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Id Subject Object Predicate Lexical cue
T1 0-39 Sentence denotes Towards treatment planning of COVID-19:
T2 40-114 Sentence denotes Rationale and hypothesis for the use of multiple immunosuppressive agents:
T3 115-168 Sentence denotes Anti-antibodies, immunoglobulins, and corticosteroids
T4 170-180 Sentence denotes Highlights
T5 181-269 Sentence denotes • IVIG, combined with moderate-dose of corticosteroids, might improve patient outcomes.
T6 270-340 Sentence denotes • The use of corticosteroids might accelerate recovery from COVID-19.
T7 341-423 Sentence denotes • No controlled clinical trials exist on the use of corticosteroids for COVID-19.
T8 424-508 Sentence denotes • IL6 correlates with severity, criticality, viral load, and prognosis of COVID-19.
T9 509-596 Sentence denotes • Tocilizumab, an anti-IL6, can confer benefit in patients with COVID-19 and high IL6.
T10 598-606 Sentence denotes Abstract
T11 607-700 Sentence denotes The novel coronavirus, SARS-CoV2, can cause a potentially fatal disease, COVID-19, in humans.
T12 701-771 Sentence denotes Here, we will provide an overview of therapeutic options for COVID-19.
T13 772-921 Sentence denotes Plasma from patients recovered from COVID-19 that contains antibodies against SARS-CoV2 has shown promising results in patients with severe COVID-19.
T14 922-1013 Sentence denotes Also, IVIG, combined with moderate-dose of corticosteroids, might improve patient outcomes.
T15 1014-1074 Sentence denotes Evidence links COVID-19 to variable degrees of inflammation.
T16 1075-1160 Sentence denotes Studies show that the use of corticosteroids might accelerate recovery from COVID-19.
T17 1161-1290 Sentence denotes There are, however, no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death.
T18 1291-1466 Sentence denotes Also, the pro-inflammatory cytokine IL6 is the best-documented cytokine in COVID-19 correlated with severity, criticality, viral load, and prognosis of patients with COVID-19.
T19 1467-1578 Sentence denotes Tocilizumab, a monoclonal antibody against IL6, could confer clinical benefit in patients with high IL6 levels.
T20 1579-1761 Sentence denotes Essential elements that process SARS-CoV2 cell entry and specific characteristics that allow SARS-CoV2 to escape the immune system have the potential as targets for COVID-19 therapy.
T21 1763-1778 Sentence denotes 1 Introduction
T22 1779-1902 Sentence denotes Several generations have been exposed to COVID-19 under different conditions of life at varying locations around the world.
T23 1903-2009 Sentence denotes As long as the COVID-19 continues to spread, its power of genome modification would probably be increased.
T24 2010-2264 Sentence denotes What concerns us more is that the 2019-nCoV, by the process of modification of genome structure, might become more and more fitted to humans to profoundly affect those who have already escaped – children and young people without a pre-existing condition.
T25 2265-2419 Sentence denotes No one can tell how much time it takes to reach a new level of perfection, and that the development of vaccines for active immunization is a long process.
T26 2420-2520 Sentence denotes Moreover, most of the best available anti-viral agents are not helpful in the treatment of COVID-19.
T27 2521-2812 Sentence denotes A randomized controlled trial of 199 hospitalized adults with confirmed COVID-19 demonstrated no actual difference between patients who received lopinavir-ritonavir and patients who received standard care alone in clinical improvement, death rate, and positive virus test rate at day 28 [1].
T28 2813-2958 Sentence denotes Here we review intermediate indicators of the pathogenesis of COVID-19 that have the potential of being considered for the treatment of COVID-19.
T29 2960-2998 Sentence denotes 2 SARS-CoV2 cell entry is not complex
T30 2999-3103 Sentence denotes Fig. 1 is a schematic illustration of the minimum proteins required to mediate the SARS-CoV2 cell entry.
T31 3104-3228 Sentence denotes The trimeric, transmembrane spike (S) glycoprotein of the virus, SARS-2-S, includes two main functional subunits: S1 and S2.
T32 3229-3383 Sentence denotes The former, in turn, consists of the four core domains, S1A, S1B, S1C, and S1D, that contribute to the attachment to the surface receptor of target cells.
T33 3384-3456 Sentence denotes Then, the latter coordinates the fusion of viral and cellular membranes.
T34 3457-3551 Sentence denotes Receptor binding activates proteases that can carry out proteolytic cleavage of the S protein.
T35 3552-3682 Sentence denotes In coronaviruses, cleavage occurs at two sites: the S1/S2 junction and at the S2′, a region close to the viral fusion peptide [2].
T36 3683-3895 Sentence denotes Proteolytic cleavage of the S protein causes conformational changes so that they cannot revert to the original structure and profound enough to prime the S2 subunit for the fusion of viral and cellular membranes.
