and especially in elderly people [164].
T449	72124-72272	Sentence	denotes	Moreover, increased dietary fiber consumption is linked to reduced mortality rates in respiratory-related diseases and improved lung function [162].
T450	72273-72407	Sentence	denotes	Thus, plant-based diets, functional foods, and supplements present a promising strategy for protecting against respiratory infections.
T451	72408-72565	Sentence	denotes	Prebiotics lead the influence of microbiota composition and undergo microbial fermentation to produce SCFAs, such as butyrate, acetate, and propionate [168].
T452	72566-72825	Sentence	denotes	Overall, it is apparent that diet and personalized nutritional interventions acting in modulation of gut microbiota especially to control dysbiosis state and to some extent even lung microbiota can influence health status such as immunity conditions (Fig. 3).
T453	72826-72914	Sentence	denotes	Fig. 3 Graphical representation of personalized nutritional intervention during COVID-19
T454	72915-73141	Sentence	denotes	In addition, probiotics which are generally defined as “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” have been shown to have profound effect on the health of the host.
T455	73142-73446	Sentence	denotes	In the intestine, the probiotics mainly refer to the genera Lactobacillus and Bifidobacterium and include many different strains such as L. johnsonii, L. fermentum, L. reuteri, L. paracasei, L. rhamnosus, L. acidophilus, L. plantarum, B. longum, B. breve, B. bifidum, and B. animalis subsp. lactis [169].
T456	73447-73533	Sentence	denotes	Fermented foods such as cultured milk products and yoghurt are enriched in probiotics.
T457	73534-73713	Sentence	denotes	They have shown good results in modulating inflammatory conditions as well as regulating innate immunity using toll-like receptors and the corresponding signalling pathways [170].
T458	73714-73910	Sentence	denotes	The capacity of probiotics to induce immunomodulation could be mediated either directly through interaction with immune cells or indirectly by supporting the challenged commensal microbiota [171].
T459	73911-74263	Sentence	denotes	Ingested probiotics with diet or through supplementation stimulate the immune system and initiate a complex of signals mediated by the whole bacteria, they then interact with intestinal epithelial cells also with immune cells associated with the lamina propria or other microbial PRRs and trigger the production of an array of cytokines and chemokines.
T460	74264-74398	Sentence	denotes	These molecules then interact with other immune cells through other pathways, leading to the activation of the mucosal immune systems.
T461	74399-74520	Sentence	denotes	As reported by many reviews specific probiotics have been demonstrated to enhance Th1 and regulatory Treg function [162].
T462	74521-74697	Sentence	denotes	It is clear that probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells.
T463	74698-74837	Sentence	denotes	Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication [170].
T464	74838-75083	Sentence	denotes	Additionally, phytochemicals including vitamins, micronutrients, and polyphenols present in fruits and vegetables have been shown a considerable importance in nutritional strategies for addressing the severity of viral respiratory diseases [65].
T465	75084-75203	Sentence	denotes	Some polyphenols influence microbiota composition and also have antioxidant, anti-inflammatory, and anti-viral effects.
T466	75204-75412	Sentence	denotes	The antiviral effect of polyphenols have been demonstrated to be mediated either by direct inhibitory effects on virus replication or through the induction of immunomodulatory and antioxidant responses [172].
T467	75413-75554	Sentence	denotes	In fact, oxidative stress has been implicated in lung tissue injury and epithelial barrier dysfunction in acute respiratory viral infections.
T468	75555-75685	Sentence	denotes	Dietary polyphenols are present in foods such as vegetables, fruits, cereals, tea, coffee, dark chocolate, cocoa powder, and wine.
T469	75686-75811	Sentence	denotes	The main groups of dietary polyphenols consist in phenolic acids, flavonoids, tannins, stilbenes and diferuloylmethane [173].
T470	75812-75986	Sentence	denotes	Many evidences revealed the excellent immunomodulatory effects of epigallocatechin-3-gallate (EGCG), abundant in green tea on both innate and adaptive immune responses [174].
T471	75987-76139	Sentence	denotes	Finally, in this context there is an important role explained by postbiotics (also known as metabiotic, biogenic, or metabolite cell-free supernatants).
T472	76140-76307	Sentence	denotes	Postbiotics are products or metabolic byproducts secreted by live bacteria or released after bacterial lysis and they provide physiological benefits to the host [175].
T473	76308-76494	Sentence	denotes	There are multiple types of postbiotics with varied structures, such as Short Chain Fatty Acids (SCFAs), peptides, enzymes, teichoic acids, exo- and endo-polysaccharides, vitamins [176].
T474	76495-76673	Sentence	denotes	A protective role of postbiotics like SCFAs has been found in the immune system modulation; particularly in regulation of neutrophil migration in acute inflammation in the colon.
T475	76674-76921	Sentence	denotes	The benefits of microbially-fermented SCFAs are suggested to be mediated through the direct actions of G-protein-coupled receptors (GPRs) expressed on the gut epithelium, adipose tissues and immune cells, including monocytes and neutrophils [177].
T476	76922-77051	Sentence	denotes	Gut-derived SCFAs have been shown to influence the functions of innate immune cells as well as impact acquired immune components.
T477	77052-77333	Sentence	denotes	Studying microbiota and therefore the human immune system and its dysregulation, or controlling the effects of postbiotics in the symbiotic status represents an important opportunity to develop new drugs, and combining probiotic supplements, with vaccines and immunotherapies [16].
T478	77335-77346	Sentence	denotes	Conclusions
T479	77347-77435	Sentence	denotes	Immunonutrition has been based on the concept that malnutrition impairs immune function.
T480	77436-77711	Sentence	denotes	Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patients’ outcomes.
T481	77712-77905	Sentence	denotes	Finally, we can conclude that personalized immunonutrition for obese patients should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patient.
T482	77906-78044	Sentence	denotes	In particular, the nutritional approach might be managed in two different strategies, considering the disease status of the obese patient.
T483	78045-78148	Sentence	denotes	First, immunonutrition can decrease the risk of infections, reducing characteristic inflammation state.
T484	78149-78280	Sentence	denotes	In addition, immunonutrition would be fundamental to support the immune response and protein synthesis in severe phase of COVID-19.
T485	78282-78295	Sentence	denotes	Abbreviations
T486	78296-78331	Sentence	denotes	GALT Gut associated lymphoid tissue
T487	78332-78353	Sentence	denotes	B cells B lymphocytes
T488	78354-78375	Sentence	denotes	T cells T lymphocytes
T489	78376-78393	Sentence	denotes	NK Natural killer
T490	78394-78418	Sentence	denotes	TC cell Cytotoxic T-cell
T491	78419-78438	Sentence	denotes	TCR T cell receptor
T492	78439-78461	Sentence	denotes	Treg Regulatory T cell
T493	78462-78479	Sentence	denotes	Ig Immunoglobulin
T494	78480-78508	Sentence	denotes	APC Antigen presenting cells
T495	78509-78545	Sentence	denotes	MHC Major histocompatibility complex
T496	78546-78557	Sentence	denotes	Th T helper
T497	78558-78572	Sentence	denotes	IL Interleukin
T498	78573-78587	Sentence	denotes	INF Interferon
T499	78588-78627	Sentence	denotes	CXCL-10 C–X–C motif chemokine ligand 10
T500	78628-78709	Sentence	denotes	RANTES Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted

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COVID-19:

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10-63

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Is there a role for immunonutrition in obese patient?

T3

65-73

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Abstract

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On December 12, 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19).

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Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19.

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371-483

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In this context, immunonutrition can play a pivotal role in improving immune responses against viral infections.

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484-572

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Immunonutrition has been based on the concept that malnutrition impairs immune function.

T8

573-846

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Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patient outcomes.

T9

847-1037

Sentence

denotes

In literature, significant evidences indicate that obesity, a malnutrition state, negatively impacts on immune system functionality and on host defense, impairing protection from infections.

T10

1038-1151

Sentence

denotes

Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function.

T11

1152-1308

Sentence

denotes

Immune system dysfunction is considered to increase the risk of viral infections, such as SARS-CoV-2, and was observed in different pathological situations.

T12

1309-1506

Sentence

denotes

Obese patients develop severe COVID-19 sequelae, due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity.

T13

1507-1635

Sentence

denotes

Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response.

T14

1636-1825

Sentence

denotes

Additionally, gut microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system, as well as contributing to develop obese phenotype.

T15

1826-1969

Sentence

denotes

The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”.

T16

1970-2196

Sentence

denotes

This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this in turn can affect the gut microbiota.

T17

2197-2328

Sentence

denotes

Therefore, the modulation of gut microbiota in obese COVID-19 patients can play a key role in immunonutrition therapeutic strategy.

T18

2329-2515

Sentence

denotes

This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.

T19

2517-2527

Sentence

denotes

Background

T20

2528-2685

Sentence

denotes

On December 2019 a new coronavirus (SARS-CoV-2) emerged in Wuhan, China, triggering a pandemic of severe acute respiratory syndrome in humans (COVID-19) [1].

T21

2686-2824

Sentence

denotes

Today, the scientific community is investing all the resources available to find any therapy and prevention strategies to defeat COVID-19.

T22

2825-2956

Sentence

denotes

At the beginning of this pandemic, it was difficult to identify COVID-19 risk factors, that can be targeted for disease prevention.

T23

2957-3034

Sentence

denotes

Working on risk factors can, in fact, prevent infection and improve outcomes.

T24

3035-3157

Sentence

denotes

Now it is well known that obesity represents a significant risk factor both for COVID-19 susceptibility and prognosis [2].

T25

3158-3307

Sentence

denotes

Applying immunonutrition to obese patients can also prevent hospitalization, representing an additional risk factor for worsening COVID-19 prognosis.

T26

3308-3489

Sentence

denotes

Moreover, immunonutrition in obese patients may be a relevant strategy to lower the burden of COVID-19 disease [3], given that obesity affects almost 13% of people in the world [4].

T27

3490-3763

Sentence

denotes

The present umbrella review seeks to answer the question of whether a nutritional approach could be used to enhance the immune system’s response to obesity in patients affected by COVID-19, focusing on the interplay between immunonutrition, inflammation and gut microbiota.

T28

3765-3805

Sentence

denotes

Immune system, inflammation and COVID-19

T29

3806-3930

Sentence

denotes

The immune system protects the human body from infections by a series of pathogen (bacteria, viruses, fungi, parasites) [5].

T30

3931-4012

Sentence

denotes

A self-tolerance system prevents the immune response from damaging human tissues.

T31

4013-4075

Sentence

denotes

The immune system is always active, carrying out surveillance.

T32

4076-4326

Sentence

denotes

The defense to first exposure to the pathogen is represented by two complementary and cooperating functional divisions, the innate immune and, on the other hand, the adaptive immune response, that represents a response based on previous exposure [6].

T33

4327-4552

Sentence

denotes

The innate immune system is represented by dendritic cells, macrophages and neutrophils, with phagocytic activity, and by eosinophils, mast cells and natural killer cells, which release specific soluble antimicrobial factors.

T34

4553-4827

Sentence

denotes

The innate immune system includes physical barriers, represented by interconnected epithelial cells (e.g. tight junctions and cellular interactions mediated by cadherin), epithelial cilia and the mucus layer of the respiratory, gastrointestinal and genitourinary epithelium.

T35

4828-5102

Sentence

denotes

Moreover, soluble proteins and small bioactive molecules such as complement proteins, defensins and ficolins 1-3, pro-inflammatory cytokines, chemokines, lipid mediators of inflammation, membrane-bound receptors and cytoplasmic proteins are part of the innate immune system.

T36

5103-5163

Sentence

denotes

Both innate and adaptive immunity is mediated by leukocytes.

T37

5164-5385

Sentence

denotes

Lymphocytes circulate between the blood system and the lymphatic system, passing through the peripheral lymphoid organs, which includes the spleen, tonsils, appendix, lymph nodes and gut-associated lymphoid tissue (GALT).

T38

5386-5620

Sentence

denotes

From a common lymphoid progenitor, four major populations of mature lymphocytes are derived, that belong to the adaptive immune system: of B lymphocytes (B cells) and T lymphocytes (T cells), natural killer (NK) cells, and NK-T cells.

T39

5621-5732

Sentence

denotes

T-cells can be further categorized to cytotoxic T-cells (TC cells), helper T-cells (Th) and suppressor T-cells.

T40

5733-5917

Sentence

denotes

The specific antigenic receptors of the adaptive response are represented by genes that code for an intact T cell receptor (TCR) and immunoglobulin genes (B cell antigen receptor; Ig).

