cord-001773-mqk0sx5n	2015	AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. RESULTS: Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1–7 receptor [MasR]) expression, and normalised urinary Ang 1–7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. We reported that insulin inhibits high glucose stimulation of rat renal Agt gene expression via two nuclear proteins-heterogeneous nuclear ribonucleoproteins F and K (hnRNP F, hnRNP K)-that interact with the insulin-responsive element (IRE) in the Agt gene promoter [25] [26] [27] [28] , and that hnRNP F overexpression in RPTCs inhibits Agt gene expression and kidney hypertrophy in Akita Hnrnpf-Tg mice [29] .
cord-002307-gk84fnb9	2016	METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. ACE-2 enzyme activity is reduced in Alzheimer''s disease in association with increasing Aβ load and tau pathology ACE-2 activity was significantly reduced by approximately 50% in the mid-frontal cortex in AD compared with age-matched controls (P < 0.0001) (Fig. 1a) . Together, these data strongly suggest that reduced ACEFig. 2 Angiotensin-converting enzyme 2 (ACE-2) activity is reduced in association with apolipoprotein E (APOE) ε4 and ACE1 (rs1799752) indel polymorphism and increased in cerebral amyloid angiopathy (CAA).
cord-002468-onpmkjaz	2017	In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. At cardiac level, there was a In serum samples, there was a significant increase of ACE2 activity in DB mice at early and late stages of diabetes as compared to CONT (p = 0.0003 and p = 0.0003, respectively) and insulin administration significantly decreased ACE2 activity in DB mice at early and late stages (p = 0.001 and p = 0.001, respectively) ( Figure 4a ). At cardiac level, there was a significant increase of ACE2 activity in DB mice in both early and late stages of DB as compared to CONT mice (p = 0.011 and p = 0.029, respectively), however, insulin administration did not modify this pattern (p = NS) (Figure 4b) .
cord-005386-p37rw8dh	2006	title: Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. As both polymorphisms are associated with an enhanced activity of the angiotensin II-AT1R axis, we postulated at a clinical level, a synergistic effect between them as regards the evolution of ischemic stroke. A synergistic effect was found between the AT1R 1166C allele and the homozygous ACE D/D genotype in the small-vessel stroke subgroup (adjusted OR, 3.54; 95% CI, 1.88-7.16; p < 0.0005), the mixed vascular type (adjusted OR, 2.41; 95% CI, 1.2-5.1; p < 0.05), and the overall ischemic stroke group (adjusted OR, 2.42; 95% CI, 1.51-3.82; p < 0.005) ( Table 3 ).
cord-005927-a9sj00y8	2005	We also assessed the effect of ACE-specific inhibitors, such as captopril and lisinopril, which bind to the catalytic center with ligation of its thiol to the zinc ion and completely inhibit the peptidase activity, but found only a minor inhibitory effect on the GPIase assay ( Fig. 1c , 1 × 10 -3 M captopril produced 40% inhibition and data not shown). We treated cells with ACE, PI-PLC or mouse glandular kallikrein (mGK), which digests EGFP protein near the carboxy termini (data not shown) and trapped the released products from the supernatants using antibody specific for GFP. We collected epididymal sperm from both wild-type and Ace knockout mice 33 and compared the distribution of GPI-anchored proteins in water-soluble and detergent-soluble fractions. In this regard, GPI-anchored proteins were not released in sperms of Ace knockout mice (Fig. 5a) .
cord-005931-iggkxbbf	2008	Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Taking the concept a step further, it was reasoned that if ANG II, formed by brain renin, was involved in hypertension, then inhibiting brain RAS would lower blood pressure. Minute injections of ANG II into key brain nuclei showed that ANG II could differentially produce pressor effects, elicit drinking, release vasopressin, inhibit the baroreflex, and increase sympathetic nervous system activity [20, 21] . In the double transgenic mice developed by Sigmund and colleagues [35] , to overexpress both human renin and human AGT so that they constantly have high ANG II levels, antisense to AT1R mRNA dramatically reduced the blood pressure. ACE-2, ANG (1-7), and Mas receptors are all localized in brain areas related to the control of cardiovascular function.
cord-006082-x1kankxd	2015	Despite the important improvements achieved with these agents in slowing the progression of established cardiorenal disease, the ACE inhibitors and the ARBs only provide a 20% reduction in the relative risk of Key points ■ Renin-angiotensin-aldosterone system (RAAS) blockade with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker provides a 20% relative risk reduction for the progression of established cardiorenal disease compared with other non-RAAS blocking therapies ■ The RAAS is an endocrine, paracrine and autocrine system that regulates blood pressure homeostasis through effects on a variety of target organs, as well as having a role in the responses to vascular injury and repair ■ The RAAS is a complex system with a variety of sites suitable for pharmacological intervention ■ Novel molecules that alter the production of various RAAS peptides or that alter receptor density, function or responsiveness to these peptides could have an important influence on haemodynamics and vascular structure and function www.nature.com/nrendo progression of cardiovascular disease when compared with non-RAAS blocking therapy.
cord-006087-hynkb0a8	2003	Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. Some differences in catalytic properties have been observed for these two sites: the N-domain site is notably 50-times more active toward the haemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) 21 , 1000-times Here, we provide an overview of ACE and the RAS, current ACE inhibitors and their clinical utility, insights from the tACE crystal structure, and the rationale and prospects for developing second-generation, domainselective inhibitors by structure-guided design. BPF was a mixture of peptides 59 , which were shown to be potent and specific inhibitors of ACE (TABLE 1), and structure-activity studies indicated that the optimal C-terminal inhibitory sequence was Phe-Ala-Pro 60 . An important caveat in considering the design and pharmacological utility of domain-selective ACE inhibitors is the potential for conformational effects that have not yet been observed in the tACE crystal structure.