T37 3896-3950 Sentence denotes Fig. 1 Proteins required for the SARS-CoV2-cell entry.
T38 3952-3991 Sentence denotes 3 Certain characteristics of SARS-CoV2
T39 3993-4096 Sentence denotes 3.1 SARS-CoV2 has acquired an S glycoprotein that highly underwent genetic variation and glycosylation
T40 4098-4128 Sentence denotes 3.1.1 Polybasic cleavage site
T41 4129-4300 Sentence denotes As evidenced by sequence analysis, there is a residue insertion formed of four amino acids (12 nucleotides) at the boundary between S1 and S2 subunits of the SARS-CoV 2 S.
T42 4301-4503 Sentence denotes It defines a polybasic furin cleavage site of RRAR for the human SARS-CoV 2 that was absent in human SARS-CoV, bat SARS-like CoVs, and pangolin SARS-like CoV while might be present in other species [3].
T43 4504-4654 Sentence denotes After the introduction of mutation to the residue insertion and furin cleavage site, the S1/S2 cleavage of the SARS-CoV 2 S did not longer take place.
T44 4655-4765 Sentence denotes However, the SARS-CoV 2 S entry raised for VeroE6 cells and remained high in BHK cells that express human ACE.
T45 4766-4856 Sentence denotes Therefore, it seems that SARS-CoV2 transmissibility does not depend on the S1/S2 cleavage.
T46 4857-4982 Sentence denotes A polybasic cleavage site explains a virus that is highly-pathogenic for humans while it is low-pathogenic for other species.
T47 4983-5131 Sentence denotes For example, using reverse genetic tools, an avian paramyxovirus type 7 (APMV-7) was developed by mutating the fusion (F) protein cleavage site [4].
T48 5132-5244 Sentence denotes The constructed APMV-7 showed furin cleavage and increased replication and syncytium formation in cell cultures.
T49 5245-5309 Sentence denotes However, chicken exposed to the virus did not exhibit infection.
T50 5311-5331 Sentence denotes 3.1.2 Glycosylation
T51 5332-5502 Sentence denotes Glycosylation and its related products, i.e., glycans, introduce changes to the viral envelope that make the virus fitted for interaction with the host cell membrane [5].
T52 5503-5600 Sentence denotes Generally, glycans are oligosaccharides linked to the dense decoration of the spike glycoprotein.
T53 5601-5761 Sentence denotes In particular, these oligosaccharides have shown to influence the folding of the S protein and proteolytic process so that they facilitate the virus cell entry.
T54 5762-5878 Sentence denotes Moreover, a virus with the glycosylated glycoprotein gains an extra feature for an escape from the immune responses.
T55 5879-5935 Sentence denotes Therefore, glycans are a good target for vaccine design.
T56 5936-5996 Sentence denotes Two main types of glycans are N-linked and O-linked glycans.
T57 5997-6034 Sentence denotes Both are released from glycoproteins.
T58 6035-6140 Sentence denotes Whereas enzymes fulfill the construction of N-glycans, chemical methods perform the release of O-glycans.
T59 6141-6318 Sentence denotes N-glycans are linked to the amino acid asparagine (Asn) residues (Asn-any amino acids except for proline- Ser or Thr) utilizing an N-glycosidic bond, mostly N-acetylglucosamine.
T60 6319-6456 Sentence denotes O-glycans are attached to the amino acid serine (Ser) and threonine (Thr) residues by the addition of an N-acetyl galactosamine (GalNAc).
T61 6457-6626 Sentence denotes For example, N-glycans exist in Hendra virus, SARS-CoV, influenza virus, hepatitis virus, HIV-1, and West Nile virus [6], and O-glycans have occurred in the Ebola virus.
T62 6627-6742 Sentence denotes The 2019-nCoV S protein includes 13 and 9N-linked glycosylation sequons in the S1 and S2 subunit, respectively [3].
T63 6743-6868 Sentence denotes All of these have previously occurred in the SARS-CoV S glycoprotein, except for four-linked glycosylation sequons in the S1.
T64 6869-7092 Sentence denotes Also, due to the existence of an amino acid proline in the polybasic cleavage site, which makes the inserted sequence PRRA, there are three O-linked glycans introduced to the 2019-nCoV RBD residues S673, T678, and S686 [7].
T65 7094-7215 Sentence denotes 3.1.3 SARS-CoV2 receptor binding domain contains six amino acids providing favorable positions for binding to human ACE2
T66 7216-7441 Sentence denotes When compared to SARS-CoV SB, the motif binding the human ACE2 to the SARS-CoV 2 SB showed a relatively higher binding affinity for human ACE2 as indicated in smaller equilibrium dissociation constant (2.9 nM vs. 7.7 nM) [3].
