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Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics
Abstract
At the time of writing this commentary (February 2020), the coronavirus COVID‐19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS‐CoV‐2 virus may take many months. Moreover, vaccines based on viral‐encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS‐CoV‐2 virus infections. This idea is based on observations that the angiotensin‐converting enzyme 2 (ACE2) very likely serves as the binding site for SARS‐CoV‐2, the strain implicated in the current COVID‐19 epidemic, similarly to strain SARS‐CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS‐CoV‐2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.
... Since each viral particle entering the cell is attached to an ACE2 molecule, it has been speculated that SARS-CoV-2 infection causes partial or total loss of ACE2 function on the cell surface with the consequent accumulation of Ang II and reduction in Ang 1-7 levels [12][13][14][15][16]. Such dysregulation of the RAS in lungs and at the systemic level has been proposed to favor a proinflammatory state that increases the severity of COVID-19 [17][18][19][20]. ...
... Endogenous and synthetic ligands are available for AT1R and B2R [23,45]. Interestingly, AT1R blockers are of common use in clinics and have been proposed for COVID-19 treatment [20]. However, their role in the mechanism of ACE2-mediated SARS-CoV-2 infection remains unclear. ...
... It has been suggested that accumulation of Ang II due to the reduction in plasma membrane ACE2 during SARS-CoV-2 infection contributes to such pro-inflammatory state [1,13,18]. AT1R blockers have been proposed to avoid the detrimental effects of Ang II accumulation [19,20]. In this regard, in a recent clinical trial in COVID-19 patients telmisartan showed potent anti-inflammatory actions as well as a reduction in the morbidity and mortality of the disease [72]. ...
Aims
Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system (RAS) recently identified as the membrane receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we aim to study whether two receptors from RAS, the angiotensin receptor type 1 (AT1R) and the bradykinin 2 receptor (B2R) modulate ACE2 internalization induced by a recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein. Also, we investigated the impact of ACE2 coexpression on AT1R and B2R functionality.
Materials and methods
To study ACE2 internalization, we assessed the distribution of green fluorescent protein (GFP) signal in HEK293T cells coexpressing GFP-tagged ACE2 and AT1R, or B2R, or AT1R plus B2R in presence of RBD alone or in combination with AT1R or B2R ligands. To estimate ACE2 internalization, we classified GFP signal distribution as plasma membrane uniform GFP (PMU-GFP), plasma membrane clustered GFP (PMC-GFP) or internalized GFP and calculated its relative frequency. Additionally, we investigated the effect of ACE2 coexpression on AT1R and B2R inhibitory action on voltage-gated calcium channels (CaV2.2) currents by patch-clamp technique.
Key findings
RBD induced ACE2-GFP internalization in a time-dependent manner. RBD-induced ACE2-GFP internalization was increased by angiotensin II and reduced by telmisartan in cells coexpressing AT1R. RBD-induced ACE2-GFP internalization was strongly inhibited by B2R co-expression. This effect was mildly modified by bradykinin and rescued by angiotensin II in presence of AT1R. ACE2 coexpression impacted on B2R- and AT1R-mediated inhibition of CaV2.2 currents.
Significance
Our work contributes to understand the role of RAS modulators in the susceptibility to SARS-CoV-2 infection and severity of COVID-19.
... Furthermore, in patients with COVID-19, plasma levels of Angiotensin II are higher than in healthy population [18] and stimulate an upregulation of aldosterone level, triggering sodium and water retention [19][20][21][22]. SARS-CoV-2 enters through ACE2, and further downregulates ACE2 [18,23,24] expression so that this enzyme is unable to exert its protective effects. The dysregulated activity of the renin angiotensin aldosterone system (RAAS) [16] is partly responsible for pulmonary edema in COVID-19 [16,24]. ...
... SARS-CoV-2 enters through ACE2, and further downregulates ACE2 [18,23,24] expression so that this enzyme is unable to exert its protective effects. The dysregulated activity of the renin angiotensin aldosterone system (RAAS) [16] is partly responsible for pulmonary edema in COVID-19 [16,24]. ...