cord-015859-5kt59ose	2007	Mice lacking the ren-1 d gene are characterized by sexually dimorphic hypotension (leading to a significant reduction of blood pressure in female mice), absence of dense secretory/storage granule formation in juxta-glomerular cells, altered morphology of the kidney, and a significant increase of plasma prorenin levels (Clark et al 1997) . Importantly, binding of (pro)renin to the (pro)renin receptor in human mesangial cells also induced Ang II-independent effects, such as an increase in DNA synthesis, activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK)1 (p44)/ERK2 (p42), and plasminogenactivator inhibitor-1 release. AT 2 receptors are involved in physiological processes like development and tissue remodeling (by inhibiting cell growth and by stimulating apoptosis), regulation of blood pressure (vasodilatation), natriuresis and neuronal activity. In vitro studies using the isolated perfused rat Langendorff heart fully confirmed the idea of renin and angiotensinogen uptake underlying tissue angiotensin production.
cord-016742-y7jgjera	2017	The binding of an agonist to the adrenergic receptor replaces guanosine diphosphate (GDP) by guanosine triphosphate (GTP), and causes the α-subunit of the G-protein to break free from the β-γ complex, and act as a primary messenger: in beta receptors, it stimulates adenylate cyclase and triggers cyclic adenosine monophosphate (cAMP) production, which, as a second messenger in the process of signal transduction, activates its target kinases that phosphorylate regulator proteins and ultimately increases intracellular calcium levels. Their main anti-ischemic effects are due to their ability to reduce myocardial O 2 consumption by depressing contractility, decreasing heart rate and systemic afterload, and increasing O 2 supply by coronary and collateral vasodilation. Verapamil decreases the heart rate by depressing sinoatrial and AV-nodal activity (hence its utility in the treatment of supraventricular arrhythmias), lowers systemic blood pressure due to myocardial depression and peripheral vasodilation, and produces moderate coronary artery dilation (preferred in essential hypertension and vasospastic angina).
cord-017585-0llgr357	2007	Although the emergence of receptor subtypes distinguishes the distinct signaling pathways of Ang II and Ang-(1-7), the post-renin enzymes that form and degrade these peptides must be considered in lieu of the overall regulation of the functional RAAS within the kidney. ACE, angiotensin converting enzyme; EPs, endopeptidases; NEP, neprilysin demonstration of endogenous levels of the peptide in the kidney, circulation and other tissues (Nagata et al 2006) . Thus, in addition to the proximal tubule epithelium, the glomerulus may be a second key site within the kidney where ACE2 may influence the local expression of angiotensin peptides and renal function. There are few studies on the regulation of the Ang-(1-7) receptor, although chronic ACE or AT 1 blockade reduced mas mRNA expression in the renal cortex of the Ren2 Lewis congenic rat .
cord-018009-8j40876m	2007	Angiotensin converting enzyme (dipeptidyl carboxypeptidase I, kininase II, EC 3.4.15.1, ACE) plays a major role in the metabolism of many different peptides, including angiotensin (Ang) I, bradykinin, kallidin, and N-acetyl-seryl-aspartyllysyl-proline (AcSDKP). Pooled analysis of the HOPE, EUROPA, and PEACE trials showed ACE inhibition reduced all cause and cardiovascular mortality, non-fatal myocardial infarction, stroke, heart failure, and coronary artery bypass surgery, leading to the recommendation that ACE inhibitors be considered in all patients with atherosclerosis (Dagenais et al 2006) . ACE inhibitor therapy did not increase either bradykinin or kallidin peptide levels in cardiac atria of patients with ischaemic heart disease, despite the reduction in Ang II levels . Bradykinin contributes to the systemic hemodynamic effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure
cord-024076-q9fw7ch1	2020	The reports urging caution in the use of ACE inhibitors and ARBs for hypertension, diabetes and cardiovascular disease are based on laboratory data which found that SARS-CoV and COVID-19 virus binds to ACE 2 receptor which is found in the epithelial cells of the lung, kidney, intestine and blood vessels. Thus, a clear causal relationship between those with cardiovascular disease, hypertension, heart failure with reduced ejection fraction (HFrEF), and diabetes with chronic kidney disease (DCKD) on ACE inhibitors or ARB treatment and an increased risk of COVID-19 does not exist. In South Africa, hypertension, HFrEF and diabetes are common non-communicable diseases, and a significant proportion of patients are being treated with generic versions of ACE inhibitors or ARBs. There is extremely strong scientific evidence for the benefit of RAAS inhibition in patients with cardiovascular disease.
cord-253862-jl1zhg13	2020	Although this novel virus is less severe than the first SARS-CoV outbreak, human-to-human transmission remains very high and the number of cases continues to rise exponentially in major urban areas, highlighting the urgent need to develop new containment, diagnostic, and treatment protocols. In the case of SARS-CoV-2, viral evasion of the innate immune system leads to an increase in cytokine production and late CD4+/CD8+ response, which then leads to pathogenic inflammation in patients with high viral loads. (ChiCTR2000029308), involving severe SARS-CoV-2 cases, compared lopinavir/ritonavir treatment with standard care alone, and they showed that the antivirals yielded no clinical benefits. In an open-label control study conducted by Cai et al., the antiviral activity of favipiravir + IFN-α was compared to that of lopinavir/ritonavir + IFN-α in patients with confirmed SARS-CoV-2 infection.
cord-256020-wrui3i2l	2020	The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease is caused by SARS-CoV-2, a zoonotic pathogen that acquired mutations as it crossed the species barrier from bat to pangolin enabling it to infect humans. 5 The clinical symptoms of COVID-19 include fever, cough, and pneumonia, which makes the disease enormously dangerous with a high case fatality rate. 11 Symptoms of human SARS-CoV-1 infections include headache, fever and respiratory complications such as cough, dyspnea, and pneumonia. 81 The main goal of SARS-CoV-2 diagnosis is to accurately detect the virus and to minimize further transmissions by timely isolation and treatment of infected patients. 112 This implies that variation in ACE-2 expression in COVID-19 patients is likely to affect susceptibility, symptoms and intervention outcomes following SARS-CoV-2 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations
cord-259933-ggx4v0bz	2020	The SARS-CoV-2, a positive strand RNA virus, has been seen to infect humans through the angiotensin converting enzyme -2 (ACE-2) receptor [9] . In individuals with hypertension, diabetes, and other cardiovascular disorders with vascular complications, the renin angiotensin system (RAS) is known to be activated with an increase in ACE activity and a downregulation of ACE-2. Therefore, it may be assumed that the inherent downregulation of the ACE-2-Ang-(1-7)-Mas axis (as seen in metabolic conditions) is exacerbated in the COVID-19 state because (i) the virus uses the peptidase domain of the enzyme for entry into the cells and (ii) there is a decrease in ACE-2 with an increase in ACE [9] . Individuals with underlying hypertension, type 2 diabetes, or cardiovascular disease are at higher risk for respiratory failure and mortality in COVID-19.