T67 7442-7826 Sentence denotes Structural analysis has demonstrated that fourteen positions critically take part in the receptor-binding domain of the SARS-CoV SB that contain eight conserved (T402, Y436, Y440, N473, Y475, T486, G488, and Y491) positions and six semi-conserved (R426 to N448, Y442 to L464, L472 to F495, N479 to Q502, Y484 to Q507, and T487 to N510) substitutions with respect to the SARS-CoV 2 SB.
T68 7828-7942 Sentence denotes 3.1.4 SARS-CoV2 receptor binding domain contains cyclic regions that can make interaction with cell-surface GRP78
T69 7943-8132 Sentence denotes Pep42 is a cyclic oligopeptide that, with its hydrophobic character, can selectively interact with cell surface glucose‐regulated protein 78 (GRP78), a member of 70 kDa heat shock proteins.
T70 8133-8354 Sentence denotes GRP78, also known as BiP or HSPA5, under endoplasmic reticulum stress, can be translocated from the endoplasmic reticulum to the membrane and helps to maintain cellular integrity under physiologic and pathological stress.
T71 8355-8546 Sentence denotes It critically contributes to various functions ranging from protein folding, transportation, and degradation to cell-signaling, proliferation, survival, apoptosis, inflammation, and immunity.
T72 8547-8590 Sentence denotes The expression of GRP78 decreases with age.
T73 8591-8745 Sentence denotes On the 2019-nCoV spike protein, 13 disulfide bonds are corresponding to 13 different cyclic regions thought to be similar to the cyclic form of Pep42 [8].
T74 8746-8911 Sentence denotes Among these, four regions I-IV take place in the outer surface of a putative receptor-binding domain (RBD) on the viral spike., including C361, C379, C391, and C480.
T75 8912-8994 Sentence denotes These regions share sequence similarity with Pep42, ranging from 15.38% to 46.15%.
T76 8995-9104 Sentence denotes However, only one of them, i.e., region IV (GRAVY = 0.08), is a hydrophobic region, like Pep42 (GRAVY = 1.1).
T77 9105-9329 Sentence denotes Structural models evaluate the energy contribution for region IV as a part of region III to the GRP78 to be about (−9.8 out of −14.0 kcal/mol), and the docking platform proposes region IV as the best region binding to GRP78.
T78 9330-9529 Sentence denotes The region IV can be linked to the substrate-binding domain β (SBDB) of GRP78 using five H-bonds (through P479, N481, E484, and N487) and four hydrophobic interactions (through T478, E484, and F486).
T79 9531-9554 Sentence denotes 4 Passive immunization
T80 9555-9652 Sentence denotes There are two main ways to induce protection against infections: active and passive immunization.
T81 9653-9792 Sentence denotes Active immunization comes to exist when the body's own immune system can produce antibodies actively following exposure to a viral antigen.
T82 9793-9968 Sentence denotes On the contrary, there is a passive working mode of the immune system that would appear following the transfer of antibodies that act directly to neutralize viral infectivity.
T83 9970-9988 Sentence denotes 4.1 Serum therapy
T84 9990-10054 Sentence denotes 4.1.1 Convalescent plasma from patients recovered from COVID-19
T85 10056-10076 Sentence denotes 4.1.1.1 Hypothesis:
T86 10077-10158 Sentence denotes Plasma from patients recovered from COVID-19 contain antibodies against 2019-nCoV
T87 10159-10274 Sentence denotes A look at the history of viral outbreaks offers convalescent plasma as the only remedy to avoid further fatalities.
T88 10275-10469 Sentence denotes The most recent examples include the pandemic of influenza A H1N1 (H1N1pdm09) in virus infection 2009, the Western African Ebola virus epidemic in 2014, and the outbreak of MERS-CoV in 2015 [9].
T89 10470-10606 Sentence denotes Meta-analysis studies have shown a reduced risk of mortality in patients with SARS-CoV and influenza receiving convalescent plasma [10].
T90 10608-10627 Sentence denotes 4.1.1.2 Rationale:
T91 10628-10725 Sentence denotes Convalescent plasma from patients recovered from COVID-19 can treat patients with severe COVID-19
T92 10726-10990 Sentence denotes A pilot study [11] recently has investigated the safety and effect of convalescent plasma that contain antibody levels higher than 1:640 combined with regular anti-viral agents and standard supportive care on clinical outcomes of ten patients with severe COVID-19.
T93 10991-11122 Sentence denotes The study showed clinical improvement of all the ten patients accompanied by an increase in lymphocyte count and a decrease in CRP.
T94 11123-11292 Sentence denotes Following transfusion of convalescent plasma, all the seven patients who were SARS-CoV2 RNA positive before transfusion of convalescent plasma turned SARS-CoV2 negative.
T95 11293-11458 Sentence denotes There were no control groups receiving convalescent plasma alone or standard therapy without convalescent therapy to evaluate the main effect of convalescent plasma.