T41

5918-6000

Sentence

denotes

TCR is capable of binding the antigen processed by antigen-presenting cells (APC).

T42

6001-6223

Sentence

denotes

Dendritic cells represent the most powerful class of APC, and express molecules of the major histocompatibility complex (MHC) of class I and II, necessary for the recognition of the antigen processed by TCR on T cells [7].

T43

6224-6368

Sentence

denotes

Following the presentation of viral antigens via MHC II, the T helper CD4+ lymphocytes are activated and switch to the T helper 1 phenotype [8].

T44

6369-6527

Sentence

denotes

The activated T helper lymphocytes proliferate and release cytokines: after stimulation by antigen and APC, the Th0 cells begin to produce interleukin (IL)-2.

T45

6528-6930

Sentence

denotes

Meanwhile, Th cells differentiate into Th1, Th2 and Th17 according to the nature of the cytokines present in the activation site: IL-12 produced by macrophages and type I Interferon (IFN) or NK cells induce differentiation towards Th1, IL-4 produced by NK1.1 + T cells, basophils or mast cells induce differentiation towards Th2, and IL-1b, IL-23, TGFβ and IL-6 induce differentiation towards Th17 [9].

T46

6931-7000

Sentence

denotes

Th17 cells produce IL-17 and IL-22, and antigen-induced Treg (iTreg).

T47

7001-7237

Sentence

denotes

The binding of the cytokine to its transmembrane cell surface receptor activates an intracellular signal transduction pathway, generally a Janus kinase (Jak), which, via a kinase cascade, phosphorylates its transcription protein (STAT).

T48

7238-7327

Sentence

denotes

Phosphorylated STAT dimers and moves to the nucleus, initiating a new gene transcription.

T49

7328-7823

Sentence

denotes

Mutation of STAT1 increases susceptibility to virus infections because it is involved in various signalling pathways, including IFN-α/β, IFN- γ, IFN-l, IL-2, IL-3, IL-6, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21, IL-22, IL-26 and IL-27 [10], and chemokines of several types such as C-X-C motif chemokine ligand 10 (CXCL-10), Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES)/Chemokine (C–C motif) ligand 5 (CCL-5), Monocyte Chemoattractant Protein-1 (MCP-1) [11].

T50

7824-7917

Sentence

denotes

IFN-γ promotes antigen-specific antibody production, increasing the activity of phagocytosis.

T51

7918-8089

Sentence

denotes

In the meantime, PRRs trigger inflammatory signalling, with activation of transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB).

T52

8090-8457

Sentence

denotes

NFκB is the key transcriptional regulator of many pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and other mediators of inflammation, as tumour necrosis factor (TNF), interleukins 1 (IL-1β), 6 (IL-6), and 12 (IL-12), promotes cellular proliferation and protects against apoptosis providing a mechanism that determines chronic inflammation.

T53

8458-8565

Sentence

denotes

The recognition of pathogens is achieved through the presence of pattern recognition receptors (PRRs) [12].

T54

8566-8668

Sentence

denotes

PRRs identify the microbe-associated molecular patterns (MAMPs), and defensive responses is activated.

T55

8669-8804

Sentence

denotes

PRRs include Toll-like receptors (TLRs), that are able to recognize viral DNA, viral double-stranded RNA and viral single-stranded RNA.

T56

8805-8918

Sentence

denotes

TLRs are expressed on macrophages, dendritic cells, neutrophils, eosinophils, epithelial cells and keratinocytes.

T57

8919-9042

Sentence

denotes

In particular, intracellular TLR-7 and TLR-8 allow the innate recognition of the single-stranded RNA of coronaviruses [13].

T58

9043-9201

Sentence

denotes

Intracellular and extracellular PRRs recognized spike glycoprotein, of the coronavirus coat, starting the inflammatory process, through the NFκB pathway [14].

T59

9202-9419

Sentence

denotes

Moreover, Nucleotide-Binding Domain, Leucine-Rich Repeat (NLR) proteins have also been identified, and NALP3 (NACHT, LRR and PYD domains-containing protein 3) has a special function in the innate immune response [15].

T60

9420-9484

Sentence

denotes

The processes involved in antiviral immunity is shown in Fig. 1.

T61

9485-9558

Sentence

denotes

Fig. 1 Graphical representation of antiviral SARS-Coronavirus 2 immunity.

T62

9559-9561

Sentence

denotes

B:

T63

9562-9823

Sentence

denotes

B lymphocyte; CTL: cytotoxic; T lymphocyte; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MHC: major histocompatibility class; NFκB: nuclear factor kappa-light- chain- enhancer of activated B cells; NK: natural killer cell; Th: helper T lymphocyte; TLR:

T64

9824-9871

Sentence

denotes

Toll-like receptor; TNF: tumour necrosis factor

T65

9872-10100

Sentence

denotes

Normal inflammation is self-limiting because the production of pro-inflammatory cytokines (Th1 cytokines) is followed almost immediately by the production of anti-inflammatory cytokines (Th2 cytokines; IL-1, IL-10, IL-13, etc.).

T66

10101-10234

Sentence

denotes

Chronic inflammation seems to result when the initiating factors persist, or there is some sort of failure of the resolution process.

T67

10235-10524

Sentence

denotes

Dysfunction of the immune system and the loss of homeostatic equilibrium between TREG cells (IL- 10) and Th17 cells (IL-17) was observed in different pathological situations [16], and it is believed to increase the risk of viral infections, including SARS- coronavirus 2 (SARS-CoV-2) [14].

T68

10525-10780

Sentence

denotes

SARS-CoV-2 is an enveloped positive-strand RNA virus in the family Coronaviridae, group 2b, which encodes the viral replicase and four structural proteins: spike (S), envelope (E) and membrane (M), present in the viral envelope, and nucleocapsid (N) [17].

T69

10781-10936

Sentence

denotes

The access route of SARS-CoV-2 is represented by a hydrophobic pocket of the extracellular catalytic domain of Angiotensin-converting enzyme 2 (ACE2) [18].

T70

10937-11100

Sentence

denotes

SARS-CoV peak S protein trimers bind ACE2, expressed in endothelial cells of the vasculature and in the epithelia of the lungs, intestine, heart, brain and kidney.

T71

11101-11164

Sentence

denotes

SARS-CoV-2 enters the cell for endocytosis and membrane fusion.

T72

11165-11368

Sentence

denotes

Once the virus has infected the cell, it follows a downregulation of ACE2 with a consequent local increase in the levels of Ang II, and the development of acute respiratory distress syndrome (ARDS) [19].

T73

11369-11522

Sentence

denotes

The role of ACE2 in the gut, for expression of neutral amino acid transporters, could explain diarrhoea and intestinal inflammation observed in COVID-19.

T74

11523-11704

Sentence

denotes

Moreover, SARS-CoV2 protein E activates the NFκB inflammatory pathway with the consequent activation of MAPK p38, resulting in exacerbation of inflammation and immunopathology [20].

T75

11705-11974

Sentence

denotes

Following the SARS-CoV-2 infection, in the incubation stage and in the non-serious form of COVID-19, the immune system activates the specific adaptive immune response to eliminate the virus, which should be sufficient to block viral propagation and disease progression.

T76

11975-12085

Sentence

denotes

The antiviral system functions well in the presence of general good health and an adequate genetic background.

T77

12086-12405

Sentence

denotes

However, the presence of concomitant pathologies (obesity, cardiovascular diseases, diabetes, neurodegenerative diseases and cancer), malnutrition, and impaired immune response determine the spread of the virus and a massive destruction of the affected tissues, especially in organs that have high ACE2 expression [21].

T78

12406-12762

Sentence

denotes

As noted earlier, SARS-CoV-2 enters the cell via ACE2; that inactivates des-Arg bradykinin, which is a potent ligand of the bradykinin receptor type 1 (BDKRB1).This receptor, localized on endothelial cells, is up-regulated by inflammatory cytokines, which is unlike the B2 receptor, that is constituently expressed and is the receptor for bradykinin (BDK).

T79

12763-13046

Sentence

denotes

BDK is produced from an inactive pre-protein kininogen through activation by the serine protease kallikrein; in addition, it is considered a potent regulator of blood pressure [22], because it induces vasodilation, natriuresis, and hypotension upon activation of the BDKRB2 receptor.

T80

13047-13161

Sentence

denotes

BDK is strongly integrated with the RAS, and the BDK receptor signaling is increased by angiotensin’s action [23].

T81

13162-13333

Sentence

denotes

Interestingly, ACE has a higher affinity for BDK [24] and therefore in conditions where ACE is low, the vasopressor system is moved toward a BDK-directed hypotensive axis.

T82

13334-13539

Sentence

denotes

BDK takes part in the inflammatory response after injury and acts to induce pain via stimulation of the BDKRB1 receptor, which also causes neutrophil recruitment and a major vascular permeability [25, 26].

T83

13540-13730

Sentence

denotes

During the infection, as long as the virus persists, there is dysfunction of ACE2 function, leading to the dysregulation of the kinin-kallikrein pathway and thus causing the angioedema [27].

T84

13731-13927

Sentence

denotes

Some evidence that the edema is bradykinin-generated includes resistance to corticosteroids, epinephrine, and antihistamines in the management of reducing the pulmonary edema in COVID-19 patients.

T85

13928-14033

Sentence

denotes

In fact, the so called Bradykinin Storm is likely responsible for most of the observed COVID-19 symptoms.

T86

14034-14276

Sentence

denotes

Inflammation plays a fundamental role in the pathogenesis and progression of COVID-19, ranging from common colds to fatal cases of pneumonia due to the cytokine release syndrome (CRS) that affected patients, determining the severe conditions.

T87

14277-14575

Sentence

denotes

In COVID-19 the homeostatic equilibrium between TREG cells (IL-10) and Th17 cells (IL-17) is broken: inflammatory cytokine levels (IL-1, TNF) are elevated in the lungs of COVID-19 patients, resulting in an increase in HA-synthase-2 (HAS2) in alveolar epithelial cells CD31+, EpCAM+ and fibroblasts.

T88

14576-14715

Sentence

denotes

The imbalance between pro-inflammatory and anti-inflammatory cytokines, leads to the CRS, an excessive and damaging host inflammation [28].

T89

14716-14856

Sentence

denotes

As a consequence of CRS [29], due to a severe infection of SARS-CoV-2 of the respiratory epithelium, the ARDS was observed in COVID-19 [30].

T90

14857-14948

Sentence

denotes

Edema and an IL-1β mediated proinflammatory response were increased in the lung parenchyma.

T91

14949-15241

Sentence

denotes

Macrophages and dendritic cells produce IL-1β through macro-molecular complexes called inflammasomes, including the major element present in the pulmonary tissue and the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome [20].

T92

15242-15507

Sentence

denotes

Following a precise stimulus, the activation and recruitment domain of caspase (ASC) and the catalytically inactive procaspase-1 assemble, the procaspase-1 turns into active caspase-1, the inactive pro-IL-1β matures in IL-1β and the NLRP3 inflammasome is activated.

T93

15508-15651

Sentence

denotes

The NLRP3 inflammasomes and IL-1β driven proinflammatory cascades correlate with worsening of several respiratory diseases, including COVID-19.

T94

15652-15880

Sentence

denotes

Patients affected by obesity showed a severe consequence of COVID-19 [31], due to the high concentrations of TNF-α, MCP-1 and IL-6 produced in the meantime by visceral and subcutaneous adipose tissue and by innate immunity [32].

T95

15881-16014

Sentence

denotes

Moreover, leptin, released by adipose tissue, helps to increase inflammatory milieu with a dysregulation of the immune response [33].

T96

16015-16201

Sentence

denotes

This umbrella review seeks to answer the question of whether a nutritional approach can be used to enhance the immune system’s response to obesity in obese patients affected by COVID-19.

T97

16202-16339

Sentence

denotes

Immunonutrition has been based on the concept that malnutrition impairs immune function, used to modify inflammatory or immune responses.

T98

16340-16481

Sentence

denotes

This concept may be applied to any situation in which a supply of specific nutrients is necessary to modify inflammatory or immune responses.

T99

16482-16595

Sentence

denotes

Immunonutrients can promote patient recovery by inhibiting inflammatory responses and regulating immune function.

T100

16596-16919

Sentence

denotes

Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides and certain trace elements and antioxidants compound, vitamins and minerals) to modulate inflammatory responses, the acquired immune response, and to improve patient outcomes [34].