cord-264828-6w13xo2a	2020	Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. 4. Renin-angiotensin-aldosterone system (RAAS)-interfering drugs are likely to affect ACE-2 receptor-SARS-CoV-2 interaction dynamics within lung, heart, vascular, kidney and gut tissues [5, 19] , while it is still not completely elucidated how such interactions are relevant to the clinical course of cardiovascular comorbidities in patients with COVID-19 [29] . Consequently, the up-regulation of human ACE-2 induced by RAAS-antagonists in SARS-CoV-2-infected patients could be clinically useful, due to the cardiovascular protection elicited by the increased activity of angiotensin(1-7), thereby attenuating angiotensin II effects on vasoconstriction and sodium retention [31, 34] .
cord-266289-dkxhbmic	2014	The involvement of ACE in processes outside of blood pressure regulation, and in particular the differences in substrate specificity of the two domains of sACE highlight the growing need for a new generation of ACE inhibitors. Interestingly, the two residues that differ; Arg381/Glu403 and Tyr369/Phe391 are located in the S 2 subsite (Fig. 5d ), further illustrating that interactions between the enzyme and inhibitors at this site are an important determinant of domain selectivity. The N domain of human angiotensin-I-converting enzyme: the role of Nglycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407 The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380
cord-266755-y2lf7ssp	2020	21, 22 Both ACE-1 and ACE-2 cleave angiotensin peptides in that ACE-1 cleaves angiotensin I and generating angiotensin (Ang) II, which causes vasoconstriction, bronchoconstriction, increases vascular permeability, inflammation, and fibrosis and enhance the development of acute respiratory disease syndrome (ARDS) and lung failure in patients infected with SARS-CoV-2. 36 The probable rational proposed for the possible relation between the use of ACEIs/ARBs, and progression to ARDS in COVID-19 is the increased availability of ACE-2 attached to surface in the lung endothelium, an inherent effect of these two classes, leading to enhanced coupling of SARS-CoV2 to ACE-2 and its consequent cell entry. Based on prior animal studies, it was suggested that proposed ACEIs and ARBs can enhance ACE2 activity and thereby increase infectivity of COVID-19 virus. 48 In severe lung injury animal models, preclinical studies have showed that ACE2 is significantly downregulated and it has been shown that the inhibition of the angiotensin type 1 receptor by ARB like losartan reduces severe acute lung injury in mice administered with the spike glycoprotein of SARS-CoV.
cord-267519-a0bcmjkn	2020	AIMS: This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). Observing that human pathogenic coronaviruses bind their target cells through angiotensin-converting enzyme 2 (ACE2) [5] [6] [7] [8] , and that a few studies reported an increase in ACE2 expression mediated by angiotensin II type-I receptor blockers (ARBs) and ACE inhibitors (more consistently on animals than in humans) [9] [10] [11] [12] [13] [14] [15] [16] , some hypothesized that the increased expression of ACE2 would facilitate infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), thus the hypertension treatment with ACE2-stimulating drugs, as well as ACE2 polymorphisms, might increase the risk of developing severe COVID-19 [17] [18] [19] .
cord-269151-r426u5dz	2020	More recently, a number of indirect comparisons with pooled analysis of several randomized placebo control trials have been done to further elucidate whether ACE inhibitors and ARBs have differing effects on the risk of myocardial infarction [16] [17] [18] [19] . Finally, in the previously mentioned Bangalore paper, a separate meta-analysis of the only head to head trials between ACE inhibitors and ARBs also showed no difference in the risk for myocardial infarction or cardiovascular death between the two classes [16] . Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have resulted in significant improvements in outcomes related to congestive heart failure, cardiovascular disease, diabetes, stroke, and kidney disease. A meta-analysis reporting effects of angiotensinconverting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis
cord-269776-hj1s3ipp	2004	Concerning HAE-I and HAE-II, just as variations in serum concentrations of APP appear to determine which individuals in a normal population develop angioedema with a second perturbation of kinin metabolism, such as the use of ACE inhibitors, 96 it could be speculated that variations in either kinin activation or inactivation pathways might contribute to the differences in severity of angioedema in individuals with a pre-existing perturbation in kinin metabolism, such as a mutation in C1-INH (as occurs in HAE). 13, 14, 27 This increase in plasma bradykinin was demonstrated both for patients with HAE with C1-INH deficiency and for patients with drug-associated angioedema who had an angioedematous attack in conjunction with ACE inhibitor treatment. The patient''s daughter had recurrent skin angioedema and gastrointestinal pain attacks since age 12 years; therefore, with a normal C1-INH concentration and activity in both mother and daughter, a diagnosis of HAE type III was assumed.
cord-275837-2avxd80i	2020	Diabetes increases the risk of pneumonia in COVID-19 infected individual and it is an important risk factor for adverse outcome. ACE inhibitor and Angiotensin II Receptor Blockers (ARBs) are the few of drugs used for the appropriate management of diabetic patients. All these may lead to increased severity of COVID-19 infection in diabetic individuals. [4] Moreover, genetic polymorphism of ACE receptor has been shown to be linked with diabetes and it might also facilitate COVID-19 infections. [4] On contrary to this, some researchers say that use of ACE inhibitor or ARBs prevents the binding of COVID-19 virus to ACE receptor and thus may prevent infection. [5] All these are the lacunae in the existing knowledge of ACE inhibitor or ARBs use in diabetic individuals. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?