T96 11460-11501 Sentence denotes 4.1.2 Serum from bats with SARS-like CoV
T97 11503-11672 Sentence denotes 4.1.2.1 Hypothesis: whole-genome sequencing and phylogenetic analysis shed light on the origin of the 2019-nCoV virus – It has been probably introduced from bats to men
T98 11673-11849 Sentence denotes Genome sequencing of a fecal bat sample, Rp3, could detect an isolate of coronaviruses, which was almost identical to the causative agent of the SARS-CoV outbreak of 2002–2003.
T99 11850-11930 Sentence denotes Hence, it attained the name SARS-like coronavirus isolate Rp3 (SL-CoV Rp3) [12].
T100 11931-12018 Sentence denotes The bronchoalveolar lavage fluid (BALF) of a patient with SARS contained the 2019-nCoV.
T101 12019-12184 Sentence denotes RNA sequencing could reveal about 90% similarity in nucleotides of the novel coronavirus and of SARS-like coronavirus that had previously related to bats [13], [14].
T102 12185-12362 Sentence denotes In particular, the S protein of the 2019-nCoV has a high sequence identity of 80–98% with the S protein of bat SARS-like CoVs, such as SARSr-CoV ZXC21 S, ZC45 S, and RaTG13 [3].
T103 12363-12516 Sentence denotes Moreover, in phylogenomic trees, branches for the 2019-nCoV are of greater length than those for the 2003 SARS-CoV, and therefore more favorable to bats.
T104 12518-12537 Sentence denotes 4.1.2.2 Rationale:
T105 12538-12594 Sentence denotes Bat serum is not able to efficiently neutralize SARS-CoV
T106 12595-12731 Sentence denotes The range of bats, belonging to the genus Rhinolophus (horseshoe bats) and the family Rhinolophidae, produce the SARS-CoV antibody [12].
T107 12732-12922 Sentence denotes Polymerase chain reaction (PCR) will confirm the presence of SARS-CoV nucleocapsid (N) and polymerase (P) proteins in fecal samples if an individual bat being seropositive for SARS-CoV [12].
T108 12923-13129 Sentence denotes There is a significant degree of resemblance of greater than 90% in the nucleotide sequence of the viral genomes between SL-CoV Rp3 [12] and the Tor2 strain of SARS-CoV – which was isolated in Toronto [15].
T109 13130-13342 Sentence denotes The differences in the genome sequences of SARS-CoV in the two species occur merely in the S gene – which encodes the S1 domain of the coronavirus spike protein and contains regions with high mutation rates [12].
T110 13343-13571 Sentence denotes The coronaviruses commonly possess five open reading frames (ORF) that correlate with the production of the replicase polyprotein (P), the spike (S), envelope (E), and membrane (M) glycoproteins and the nucleocapsid (N) protein.
T111 13572-13729 Sentence denotes The human SARS-CoV Tor2 and bat SL-CoV Rp3 strains remain more than 90% identical at the proteins P, E, M, and N. the protein S consists of two main domains:
T112 13730-13869 Sentence denotes 1) the S1 domain conveys the role of receptor binding and 2) the S2 domain assumes the role of the fusion of viral and host-cell membranes.
T113 13870-14004 Sentence denotes In particular, the human SARS-CoV Tor2 strain shows a noticeable degree of difference in the S1 domain from the bat SL-CoV Rp3 strain.
T114 14005-14221 Sentence denotes This diversity would suffice to produce functional differences between the species, and is an apparent reason why bat sera having high levels of cross-reactive antibodies not acted efficiently to neutralize SARS-CoV.
T115 14223-14267 Sentence denotes 4.1.3 Serum from convalescent SARS patients
T116 14269-14390 Sentence denotes 4.1.3.1 Hypothesis: SARS-CoV and SARS-CoV2 are ideally similar in the structure and the cell entry receptor and protease
T117 14391-14753 Sentence denotes SARS-CoV and SARS-CoV2 share absolutely the same cleavage junctions, almost the same sequence (96%) of their main protease, a high degree (76%) of similarity in the amino acid sequence of their S protein, a similar S2′ cleavage site, a similar spectrum of cells they can enter, and the similarity of the most residues essential for binding ACE2 [16], [17], [18].
T118 14754-14839 Sentence denotes Also, both of them utilize the same domain of S1B to interact with the ACE2 receptor.
T119 14840-14902 Sentence denotes However, they differ in proteolytic processing to some degree.
T120 14903-15097 Sentence denotes Study [16] of the human embryonic kidney (HEK) cell line, 293 T, has shown that a signal for the S2 subunit is present in cells inoculated with SARS-2-S, but not in cells inoculated with SARS-S.