T101

16920-17091

Sentence

denotes

Personalized immunonutrition for patients with obesity should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patients.

T102

17092-17184

Sentence

denotes

That therapeutic strategy could be effective in case of other potential epidemic infections.

T103

17185-17292

Sentence

denotes

It would also allow a reduction of the enormous medical care cost supported by the National Health Service.

T104

17294-17321

Sentence

denotes

Immunonutrition and obesity

T105

17322-17601

Sentence

denotes

According to the World Health Organization (WHO), obesity is defined as a condition in which percentage of body fat (PBF) is increased to an extent in which health and well-being are impaired, and, due to the alarming prevalence increase, declared it as a “global epidemic” [35].

T106

17602-17747

Sentence

denotes

It is characterized by a state of low-grade, chronic inflammation, in addition to altered levels of circulating nutrients and metabolic hormones.

T107

17748-17937

Sentence

denotes

The condition of obesity is a multifactorial pathology that can be related to an altered nutritional behaviour or secondary to genetic, hypothalamic, iatrogenic or endocrine disorders [36].

T108

17938-18039

Sentence

denotes

Underlining the importance of nutritional behaviour, it depends directly on food nutritional quality.

T109

18040-18125

Sentence

denotes

Obesity is considered as a malnutritional status due to the poor quality of the diet.

T110

18126-18207

Sentence

denotes

The chance to get healthy foods is largely determined by one’s own profitability.

T111

18208-18349

Sentence

denotes

Nowadays, the most vulnerable communities fight disadvantage conditions because of socioeconomic, educational, and environmental disparities.

T112

18350-18455

Sentence

denotes

People, who follow a poor quality of diet combined with economic disparity, are at major risk of obesity.

T113

18456-18577

Sentence

denotes

The expansion of fat mass, in turn, is linked to various chronic diseases, including cardiovascular disease and diabetes.

T114

18578-18756

Sentence

denotes

In the context of Covid-19 pandemic, these conditions affect severe outcomes from SARS-CoV-2 infection, as well as contribute to increasing the risk of mortality in general [37].

T115

18757-18834

Sentence

denotes

Adiposopathy, also known as “sick fat”, is at the basis of obesity condition.

T116

18835-18933

Sentence

denotes

It is defined as pathological dysfunction of both anatomical and functional within adipose tissue.

T117

18934-19072

Sentence

denotes

It is promoted by an excess of caloric energy intake and a sedentary lifestyle in genetically and environmentally susceptible individuals.

T118

19073-19164

Sentence

denotes

This latter may cause or worsen metabolic disease in adverse endocrine and immune response.

T119

19165-19334

Sentence

denotes

Modifiable lifestyle choices play a role in fat function and dysfunction, but the strong genetic component has a real chance on predisposition to dysfunctional fat [38].

T120

19335-19651

Sentence

denotes

The disruption of adipose tissue processes, as occurs in adipocyte hypertrophy and visceral fat accumulation, results in the production of pro-inflammatory components (like the plethora of cytokines) and adipocyte factors dysregulation, which may be both genesis and/or main contributors to metabolic disorders [39].

T121

19652-19747

Sentence

denotes

Adipose tissue is not only part of the endocrine system, but it is an active immune organ [40].

T122

19748-20024

Sentence

denotes

As an organ suitable to manage the adaptive and innate immune responses, in healthy lean individuals, its immune cells have the main role in the formation of extracellular matrix modelling, insulin sensitivity, adipogenesis, angiogenesis and clearance of apoptotic adipocytes.

T123

20025-20192

Sentence

denotes

On the contrary, during the expansion of adipose tissue like in obesity, inflammation results in adipocyte hypertrophy, cell death, fibrosis and metabolic dysfunction.

T124

20193-20320

Sentence

denotes

The inflammatory process, involving both innate and adaptive immune cells, plays an important role in adipose immunometabolism.

T125

20321-20453

Sentence

denotes

Among those, macrophages are fundamental for adipose tissue homeostasis and are most thoroughly studied in response to obesity [41].

T126

20454-20575

Sentence

denotes

As a result of the augmentation of the PBF in obesity, there is the proportional increment of adipose tissue macrophages.

T127

20576-20861

Sentence

denotes

Consequently, the system undergoes to a massive pro-inflammatory response resulting by adipose tissue secretion of pro-inflammatory factors, the adipocytes stimulation of inflammation-inducing factors in other tissues and the reduction of anti-inflammatory and protective factors [42].

T128

20862-21256

Sentence

denotes

Understanding the relationship between the adipose tissue, classified as an endocrine organ, and its immune function, the development of new therapeutic and immunonutritional strategies for obesity in COVID-19, may have important implications especially because it may act as a reservoir for more severe viral spread, with increased shedding, immune activation, and cytokine amplification [43].

T129

21257-21370

Sentence

denotes

In the cytokine storm milieu in obesity and COVID-19, over 50 adipokines with diverse roles have been identified.

T130

21371-21516

Sentence

denotes

Leptin, adiponectin, IL-6 and TNF-α mainly act in adipocyte metabolism, insulin sensitivity and metabolic disorders associated with obesity [44].

T131

21517-21692

Sentence

denotes

Leptin is an adipocyte-derived hormone with an important role in the central control of energy metabolism and with many pleiotropic effects in different physiological systems.

T132

21693-21832

Sentence

denotes

One of these is the regulatory role between energy metabolism and the immune system, being a pillar in the new concept of immunometabolism.

T133

21833-21943

Sentence

denotes

Leptin receptor, expressed overall in the immune system, acts in both innate and adaptive immune system cells.

T134

21944-22033

Sentence

denotes

As an adipokine, leptin is responsible for the inflammatory state found in overnutrition.

T135

22034-22130

Sentence

denotes

Moreover, in undernutrition status, it plays as crucial mediator of the immunosuppressive state.

T136

22131-22328

Sentence

denotes

New research frontiers for immunometabolic pathophysiology are considering leptin and leptin receptor as markers of inflammation and immune activation in the context of innate-adaptive system [45].

T137

22329-22436

Sentence

denotes

In the light of above mentioned, leptin represents a connection between metabolism and the immune response.

T138

22437-22548

Sentence

denotes

Its dysregulatory activity would have serious consequences during an eventual infection, such as COVID-19 [46].

T139

22549-22719

Sentence

denotes

By altering the metabolic setting, hyperleptinemia and insulin resistance in obesity disrupt T-cell function, resulting in a suppressed T-cell response to infection [47].

T140

22720-22909

Sentence

denotes

This metabolic condition compromises the immune response and leads patients to morbidity and mortality from SARS-CoV-2 infection, coupled with the lack of containing viral replication [46].

T141

22910-23038

Sentence

denotes

The pivotal role of IL-6 in mediating the acute phase response seems to interest the strategical treatment in COVID-19 patients.

T142

23039-23289

Sentence

denotes

Researches are still in progress and it would be intriguing to investigate whether people with obesity and higher circulating IL-6 levels, compared with lean controls, respond more favourably to IL-6 inhibition strategies in SARS-CoV-2 pandemic [43].

T143

23290-23394

Sentence

denotes

TNF-α is a pyrogen cytokine released in the acute phase of inflammation by macrophages and immune cells.

T144

23395-23516

Sentence

denotes

It is well known that during influenzae and viral infections, the expression of TNF-α in lung epithelial cells is higher.

T145

23517-23632

Sentence

denotes

In patients with COVID-19 and obesity, the IL-6 and TNF-α high serum levels are negatively associated with T-cells.

T146

23633-23727

Sentence

denotes

On the contrary, T cell levels are restored by reducing concentrations of both IL-6 and TNF-α.

T147

23728-23840

Sentence

denotes

These findings suggested that these cytokines could represent important targets of anti-COVID-19 therapies [48].

T148

23841-23937

Sentence

denotes

Infectious diseases, like COVID-19, are characterized by an increased production of adiponectin.

T149

23938-24239

Sentence

denotes

In fact, it seems that adiponectin can reduce innate and adaptive immune cell proliferation and polarization on two fronts: acting on the production blockage of pro-inflammatory cytokines such as TNF-α, IL-2, and IL-6, and enhancing the secretion of anti-inflammatory cytokines such as IL-10 [49, 50].

T150

24240-24340

Sentence

denotes

It seems interesting the possibility to improve the action of adiponectin through diet intervention.

T151

24341-24479

Sentence

denotes

A healthy lifestyle and a Mediterranean diet seem to ameliorate adiponectin levels in human, working on omega-3 biochemical pathways [51].

T152

24480-24608

Sentence

denotes

Finally, in light of the above, a possible COVID-19 therapy would combine drug therapy with a personalized immunonutrition [48].

T153

24609-24790

Sentence

denotes

Whereas healthy adipose tissue is essential to achieve a metabolic health status, sick inflamed fat leads to metabolic pathways dysregulation and different chronic pathologies [52].

T154

24791-25147

Sentence

denotes

According to what mentioned above and considering the endocrine and inflammatory role of the adipose tissue, it is necessary to classify obesity on the basis of body fat composition and distribution [53], rather than simply anthropometric measurements, e.g. Body Mass Index (BMI) classification, that could lead to a large error and misclassification [54].

T155

25148-25429

Sentence

denotes

As different phenotypes of obesity can be diagnosed according to percentage of total bodyfat mass (PBF), associated with an early inflammatory status, and high oxidative stress level [55], to identify obese subjects at risk of COVID-19 it is necessary to evaluate body composition.

T156

25430-25576

Sentence

denotes

Moreover, obesity and adiposopathy contribute to the pathways related to appetite regulation, fat storage and alteration of intestinal microbiota.

T157

25577-25683

Sentence

denotes

Dysbiosis of gut microbiota can influence the onset and progression of chronic degenerative diseases [56].

T158

25684-25785

Sentence

denotes

The impact of these metabolic abnormalities has undergone intense investigation over the past decade.

T159

25786-25944

Sentence

denotes

Although that, it is still not clear how the immune system and host defense are influenced by the pro-inflammatory and excess energy milieu of the obese [57].

T160

25945-26119

Sentence

denotes

There is strong evidence in literature indicating that abundant adiposity negatively impacts on immune system functionality and host defense in individuals with obesity [57].

T161

26120-26254

Sentence

denotes

In people with obesity, the caloric balance surplus is not directly proportional to the high nutritional food components quality [53].

T162

26255-26431

Sentence

denotes

Hence, the overfed malnourished patient may be compared to the underfed malnourishment, because malnutrition is considered the primary cause of immunodeficiency worldwide [58].

T163

26432-26529

Sentence

denotes

Chronic diseases, such as obesity, have been recognized as virulence factors for severe COVID-19.

T164

26530-26655

Sentence

denotes

These morbidities are usually coupled to protein-energy malnutrition, which is demonstrated to impair immune cell activation.

T165

26656-26756

Sentence

denotes

This process allows longer viral persistence and increased dealing of pro-inflammatory factors [59].

T166

26757-26867

Sentence

denotes

This will allow you to make a personalized emergency intervention, in all the subjects suffering from obesity.

T167

26868-27000

Sentence

denotes

In the onset of COVID-19 era, the nutritional approach might be managed in two different strategies, considering the disease status.

T168

27001-27232

Sentence

denotes

In a severe phase of COVID-19 in a patient with obesity, immunonutrition would be fundamental to support the immune response and protein synthesis, and, at the same time, to reduce inflammation caused by the pathological condition.

T169

27233-27388

Sentence

denotes

The organism fights both the acute inflammatory state triggered by COVID-19 and, in addition, the latent chronic inflammation due to the obesity condition.

T170

27389-27593

Sentence

denotes

This latter is employed in the case of malnourished surgical patients, where immunonutrition significantly reduced the risk of acquired infections, wound complications, and length of stay at the hospital.

T171

27594-27737

Sentence

denotes

In this context, immunomodulating diets (IMDs) have been demonstrated to improve immune system response and modulate inflammation cascade [60].

T172

27738-27966

Sentence

denotes

Furthermore, the nutritional approach should be firstly preventive to reduce the large number of complications linked to obesity condition; and, secondly, could be predictive to act on the etiopathogenesis of SARS-CoV-2 disease.

T173

27967-28080

Sentence

denotes

In the current pandemic panorama, the connection between nutrition science and virology takes a predictable turn.

T174

28081-28180

Sentence

denotes

It is worth that nutritional innovation must correlate all the previously treated clinical aspects.