... The RAAS can be envisioned as a dual function system in which the vasoconstrictor/proliferative or vasodilator/antiproliferative actions are primarily driven by the ACE-ACE2 balance [19]. According to that, an increased ACE/ACE2 activity ratio generated by the downregulation action of SARS-CoV2 on ACE2 [18,[22][23][24] will lead to increased Angiotensin II [18] and increased catabolism of Angiotensin 1-7, towards vasoconstriction, endothelial dysfunction, prothrombosis, proinflammatory, and antinatriuretic effect [19,22]. ...
In COVID-19, pulmonary edema has been attributed to “cytokine storm”. However, it is known that SARS-CoV2 promotes angiotensin-converting enzyme 2 deficit, increases angiotensin II, and this triggers volume overload. Our report is based on COVID-19 patients with tomographic evidence of pulmonary edema and volume overload to whom established a standard treatment with diuretic (furosemide) guided by objectives: Negative Fluid Balance (NEGBAL approach). Retrospective observational study. We reviewed data from medical records: demographic, clinical, laboratory, blood gas, and chest tomography (CT) before and while undergoing NEGBAL, from 20 critically ill patients. Once the NEGBAL strategy was started, no patient required mechanical ventilation. All cases reverted to respiratory failure with NEGBAL, but subsequently two patients died from sepsis and acute myocardial infarction (AMI). The regressive analysis between PaO2/FiO2BAL and NEGBAL demonstrated correlation (p < 0.032). The results comparing the Pao2Fio2 between admission to NEGBAL to NEGBAL day 4, were statistically significant (p < 0.001). We noted between admission to NEGBAL and day 4 improvement in CT score (p < 0.001), decrease in the superior vena cava diameter (p < 0.001) and the decrease of cardiac axis (p < 0.001). Though our study has several limitations, we believe the promising results encourage further investigation of this different pathophysiological approach.
... The median age of patients was 65 years [IQR, 57-73] and 481 were male (65%). The median Sepsis-related Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation II (APACHE-II) score were 6 [IQR, [4][5][6][7][8][9] and 17 [IQR, [12][13][14][15][16][17][18][19][20][21][22][23][24], respectively. ...
... Despite the improved in-hospital mortality, patients with ACEi/ARB showed a longer length of ICU and general ward stay. In the retrospective study, targeting from non-severe to severe hospitalized COVID-19 patients, Li et al. reported that ACEi/ARB group (n = 115) and non-ACEi/ARB group (n = 247) did not have a significant difference in hospital stay {median 19 days [IQR [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and median 19 days [IQR [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27], respectively} in contrast to this study. However, when they compared the length of hospital stay of COVID-19 patients with hypertension (n = 362) between survivors 737); B ACEi/ARB group; and C Non-ACEi/ARB group. ...
... Despite the improved in-hospital mortality, patients with ACEi/ARB showed a longer length of ICU and general ward stay. In the retrospective study, targeting from non-severe to severe hospitalized COVID-19 patients, Li et al. reported that ACEi/ARB group (n = 115) and non-ACEi/ARB group (n = 247) did not have a significant difference in hospital stay {median 19 days [IQR [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and median 19 days [IQR [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27], respectively} in contrast to this study. However, when they compared the length of hospital stay of COVID-19 patients with hypertension (n = 362) between survivors 737); B ACEi/ARB group; and C Non-ACEi/ARB group. ...
Background
The influence of renin–angiotensin–aldosterone system (RAAS) inhibitors on the critically ill COVID-19 patients with pre-existing hypertension remains uncertain. This study examined the impact of previous use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on the critically ill COVID-19 patients.
Methods
Data from an international, prospective, observational cohort study involving 354 hospitals spanning 54 countries were included. A cohort of 737 COVID-19 patients with pre-existing hypertension admitted to intensive care units (ICUs) in 2020 were targeted. Multi-state survival analysis was performed to evaluate in-hospital mortality and hospital length of stay up to 90 days following ICU admission.
Results
A total of 737 patients were included—538 (73%) with pre-existing hypertension had received ACEi/ARBs before ICU admission, while 199 (27%) had not. Cox proportional hazards model showed that previous ACEi/ARB use was associated with a decreased hazard of in-hospital death (HR, 0.74, 95% CI 0.58–0.94). Sensitivity analysis adjusted for propensity scores showed similar results for hazards of death. The average length of hospital stay was longer in ACEi/ARB group with 21.2 days (95% CI 19.7–22.8 days) in ICU and 6.7 days (5.9–7.6 days) in general ward compared to non-ACEi/ARB group with 16.2 days (14.1–18.6 days) and 6.4 days (5.1–7.9 days), respectively. When analysed separately, results for ACEi or ARB patient groups were similar for both death and discharge.
