LitCovid-sentences  

PMC:7408073 / 15277-24752 JSONTXT 11 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T76 0-211 Sentence denotes (s)ACE2 or Ang (1–7) upregulation have been associated to some pathological conditions such as inflammation of the renal and gastrointestinal tract, cardiac dysfunction, human cirrhosis and lung injury/fibrosis.
T77 212-375 Sentence denotes Tissue/organ specific effects of excessive pathway activation that in some case resemble those produced by excessive Ang II/AT1R pathway activation (see Figure 1).
T78 376-515 Sentence denotes For example, systemic infusion of Ang (1–7) into mice had renal proinflammatory properties mediated by Mas receptor (MasR) activation [47].
T79 516-666 Sentence denotes Moreover, Ang (1–7) infusion was associated with increases in blood pressure, cardiac hypertrophy and fibrosis in rats with subtotal nephrectomy [48].
T80 667-847 Sentence denotes Similarly, elevated plasma sACE2 activity was associated both with greater severity of myocardial dysfunction and with an independent prediction of adverse clinical events [22,49].
T81 848-1108 Sentence denotes Transgenic mice with increased cardiac ACE2 expression suffered from lethal ventricular arrhythmia (heart block, ventricular tachycardia and terminal ventricular fibrillation) consequent upon downregulation of connexins involved in gap junction formation [50].
T82 1109-1257 Sentence denotes In another model, ACE2 transgenic mice suffered from cardiac fibrosis with concomitant deficits in ejection fraction and fractional shortening [51].
T83 1258-1651 Sentence denotes Interestingly, in a rat model of myocardial infarction following coronary artery ligation, there is evidence that C16/MLN-4760 (a specific ACE2 inhibitor, see later) administration inhibits fibrosis and hypertrophy of non-infarcted myocardium and increases diastolic relaxation, raising the possibility that ACE2 activity may have some adverse effects on post-myocardial infarction heart [52].
T84 1652-1790 Sentence denotes The risk factors for cardiovascular disease include alterations in platelet function and coagulation with an increased risk of thrombosis.
T85 1791-1967 Sentence denotes Ang II and hypercholesterolemia are known to participate in microvascular thrombosis and enhanced thrombus formation in the microvasculature may contribute to microinfarctions.
T86 1968-2164 Sentence denotes To this end, in a rat model in which AT1R activation produce baseline thrombosis by platelet aggregation, Ang (1–9), known to bind AT2R [42], has been shown to enhance the thrombotic process [53].
T87 2165-2474 Sentence denotes Moreover, in a mouse model, AT2R activation (inhibited by AT2R antagonist, PD12319) mediated the onset of arteriolar microvascular thrombosis following chronic Ang II infusion [54], indicating both the recruitment of the AT2R pathway downstream of AT1R activation and its involvement in arteriolar thrombosis.
T88 2475-2784 Sentence denotes Of interest, disseminated intravascular coagulation is associated with hypoproteinaemia and deficit of coagulation and anticoagulation proteins, which can originate by their renal loss (and consequent proteinuria) and/or by their increased (pathological) consumption and/or by their reduced hepatic synthesis.
T89 2785-2993 Sentence denotes To this end, in healthy livers, ACE2 is limited to perivenular hepatocytes and endothelial cells; instead, in human hepatitis C cirrhosis, ACE2 protein expression is widespread in the hepatic parenchyma [55].
T90 2994-3185 Sentence denotes Notably, human hepatocytes cultured in hypoxic conditions upregulated ACE2 protein expression [55] and ACE2 mRNA, protein and activity were increased in response to hypoxia and by IL-1β [56].
T91 3186-3389 Sentence denotes In line with these observations, in peripheral blood human CD34+ cells, MasR expression and ACE2 expression, activity and shedding (of sACE2 catalytically active forms) were increased under hypoxia [57].
T92 3390-3647 Sentence denotes Moreover, under hypoxic conditions human pulmonary artery smooth muscle cells upregulated both (arms of the RAS) ACE and ACE2 mRNA and protein expression, and ACE2 was subsequently downregulated by (ACE-derived) Ang II through an AT1R-mediated process [58].
T93 3648-3833 Sentence denotes Similarly, both ACE and ACE2 expression were increased in vascular endothelium and smooth muscle of human left ventricle from patients with ischaemic (local hypoxia) heart disease [59].
T94 3834-3956 Sentence denotes Concomitant upregulation of both arms of the RAS that suggests a tight link between ACE and ACE2 under hypoxic conditions.
T95 3957-4095 Sentence denotes Indeed, several reports have shown a complex interplay of regulation between the two arms of the RAS independently on hypoxia (see Box 2).
T96 4096-4633 Sentence denotes Interestingly, chronic hypoxia induced activation of ACE2/Ang (1–7)/MasR axis and suppression of ACE/Ang II/AT1 receptor axis in lungs of pulmonary hypertensive Ren-2 transgenic rats (constructed by inserting the mouse Ren-2 renin gene) but not in normotensive transgene-negative control rats [60], suggesting that the baseline renin activity in hypertensive rats may be crucial to determine the differential response to hypoxia and that renin inhibition might be useful to inhibit the ACE to ACE2 pathway shift under hypoxic conditions.
T97 4634-4809 Sentence denotes Of interest, hypoxia alone or combined with hypercapnia has been shown to significantly increase both plasma renin expression or activity and plasma Ang II expression [61,62].