cord-277766-rxmpi61o	2012	In a classical RAS, the substrate angiotensinogen (AGT), which is released into the circulation from the liver, is degraded by the enzyme renin that originates in the kidney, generating the inactive angiotensin I (Ang I). The initial drug development of clinical ACE inhibitors was based on the assumption of an active site related to that of carboxypeptidase A but organized to remove a dipeptide rather than a single amino acid from the Cterminus of its substrate. The protective role of XNT against hypertension-induced cardiac fibrosis is associated with activation of ACE2, increases in Ang-(1-7) and inhibition of extracellular signal-regulated kinases [83] . The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensinconverting enzyme The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases
cord-282256-lqmixm7s	2020	4 The only available meta-analysis from Wuhan of 46248 cases, supports that hypertension constitutes the most prevalent comorbidity in 17% of patients infected with the novel coronavirus. In Italy the most current analysis shows that of 69.1% of the deceased patients were hypertensives and 30% used angiotensin converting enzyme inhibitors (ACEIs) and 17% angiotensin receptor blockers (ARBs). 18 After adjustment for confounders there was no independent association for the use of ACEIs/ARBs with susceptibility for infection or worse clinical outcome in contrast to loop diuretics that were linked to enhanced risk. Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19 Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19
cord-286638-bqxyb61p	2020	The disease burden of coronavirus infectious disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) has been increasing continuously with more than a million confirmed patients and more than 45 thousand deaths globally [1] . Emerging data suggests that COVID-19 is common in patients with diabetes, hypertension, and cardiovascular disease (CVD), although the prevalence rate varied in different studies as well in country-wise data. Evolving data also suggest that patients of COVID-19 with diabetes are more often associated with severe or critical disease varying from 14 to 32% in different studies [15e18, 20, 22, 24] . Though there is limited data about the association of blood glucose levels with disease course in COVID-19 at present, data from other infections like SARS and influenza H1N1 has shown that patients with poor glycemic control have increased risk of complications and death [60, 61] .
cord-286825-bu7j7kdr	2004	Because this peptide has been found to be an in vivo substrate specific for the N domain of sACE, it is suggested that ACE is implicated in the process of hematopoietic stem cell regulation by permanently degrading this natural circulating inhibitor (Azizi et al., 2001; Rousseau et al., 1995) . At present mammalian M13 family of zinc proteases consists of seven known members: neutral endopeptidase (NEP); the endothelin-converting enzymes ECE-1, ECE-2, and ECE-3; the Kell blood group antigen (Kell); the phosphate regulating gene (PEX); X-converting enzyme (XCE); and secreted endopeptidase (SEP). Sequencing, expression and biochemical characterization of the Porphyromonas gingivalis pepO gene encoding a protein homologous to human endothelin-converting enzyme Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme Peptidyl dipeptidases (Ance and Acer) of Drosophila melanogaster: Major diVerences in the substrate specificity of two homologs of human angiotensin I-converting enzyme
cord-289144-d6fgs8qg	2020	Moreover, there is evidence that ACE genotype affects the outcomes of acute respiratory distress syndrome (ARDS) treatment, the most severe consequence of SARS-CoV-2 infection. 8, 13 The aim of this narrative review was to analyze and identify the mechanisms of ACE-I and ARBs with particular emphasis on angiotensin receptors and their polymorphism in the light of COVID-19 pandemic as these medications are commonly prescribed to elderly patients. 8, 13 The aim of this narrative review was to analyze and identify the mechanisms of ACE-I and ARBs with particular emphasis on angiotensin receptors and their polymorphism in the light of COVID-19 pandemic as these medications are commonly prescribed to elderly patients. 63 This upregulation of the ACE2 receptor causes an increase in SARS-CoV-2 binding sites, which can lead to COVID-19 infection. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19
cord-289477-cjm7qhr4	2005	Synthetic analogues of the bradykinin potentiating nonapeptide BPP(9α) indicate significantly different structural requirements for potentiation of the bradykinin (BK)-induced smooth muscle contraction (GPI) and the inhibition of isolated somatic angiotensin I-converting enzyme (ACE). As initial experimentation on the potentiation of the bradykinin action was primarily performed on isolated smooth muscle organs, in the last decade the potentiating activity was mainly investigated on the affinity and density of the receptor [54] , the intracellular mobilization of Ca 2+ [49, 54] , the release of arachidonic acid [49, 54] , of inositol phosphates [54] , and of nitric oxide [37] . Table 1 Analogues of the bradykinin potentiating peptide BPP 9␣ (TEPROTIDE) with distinct differences between potentiation of the BK-induced contraction of the isolated guinea pig ileum (GPI) and inhibition of the isolated angiotensin I-converting enzyme (ACE)
cord-290148-6cxndab8	2020	The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARSCoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). However, they differ markedly: ACE-1 cleaves the dipeptide His-Leu from angiotensin I, thus generating angiotensin (Ang) II, which causes vaso-and broncho-constriction, increases vascular permeability, inflammation, and fibrosis and thereby promotes the development of ARDS and lung failure in patients infected with the SARS-CoV and SARS-CoV-2 (Yang et al., 2015) (Figure 1, panel B) . In one commentary ACE-2 was suggested to be secreted at higher amounts in patients with cardiovascular disease than in healthy individuals, and in another, it was also stated that ''ACE-2 levels can be increased by the use of ACEIs'' , albeit no evidence of this occurring in the lungs Mechanisms of COVID-19 by which the SARS-COV-2 virus infects the lower airway cells and modalities to increase circulating soluble ACE-2 for therapeutic use.
cord-291146-f3e5ynhu	2020	The specificity of hypertension and cardiovascular disease as underlying causes for severity of COVID-19 infection, the inherent role of ACE-mediated generation of Ang-II and downstream signalling to potentially exacerbate inflammation and organ damage along with genotypic impact on ACE status provide compelling support of the use of ACE-I and ARBs in the clinical management of patient with positive diagnosis of COVID-19. The significant genetic, scientific and clinical data supporting a potential role for increased ACE levels and associated Ang-II effect in target organs provides compelling argument for use of ACE-I and ARBs in the clinical management of patients with COVID-19 infections to improve outcomes. In summary, this study describes the biological relevance of genetic polymorphism of ACE deletion with higher prevalence in certain ethnic populations including African Americans in context of COVID-19 infection and rationale for the use of ACE-I/ARBs for therapeutic management of severity of morbidity and improving outcomes associated with COVID-19.