Conclusions
In critically ill COVID-19 patients with comorbid hypertension, use of ACEi/ARBs prior to ICU admission was associated with a reduced risk of in-hospital mortality following adjustment for baseline characteristics although patients with ACEi/ARB showed longer length of hospital stay.
Clinical trial registration The registration number: ACTRN12620000421932; The date of registration: 30, March 2020; The URL of the registration: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12620000421932 .
... Obviously, the ultimate solution is producing a SARS-CoV-2 vaccine [58], since there isn't any effective eradicative treatment for COVID-19 at present [33]. One of the key components in developing virus neutralizing antibodies or a vaccine design is the CoVs S protein [59,60]. ...
... Research institutions and pharmaceutical companies worldwide are stepping up research and development for a coronavirus vaccine. Most of these vaccine would be either as inactivated vaccines, subunit vaccines or viral vectored vaccines (VVV) and should pass the 3 phases of trials before approval and licensing [60], including the mRNA-based vaccines, that were granted the first historic authorization for emergency use [61], but even once a vaccine is approved for human use, high virus mutation rates, would mean that a new vaccine may be need to be developed for each outbreak [58]. A particularly effective vaccine would show results earlier as the difference with the control group would be greater but, most trials would not expect results before the first half of 2021 [62]. ...
Several vaccines are found for the novel coronavirus SARS-CoV-2, responsible for the Coronavirus Disease 'COVID-19' but with a no clear, unified and effective treatment plan, nor definitive therapies for it, but only a variety of potential approaches. The objective of this work was to present, an overview of a variety of therapeutic and preventive approaches that have been applied instead, in a matter to calm the fatal viral pneumonia and developing safe, effective, anti-coronavirus therapeutic agents from naturally derived compounds would make a hopeful solution to end this pandemic. A number of experimental therapies have been rushed into clinical trials for COVID-19 patients, and with medical journals publishing new COVID-19 research studies at breakneck speed, it can be difficult to keep up with the latest news and guidelines. Potential anti-coronavirus therapies can be divided into two categories depending on the target, one acting on the human immune system or human cells, and another, on the virus itself.
... The crucial effect of downregulation concerns the lack of protective effect on organs exerted by ACE2. No hypothesis has ever demonstrated that the continuous activity of angiotensin II may be partly responsible for organ damage in patients with COVID-19 [82,83]. SARS-CoV-2 saturating the ACE2 involved in the binding with the spike leads to the subsequent down-regulation of the fullness of ACE2 receptors in host cells' surface [47]. ...
... In addition, they evaluated the gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18 in myocardial tissue of patients infected with SARS-CoV-2. The study included 39 consecutive autopsy cases with a median (interquartile range) patient age of 85 (78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89) years, with 59.0% being women. The presence of SARS-CoV-2 was recorded at a rate of 61.5% of patients and viral load with a concentration of 1000 copies per µg of RNA was reported at a rate of 41.0%, respectively. ...
One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways; however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following SARS-CoV-2 infection while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection a pandemic with similarities to the influenza virus.
... Most importantly, low ACE2 levels expose the lungs to acute inflammation , and ACE2 is low in most common chronic pathologies including hypertension, angiocardiopathy, type 2 diabetes, chronic renal failure, pulmonary diseases and liver diseases (Li et al., 2020a;Pagliaro and Penna, 2020). For these reasons, several authors proposed that the severity of Covid-19 is exacerbated by the degradation of ACE2 by the virus (Annweiler et al., 2020;Sun et al., 2020a;Ciaglia et al., 2020;Gurwitz, 2020;Offringa et al., 2020;Verdecchia et al., 2020). ...
... Moreover, Ang-II can be also formed through other peptidases. The possible therapeutic role of ARB and ACE-I was suggested by several groups already at the time of SARS 2003 and later proposed for SARS-COV-2 (Annweiler et al., 2020;Sun et al., 2020a;Ciaglia et al., 2020;Gurwitz, 2020;Offringa et al., 2020;Verdecchia et al., 2020). ...