T121 15098-15259 Sentence denotes Two main proteases for both SARS-S and SARS-2-S are endosomal cysteine proteases cathepsin B and L (CatB/L) and the transmembrane protease, serine 2TMPRSS2 [16].
T122 15260-15439 Sentence denotes In 293 T cells lacking 2TMPRSS2, blocking CatB/L activity through increasing the endosomal pH by ammonium chloride could significantly limit the entry of both SARS-S and SARS-2-S.
T123 15440-15526 Sentence denotes In TMPRSS2 + Caco-2 cells, the effect of ammonium chloride existed to a lesser extent.
T124 15527-15696 Sentence denotes A combination of camostat mesylate, a blocker of TMPRSS2, and E-64d, an inhibitor of CatB/L, yielded the complete inhibition of SARS-2-S entry in TMPRSS2 + Caco-2 cells.
T125 15697-15946 Sentence denotes In both the human lung cancer cell line Calu-3 and the primary human lung cells, there was a reduction of the entry of both SARS-S and SARS-2-S by camostat mesylate, indicating that SARS-S and SARS-2-S partially require TMPRSS2 for a lung infection.
T126 15948-15966 Sentence denotes 4.1.3.2 Rational:
T127 15967-16048 Sentence denotes Serum from convalescent SARS patients is able to neutralize SARS-CoV2 efficiently
T128 16049-16227 Sentence denotes Antiserum that contains antibodies against human ACE2 could hinder the entry of both SARS-S and SARS-2-S pseudotypes while not affected the entry of VSV-G and MERS-S pseudotypes.
T129 16228-16450 Sentence denotes It supports the notion that SARS-S and SARS-2-S utilize the same primary entry receptor, i.e., ACE2, which is different from the primary receptors VSV-G and MERS-S engage for cell entry that is LDLR and DPP4, respectively.
T130 16451-16563 Sentence denotes Sera from three convalescent SARS patients reduced the SARS-S entry and, to e lesser degree, the SARS-2-S entry.
T131 16564-16625 Sentence denotes The patient serum effect was in a dose-dependent manner [16].
T132 16627-16672 Sentence denotes 4.1.4 Serum from rabbits immunized with SARS
T133 16674-16694 Sentence denotes 4.1.4.1 Hypotheses:
T134 16695-16794 Sentence denotes Serum from rabbits immunized with SARS is more effective than serum from convalescent SARS patients
T135 16795-16900 Sentence denotes Paraoxonases (PON) are mammalian enzymes associated with anti-oxidant and anti-inflammatory effects [19].
T136 16901-17009 Sentence denotes Rabbit PON differs from human PON in terms of more activity and more stability under the circumstances [20].
T137 17011-17029 Sentence denotes 4.1.4.2 Rational:
T138 17030-17137 Sentence denotes Serum from rabbits immunized with the S1 subunit of SARS-S is able to neutralize SARS-CoV2 very efficiently
T139 17138-17264 Sentence denotes Sera from rabbits immunized with the S1 subunit of SARS-S could effectively reduce the entry of both SARS-S and SARS-2-S [16].
T140 17265-17403 Sentence denotes When compared with patient serum, rabbit serum revealed to us higher efficiency in inhibition of SARS-2-S entry at the same concentration.
T141 17405-17444 Sentence denotes 4.2 Intravenous immunoglobulins (IVIG)
T142 17446-17511 Sentence denotes 4.2.1 Hypothesis: IVIG contains a large pool of human antibodies
T143 17512-17699 Sentence denotes IVIG is an immunomodulatory treatment currently useful for a variety of human diseases that share an idiopathic origin, ranging from autoimmune disorders to primary antibody deficiencies.
T144 17700-18008 Sentence denotes Also, IVIG has shown promising results in case of severe (such as sepsis, Parvovirus B19 infection, West Nile virus encephalitis, HIV, Clostridium difficile infections, Mycobacterium avium, Mycobacterium tuberculosis, and Nocardia infections) and recurrent infections in primary antibodies deficiencies [21].
T145 18009-18128 Sentence denotes Most patients develop antibodies against the NP and RBD of 2019-nCoV during the second week after infection onset [22].
T146 18129-18324 Sentence denotes Analysis of serum samples collected 14 or more days after symptom onset revealed detection of IgG and IgM antibodies against NP in 94% and 88% and RBD in 100% and 94% among patients with COVID19.
T147 18325-18450 Sentence denotes Studies consistently show that increased immunoglobulin levels accompany the transition from early to late course of COVID19.
T148 18451-18542 Sentence denotes It poses the possibility that IVIG therapy might help to accelerate recovery from COVID-19.
T149 18544-18626 Sentence denotes 4.2.2 Rationale: IVIG might help to improve the outcome of patients with COVID-19
T150 18627-18926 Sentence denotes The study [23] included ten patients with COVID-19 who demonstrated worsening symptoms, e.g., decreased lymphocyte count and decreased PaO2/FIO2 ratio and oxygen saturation, following treatment with a short-term moderate-dose corticosteroid (methylprednisolone 80 mg/d) plus immunoglobulin (10 g/d).