cord-295041-5vpawtef	2020	Numerous clinical studies have reported neurological symptoms in COVID-19 patients since the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from the atypical signs of pneumonia. Angiotensin-converting enzyme-2 (ACE-2), a potential receptor for SARS-CoV-2 entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. The resident CNS cells like astrocytes and microglia also express ACE-2, thus highlighting the vulnerability of the nervous system to SARS-CoV-2 infection. Furthermore, the presence of SARS-CoV-2 in cerebrospinal fluid (CSF) of COVID-19 patients is confirmed through genome sequencing [4] ; however, experimental evidence is needed to validate virusmediated neurological damage. Furthermore, the interaction of SARS-CoV-2 and ACE-2-expressing neuronal/glial cells may facilitate virus entry into the nervous system through different routes.
cord-296683-fjn29oal	2020	Novel Corona Virus infection (COVID-19) is a highly infective disease with rapid global spread since January 2020 and was declared as pandemic by World Health Organization. 1 Angiotensin Converting Enzyme 2 (ACE 2), present on the cell surfaces of some important organs, has been identified as target receptor for COVID-19 virus entry into the host cells. 3 In addition, ACE 2 has been reported to be present at various locations in the oral cavity and hence, oral cavity is considered as a potential site for the COVID 19 virus. 8 Thus, the less availability of ACE 2 in the oral cavity might have compromised the binding of COVID 19 virus. The other way round, if OSMF patient is affected with COVID-19, then it may cause further exhaustion of ACE 2. As ACE 2 is the binding site for COVID-19, it may compromise the infectivity of the virus.
cord-298515-5n7hxhbg	2015	We report here the findings that ACE-2 protein and enzyme activity are severely decreased by hyperoxia in human fetal lung fibroblast cultures. Figure 6 shows that the treatment of hyperoxia followed by normoxic recovery significantly increased ADAM17/TACE immunoreactive protein by threefold in the IMR90 cells (P < 0.05). IMR90 cells were exposed to hyperoxic or normoxic gas as described in Figure 1 (with recovery), but in the presence or absence of the ADAM17/ TACE inhibitor TAPI-2. IMR90 cells were exposed to hyperoxic or normoxic gas as described in Figure 1 (with recovery), but in the presence or absence of the ADAM17/ TACE inhibitor TAPI-2. IMR90 cells were exposed to hyperoxic or normoxic gas as described in Figure 1 (with recovery), then were recovered for western blotting of ADAM17/TACE as described in Materials and Methods.
cord-300850-59j1m2tm	2020	Toward this, we raise two main points, i) increased ACE-2 expression in pulmonary and heart tissues in users of chronic angiotensin 1 receptor (AT1R) blockers; and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. Toward this, we raise two main points of discussion, i) the increased angiotensin-converting enzyme-2 (ACE-2) expression in pulmonary and heart tissues of hypertensive patients with chronic use of AT1R blockers and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. SARS-CoV-2 spike proteins bind to angiotensin-converting enzyme-2 (ACE-2), which is expressed in the epithelial cells of the lungs (8, 9) . We believe that i) increased expression of ACE-2 in hypertensive patients being treated with ACE inhibitors and AT1R blockers and ii) previous exposure to circulating coronaviruses with low neutralizing capacity to SARS-CoV-2 may greatly contribute to the increased susceptibility of the elderly patients to COVID-19.
cord-301546-yck1t3pp	2007	title: Comparison of two acetylcholinesterase gene cDNAs of the lesser mealworm, Alphitobius diaperinus, in insecticide susceptible and resistant strains Two cDNAs encoding different acetylcholinesterase (AChE) genes (AdAce1 and AdAce2) were sequenced and analyzed from the lesser mealworm, Alphitobius diaperinus. Partial cDNA sequences of the Alphitobius Ace genes were compared between two tetrachlorvinphos resistant (Kennebec and Waycross) and one susceptible strain of beetles. The alignment of this gene with the Drosophila Ace paralogous AChEs showed that, as expected for an insecticide-susceptible strain, beetles from the Denmark-S strain had an organophosphate and carbamate sensitive type. The Drosophila Ace orthologous gene, AdAce1, was sequenced from two susceptible Denmark-S, four Waycross (tetrachlorvinphos-resistant), and two Kennebec (tetrachlorvinphos-resistant) adults. diaperinus is not due to mutations in the Ace genes (i.e., is not an altered acetylcholinesterase).Alignments of the deduced amino acid sequences from the Drosophila Ace orthologous and paralogous genes in Coleoptera are shown in Figures 4 and 5, respectively.