T175

28181-28472

Sentence

denotes

By referring to WHO guidelines, it is fundamental to follow healthy eating habits and lifestyle to achieve an optimal health status supporting immune cells system, and to switch from an unhealthy condition of dysbiosis to a healthy condition of eubiosis and modulating systemic inflammation.

T176

28473-28592

Sentence

denotes

This is essentially possible pursuing a balanced diet based on the Mediterranean concept and staying physically active.

T177

28594-28656

Sentence

denotes

Immunonutrition: the role of specific nutrients and microbiota

T178

28657-28802

Sentence

denotes

An optimal nutritional status guarantees the main modulating processes of inflammatory and oxidative stress, both connected to the immune system.

T179

28803-28908

Sentence

denotes

The metabolic system applied for biosynthesis and energy request needs many different dietary components.

T180

28909-29117

Sentence

denotes

In fact, some nutrients and their metabolites are direct regulators of gene expression of the immune compartment and play a key role in the maturation, differentiation and responsiveness of immune cells [61].

T181

29118-29250

Sentence

denotes

It is easy to understand that an adequate and balanced supply of these nutrients is essential to set an appropriate immune response.

T182

29251-29385

Sentence

denotes

Basically, good nutrition creates a setting in which the immune system can respond appropriately to challenge, whatever this might be.

T183

29386-29497

Sentence

denotes

On the contrary, poor nutrition produces an environment in which the immune system cannot respond well [62–64].

T184

29498-29644

Sentence

denotes

Furthermore, nutritional status, the role of diet and lifestyle may play an important part in different severe infections, especially in COVID-19.

T185

29645-29823

Sentence

denotes

The importance of nutrition as a mitigation strategy to support immune function, is reachable identifying food groups and key nutrients as defense against respiratory infections.

T186

29824-30045

Sentence

denotes

A balanced diet, rich in some foods, is associated with anti-inflammatory and immunomodulatory compounds, including vitamins (C, D, and E) and minerals (zinc and selenium), and may influence human nutritional status [16].

T187

30046-30132

Sentence

denotes

During this COVID-19 pandemic many myths surfaced on how strengthen the immune system.

T188

30133-30266

Sentence

denotes

Several research publications have focused on the role of diet and specific nutrients, some focusing on respiratory viral infections.

T189

30267-30394

Sentence

denotes

The most of micronutrients have been identified as the main responsible for maintenance the complex needs of the immune system.

T190

30395-30488

Sentence

denotes

Below we will focus on the main nutrients with specific reference to respiratory health [65].

T191

30490-30509

Sentence

denotes

Omega 3 fatty acids

T192

30510-30658

Sentence

denotes

Reactive oxygen species create a pro-oxidant environment against which the body needs protection through vitamins, enzymes and antioxidant feedings.

T193

30659-30871

Sentence

denotes

Particularly, omega-3 fatty acids are known to exert anti-inflammatory and antioxidant properties [66, 67], and to support the immune system, specifically by helping to resolve the inflammatory response [63, 68].

T194

30872-31057

Sentence

denotes

The intake of omega-3 fatty acids from fish and seafood has been shown to trigger anti-inflammatory reactions via oxygenated metabolites (oxylipins), including resolvins and protectins.

T195

31058-31297

Sentence

denotes

Omega-3 fatty acids include linolenic acid (ALA) consumed from various plant sources and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) consumed especially from fish and seafood sources, such as salmon, mackerel, and tuna [69].

T196

31298-31509

Sentence

denotes

Notably, the omega-3 fatty acids EPA and DHA involved in the inflammation process, are enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins [66, 67].

T197

31510-31673

Sentence

denotes

These molecules, alongside with others, function together to orchestrate the resolution of inflammation and to support healing, including in the respiratory tract.

T198

31674-31796

Sentence

denotes

Deficiencies of omega-3 fatty acids EPA and DHA are accountable for delayed or suboptimal resolution of inflammation [70].

T199

31797-31959

Sentence

denotes

This could be very important in the context of severe COVID-19, which manifests as uncontrolled inflammation, the so-called cytokine storm, linked with ARDS [71].

T200

31961-31979

Sentence

denotes

Oleoylethanolamide

T201

31980-32143

Sentence

denotes

Oleoylethanolamide (OEA), synthesized in the gastrointestinal tract, is a bioactive lipid mediator derived from the omega-9 monounsaturated fatty acid, oleic acid.

T202

32144-32335

Sentence

denotes

Based on previous evidences, OEA showed anti-inflammatory activities, a role in modulation of immune response, anti-oxidant effects and stimulation of lipolysis and fatty acid oxidation [72].

T203

32336-32543

Sentence

denotes

In this context OEA is considered an endocannabinoid-like lipid, which interacts with the peroxisome proliferator-activated receptor-alpha (PPAR-α) and intervenes during the anti-inflammatory processes [73].

T204

32544-32762

Sentence

denotes

Scientific researchers recently showed that endocannabinoid system is involved in the management of infectious agents such as viruses, bacteria, and some protozoa, also reducing inflammation and pain in the lungs [74].

T205

32763-33074

Sentence

denotes

In view of the fact that SARS-CoV-2 infection leads to increase the pro-inflammatory cytokines, including IL-6 and IL-1β in COVID-19 patients via binding to the TLRs, an important components of the innate immune system, it is assumed that OEA inhibits this pathway through its anti-inflammatory properties [75].

T206

33075-33292

Sentence

denotes

OEA binds with high affinity to PPAR-α receptors and increases the expression level of anti-inflammatory cytokine such as IL-10, then initiates a cascade of events, which can attenuate the inflammatory responses [73].

T207

33293-33450

Sentence

denotes

Furthermore, OEA attenuates the inflammatory responses modulating the expression of TLR-4, and interfering with the ERK1/2/AP-1/STAT3 signaling cascade [73].

T208

33451-33598

Sentence

denotes

OEA may modulate cross-talk between PPAR-α and TLRs and regulates the inflammatory responses with beneficial synergistic effect against SARS-CoV-2.

T209

33599-33934

Sentence

denotes

Nowadays, discovering therapeutic options from currently available agents appears to be essential for the treatment and prophylaxis of this pandemic, especially in obese patients with comorbidities [76] and this bioactive lipid mediator can be considered as a novel potential pharmacological alternative for the management of COVID-19.

T210

33936-33945

Sentence

denotes

Vitamin A

T211

33946-34078

Sentence

denotes

The role of vitamin A and its metabolites in the immune system and host susceptibility is discussed in a series of reviews [77, 78].

T212

34079-34398

Sentence

denotes

This nutrient is involved in normal differentiation of epithelial tissue, furthermore retinoic acid is essential for imprinting T and B cells with gut-homing specificity and T array cells and IgA cells in intestinal tissues [79], thus enhancing the intestinal immune response and supporting the intestinal barrier [80].

T213

34399-34624

Sentence

denotes

Carotenoids (both provitamin A and non-provitamin A carotenoids) have immunoregulatory actions including the reduction of the toxic effects of ROS and the regulation of membrane fluidity and gap-junctional communication [81].

T214

34625-34753

Sentence

denotes

Vitamin A deficiency impairs barrier function, impairs immune responses and increases susceptibility to a variety of infections.

T215

34754-34859

Sentence

denotes

Furthermore, many aspects of innate immunity, in addition to barrier function, are affected by vitamin A.

T216

34860-35084

Sentence

denotes

For example, vitamin A regulates the number and function of NK cells [82], contributes to the phagocytic and oxidative activity of the macrophage burst [79] and controls the maturation of neutrophils and its deficiency [83].

T217

35085-35167

Sentence

denotes

The activity of natural killer cells is therefore reduced by vitamin A deficiency.

T218

35168-35320

Sentence

denotes

The impact of vitamin A on acquired immunity is however clear since it is involved in the development and differentiation of Th1 and Th2 cells [62, 79].

T219

35321-35508

Sentence

denotes

Moreover there is evidence that vitamin A deficiency alters the balance of Th1 and Th2 cells, decreasing the Th2 response, without affecting or, in some cases, enhancing the Th1 response.

T220

35509-35586

Sentence

denotes

This suggests that vitamin A increases the Th1 cell average in immunity [84].

T221

35587-35920

Sentence

denotes

However, studies in several experimental models have shown how the retinoic acid metabolite of vitamin A reduces the responses of Th1-type cells (cytokines, cytokine receptors and the transcription factor T-bet, which promotes Th1), improving responses to Th2-type cells (cytokines and Th2-favoring transcription factor GATA-3) [62].

T222

35921-36063

Sentence

denotes

Indeed, it maintains the normal Th2 response mediated by antibodies by suppressing the production of IL-12, TNF-α and IFN-γ by Th1 cells [85].

T223

36064-36259

Sentence

denotes

Vitamin A appears to be important in the differentiation of regulatory T lymphocytes by suppressing Th17 differentiation, which have implications for the control of adverse immune reactions [86].

T224

36260-36439

Sentence

denotes

It helps regulate the production of IL-2 and the pro-inflammatory TNF-γ, which activates the phagocytic and oxidative action of the macrophages activated during inflammation [79].

T225

36440-36563

Sentence

denotes

It ensures the normal functioning of B lymphocytes, necessary for the generation of antibody responses to the antigen [85].

T226

36564-36750

Sentence

denotes

Retinoic acid appears to promote the movement of T cells to gut-associated lymphoid tissue and, interestingly, some gut-associated immune cells are able to synthesize retinoic acid [87].

T227

36751-36927

Sentence

denotes

Vitamin A deficiency is associated with increased morbidity and mortality in children and appears to predispose to respiratory infections, diarrhea and severe measles [88, 89].

T228

36928-37058

Sentence

denotes

Moreover, supplementing vitamin A in deficient children improves recovery from infectious diseases and reduces mortality [78, 90].

T229

37059-37152

Sentence

denotes

The Recommended Dietary Allowance (RDA) for vitamin A reports a range of 900–700 µg/day [91].

T230

37154-37163

Sentence

denotes

Vitamin C

T231

37164-37274

Sentence

denotes

The role of vitamin C in immunity and in host susceptibility to infection has been scientifically proven [92].

T232

37275-37435

Sentence

denotes

Vitamin C, in fact, is necessary for the biosynthesis of collagen and is essential for maintaining epithelial integrity and protecting against oxidative stress.

T233

37436-37683

Sentence

denotes

It protects cell membranes from damage caused by free radicals, so as to support the integrity of the epithelial barriers [79], also improves keratinocytic differentiation and lipid synthesis as well as fibroblast proliferation and migration [92].

T234

37684-38099

Sentence

denotes

It plays a role in various aspects of immunity, in fact it is involved in the proliferation, function and movement of neutrophils, monocytes and phagocytes [82] and the migration of leukocytes to sites of infection, phagocytosis and bacterial killing, in the activity of natural killer cells and in the function of T lymphocytes (especially CD8 cytotoxic T lymphocytes) and in the production of antibodies [79, 82].

T235

38100-38323

Sentence

denotes

Vitamin C is also involved in apoptosis and elimination of depleted neutrophils from macrophage infection sites [92] and attenuates the formation of extracellular trap (NET), thus reducing the associated tissue damage [92].

T236

38324-38457

Sentence

denotes

Infections have a significant impact on vitamin C levels, due to the increased energy needs required by the body during inflammation.

T237

38458-38597

Sentence

denotes

This nutrient, in fact, promotes the proliferation of lymphocytes, with a consequent increase in the generation of antibodies [79, 85, 92].

T238

38598-38868

Sentence

denotes

It is well known that infections increase oxidative stress and usually activate phagocytes that release ROS, so vitamin C is a well-known antioxidant that can counteract these effects by increasing phagocytosis and ROS generation and improving microbial killing [92–94].

T239

38869-38994

Sentence

denotes

Furthermore, supplementation with vitamin C appears to be able to prevent and treat respiratory and systemic infections [92].

T240

38995-39172

Sentence

denotes

High levels of this nutrient can enhance antimicrobial effects and increase serum levels of complement proteins, also playing an important role in IFN-γ production [85, 92, 95].

T241

39173-39296

Sentence

denotes

Low levels of vitamin C are responsible for an increased susceptibility to severe respiratory infections such as pneumonia.

T242

39297-39487

Sentence

denotes

Indeed, a meta-analysis reported a significant reduction in the risk of pneumonia with vitamin C supplementation, particularly in individuals with a low dietary intake of this nutrient [96].

T243

39488-39699

Sentence

denotes

Vitamin C supplementation has also been demonstrated to reduce the duration and severity of upper respiratory tract infections, such as the common cold, especially in people under increased physical stress [96].