T151 18927-19106 Sentence denotes After switching to the double dose of 1600 mg/d methylprednisolone plus 20 g/d immunoglobulin, all of the patients improved in the clinical, laboratory, and paraclinical outcomes.
T152 19107-19238 Sentence denotes Passive immunization protects against disease, and so it should be administered as early as possible when the patient is diagnosed.
T153 19239-19470 Sentence denotes Studies show that the viral RNA of 2019-nCoV reaches its peak during the first week and then gradually decreases and that IgG and IgM begin to rise from the 10th day so that most patients have anti-viral antibodies by the 14th day.
T154 19472-19497 Sentence denotes 5 Recombinant type I IFN
T155 19499-19555 Sentence denotes 5.1 Hypothesis: IFNs play a role in anti-viral immunity
T156 19556-19729 Sentence denotes Type I IFNs play a primary role in the inhibition of viral replication through the coordination of anti-viral immune responses and modulation of inflammatory responses [24].
T157 19731-19745 Sentence denotes 5.2 Rational:
T158 19746-19814 Sentence denotes Recombinant type I IFN can effectively inhibit SARS-CoV2 replication
T159 19815-20003 Sentence denotes In 24–48 h after infection, SARS-CoV2 replication reaches titer that causes the cytopathic effect in Vero E6 cells, which express ACE2 and thus are susceptible to SARS-CoV2 infection [25].
T160 20004-20070 Sentence denotes It is similar to the viral replication kinetics for SARS-CoV [25].
T161 20071-20201 Sentence denotes Pretreatment with recombinant type I IFN could effectively inhibit SARS-CoV2 replication at both 24 and 48 h after infection [25].
T162 20202-20291 Sentence denotes For SARS-CoV, such an effect was present at 24 h but absent at 48 h after infection [25].
T163 20292-20478 Sentence denotes The difference between SARS-CoV2 and SARS-CoV in response to type I IFN treatment may be due to differences in structural proteins of these viruses, including NSP3, ORF3b, and ORF6 [25].
T164 20480-20531 Sentence denotes 6 Development of a human monoclonal antibody (mAb)
T165 20533-20561 Sentence denotes 6.1 Targeting the S protein
T166 20563-20581 Sentence denotes 6.1.1 Hypothesis:
T167 20582-20659 Sentence denotes A mAb against the binding domain of the virus can inhibit SARS-CoV2 infection
T168 20660-20946 Sentence denotes Recently, hybridoma supernatants containing antibody repertoires from immunized transgenic mice that express the human immunoglobulin heavy and light chains and rat origin immunoglobulin constant regions were used to detect antibodies that can cross neutralize SARS-S and SARS-2-S [26].
T169 20947-21167 Sentence denotes One chimeric 47D11 H2L2 antibody displayed such a cross-neutralizing activity, decreased syncytia formation induced by SARS-S and SARS2-S, and could protect VeroE6 cells against SARS-S and SARS2-S pseudotyped virus [26].
T170 21168-21300 Sentence denotes It may lie in its similar affinities for interacting with the same domain of the S1 subunit, i.e., S1B, of each SARS-S and SARS-2-S.
T171 21302-21318 Sentence denotes 6.1.2 Rational:
T172 21319-21403 Sentence denotes The chimeric 47D11 H2L2 might not be effective in human lung cells as it is in vitro
T173 21404-21504 Sentence denotes 47D11 carried a higher affinity for interacting with the S2 subunit of SARS-S than that of SARS-2-S.
T174 21505-21686 Sentence denotes It is important that for both SARS-S and SARS-2-S, the binding of the 47D11 antibody to the target – the S1B domain – does not block the binding of S1B and S2 to ACE2 receptor [26].
T175 21687-21806 Sentence denotes By contrast, neutralizing antibodies that specifically target SARS-S could compete with S1B and S2 for binding to ACE2.
T176 21808-21849 Sentence denotes 6.2 Targeting pro-inflammatory cytokines
T177 21851-21869 Sentence denotes 6.2.1 Hypothesis:
T178 21870-21920 Sentence denotes A mAb against IL6 can attenuate hyper inflammation
T179 21921-22249 Sentence denotes Tocilizumab, also known as atlizumab, is a humanized anti-human IL6 receptor antibody approved by FDA for several inflammatory and autoimmune diseases severe, such as cytokine release syndrome, rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systematic juvenile idiopathic arthritis.
T180 22250-22331 Sentence denotes It is safe and effective for both adults and children two years of age and older.