cord-302316-raf5rlkq	2020	US researchers studied the viral and cellular transcriptional response upon infection of cell cultures and in animal models with different respiratory viruses including influenza A virus and SARS-CoV-2. A French study randomizing 181 COVID-19 patients with pneumonia on hydroxychloroquine or placebo, observed, however, no significant effect of treatment on transfer to ICU, mortality, or in the prevention of development of acute respiratory distress syndrome (Mah evas et al., 2020). A total of 86 COVID-19 cases of patients from China with mild/moderate disease were randomized on the antiviral lopinavir (an inhibitor of HIV protease combined with ritonavir, which prolongs the presence of drugs in the body) or the antiviral arbidol (an influenza virus fusion inhibitor only registered in Russia) or in a control group in a 2:2:1 ratio. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial
cord-304742-ytf2ilw4	2020	The transmembrane protease serine 2 TMPRSS2, an androgendependent enzyme, acts in reinforcing the ACE-2 receptor activity in allowing cell entry to a number of viral pathogens as well as to SARS-CoV-2 as reported in our Point of View [2] . Yet in trisomy 21 individuals a TMPRSS2 protease overexpression has been documented, as mentioned in the comment of Dr De Cauwer [1] , with this leading to an increased viral infection''s rate of susceptible host''s cells and tissues. In conclusion, the interesting comment by Dr De Cauwer points out the complex interactions between ACE-2 and TMPRSS2 with reference to the clinical course of CoViD-19 as well as to SARS-CoV-2 infection''s pathogenic evolution and severity degree in given population segments of infected individuals, like male individuals and Down syndromeaffected patients [1] . The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACEinhibitor-and angiotensin II receptor blocker-based cardiovascular therapies: comment The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor-and angiotensin II receptor blocker-based cardiovascular therapies
cord-306739-4lokd97u	2020	Bei COVID-19 wird neben der meist vorherrschenden akuten Lungenschädigung (ARDS) auch eine relevante Rate an myokardialen Schäden (Anstieg von Troponin) und akutem Nierenversagen beobachtet. Bereits aus der Zeit von SARS gibt es experimentelle Daten, die eine entsprechende Interaktion zwischen SARS-CoV-1 und dem RAAS belegen [2] . Ebenso gibt es experimentelle Studien, die einen krankheitsfördernden Effekt einer RAAS-Aktivierung bei ARDS nicht infektiöser Genese nahelegen [3] . Die dargestellten britischen Daten dürfen als erstes Signal gewertet werden, dass ACE-Hemmer auch bei COVID-19 einen günstigen Effekt auf den Krankheitsverlauf haben könnten. Weitere klinische Studien sind also dringend erforderlich, bevor den ACE-Hemmern ein therapeutischer Effekt bei COVID-19 zugeschrieben werden kann. Vorerst darf folgendes Fazit gezogen werden, das von nationalen und internationalen Fachgesellschaften unterstützt wird: Eine vorbestehende Therapie mit einem ACE-Hemmer, die für Patienten mit kardiovaskulären Erkrankungen und Diabetes mellitus einen relevanten organprotektiven und damit prognostischen Wert hat, sollte in der aktuellen Pandemie-Situation und insbesondere bei Diagnose einer SARS-CoV-2-Infektion nicht abgesetzt werden.
cord-306755-9q1mawfs	2007	Interestingly, in silico databank analysis revealed that bacterial DNA sequences could encode putative ACE-like proteins, strikingly similar to vertebrates'' enzymes. Interestingly, and though in silico evidence suggest the presence of a two-domain ACE-related protein in mosquitoes (Burnham et al., 2005) , all the cloned genes encode soluble, single active site enzymes (Tatei et al., 1995; Taylor et al., 1996; Wijffels et al., 1996) . The protein encoded by this gene, referred to as XcACE (Xanthomonas citri angiotensin-converting enzyme), is a 672 amino-acid protein. Key active site residues such as the zinc-binding motif, His 513 and Tyr 526 (tACE numbering) are conserved in XcACE and many other ACE-like enzymes. However, in line with the assay results, the non-conserved active site residues are neither identical to the C-or N-domain of human ACE, and are the presumed cause of the different substrate selectivity and inhibition profile of XcACE. Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme
cord-311099-59pnm4fn	2008	Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. 42 A great deal of evidence supporting the role of the RAS in hepatic fibrosis has come from animal studies using ACE inhibitors and angiotensin receptor blockers (ARB). A pilot study examining the effects of 6 months of losartan treatment on liver fibrosis in chronic hepatitis C demonstrated a significant decrease in fibrosis stage in the treated group compared to control patients.
cord-314868-ei2b8oqn	2020	Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID19, we determined whether ACE2 expression in the lower airways was related to COPD and cigarette smoking. Results: In the discovery cohort (n=42 participants), we found that ACE2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52 (0.66) log2 counts per million reads (CPM) versus non-COPD= 1.70 (0.51) CPM , p=.000762). In summary, active cigarette smoking and COPD up-regulate ACE-2 expression in lower airways, which in part may explain the increased risk of severe COVID-19 in these sub-populations. The P-value was obtained from the robust linear model Abbreviations: ACE-2, angiotensin converting enzyme II; COPD, chronic obstructive pulmonary disease; CPM, counts per million reads . 18.20038455 doi: medRxiv preprint Abbreviations: ACE-2, angiotensin converting enzyme II; COPD, chronic obstructive pulmonary disease; CPM, counts per million reads ACE-2 gene expression in airway epithelia is inversely related to FEV1% predicted (p=0.0348)
cord-315754-dq2empne	2020	Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Genomic analysis of the new CoV has shown that its SP differs from that of other viruses (Du et al., 2017; Li, 2016) , indicating that the protein has a site activated by a HC enzyme called furin (Millet & Whittaker, 2015) (Figure 1 ). The furin activation site (FAS) makes the new CoV much different in cell entry than SARS, and probably affects the stability of the virus and, consequently, the transmission process (Li et al., 2015; Millet & Whittaker, 2014; Yamada & Liu, 2009) . A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2
cord-317878-bqpj0ey0	2020	Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer—all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. Subpopulations manifesting higher rates of COVID-19 mortality-including hypertensives, the elderly, the obese, diabetics, men, and African-Americans-correlate with preexisting RAS imbalance, with ACE overactivity and/or ACE2 underactivity priming these patients for more severe COVID-19 outcomes. 159 Males generally have higher levels of RAS than premenopausal females, 160 perhaps explaining why male hypertensive rats show a greater blood pressure decrease with ACEIs. 161 Estrogen downregulates the expression of the AT1 gene 162, 163 and suppresses both ROS production in vascular smooth muscle and the enzymatic activity of ACE.
cord-318327-9sh2eksm	2012	Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. The contemporary view of the RAS has evolved from that of a simple linear pathway involving the conversion of angiotensinogen to angiotensin II (Ang II) via a two-step process facilitated by renin and angiotensin converting enzyme (ACE), to a much more complex system involving homologues of ACE and multiple angiotensin peptides which play supplementary and counter-regulatory roles ( Figure 1 ). Angiotensin converting enzyme inhibition or angiotensin receptor antagonism have been shown to produce a number of beneficial anti-inflammatory effects in rodent models of intestinal inflammation.