T244

39700-39804

Sentence

denotes

Currently, there are limited recommendations for taking vitamin C supplementation against COVID-19 [97].

T245

39805-39974

Sentence

denotes

Nevertheless, there is sufficient evidence to conduct several clinical trials to assess vitamin C efficacy in COVID-19 prevention and treatment (www.clinicaltrials.gov).

T246

39975-40064

Sentence

denotes

Previously, doses of 1–2 g/day were effective in preventing upper respiratory infections.

T247

40065-40209

Sentence

denotes

As those levels are not attainable through dietary sources, supplementation may be advised for those at a higher risk of respiratory infections.

T248

40210-40284

Sentence

denotes

Doses above 200 mg/day may not be beneficial for healthy individuals [98].

T249

40286-40295

Sentence

denotes

Vitamin D

T250

40296-40418

Sentence

denotes

Many reviews discuss the role of vitamin D and its metabolites in host immunity and susceptibility to infections [99–101].

T251

40419-40645

Sentence

denotes

Vitamin D receptors have been identified in most immune cells, of which some can also synthesize the active form of vitamin D from its precursor, therefore suggesting that might have important immunoregulatory properties [99].

T252

40646-40812

Sentence

denotes

Vitamin D is synthesized at skin level in the presence of UV-light from cholesterol and it is also taken up from the diet (fish, eggs, fortified milk, and mushrooms).

T253

40813-41120

Sentence

denotes

The active form of vitamin D, calcitriol (1,25-dihydroxy vitamin D3), formed following kidney and liver hydroxylation, is most renowned for its regulating role in calcium homeostasis and bone health status, but it has also been shown to regulate the immune system, mainly in the functioning of T-cell [102].

T254

41121-41395

Sentence

denotes

Among the main functions of vitamin D, its ability to improve the integrity of the epithelium has mainly been observed as well as the ability to induce the synthesis of an antimicrobial peptide in epithelial cells and macrophages, thus directly improving host defense [103].

T255

41396-41605

Sentence

denotes

Vitamin D also promotes the differentiation of monocytes from macrophages [95], promotes the movement and phagocyability of macrophages [79], superoxide production and bacterial killing by innate immune cells.

T256

41606-41689

Sentence

denotes

Hence, it promotes the processing of antigen presentation by dendritic cells [104].

T257

41690-41837

Sentence

denotes

Calcitriol regulates the expression of antimicrobial proteins (cathelicidin and defensin), which directly kill pathogens, especially bacteria [99].

T258

41838-42017

Sentence

denotes

It inhibits the production of IFN-γ [71] and reduces the expression of pro-inflammatory cytokines by increasing the expression of anti-inflammatory cytokines by macrophages [105].

T259

42018-42225

Sentence

denotes

Calcitriol modulates antimicrobial proteins (cathelicidin and β-defensin), responsible for modifying the intestinal microbiota, favoring a healthy composition and supporting the intestinal barrier [80, 106].

T260

42226-42478

Sentence

denotes

It also helps protect the lungs against infection, increases the expression of the tight junction protein, E-cadherin and connexion 43 in the intestine, maintains renal-epithelial barrier function and improves corneal epithelial barrier function [104].

T261

42479-42662

Sentence

denotes

The 1,25-dihydroxyvitamin D3 can bind to a specific nuclear receptor (vitamin D receptor, VDR) and its role for both the innate and adaptive immune systems has been highlighted [107].

T262

42663-42767

Sentence

denotes

Moreover, vitamin D has been controversially discussed for its role in influenza prevention and therapy.

T263

42768-42910

Sentence

denotes

As shown in literature, 1,25-dihydroxyvitamin D3 undoubtedly plays a strong role as an immunomodulating agent in adaptive and innate immunity.

T264

42911-43058

Sentence

denotes

Different reviews have also reported that individuals with low vitamin D status have a higher risk of viral respiratory tract infections [99, 108].

T265

43059-43389

Sentence

denotes

Several systematic reviews show that levels of this vitamin are inversely related to respiratory tract infection [109, 110] and underlines that individuals with low vitamin D levels show an increased risk of viral tract infections, concluding that its supplementation can reduce the risk of respiratory tract infections [82, 111].

T266

43390-43580

Sentence

denotes

Some studies on the influenza prevention provide a negative correlation between the enhanced post-immunization vaccine and obese patients, because obesity involves a deficiency of vitamin D.

T267

43581-43768

Sentence

denotes

According to most authors, more randomized controlled trials with large populations are needed to explore the preventive effect of vitamin D supplementation on viral flu infections [107].

T268

43770-43779

Sentence

denotes

Vitamin E

T269

43780-43953

Sentence

denotes

Vitamin E exists mainly in the form of tocopherols present in high amounts in nuts and vegetable oils, whereas tocotrienols are found predominantly in some seeds and grains.

T270

43954-44034

Sentence

denotes

This vitamin is involved in immunity and host susceptibility to infection [112].

T271

44035-44271

Sentence

denotes

A positive association was demonstrated between plasma vitamin E and cell-mediated immune responses, while a negative association was observed among plasma vitamin E and the risk of infections in healthy adults over 60 years of age [8].

T272

44272-44390

Sentence

denotes

It protects cell membranes from damage caused by free radicals and supports the integrity of epithelial barriers [79].

T273

44391-44551

Sentence

denotes

Vitamin E has also been shown to regulate the maturation and functions of dendritic cells, which are important for the innate and adaptive immune systems [112].

T274

44552-45049

Sentence

denotes

The immune response mechanisms in which vitamin E is involved are as follows: (i) maintains or improves the cytotoxic activity of NK cells [82] and reduces prostaglandin E2 (PGE2) production by the inhibition of cyclooxygenase-2 (COX-2) activity, mediated through decreasing of nitric oxide production [64, 112, 113]; (ii) the improvement of immune synapse formation in naive T cells, increasing the percentage of memory experienced with the antigen [112]; (iii) the modulation of Th1/Th2 balance.

T275

45050-45196

Sentence

denotes

Indeed it improves lymphocyte proliferation and T cell mediated functions, optimizes and improves the Th1 response and suppress Th2 response [95].

T276

45197-45347

Sentence

denotes

The role of this vitamin in the prevention of infections such as influenza has been discussed, but more controlled studies in humans are needed [114].

T277

45348-45538

Sentence

denotes

Notably, it is accepted that vitamin E may exert its immune-enhancing effects by scavenging oxygen species to reduce oxidative stress [112] and it may induce anti-inflammatory effects [113].

T278

45539-45723

Sentence

denotes

In particular, it appears to be an important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain breaking effect) and protects cells from them [95].

T279

45725-45729

Sentence

denotes

Zinc

T280

45730-45987

Sentence

denotes

Zinc is considered a “guardian” for the body, as it plays an essential role in the functioning of the immune system [115], plays a central role in cell growth and differentiation of the immune system cells that have rapid differentiation and turnover [116].

T281

45988-46276

Sentence

denotes

Most of the studies have recently reported a very interesting evaluation of the function of zinc in antiviral immunity, suggesting how it can play a role in host defense against RNA viruses, inhibiting the RNA polymerase required by RNA viruses (such as coronaviruses) to replicate [117].

T282

46277-46363

Sentence

denotes

The zinc-binding metallothionein seems to play an important role in antiviral defense.

T283

46364-46579

Sentence

denotes

Zinc deficiency has a marked impact on bone marrow, decreasing the number of immune precursor cells, with reduced output of naive B lymphocytes, and causes thymic atrophy, reducing the output of naive T lymphocytes.

T284

46580-46741

Sentence

denotes

Therefore, zinc is essential for cell growth and differentiation of immune cells, helping to modulate the cytokine release and trigger CD8+ T cell proliferation.

T285

46742-47022

Sentence

denotes

Among the main activities of zinc in immune function there are: maintaining skin and mucosal integrity (e.g., cofactor for metalloenzymes required for cell membrane repair) [118]; improving the cytotoxic activity of NK cells [79, 82] and the phagocytic capacity of monocytes [64].

T286

47023-47279

Sentence

denotes

It is involved in the complement activity and in the production of IFN-γ [92, 95]; it is an important anti-inflammatory agent [119] and helps modulate the release of cytokines [95] by attenuating the development of pro-inflammatory Th17 and Th9 cells [64].

T287

47280-47452

Sentence

denotes

Furthermore, by influencing the generation of cytokines such as IL-2, IL-6 and TNF, it has antioxidant effects that protect against ROS and reactive nitrogen species [120].

T288

47453-47606

Sentence

denotes

Zinc also induces the proliferation of cytotoxic T cells [62] and is involved in the production of Th1 cytokines and thus supports the Th1 response [95].

T289

47607-47880

Sentence

denotes

It is essential for the intracellular binding of tyrosine kinase to T cell receptors, which is required for T cell development, differentiation and activation [118] and induces the development of Treg cells and is therefore important for maintaining immune tolerance [120].

T290

47881-48045

Sentence

denotes

Finally, zinc is involved in the production of antibodies [79, 121] and it is important to maintain immune tolerance in recognizing the “self” from “non-self” [64].

T291

48046-48167

Sentence

denotes

Low zinc status impairs many aspects of innate immunity, including phagocytosis, respiratory burst and NK cells activity.

T292

48168-48262

Sentence

denotes

Zinc also supports the release of neutrophil extracellular traps, that capture microbes [122].

T293

48263-48393

Sentence

denotes

Zinc malabsorption also displays severe immune impairments and increased susceptibility to bacterial, viral and fungal infections.

T294

48394-48562

Sentence

denotes

It has widely been suggested that increasing zinc intakes may be useful against COVID-19 infections, by reducing viral replication and lower respiratory symptoms [123].

T295

48563-48774

Sentence

denotes

Recent systematic reviews report a shorter duration of the common cold in adults with a good level of zinc and a reduced incidence of mortality when it is supplemented to adults with severe pneumonia [124, 125].

T296

48775-48855

Sentence

denotes

Further research will be necessary to support a zinc supplementation in advices.

T297

48856-49120

Sentence

denotes

The RDA of zinc, according to the Dietary Recommendation Intake (DRI), is 8–11 mg/day for adults (tolerable upper intake level 40 mg/day), suggesting that a zinc intake of 30–50 mg/day might aid in the RNA viruses control, such as influenza and coronaviruses [98].

T298

49122-49130

Sentence

denotes

Selenium

T299

49131-49259

Sentence

denotes

Selenium is an essential micronutrient that plays a significant role in many physiological processes including immune responses.

T300

49260-49412

Sentence

denotes

The immune system needs an adequate intake of this nutrient mostly through its incorporation into selenoproteins to exerts its biological effects [126].

T301

49413-49586

Sentence

denotes

In fact, it has an important antioxidant role to quench ROS, influencing leukocyte and NK cell function and consequently modulating the host antioxidant defense system [85].

T302

49587-49734

Sentence

denotes

In fact, selenoproteins act as redox regulators and cellular antioxidants, potentially counteracting the ROS produced during oxidative stress [82].

T303

49735-49861

Sentence

denotes

Selenium is involved in T-lymphocyte proliferation and the humoral system [85], especially in immunoglobulin production [127].

T304

49862-49976

Sentence

denotes

It helps improve Th cell counts and maintain antibody levels [85] and also increases the production of IFN-γ [95].

T305

49977-50177

Sentence

denotes

Selenium deficiencies have been associated with viral infections such as influenza, determining adaptive and innate immunity responses and leading to a high level of virus-related pathogenicity [128].

T306

50178-50314

Sentence

denotes

Low concentrations of selenium in humans have been linked to the reduced activity of NK cells and the increase in mycobacterial disease.

T307

50315-50464

Sentence

denotes

Moreover, selenium deficiency has been shown to allow mutations of coxsackievirus, poliovirus and murine influenza virus, increasing their virulence.

T308

50465-50587

Sentence

denotes

Dietary selenium supplementations were suggested as adjuvant therapies of influenza, supporting the immune response [129].

T309

50588-50801

Sentence

denotes

The beneficial effects of a higher selenium status have been supported for some viral infections, although there are some studies that do not conclusively demonstrate effective improvements in anti-viral immunity.

T310

50802-50941

Sentence

denotes

On the contrary, the antioxidant properties of some selenoproteins have been suggested to contribute to boosting anti-viral immunity [129].