T181 22333-22350 Sentence denotes 6.2.2 Rationale:
T182 22351-22430 Sentence denotes Tocilizumab can treat lung injury in patients with critical and severe COVID-19
T183 22431-22578 Sentence denotes In the study [27], 21 patients with COVID-19 whose condition was severe or critical received one or two doses of Tocilizumab plus standard therapy.
T184 22579-22797 Sentence denotes Patients who had a mean IL6 level of more than 100 pg/ml before tocilizumab treatment showed improvement in clinical symptoms and peripheral oxygen saturation and normalization for lymphocyte proportion and CRP levels.
T185 22798-22856 Sentence denotes Also, lung lesion opacity was absorbed in 90% of patients.
T186 22857-22936 Sentence denotes Neither serious adverse effects nor deaths occurred with tocilizumab treatment.
T187 22937-23043 Sentence denotes There are ongoing clinical trials for tocilizumab treatment in patients with moderate and severe COVID-19.
T188 23044-23259 Sentence denotes Currently, the use of Tocilizumab is recommended for patients with COVID-19 who have warning signs of hyper inflammation, as can be measured by IL6, ferritin, platelet counts, inflammatory markers, and H score [28].
T189 23261-23279 Sentence denotes 7 Corticosteroids
T190 23281-23297 Sentence denotes 7.1 Hypothesis:
T191 23298-23339 Sentence denotes Corticosteroids can modulate inflammation
T192 23340-23429 Sentence denotes Corticosteroids are commonly used for modulation of a variety of inflammatory conditions.
T193 23430-23547 Sentence denotes In addition to a daily regimen, they can be used in the form of pulse therapy to treat flares of autoimmune diseases.
T194 23548-23746 Sentence denotes However, caution in the use of corticosteroids is needed due to the potential serious side effects associated with corticosteroid drugs and that corticosteroids generally suppress the immune system.
T195 23747-23921 Sentence denotes The latter means that corticosteroids modulate hyper inflammation and, on the other hand, inhibit immune responses that are vital for the host defense against the virus [29].
T196 23923-23938 Sentence denotes 7.2 Rationale:
T197 23939-23999 Sentence denotes Corticosteroids might help accelerate recovery from COVID-19
T198 24000-24170 Sentence denotes The study [30] investigated the effect of inhaled corticosteroids ciclesonide, cortisone, prednisolone, dexamethasone, and fluticasone on the replication of the MERS-CoV.
T199 24171-24262 Sentence denotes Among the four compounds, the only ciclesonide was capable of inhibiting viral replication.
T200 24263-24570 Sentence denotes Also, ciclesonide induced a significant inhibition of viral replication of other human coronaviruses, such as HCoV-229E and SARS-CoV, and another positive-strand RNA virus, rubella virus, while not affect the viral replication of negative-strand RNA viruses, e.g., influenza and respiratory syncytial virus.
T201 24571-24669 Sentence denotes For the MERS-CoV, a nonstructural protein 15 (NSP15) appeared to act as the target of ciclesonide.
T202 24670-24770 Sentence denotes An amino acid substitution in the NSP15 conferred resistance of the mutated MERS-CoV to ciclesonide.
T203 24771-24836 Sentence denotes Mometasone could help deal effectively with the mutated MERS-CoV.
T204 24837-24964 Sentence denotes For the SARS-CoV2, all three ciclesonide, mometasone, and lopinavir were able to inhibit viral replication to a similar degree.
T205 24965-25122 Sentence denotes Interestingly, their effect was more noticeable than serine protease inhibitors, e.g., nafamostat and camostat in cells that Vero cells that express TMPRSS2.
T206 25123-25277 Sentence denotes It indicates the tendency of the SARS-CoV2 to enter the cell through the cathepsin/endosomal pathway rather than through the TMPRSS2/cell surface pathway.
T207 25278-25482 Sentence denotes The study [31] included 46 patients with severe COVID-19, of these 26 patients received methylprednisolone (1–2 mg/kg/d for 5–7 days), and 20 patients received standard therapy without methylprednisolone.
T208 25483-25629 Sentence denotes The first group achieved faster improvement in clinical symptoms (fever and peripheral oxygen saturation) and lung lesions detected by CT imaging.
T209 25630-25712 Sentence denotes However, two deaths occurred in the first group and one death in the second group.
T210 25713-25897 Sentence denotes Moreover, the two groups did not differ in laboratory parameters, including WBC, lymphocyte count, monocyte count, and cytokines (IL-2, IL-4, IL-6, and IL-10) six days after treatment.
T211 25898-26011 Sentence denotes There is a report of the patient with COVID-19 treated with methylprednisolone since day 8 of the disease course.
T212 26012-26102 Sentence denotes However, his situation worsened and developed respiratory failure and died on day 14 [32].
T213 26104-26142 Sentence denotes 8 Eggs for increasing ACE2 and copper
T214 26143-26312 Sentence denotes Egg ovotransferrin contains an angiotensin-converting enzyme (ACE) inhibitory peptide, known as IRW, that has shown to decrease blood pressure in hypertensive rats [33].