cord-319022-1twsxzcd	2020	BACKGROUND: There is a great deal of debate about the role of cardiovascular comorbidities and the chronic use of antihypertensive agents (such as ACE-I and ARBs) on mortality on COVID-19 patients. The aim of the study was to evaluate the role of chronic treatment with ACE-I or ARBs and other clinical predictors on in-hospital mortality in a cohort of COVID-19 patients. As for today, there are discordant results regarding the use of either angiotensin converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARBs) as for their possible impact on COVID-19 mortality. We found that ACE-I, which acts by inhibiting the conversion from angiotensin I to angiotensin II, showed a trend in protecting from mortality from COVID-19 and was significant in delaying mortality as shown by multivariate Cox regression analysis unlike ARBs, which antagonize the effects of angiotensin II on its receptors 2,3 . Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19
cord-322966-o65fo853	2020	title: COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks? ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate has arisen due to the finding that underlying cardiovascular disease and hypertension are associated with significantly increased risk of hospitalisation and death in COVID-19 [1, 2] , in addition to the viral receptor being angiotensin-converting enzyme-2 (ACE-2) [3 -5] . Association of renin-angiotensin system inhibitorswith severity or risk of death in patients with hypertension hospitalised for coronavirus disease 19 (COVID-19) infection in Wuhan, China
cord-326405-3446eyi3	2008	The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. [41] , primarily describing an Ace2 knockout and its associated cardiac pathology, also reported that ACE2 was reduced at the gene and protein level in kidneys from three separate rat models of spontaneous and diet-induced hypertension. Investigating the role of ACE2 in those two prevalent diseases and whether its effects are mediated by ANG II or ANG-(1-7) and other biologically active peptides, which are also substrates of ACE2, opens the way for developing new therapeutic targets in hypertension. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice Also, pharmacologic ACE2 inhibition was associated with increased albuminuria, suggesting a role of glomerular ACE2 in diabetic kidney injury
cord-326820-11sl17ap	2020	title: Is diet partly responsible for differences in COVID-19 death rates between and within countries? The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit. Although there are large differences between countries in death rates, the age-dependent severity of COVID-19 is similar between Asian, European and American countries. Identifying whether countries with high or low ACE activity have different death rates would be of great interest in understanding the clinical importance of interventions.
cord-327697-80msva10	2020	Concern has arisen about the role played in coronavirus disease 2019 (COVID-19) infection by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). In the first half of 2020, it was speculated that angiotensinconverting enzyme inhibitors (ACE-i)/angiotensin receptor blockers (ARBs) may make patients more susceptible to COVID-19 disease and lead to worse outcomes. Observational studies have reported that patients taking ACE-i/ARBs treatment are at increased risk of becoming infected with SARS-CoV2 and developing severe forms of COVID-19 disease. The strategy for repeating therapy was the same in all physicians, and the practice of starting new ACE-i/ARBs reported by the cardiologists was statistically different from that of both internal medicine and family medicine/general practitioners (8.0 ± 4 vs 8.0 ± 4 vs 9.0 ± 3, p < 0.05) ( Table 2) . The present survey is the first study to have provided a snapshot showing behaviors of Turkish physicians toward prescribing ACE-i/ARBs treatment during the COVID-19 pandemic.
cord-330093-asba80bi	2020	Both research teams are reporting increased angiotensin-converting enzyme 2 (ACE-2) expression in airways of current smokers and those with COPD, with important implications for coronavirus disease 2019 (COVID-19) patients. Since ACE-2 has been shown to be the main receptor utilised by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter the host cells [2] , the authors conclude that nicotine is a risk factor for COVID-19. Here, we bring to the discussion whether the increased susceptibility and virulence of SARS-CoV-2 via α7-nAChR and the upregulation of small airway ACE-2 expression may also be relevant for those who vape using nicotine-based e-cigarettes. While smoking may not necessarily increase one''s risk for contracting COVID-19, the biological and inflammatory cascade that occurs upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be particularly devastating for a smoker.
cord-332680-zfn81hew	2020	The following variables were extracted: author, journal, publication year, study design, geographic location, participants'' details (number, study population, age, sex, and comorbidities, including hypertension, diabetes mellitus, heart failure, and chronic kidney disease), use of antihypertensive drugs, such as ACE inhibitors, ARBs, calcium-channel blockers, beta-blockers, diuretics, outcomes (including positive SARS-CoV-2 test results and disease prognosis/severity, if available). The systematic review findings of the 7 high-quality studies (with comparative data on the controls) on SARS-COV-2 infection provide the best available evidence proving that therapy with ACE inhibitors or ARBs is not associated with an increase of positive SARS-CoV-2 test result and the severity of COVID-19 disease or overall population mortality as a whole in case-population and cohort studies. ACE indicates angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; BMI, body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension; ICU, intensive care unit; N/A, not applicable; OHA, oral hypoglycemic agents; RAASi, renin-angiotensin-aldosterone system inhibitors; and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
cord-334490-42gykxdx	2020	The specific causes of troponin rise in COVID-19 in patients without cardiac conditions, such as acute coronary syndrome (ACS), aortic stenosis, hypertrophic cardiomyopathy, and tachycardia A. Cardiac injury, defined as elevated troponin levels, is frequently observed in patients with COVID-19. The European Association of Percutaneous Cardiovascular Interventions (EAPCI) issued a position statement on invasive management in patients with ACS during the COVID-19 pandemic [19] . The EAPCI recommends that in cases of mild troponin elevation (<2-3 times the upper limit of normal), particularly in older patients with pre-existing cardiac conditions, a work-up for type 1 MI is not indicated, unless strongly indicated by clinical presentation and electrocardiograph (ECG) findings. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China Association of Renin-Angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for Coronavirus disease 2019 (COVID-19) infection in Wuhan, China
cord-338417-7kw9lws0	2020	RESULTS: From the pooled data of all ten available Chinese studies (n = 2209) that have reported the characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%, followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of patients. Emerging data suggests that older COVID-19 patients with other comorbid conditions such as diabetes, hypertension, cardiac and pulmonary disease are in particular more susceptible, compared to general populations and have higher mortality. We have systematically searched the PubMed medical database up till March 27, 2020 using MeSH key words that include Covid-19, coronavirus, hypertension, diabetes, cardiovascular disease, angiotensin receptor blockers, angiotensin converting enzyme inhibitors. Interestingly, in the pooled data from the ten Chinese studies (n ¼ 2209) that have reported the characteristics of comorbidities in patients with COVID-19; associations of hypertension, diabetes and presence of established cardiovascular disease (CVD) are larger, varying from 15 to 30% (average 21%), 5e20% (average 11%) and 2e40% (average 7%) respectively (Table 1) .