Covid-19 is particularly mild with children, and its severity escalates with age. Several theories have been proposed to explain these facts. In particular, it was proposed that the lower expression of the viral receptor ACE2 in children protects them from severe Covid-19. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we review the seemingly contradicting observations on ACE2 expression at the levels of mRNA, membrane protein and serum protein in humans and rodents and try to reconcile them at the light of the Renin-Angiotensin system (RAS) and bradykinin system, which constitute an integrated inflammatory system connected by common peptidases and interacting receptors. We find that ACE2 level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases, consistently with almost all existing data. The increase with age of the protease Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), also known as ADAM17 (a disintegrin and metalloproteinase 17) that sheds ACE2 from the cell membrane to the serum predicts that the decrease occurs before and is steeper for ACE2 cell protein than for its mRNA. This negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF-α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6). Here we propose that ACE2 contributes essentially to reverse this inflammatory state by downregulating the pro-inflammatory peptides of the angiotensin-bradykinin system, and that failure to do this, possibly induced by the degradation of ACE2 by SARS-COV-2, may underlie both severe CoViD-19 infection and its many post-infection manifestations, including the multi-inflammatory syndrome of children (MIS-C). Within this view, lower severity in children despite lower ACE2 expression may be consistent with their higher expression of the alternative angiotensin II receptor ATR2 and in general of the anti-inflammatory arm of the RAS at young age.
... ARBs, a well-known antihypertensive drug group that blocks AT1R, have been postulated as tentative pharmacological agents to treat COVID-19-induced lung inflammation [112]. Therefore, it is common for individuals with hypertension to use ARBs in order to control their blood pressure. ...
... On the other hand, many other studies contradicted such claims and implied that RAS inhibitors are effective in SARS-CoV-2 patients. ARBs are then believed to reduce acute lung injury in SARS-CoV-2 viral illness by the following mechanisms [112,[131][132][133][134][135]: (1) blockade of AT1R may reduce the detrimental effects of Ang-II; (2) administration of ARBs may increase ACE2 expression, which may reduce the detrimental effects of Ang-II [118]; (3) AT1R blockade at the cell surface may reduce the internalization of the virus and consequently limit the decrease in ACE2 caused by the infection [65,118]. ...
The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its down-regulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
... However, losartan and other AT1R blockers have been reported to increase ACE2 expression in the kidney of spontaneously hypertensive rat and heart of mice or rat with cardiac hypertrophy and dysfunction caused by transverse aortic constriction or coronary artery ligation [10,11]. It has been suggested that angiotensin receptor 1 (AT1R) blockers may be used to reduce the cardiac damage in SARS-CoV-2 infection [12]. Retrospective studies found that hospitalized hypertensive patients with SARS-CoV-2 infection treated with ACE inhibitors or AT1R blockers have a lower risk of all-cause mortality than those treated with other drugs [13]. ...
... The protective effect of AT1R blockers in hypertensive COVID-19 patients has been reviewed recently [12,[43][44][45]. As aforementioned, SARS-CoV-2 uses ACE2 to enter the cell [5,17,46]. ...
Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis.
... However, its expression is lower in the lungs than in other organs, such as the kidney and heart [36]. ACEIs can increase Ang (1-7) levels, while ARBs increase both Ang II and Ang (1-7) levels, and thus, reduce organ injuries [37,38]. In a population-based study, it was proposed that the mortality rate in patients with pneumonia was significantly reduced using ACEIs and ARBs [39]. ...
... There is a divided expert outlook on the subsequent impact of ACEI/ARBs and hrsACE2 therapies in treating COVID-19. The use of ACEIs/ARBs, renin inhibitors, and Ang (1-7) analogs can attenuate organ injury [37]. Several studies have shown that AT1R blockers alter ACE2 expression more consistently at the mRNA and protein levels [38]. ...
As of August 16, 2021, there have been 207,173,086 confirmed cases and 4,361,996 deaths due to the coronavirus disease (COVID-19), and the pandemic remains a global challenge. To date, no effective and approved drugs are available for the treatment of COVID-19. Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in the invasion into host cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Notably, ACE2 density is influenced by medical conditions, such as hypertension, or by drugs, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can change the fate of SARS-CoV-2 infectivity. ACE2 is a target for these drugs and can be manipulated to limit the viral entry and replication within the cells. Different strategies that are aimed at blocking ACE2 with small molecules, peptides, and antibodies, or by neutralizing the virus through its competitive binding with human recombinant soluble ACE2 (hrsACE2) are currently under investigation. In this article, we review the current state of knowledge that emphasizes the need to find effective therapeutic agents against COVID-19 by exploiting ACE2 as a potential target. The increased soluble ACE2 levels and the application of hrsACE2 in patients with COVID-19 can be implemented to control the disease. It has not yet been established whether hypertension and other comorbidities, independent of age, have a direct role in COVID-19. Therefore, the use of renin-angiotensin system inhibitors, ACEIs and ARBs, should not be discontinued during COVID-19 treatment.