T215 26313-26495 Sentence denotes Through the up-regulation of ACE2, E-cadherin, ABCB-1, and IRF-8, IRW can decrease RAS activity, hyperplasia, and vascular inflammation and aid differential regulation of leukocytes.
T216 26496-26665 Sentence denotes On the other hand, by the down-regulation of pro-inflammatory molecules, e.g., ICAM-1 and VCAM-1, IRW can reduce the recruitment of leukocytes and vascular inflammation.
T217 26666-26729 Sentence denotes Copper might help the immune system to combat viral infections.
T218 26730-26802 Sentence denotes A High-content of copper exists in eggs and eggshells of domestic birds.
T219 26803-26941 Sentence denotes In particular, the eggshell of pigeon (4 ± 0.29 μg/g) and the egg of quail (4.67 ± 1.08 μg/g) contains high concentrations of copper [34].
T220 26943-26956 Sentence denotes 9 Conclusion
T221 26957-27050 Sentence denotes The novel coronavirus, SARS-CoV2, can cause a potentially fatal disease, COVID-19, in humans.
T222 27051-27231 Sentence denotes The infection of human cells by SARS-CoV2 includes two sequential steps: attachment of the virus to the surface receptor of target cells and the fusion of viral and host membranes.
T223 27232-27410 Sentence denotes The former requires at least a receptor-binding domain on the SARS-CoV2 Spike protein that can interact with a cell surface receptor, for example, ACE2, expressed on human cells.
T224 27411-27612 Sentence denotes The latter requires at least the host protease(s) to mediate proteolytic cleavage of the SARS-CoV2 Spike protein into S1 and S2 subunits and consequently promote the fusion of viral and host membranes.
T225 27613-27859 Sentence denotes Also, SARS-CoV2 possesses a polybasic cleavage site that can explain the high pathogenicity of SARS-CoV2, N-glycans and O-glycans that make the dense decoration of SARS-CoV2 S protein, and cyclic regions that can interact with cell-surface GRP78.
T226 27860-28042 Sentence denotes Essential elements that process SARS-CoV2 cell entry and specific characteristics that allow SARS-CoV2 to escape the immune system have the potential as targets for COVID-19 therapy.
T227 28043-28239 Sentence denotes Lack of specific treatments for COVID-19 and the very time-consuming process of vaccine development lead us to trust traditional notions of immunization using passive transfer of humoral immunity.
T228 28240-28311 Sentence denotes Passive immunization can be done using plasma therapy and IVIG therapy.
T229 28312-28461 Sentence denotes Plasma from patients recovered from COVID-19 that contains antibodies against SARS-CoV2 has shown promising results in patients with severe COVID-19.
T230 28462-28569 Sentence denotes Also, SARS-CoV and SARS-CoV2 are ideally similar in the structure and the cell entry receptor and protease.
T231 28570-28719 Sentence denotes Studies show that serum from convalescent SARS patients and serum from rabbits immunized with SARS are both able to neutralize SARS-CoV2 efficiently.
T232 28720-28824 Sentence denotes However, serum from bats immunized with SARS-lice coronavirus SL-CoV Rp3 could not exert such an effect.
T233 28825-28954 Sentence denotes It is due to a noticeable degree of difference in the S1 domain in the S1 domain between the bat SL-CoV Rp3 strain and SARS-CoV2.
T234 28955-29068 Sentence denotes A short-term moderate dose of IVIG combined with moderate-dose of corticosteroids might improve patient outcomes.
T235 29069-29300 Sentence denotes Studies show that the viral RNA of SARS-CoV2 reaches its peak during the first week and then gradually decreases and that IgG and IgM begin to rise from the 10th day so that most patients have anti-viral antibodies by the 14th day.
T236 29301-29432 Sentence denotes Passive immunization protects against disease, and so it should be administered as early as possible when the patient is diagnosed.
T237 29433-29493 Sentence denotes Evidence links COVID-19 to variable degrees of inflammation.
T238 29494-29550 Sentence denotes Corticosteroids offer a potent anti-inflammatory option.
T239 29551-29663 Sentence denotes However, they do not dictate precise actions and might cause suppression of anti-viral immune responses as well.
T240 29664-29749 Sentence denotes Studies show that the use of corticosteroids might accelerate recovery from COVID-19.
T241 29750-29869 Sentence denotes There are no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death.
T242 29870-30049 Sentence denotes Moreover, the pro-inflammatory cytokine IL6 is the best-documented cytokine in COVID-19 correlated with severity, criticality, viral load, and prognosis of patients with COVID-19.
T243 30050-30161 Sentence denotes Tocilizumab, a monoclonal antibody against IL6, could confer clinical benefit in patients with high IL6 levels.