cord-342786-dl8vjwfn	2020	Abstract Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. The infected patients may also present with cardiovascular disease (CVD) like acute coronary syndrome(ACS) and congestive cardiac failure(CHF) [6] . The systemic inflammation in COVID-19 may also dysregulate the post-translational modification of cardiac ion channels resulting in arrhythmia [25, 26] It is also noteworthy that viral proteins of SARS-CoV-2, ORF3 and ORF8, activate NLRP3 inflammasomes which inturn promotes atrial fibrillation [27, 28] .
cord-346811-gorp9n1g	2020	We report a large, population-based study where we examined the drug histories of approximately 20% of all patients tested positive for coronavirus in England to determine if there was an independent association between ACE inhibitor and ARB drug prescription and severe COVID-19 disease susceptibility and progression. We extracted data from the GP record for explanatory and potential confounding variables including variables with some evidence of being risk factors for COVID-19 disease or severe disease as measured by ICU admission and variables likely to influence prescribing of ACE inhibitors and ARB medications. In this very large population-based study, ACE inhibitor and ARB prescriptions were associated with a reduced risk of COVID-19 RT-PCR positive disease, having adjusted for a wide range of demographic factors, potential comorbidities and other medication. 11 In our study, prior prescription of ACE inhibitor and ARB drugs did not have a significant effect on the risk of patients developing COVID-19 disease severe enough to require ICU care.
cord-346912-o09qmp7x	2020	We develop an SIR model of the COVID-19 pandemic which explicitly considers herd immunity, behavior-dependent transmission rates, remote workers, and indirect externalities of lockdown. Additionally, if we incorporate a behavior-dependent transmission rate which represents increased personal caution in response to increased infection levels, both output loss and total mortality are lowered. Overall, our model predicts that a lockdown which ends at the arrival of herd immunity, combined with individual actions to slow virus transmission, can reduce total mortality to one-third of the no-lockdown level, while allowing high-risk individuals to leave lockdown well before vaccine arrival. • Increasing the level of remote work reduces the impact of COVID-19 by decreasing both mortality and output loss, even though a longer lockdown is imposed. Recreation of [Ace+20] model (two groups and no herd immunity), parameters from Table 1 Output Loss: 8.9676%, Total Deaths: 1.3121% All rights reserved.
cord-349445-yh6ndtgm	2020	Therefore, researchers suggested that the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), may show a positive trend towards the severe inflammatory reactions and endothelial dysfunction caused by stimulating the function of ACE/Ang II/AT-1 axis and thereby, towards the bad pulmonary effects associated with the COVID-19 infection [29, 30] . Since IL-6 would inactivate endothelial nitric oxide synthase (eNOS), it could disrupt NO production [90] , decreasing its level and inducing a state of oxidative stress that may lead to Ang II-induced impairment in endothelial responses [91] Postulating impaired endothelium functions as a principal factor in the pathogenesis of heart failure, hypertension and diabetes, it will be expected to classify the patients of such diseases as high risk groups for COVID-19 development [92] [93] [94] . Taken into consideration the numerous harmful effects possibly induced by Ang II during COVID-19 pathogenesis, we found that most novel studies aim to use the anti-hypertensive drugs which act either by inhibiting the ACE activity or by blocking AT1 receptor, suggesting that action may mitigate the disease severity in COVID-19 patients.
cord-351567-ifoe8x28	2020	However, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. To assess the magnitude of the risk posed by the SARS-CoV-2, we review four parameters that we believe important: the transmission rate, the incubation period, the case fatality rate (CFR), and the determination of whether asymptomatic transmission can occur. A small study of 17 patients showed that nasal viral load peaks within days of symptom onset, suggesting that transmission of disease is more likely to occur early in the course of infection [40] . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19)-China 2020 Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia
cord-352230-8mazd3eu	2020	Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs. COVID-19 is a devastating disease caused by a coronavirus related to the one that caused outbreaks of Severe Acute Respiratory Syndrome (SARS) in the year 2002 (1, 2) .
cord-353707-3n2nji8l	2020	title: Chronic Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Is High Among Intensive Care Unit Patients With Non–COVID-19 Sepsis but Carries a Moderately Increased Risk of Death We, therefore, examined the chronic use of ACE inhibitors/ARBs and associated mortality in a historic cohort of septic patients admitted to the Intensive Care Unit. Data were collected between January 2008 and December 2015 on a nationwide Swedish cohort of 2700 patients, aged 18 years and over, with community-acquired severe sepsis and septic shock admitted to the Intensive Care Unit within 24 hours of arrival to any of 32 emergency departments throughout the country. ACE inhibitors/ ARB use was common among patients admitted to the Intensive Care Unit because of sepsis. ACE inhibitors/ARB use and associated mortality among critically ill COVID-19 patients can be compared with this data. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19
cord-355807-q3bngari	2020	Molecular modeling was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (cat''s claw) focusing on the binding interface of the RBD–ACE-2 and the viral spike protein. tomentosa against focusing both on the binding interface of the RBD-ACE-2 and inside SARS-CoV-2 RBD spike protein, (2) simulations of ligand pathway of the best predicted compounds from step 1 to evaluate convenient entrance mechanism of the compounds to the binding site, (3) MD simulation to assess the stability of the best protein-ligand complexes from 1, (4) calculation of pharmacokinetics parameters for the most qualified compounds resulting from the previous parts of the docking protocol. Next, we used the cryo-EM structure of SARS-CoV-2 spike protein (PDB code: 6VYB) in their open state (Lipinski et al., 2012) to explore the potential inhibition of components of the cat''s claw, selecting ACE-2-binding pocket to this study.