T311

50942-51187

Sentence

denotes

Currently, the recommended amounts of adequate selenium intake for adults range between 25 and 100 μg/die [130], with an average of 60 μg/die for men and 53 μg/die for women [131]; the tolerable upper intake level is set at 300–450 μg/die [132].

T312

51188-51292

Sentence

denotes

More research is needed to improve knowledge of selenium metabolism and requirements for optimal health.

T313

51293-51446

Sentence

denotes

The relationships between selenium dietary intake and health status, or risk of disease, are complex and require elucidation to inform clinical practice.

T314

51448-51452

Sentence

denotes

Iron

T315

51453-51551

Sentence

denotes

The role of iron in immunonutrition has been widely discussed and confirmed by many studies [133].

T316

51552-51752

Sentence

denotes

Iron is required for a number of different cellular functions and there is a constant balance between iron uptake, transport, storage, and utilization required to maintain iron homeostasis [134, 135].

T317

51753-51885

Sentence

denotes

As the body lacks a defined mechanism for the active excretion of iron, iron balance is mainly regulated at the point of absorption.

T318

51886-51998

Sentence

denotes

Iron deficiency induces thymus atrophy and has multiple effects on immune function in human subjects [133, 136].

T319

51999-52232

Sentence

denotes

The effects of this micronutrient in modulating the immune system include the regulation of T cell differentiation and proliferation [85], also helping to regulate the interplay between helper T cells and cytotoxic T cells [95, 137].

T320

52233-52405

Sentence

denotes

It also play a role in IFN-γ production and participates in the production of cytokines, in fact it is involved in the regulation of the production and action of cytokines.

T321

52406-52639

Sentence

denotes

It forms highly toxic hydroxyl radicals, involved in the killing of bacteria by neutrophils and it is a component of enzymes critical for the functioning of immune cells (e.g. ribonucleotide reductase involved in DNA synthesis) [95].

T322

52640-52766

Sentence

denotes

The iron-rich state promotes the M2-like macrophage phenotype and negatively regulates the M1 pro-inflammatory response [138].

T323

52767-52890

Sentence

denotes

This nutrient is necessary for the generation of ROS, that kill pathogens (by neutrophils) during the oxidative burst [85].

T324

52891-52988

Sentence

denotes

Finally, it appears to be essential for the differentiation and growth of epithelial tissue [95].

T325

52989-53128

Sentence

denotes

Iron at doses above the upper threshold has been associated with increased risk of malaria and other infections, including pneumonia [139].

T326

53129-53259

Sentence

denotes

Obviously it should be noted that treatment for anemia in a malarious area must be preceded by an effective anti-malarial therapy.

T327

53260-53383

Sentence

denotes

Notably, iron rich status promotes M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response [65].

T328

53384-53460

Sentence

denotes

On the other hand, iron overload causes impairment of immune function [140].

T329

53461-53613

Sentence

denotes

Iron excess increases the harmfulness of inflammation and the microorganisms themselves require iron as it can contribute to the growth of the pathogen.

T330

53614-53664

Sentence

denotes

RDA for iron reports a range of 8–18 mg/day [138].

T331

53666-53675

Sentence

denotes

Glutamine

T332

53676-53822

Sentence

denotes

The consumption of high biological value proteins is an essential component for a healthy diet and for the optimal production of antibodies [141].

T333

53823-53946

Sentence

denotes

Proteins, or amino acids, deficiency is known to impair immune function and increase susceptibility to infectious diseases.

T334

53947-54025

Sentence

denotes

In fact, some amino acids modulate both metabolism and immune functions [142].

T335

54026-54265

Sentence

denotes

Most reviews indicate an important role for amino acids in the immunity by regulating the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; cellular redox state, gene expression and lymphocyte proliferation.

T336

54266-54458

Sentence

denotes

Evidence shows that the dietary integration of specific amino acids in humans with malnutrition and infectious diseases improves the immune status, thus reducing morbidity and mortality [141].

T337

54459-54652

Sentence

denotes

Glutamine is the most abundant and versatile amino acid present in the body and its level in the immune cells is similar to, or even greater than, glucose in both health and disease conditions.

T338

54653-54840

Sentence

denotes

The biological activities of this nutrient are also associated with the reduced cellular potential of oxygen, which mainly depends on the ratio between reduced/oxidized glutathione [143].

T339

54841-55028

Sentence

denotes

In addition, glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytes plus secretory activities and bacterial killing of neutrophils.

T340

55029-55255

Sentence

denotes

In immune cells, glucose is mainly converted into lactate (glycolysis), while glutamine is converted into glutamate, aspartate and alanine undergoing a partial oxidation in carbon dioxide, in a process of glutaminolysis [142].

T341

55256-55341

Sentence

denotes

This unique conversion plays a crucial role in the effective functioning of immunity.

T342

55342-55680

Sentence

denotes

Glutamine is necessary for the expression of a variety of immune system genes [144], in particular through the activation of proteins, such as the ERK and JNK kinases which are involved in the activation of transcription factors, including JNK and AP-1, finally promoting the transcription of genes that participate in cell proliferation.

T343

55681-55870

Sentence

denotes

Besides, a sufficient level of glutamine is important to express the key markers of the cell surface of the lymphocytes and also various cytokines, for example, IL-6, IFN and TNF [143–145].

T344

55871-56197

Sentence

denotes

In healthy subjects with a balanced diet, glutamine supplementation does not increase the effectiveness of immune surveillance or prevent disease episodes, as reported by some reviews, but in some catabolic situations or in a low glutamine intake obtained from the diet, the amino acid supplementation could be required [142].

T345

56199-56207

Sentence

denotes

Arginine

T346

56208-56367

Sentence

denotes

The modulation of metabolism and immune functions, essential in the interaction and susceptibility to infectious diseases, is also regulated by arginine [146].

T347

56368-56497

Sentence

denotes

Arginine is a precursor for the synthesis of proteins, nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine.

T348

56498-56861

Sentence

denotes

The role and relationships between the pathways of arginine synthesis and catabolism are complex, due to the compartmentalized expression of various enzymes in different organs (e.g. liver, small intestine and kidney) and subcellular compartments (cytosol and mitochondria), as well as changes in gene expression in response to diet, hormones and cytokines [147].

T349

56862-57134

Sentence

denotes

As reported by several studies, arginine is the precursor of macrophages and it is now clear that arginine metabolism of immune cells is particularly involved in cancer, inflammation, infections, fibrotic diseases, pregnancy and the regulation of immune system [148, 149].

T350

57135-57251

Sentence

denotes

Macrophage arginine metabolism influences the outcome of immune responses in which innate immune cells are involved.

T351

57252-57412

Sentence

denotes

Arginine supplementation is reported to increase T lymphocyte response and Th cell numbers, suggesting a possible role in prolonged or repeated infection [150].

T352

57413-57672

Sentence

denotes

The importance of arginine metabolism as a new field of investigation includes that its depletion delays the growth of some types of tumours, while others report that its integration improves anticancer effects, probably by ameliorating immune function [150].

T353

57673-57817

Sentence

denotes

As discussed, vitamins E, C, D, zinc and selenium are important examples of nutrients that play a key role in supporting the immune system [65].

T354

57818-57859

Sentence

denotes

They can work individually or in synergy.

T355

57860-57981

Sentence

denotes

Furthermore, other dietary components are likely to play a role in modulating immunity, but have not yet been identified.

T356

57982-58058

Sentence

denotes

It is clear how nutritional deficiencies can compromise the immune response.

T357

58059-58235

Sentence

denotes

In addition, inflammation related to unhealthy eating habits has reached alarming proportions, particularly concerning chronic non-communicable diseases [100] (Tables 1 and 2).

T358

58236-58298

Sentence

denotes

Table 1 Dietary sources and immune function roles of nutrients

T359

58299-58350

Sentence

denotes

Nutrient Good dietary sources Immune function roles

T360

58351-58775

Sentence

denotes

Vitamin A Milk and cheese, eggs, liver, oily fish, fortified cereals, dark orange or green vegetables (e.g., carrots, sweet potatoes, pumpkin, squash, kale, spinach, broccoli), orange fruits (e.g., apricots, peaches, papaya, mango, cantaloupe melon), tomato juice Normal differentiation of epithelial tissue; retinoic acid ↑ T and B cells with gut-homing specificity and array T cells and IgA + cells into intestinal tissues

T361

58776-58941

Sentence

denotes

Supporting the gut barrier; carotenoids; ↑immunoregulatory actions including ↓ toxic effects of ROS and regulating membrane fluidity and gap-junctional communication

T362

58942-59043

Sentence

denotes

Regulates number and function of NK cells,↑ to phagocytic and oxidative burst activity of macrophages

T363

59044-59072

Sentence

denotes

Downregulates IFN production

T364

59073-59277

Sentence

denotes

Helps to regulate the production of IL-2 and the pro-inflammatory TNF-γ, ↑ microbial action of macrophages; involved in phagocytic and oxidative burst activity of macrophages activated during inflammation

T365

59278-59477

Sentence

denotes

Development and differentiation of Th1 and Th2 cells; ↑ TGF- β-dependent conversion of naïve T cells into regulatory T cells; plays a role in acquisition of mucosal-homing properties by T and B cells

T366

59478-59643

Sentence

denotes

Development and differentiation of Th 1 and Th2 cells; maintains normal antibody-mediated Th2 response by suppressing IL-12, TNF-α, and IFN-γ production of Th1 cells

T367

59644-59846

Sentence

denotes

Normal functioning of B cells, necessary for generation of antibody responses to antigen; required for B cell-mediated IgA antibody responses to bacterial polysaccharide antigens [62, 79–82, 85, 92, 95]

T368

59847-60155

Sentence

denotes

Vitamin C Oranges and orange juice, red and green peppers, strawberries, blackcurrants, kiwi, broccoli, brussels sprouts, potatoes ↑ collagen synthesis and protects cell membranes from damage caused by free radicals; ↑ keratinocyte differentiation; ↑ lipid synthesis; ↑ fibroblast proliferation and migration

T369

60156-60271

Sentence

denotes

Proliferation, function, and movement of neutrophils, monocytes and phagocytes; ↑ NK cell activities and chemotaxis

T370

60272-60326

Sentence

denotes

↑ Phagocytosis and ROS generation; ↑ microbial killing

T371

60327-60412

Sentence

denotes

↑ Apoptosis and clearance of spent neutrophils from sites of infection by macrophages

T372

60413-60466

Sentence

denotes

↓ Extracellular trap (NET) formation, ↓ tissue damage

T373

60467-60529

Sentence

denotes

↑ Antimicrobial effects; ↑ serum levels of complement proteins

T374

60530-60780

Sentence

denotes

Maintains redox homeostasis within cells and protects against ROS and RNS during oxidative burst; regenerates other important antioxidants, such as glutathione and vitamin E, to their active state; modulates cytokine production and ↓ histamine levels

T375

60781-60961

Sentence

denotes

Roles in production, differentiation, and proliferation of T cells, particularly cytotoxic T cells; ↑ proliferation of lymphocytes, ↑ generation of antibodies [79, 85, 92, 95, 120]

T376

60962-61406

Sentence

denotes

Vitamin D Oily fish, liver, eggs, fortified foods (spreads and some breakfast cereals) Regulates antimicrobial proteins (cathelicidin and β-defensin), modifying intestinal microbiota to a healthier composition and supporting the gut, as well as protecting the lungs against infection; ↑ tight junction protein expression, E-cadherin and connexion 43 in the gut; maintains renal epithelial barrier function; ↑ corneal epithelial barrier function

T377

61407-61581

Sentence

denotes

Vitamin D receptor found in, e.g., monocytes, macrophages, and DCs; ↑ differentiation of monocytes to macrophages; calcitriol ↑ movement and phagocytic ability of macrophages

T378

61582-61724

Sentence

denotes

Regulates antimicrobial protein expression (cathelicidin and defensin), which directly kill pathogens, especially bacteria; ↓ IFN-γ production

T379

61725-61932

Sentence

denotes

↑ The oxidative burst potential of macrophages; increases superoxide synthesis; reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages

T380

61933-62317

Sentence

denotes

Homing of T cells to the skin; ↓ T-cell proliferation; inhibitory effects mainly in adaptive immunity (e.g., Th1-cell activity); stimulatory effects in innate immunity; ↓ the effector functions of T helper cells and cytotoxic T cells; ↑ the production of Tregs; inhibitory effect on the differentiation and maturation of the antigen-presenting DCs, and helps program DCs for tolerance