T98 4810-5305 Sentence denotes Moreover, hypercapnic acidosis (pH 6.8/6.9, a condition that could occur in SARS) induced in isolated rat lungs has been shown to induce a (compensatory) venular dilatation mediated by cyclooxygenase activation (inhibited by indomethacin) [63], an enzyme that has been shown to be induced downstream of Ang (1–7)/MasR pathway in isolated rat hearts (again inhibited by indomethacin) [64], suggesting the involvement of ACE2/Ang (1–7) pathway in mediating CO2-dependent lung venular vasodilation.
T99 5306-5701 Sentence denotes Altogether these observations indicate that there is a high probability that hypoxia/hypercapnia, a condition that occurs in SARS patients, might upregulate the activity of both arms of the RAS by suppling high amounts of renin product, Ang I, to ACE and ACE2, which, together, can produce high amounts of Ang II, Ang (1–9), Ang (1–7) and its (ACE-produced) metabolite, Ang (1–5) (see Figure 1).
T100 5702-5987 Sentence denotes Similarly to both Ang (1–7)/MasR and Ang (1–9)/AT2R pathways, Ang (1–5) has been shown to induce the secretion of atrial natriuretic peptide via MasR/NOS pathway in isolated perfused rat atria [65], indicating that Ang (1–5) is a heart active peptide (at least in Sprague-Dawley rats).
T101 5988-6154 Sentence denotes Interestingly, in the plasma of patients with inflammatory bowel disease, Ang (1–7) concentrations and (s)ACE2 activity were higher compared to healthy subjects [66].
T102 6155-6308 Sentence denotes Moreover, Ang (1–7) alone can either activate the Bax/Caspase–dependent apoptotic pathway or upregulate NF-kB signaling in lung fibroblast cultures [67].
T103 6309-6582 Sentence denotes Moreover, in vivo administration of Ang (1–7) alone (in Wistar rats) promoted morphological lung alterations, extracellular matrix accumulation and inflammatory cytokine production (including TNF-α and IL-6), characteristics of lung inflammation in pulmonary fibrosis [67].
T104 6583-6680 Sentence denotes Thereby, a condition that deteriorates respiratory compliance, could lead to hypoxia/hypercapnia.
T105 6681-6892 Sentence denotes Hypoxia, in turn, will induce ACE2 upregulation which possibly increases cardiac/lung detrimental effects mediated by Ang (1–7)/MasR pathway activation finally leading to further ACE2 cell membrane upregulation.
T106 6893-7128 Sentence denotes A condition that in COVID-19 can increase the probability of both SARS-CoV-2 entry and ACE2 shedding/systemic activity, finally generating positive feedback loops that might sustain SARS independently of viral infection (see Figure 2).
T107 7129-7446 Sentence denotes This hypothesis is supported by the observations that, in lung aspirates of acid- and/or spike-treated mice, Ang II and ACE2 are synergistically upregulated and cell surface downregulated (shed), respectively, suggesting their involvement in the increased lung microvascular permeability and pulmonary oedema [14,15].
T108 7447-7654 Sentence denotes Indeed, this condition might subsequently favour the diffusion, in neighbouring lung tissues and systemic circulation, of both (s)ACE2, Ang II and Ang (1–7), the Ang II-derived product of (s)ACE2 processing.
T109 7655-7844 Sentence denotes As already proposed, enhanced ACE2 shedding may locally reduce ACE2 activity in lung, however, it likely increases ACE2 systemic activity and subsequent production of circulating Ang (1–7).
T110 7845-7982 Sentence denotes Interestingly, Ang (1–7) has been also reported to promote eosinophil apoptosis in lungs and in bronco-alveolar lavage fluid (BALF) [40].
T111 7983-8254 Sentence denotes Moreover, Ang (1–7)/MasR axis inhibits allergic airway inflammation and eosinophil cell counts in the BALF of a murine model of asthma, indicating both that an impairment of ACE2 pathway may favour asthma and that ACE2 pathway activation can reduces asthma symptoms [68].
T112 8255-8486 Sentence denotes Moreover, a compound that mimics the Ang (1–7) actions has been shown to induce IL-10 upregulation via a MasR-dependent pathway in BALF [69] and IL-10 is thought to mediate anti-inflammatory effects of MasR pathway activation [70].
T113 8487-8607 Sentence denotes IL-10 secretion in mouse plasma was also induced by an AT2 receptor agonist and downstream nitric oxide signalling [71].
T114 8608-8801 Sentence denotes Increased IL-10 production (e.g., by T regulatory cells) is often associated with immune tolerance, which is the consequence of reduced number and function of specific immune compartments [72].
T115 8802-9162 Sentence denotes Indeed, IL-10 has been shown not only to suppress antigen-specific Th2-mediated immune responses including eosinophil expansion in allergic inflammation [72], but also to augment airway reactivity, suggesting that despite its potent anti-inflammatory activity, an excess of IL-10, as well as Ang (1–7), may contribute to the decline in pulmonary function [73].
T116 9163-9475 Sentence denotes Of note, IL-10 is one of the cytokines downstream ACE2 pathway [25] and is significantly upregulated in the most severe forms of COVID-19 [2,8,9], indicating an important correlation between ACE2/Ang (1–7) axis activation and IL-10 upregulation which might lead to eosinopaenia/lymphopaenia in COVID-19 patients.