T381

62318-62350

Sentence

denotes

↓ Antibody production by B cells

T382

62351-62457

Sentence

denotes

↑ Antigen processing; role in the down-regulation of MHC-II) [64, 71, 79–81, 85, 95, 99, 104–106, 151–153]

T383

62458-62637

Sentence

denotes

Vitamin E Many vegetable oils, nuts and seeds, wheat germ (e.g., in cereals) Protects cell membranes from damage caused by free radicals and ↑ the integrity of epithelial barriers

T384

62638-62745

Sentence

denotes

↑ NK cell cytotoxic activity; ↓ PGE2 production by macrophages (thus indirectly protecting T-cell function)

T385

62746-62973

Sentence

denotes

Important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain-breaking effect) and protects cells against them; ↑ IL-2 production; ↓ production of PGE2 (indirectly protecting T-cell function)

T386

62974-63191

Sentence

denotes

↑ Lymphocyte proliferation and T-cell-mediated functions; ↑ Th1 response; ↓ Th2 response; helps to form effective immune synapses between Th cells; ↑ proportion of antigen-experienced memory [64, 79, 82, 95, 112, 113]

T387

63192-63405

Sentence

denotes

Zinc Shellfish, meat, cheese, some grains and seeds, cereals, seeded or whole grain breads Helps maintain integrity of skin and mucosal membrane (e.g., cofactor for metalloenzymesrequired for cell membrane repair)

T388

63406-63586

Sentence

denotes

↑ NK cell cytotoxic activity; central role in cellular growth and differentiation of immune cells that have a rapid differentiation and turnover; ↑ phagocytic capacity of monocytes

T389

63587-63644

Sentence

denotes

Involved in complement activity; role in IFN-γ production

T390

63645-63969

Sentence

denotes

Anti-inflammatory agent; helps to modulate cytokine release by dampening the development of pro-inflammatory Th17 and Th9 cells and influencing the generation of cytokines such as IL-2, IL-6, and TNF; has antioxidant effects that protect against ROS and reactive nitrogen species; influences activity of antioxidant proteins

T391

63970-64299

Sentence

denotes

↑ Proliferation of cytotoxic T cells; involved in Th1 cytokine production and thus supports Th1 response; essential for intracellular binding of tyrosine kinase to T cell receptors, required for T cell development, differentiation, and activation; ↑ development of Treg cells and is thus important in maintaining immune tolerance

T392

64300-64506

Sentence

denotes

Involved in antibody production, particularly IgG; involved in antibody response; important in maintaining immune tolerance (i.e., the ability to recognize “self” from “non-self”) [64, 82, 95, 116, 118–121]

T393

64507-64595

Sentence

denotes

Selenium Fish, shellfish, meat, eggs, some nuts especially brazil nuts ↑ IFN-γproduction

T394

64596-64698

Sentence

denotes

Selenoproteins important for antioxidant host defense system, affecting leukocyte and NK cell function

T395

64699-64858

Sentence

denotes

Essential for function of selenoproteins that act as redox regulators and cellular antioxidants, potentially counteracting ROS produced during oxidative stress

T396

64859-64912

Sentence

denotes

Roles in differentiation and proliferation of T cells

T397

64913-64978

Sentence

denotes

↑ Th cell counts and to maintain antibody levels [82, 85, 92, 95]

T398

64979-65201

Sentence

denotes

Iron Meat, liver, beans, nuts, dried fruit (e.g., apricots), wholegrains (e.g., brown rice), fortified cereals, most dark green leafy vegetables (spinach, kale) Essential for differentiation and growth of epithelial tissue

T399

65202-65557

Sentence

denotes

Forms highly-toxic hydroxyl radicals, thus involved in killing of bacteria by neutrophils; component of enzymes critical for functioning of immune cells (e.g., ribonucleotide reductase involved in DNA synthesis); involved in regulation of cytokine production and action; ↑ M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response

T400

65558-65582

Sentence

denotes

Role in IFN-γ production

T401

65583-65726

Sentence

denotes

Involved in regulation of cytokine production and action; required for generation of pathogen-killing ROS by neutrophils during oxidative burst

T402

65727-65868

Sentence

denotes

Important in differentiation and proliferation of T cells; helps to regulate ratio between T helper cells and cytotoxic T cells [85, 95, 138]

T403

65869-66087

Sentence

denotes

Long chain omega-3 fatty acids (EPA and DHA) Oilyfish Anti-inflammatory and antioxidant properties when enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins

T404

66088-66165

Sentence

denotes

↑ Immune system, by helping to resolve the inflammatory response [63, 66, 67]

T405

66166-66247

Sentence

denotes

Table 2 Nutrient’s supplementation suggested in support of respiratory infections

T406

66248-66331

Sentence

denotes

Nutrient Recommended supplementation suggested in support of respiratory infections

T407

66332-66366

Sentence

denotes

Omega 3 fatty acids 2–4 g/day [68]

T408

66367-66399

Sentence

denotes

Vitamin D 20,000–50,000 IU [154]

T409

66400-66426

Sentence

denotes

Vitamin E 135 mg/day [114]

T410

66427-66449

Sentence

denotes

Zinc 30–50 mg/day [98]

T411

66450-66478

Sentence

denotes

Selenium 25–100 μg/day [130]

T412

66479-66524

Sentence

denotes

Arginine and glutamine 25–35 g/day [142, 146]

T413

66525-66549

Sentence

denotes

Vitamin C 1–2 g/day [98]

T414

66550-66579

Sentence

denotes

Vitamin A 900–700 µg/day [91]

T415

66580-66602

Sentence

denotes

Iron 8–18 mg/day [138]

T416

66604-66658

Sentence

denotes

The role of gut microbiota in COVID-19 immunonutrition

T417

66659-66741

Sentence

denotes

The human intestine hosts a complex bacterial community called the gut microbiota.

T418

66742-66861

Sentence

denotes

The microbiota is specific to each individual despite the existence of several bacterial species shared by most adults.

T419

66862-66931

Sentence

denotes

Scientific studies reveal its influence on human health and diseases.

T420

66932-67136

Sentence

denotes

In particular they have shown that the intestinal microbiota can play a causal role in the development of obesity and associated metabolic disorders, leading to the identification of different mechanisms.

T421

67137-67369

Sentence

denotes

In humans, differences are observed in the composition of the microbiota, in the functional genes and in the metabolic activities between obese and lean individuals, that suggest a contribution of the microbiota to these phenotypes.

T422

67370-67584

Sentence

denotes

Finally, the evidence linking intestinal bacteria to host metabolism could allow the development of new therapeutic strategies based on the modulation of the intestinal microbiota to treat or prevent obesity [155].

T423

67585-67710

Sentence

denotes

Microbiota plays a crucial role in the maturation, development and functions of both innate and adaptive immune system [156].

T424

67711-67854

Sentence

denotes

The gut microbiota has been shown to affect lung health through a vital crosstalk between gut microbiota and lungs, called the “gut-lung axis”.

T425

67855-68083

Sentence

denotes

This axis communicates through a bi-directional pathway in which endotoxins, or microbial metabolites, may affect the lung through the blood and when inflammation occurs in the lung, this, in turn, can affect the gut microbiota.

T426

68084-68206

Sentence

denotes

The immunological health of the gut, primarily mediated by the microbiota, influences lung health via the “gut-lung axis”.

T427

68207-68380

Sentence

denotes

In addition, microbial communities inhabiting the mucosal surfaces of the respiratory tract also contribute towards host defense against viral respiratory infections (VRIs).

T428

68381-68511

Sentence

denotes

Acute VRIs are associated with microbial dysbiosis in these communities, thus acting the optimal functioning of the immune system.

T429

68512-68752

Sentence

denotes

Alterations in the microbiota during influenza virus infection contributes to the pathogenesis of secondary bacterial infections, thus increasing the severity of the clinical course in the absence of appropriate immune responses [157, 158].

T430

68753-68967

Sentence

denotes

It is also known that alterations of the immune functions associated with chronic inflammation and related metabolic dysfunctions lead to a compromise of innate and acquired immune functions in the host [159, 160].

T431

68968-69150

Sentence

denotes

Moreover, chronic inflammation and the use of antibiotics are known to accompany disorders in the gut microbiota, resulting in dysbiosis and aggravation of immune dysfunctions [161].

T432

69151-69433

Sentence

denotes

In addition, the prevalence of comorbid conditions (including chronic lung disease, diabetes, hypertension and cardiovascular diseases) and old age predispose to infection, the development of ARDS and pneumonia, factors already observed for other infections such as influenza [162].

T433

69434-69549

Sentence

denotes

This point raises an interesting possibility that the new SARS-Cov-2 may also have an impact on the gut microbiota.

T434

69550-69683

Sentence

denotes

Indeed, several studies have shown that respiratory infections are associated with a change in the composition of the gut microbiota.

T435

69684-69833

Sentence

denotes

Numerous experimental and clinical observations have suggested that the gut microbiota plays a key role in the pathogenesis of sepsis and ARDS [163].

T436

69834-70057

Sentence

denotes

Moreover, it is known that the signals derived from the intestinal microbiota tune the cells of the immune system for pro and anti-inflammatory responses which thus influence the susceptibility to various diseases (Fig. 2).

T437

70058-70163

Sentence

denotes

Fig. 2 Graphical representation of immune homeostasis disequilibrium during SARS-Coronavirus 2 infection.

T438

70164-70290

Sentence

denotes

ARDS: acute respiratory distress syndrome; T lymphocyte; IL: interleukin; Th: helper T lymphocyte; TNF: tumour necrosis factor

T439

70291-70384

Sentence

denotes

It is also known that respiratory virus infection causes perturbations in the gut microbiota.

T440

70385-70510

Sentence

denotes

Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity [164].

T441

70511-70616

Sentence

denotes

There is growing evidence that supports the roles of the gut microbiota and diet to shape immunity [165].

T442

70617-70787

Sentence

denotes

Modulating the composition and metabolic capacity of the microbiome for specific dietary components is a promising strategy for influencing immune responses against VRIs.

T443

70788-71008

Sentence

denotes

Functional food components including probiotics, prebiotics and other bioactive ingredients of plant origin have been associated with immune benefits, mainly via microbiota modulation and impact on oxidative stress [65].

T444

71009-71235

Sentence

denotes

Several papers, regarding body composition, evaluated the correlation between fat mass and disease risk and then identified a new frontier of gut microbiota composition in the bodyweight decrease and anti-inflammatory effects.

T445

71236-71587

Sentence

denotes

As shown, the prevention of cardiometabolic diseases, considering the relationship with obesity, may be possible reducing the inflammatory state, acting on the gut-microbiota and on the intestinal permeability improving the health of the intestinal flora, with 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols [166].

T446

71588-71772

Sentence

denotes

Prebiotic from fruits and vegetables is well-established to modulate the gut microbiota and numerous benefits have been reported in chronic inflammatory and metabolic conditions [167].

T447

71773-71951

Sentence

denotes

In fact, dietary fibers are a good source of accessible carbohydrates for microbiota then prebiotics have been studied in the context of modification of the human gut microbiota.

T448

71952-72123

Sentence

denotes

The compounds such as inulin, polydextrose, maize fiber have been shown to improve the immunity, gut diversity, digestion in humans and especially in elderly people [164].

T449

72124-72272

Sentence

denotes

Moreover, increased dietary fiber consumption is linked to reduced mortality rates in respiratory-related diseases and improved lung function [162].

T450

72273-72407

Sentence

denotes

Thus, plant-based diets, functional foods, and supplements present a promising strategy for protecting against respiratory infections.

T451

72408-72565

Sentence

denotes

Prebiotics lead the influence of microbiota composition and undergo microbial fermentation to produce SCFAs, such as butyrate, acetate, and propionate [168].

T452

72566-72825

Sentence

denotes

Overall, it is apparent that diet and personalized nutritional interventions acting in modulation of gut microbiota especially to control dysbiosis state and to some extent even lung microbiota can influence health status such as immunity conditions (Fig. 3).

T453

72826-72914

Sentence

denotes

Fig. 3 Graphical representation of personalized nutritional intervention during COVID-19

T454

72915-73141

Sentence

denotes

In addition, probiotics which are generally defined as “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” have been shown to have profound effect on the health of the host.

T455

73142-73446

Sentence

denotes

In the intestine, the probiotics mainly refer to the genera Lactobacillus and Bifidobacterium and include many different strains such as L. johnsonii, L. fermentum, L. reuteri, L. paracasei, L. rhamnosus, L. acidophilus, L. plantarum, B. longum, B. breve, B. bifidum, and B. animalis subsp. lactis [169].

T456

73447-73533

Sentence

denotes

Fermented foods such as cultured milk products and yoghurt are enriched in probiotics.

T457

73534-73713

Sentence

denotes

They have shown good results in modulating inflammatory conditions as well as regulating innate immunity using toll-like receptors and the corresponding signalling pathways [170].

T458

73714-73910

Sentence

denotes

The capacity of probiotics to induce immunomodulation could be mediated either directly through interaction with immune cells or indirectly by supporting the challenged commensal microbiota [171].

T459

73911-74263

Sentence

denotes

Ingested probiotics with diet or through supplementation stimulate the immune system and initiate a complex of signals mediated by the whole bacteria, they then interact with intestinal epithelial cells also with immune cells associated with the lamina propria or other microbial PRRs and trigger the production of an array of cytokines and chemokines.

T460

74264-74398

Sentence

denotes

These molecules then interact with other immune cells through other pathways, leading to the activation of the mucosal immune systems.

T461

74399-74520

Sentence

denotes

As reported by many reviews specific probiotics have been demonstrated to enhance Th1 and regulatory Treg function [162].

T462

74521-74697

Sentence

denotes

It is clear that probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells.

T463

74698-74837

Sentence

denotes

Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication [170].

T464

74838-75083

Sentence

denotes

Additionally, phytochemicals including vitamins, micronutrients, and polyphenols present in fruits and vegetables have been shown a considerable importance in nutritional strategies for addressing the severity of viral respiratory diseases [65].

T465

75084-75203

Sentence

denotes

Some polyphenols influence microbiota composition and also have antioxidant, anti-inflammatory, and anti-viral effects.

T466

75204-75412

Sentence

denotes

The antiviral effect of polyphenols have been demonstrated to be mediated either by direct inhibitory effects on virus replication or through the induction of immunomodulatory and antioxidant responses [172].

T467

75413-75554

Sentence

denotes

In fact, oxidative stress has been implicated in lung tissue injury and epithelial barrier dysfunction in acute respiratory viral infections.

T468

75555-75685

Sentence

denotes

Dietary polyphenols are present in foods such as vegetables, fruits, cereals, tea, coffee, dark chocolate, cocoa powder, and wine.

T469

75686-75811

Sentence

denotes

The main groups of dietary polyphenols consist in phenolic acids, flavonoids, tannins, stilbenes and diferuloylmethane [173].

T470

75812-75986

Sentence

denotes

Many evidences revealed the excellent immunomodulatory effects of epigallocatechin-3-gallate (EGCG), abundant in green tea on both innate and adaptive immune responses [174].

T471

75987-76139

Sentence

denotes

Finally, in this context there is an important role explained by postbiotics (also known as metabiotic, biogenic, or metabolite cell-free supernatants).

T472

76140-76307

Sentence

denotes

Postbiotics are products or metabolic byproducts secreted by live bacteria or released after bacterial lysis and they provide physiological benefits to the host [175].

T473

76308-76494

Sentence

denotes

There are multiple types of postbiotics with varied structures, such as Short Chain Fatty Acids (SCFAs), peptides, enzymes, teichoic acids, exo- and endo-polysaccharides, vitamins [176].

T474

76495-76673

Sentence

denotes

A protective role of postbiotics like SCFAs has been found in the immune system modulation; particularly in regulation of neutrophil migration in acute inflammation in the colon.

T475

76674-76921

Sentence

denotes

The benefits of microbially-fermented SCFAs are suggested to be mediated through the direct actions of G-protein-coupled receptors (GPRs) expressed on the gut epithelium, adipose tissues and immune cells, including monocytes and neutrophils [177].

T476

76922-77051

Sentence

denotes

Gut-derived SCFAs have been shown to influence the functions of innate immune cells as well as impact acquired immune components.

T477

77052-77333

Sentence

denotes

Studying microbiota and therefore the human immune system and its dysregulation, or controlling the effects of postbiotics in the symbiotic status represents an important opportunity to develop new drugs, and combining probiotic supplements, with vaccines and immunotherapies [16].

T478

77335-77346

Sentence

denotes

Conclusions

T479

77347-77435

Sentence

denotes

Immunonutrition has been based on the concept that malnutrition impairs immune function.

T480

77436-77711

Sentence

denotes

Therefore, immunonutrition involves feeding enriched with various pharmaconutrients (Omega 3 Fatty Acids, Vitamin C, Arginine, Glutamine, Selenium, Zinc, Vitamin, E and Vitamin D) to modulate inflammatory responses, acquired immune response and to improve patients’ outcomes.

T481

77712-77905

Sentence

denotes

Finally, we can conclude that personalized immunonutrition for obese patients should be the first therapeutic choice to reduce the risk of infections and the disease course in COVID-19 patient.

T482

77906-78044

Sentence

denotes

In particular, the nutritional approach might be managed in two different strategies, considering the disease status of the obese patient.

T483

78045-78148

Sentence

denotes

First, immunonutrition can decrease the risk of infections, reducing characteristic inflammation state.

T484

78149-78280

Sentence

denotes

In addition, immunonutrition would be fundamental to support the immune response and protein synthesis in severe phase of COVID-19.

T485

78282-78295

Sentence

denotes

Abbreviations

T486

78296-78331

Sentence

denotes

GALT Gut associated lymphoid tissue

T487

78332-78353

Sentence

denotes

B cells B lymphocytes

T488

78354-78375

Sentence

denotes

T cells T lymphocytes

T489

78376-78393

Sentence

denotes

NK Natural killer

T490

78394-78418

Sentence

denotes

TC cell Cytotoxic T-cell

T491

78419-78438

Sentence

denotes

TCR T cell receptor

T492

78439-78461

Sentence

denotes

Treg Regulatory T cell

T493

78462-78479

Sentence

denotes

Ig Immunoglobulin

T494

78480-78508

Sentence

denotes

APC Antigen presenting cells

T495

78509-78545

Sentence

denotes

MHC Major histocompatibility complex

T496

78546-78557

Sentence

denotes

Th T helper

T497

78558-78572

Sentence

denotes

IL Interleukin

T498

78573-78587

Sentence

denotes

INF Interferon

T499

78588-78627

Sentence

denotes

CXCL-10 C–X–C motif chemokine ligand 10

T500

78628-78709

Sentence

denotes

RANTES Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted

T501

78710-78746

Sentence

denotes

CCL-5 Chemokine (C–C motif) ligand 5

T502

78747-78787

Sentence

denotes

MCP-1 Monocyte Chemoattractant Protein-1

T503

78788-78822

Sentence

denotes

TGF-β Transforming growth factor-β

T504

78823-78839

Sentence

denotes

Jak Janus kinase

T505

78840-78893

Sentence

denotes

STAT Signal transducer and activator of transcription

T506

78894-78961

Sentence

denotes

NFκB Nuclear factor kappa-light-chain-enhancer of activated B cells

T507

78962-78988

Sentence

denotes

TNF Tumour necrosis factor

T508

78989-79023

Sentence

denotes

PRRs Pattern recognition receptors

T509

79024-79067

Sentence

denotes

MAMPs Microbe-associated molecular patterns

T510

79068-79092

Sentence

denotes

TLRs Toll-like receptors

T511

79093-79143

Sentence

denotes

NLR Nucleotide-Binding Domain, Leucine-Rich Repeat

T512

79144-79197

Sentence

denotes

NALP3 NACHT, LRR and PYD domains-containing protein 3

T513

79198-79227

Sentence

denotes

SARS-CoV-2 SARS-coronavirus 2

T514

79228-79235

Sentence

denotes

S Spike

T515

79236-79246

Sentence

denotes

E Envelope

T516

79247-79257

Sentence

denotes

M Membrane

T517

79258-79272

Sentence

denotes

N Nucleocapsid

T518

79273-79309

Sentence

denotes

ACE2 Angiotensin-converting enzyme 2

T519

79310-79324

Sentence

denotes

BDK Bradykinin

T520

79325-79365

Sentence

denotes

BDKRB1 or 2 Bradykinin receptor B1 or B2

T521

79366-79406

Sentence

denotes

ARDS Acute respiratory distress syndrome

T522

79407-79429

Sentence

denotes

OEA Oleoylethanolamide

T523

79430-79485

Sentence

denotes

PPAR-α Peroxisome proliferator-activated receptor-alpha

T524

79486-79519

Sentence

denotes

NET Neutrophil extracellular trap

T525

79520-79566

Sentence

denotes

MAPK p38 p38 mitogen-activated protein kinases

T526

79567-79596

Sentence

denotes

CRS Cytokine release syndrome

T527

79597-79615

Sentence

denotes

HAS2 HA-synthase-2

T528

79616-79661

Sentence

denotes

NOD Nucleotide-binding oligomerization domain

T529

79662-79692

Sentence

denotes

ASC Caspase recruitment domain

T530

79693-79733

Sentence

denotes

MCP-1 Monocyte chemoattractant protein 1

T531

79734-79763

Sentence

denotes

WHO World Health Organization

T532

79764-79790

Sentence

denotes

PBF Percentage of body fat

T533

79791-79810

Sentence

denotes

BMI Body mass index

T534

79811-79836

Sentence

denotes

NWO Normal Weight Obesity

T535

79837-79864

Sentence

denotes

IMDs Immunomodulating diets

T536

79865-79883

Sentence

denotes

ALA Linolenic acid

T537

79884-79909

Sentence

denotes

EPA Eicosapentaenoic acid

T538

79910-79934

Sentence

denotes

DHA Docosahexaenoic acid

T539

79935-79975

Sentence

denotes

SPMs Specialized pro-resolving mediators

T540

79976-79998

Sentence

denotes

VDR Vitamin D receptor

T541

79999-80020

Sentence

denotes

PGE2 Prostaglandin E2

T542

80021-80043

Sentence

denotes

COX-2 Cyclooxygenase-2

T543

80044-80077

Sentence

denotes

RDA Recommended Dietary Allowance

T544

80078-80111

Sentence

denotes

DRI Dietary Recommendation Intake

T545

80112-80139

Sentence

denotes

ROS Reactive oxygen species

T546

80140-80181

Sentence

denotes

ERK Extracellular signal-regulated kinase

T547

80182-80209

Sentence

denotes

JKN c-Jun N-terminal kinase

T548

80210-80234

Sentence

denotes

AP-1 Activator protein-1

T549

80235-80268

Sentence

denotes

VRIs Viral respiratory infections

T550

80269-80300

Sentence

denotes

EGCG Epigallocatechin-3-gallate

T551

80301-80330

Sentence

denotes

SCFAs Short Chain Fatty Acids

T552

80331-80363

Sentence

denotes

GPRs G-protein-coupled receptors

T553

80364-80383

Sentence

denotes

DCs Dendritic cells

T554

80384-80400

Sentence

denotes

Publisher's Note

T555

80401-80519

Sentence

denotes

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

T556

80521-80537

Sentence

denotes

Acknowledgements

T557

80538-80646

Sentence

denotes

We thank Fondazione Umberto Veronesi for supporting Dr. Francesca Pivari with Post-Doctoral Fellowship 2020.

T558

80647-80730

Sentence

denotes

The authors thank Fulvia Mariotti for the editorial and English language revisions.

T559

80732-80754

Sentence

denotes

Authors’ contributions

T560

80755-80860

Sentence

denotes

LDR and LS conceived and wrote the review; PG, FP, AA, CL, GC, EC, MGT, GC, GM, AMP, RD wrote the review.

T561

80861-80891

Sentence

denotes

LDR, EC, GC drawn the figures.

T562

80892-80945

Sentence

denotes

ADL had primary responsibility for the final content.

T563

80946-81022

Sentence

denotes

All authors have read and agreed to the published version of the manuscript.

T564

81023-81074

Sentence

denotes

All authors read and approved the final manuscript.

T565

81076-81083

Sentence

denotes

Funding

T566

81084-81133

Sentence

denotes

This research does not received external funding.

T567

81135-81169

Sentence

denotes

Availability of data and materials

T568

81170-81185

Sentence

denotes

Not applicable.

T569

81187-81229

Sentence

denotes

Ethics approval and consent to participate

T570

81230-81245

Sentence

denotes

Not applicable.

T571

81247-81270

Sentence

denotes

Consent for publication

T572

81271-81286

Sentence

denotes

Not applicable.

T573

81288-81307

Sentence

denotes

Competing interests

T574

81308-81352

Sentence

denotes

The authors declare no conflict of interest.

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