... As a result, lower levels of ACE-2 lead to higher levels of angiotensin II and further activate the inflammatory state. 103 In addition, it has been revealed that testosterone increases the ACE2 expression. 104 The analysis of ACE2 expression patterns in adult human testis showed that ACE2 is often highly expressed in leydig, sertoli, and spermatogonia cells. ...
Varicocele is recognized as one of the main attributable causes of male infertility which can affect spermatogenesis by various pathophysiological mechanisms. Recent studies have identified oxidative stress and reduction in antioxidant, hyperthermia, hypoxia, hormonal dysfunction, and inflammatory conditions as major factors in the pathophysiology of varicocele, all of which have known direct associations with the coronavirus disease 2019 (COVID-19) and can significantly increase the risk of detrimental COVID-19-related outcomes. Emerging data have shown an association between COVID-19 and inflammation, overproduction of cytokine, and other pathophysiological processes. The present review, summarizes the current understanding of the pathophysiology of varicocele and investigates the potential correlation between the severity of COVID-19 and the varicocele disease. In addition, various possible treatments which can be effective in both diseases were examined. Despite numerous challenges associated with the prevalence of COVID-19 in healthcare systems in infected countries, special attention should be given to maintaining a high level of care for complex patients with a pre-existing disease such as varicocele and providing appropriate practical advice for optimal control of the COVID-19 disease.
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... An increase in Bax, an apoptotic protein, and a decrease in Bcl2, an anti-apoptotic protein, have been observed in COVID-19 infection (Rockx et al., 2020). Coronaviruses can induce intrinsic and extrinsic apoptotic pathways by some unknown mechanism causing mitochondrial dysfunction upon generation of ROS (Gurwitz, 2020). Alternatively, it can be proposed that as the virus's proliferation occurs in the lung cells, it might trigger inflammatory responses leading to alveolar disorders that cause hypoxia in the CNS and apoptosis of brain cell mitochondria . ...
Novel coronavirus SARS-CoV-2 is being speculated to have a profound effect on the neurological health of children. This chapter addresses the risk of neurological symptoms in children susceptible to COVID-19, which might help pediatric neurologists. As existing research has been mainly focused on adults, this chapter is a compilation of past and present data to understand better the diseases associated with pediatric neurology and COVID-19 and its repercussions. Consequently, this chapter aims to enlighten the level of alertness in pediatric specialists to assess potential neurological involvement of this virus and its probable long-term neuropsychiatric and medical consequences.
... SARS-CoV-2'nin reseptör olarak insan (hACE2'yi kullandığını bildirmiştir. Birkaç çalışma aynı şekilde, yeni SARS-CoV-2'nin muhtemelen hACE2 reseptörüne bağlandığını, ancak orijinal SARS virus suşundan daha yüksek bir afinite ile bağlandığını göstermiştir [81,115,167,222,228]. Viral zarfın S proteinine maruz kalmasıyla konformasyonel modifikasyonu ve konak hücre membranı ile füzyon, hücre girişinin ilk aşamasını oluşturur. ...
Abstract.
In mid-August 2021, WHO reported 456.225.677 (4.400.284 death) confirmed cases of
coronavirus-19 in the world and 8.641.372 (53.891 death) cases in Turkey.
Corona-virus 19 produces severe acute respiratory syndrome characterized by cytokine
release. Possible treatments for cytokine-mediated hyperinflammation need to be
urgently investigated to reduce rising death rates.
Although vaccine applications have been made, information is not yet available about
vaccine's potential long-term effects. Also, there are no definitely approved treatments
for Corona-viruses. Numerous aromatic herbs and phytochemicals await therapeutic
use against genetically and functionally diverse viruses, including coronaviruses.
Turkey has a high potential for research on this subject with its rich ethnomedical
experience and rich flora (34% endemic). Plants that have been used against influenza
for centuries can offer effective alternatives.
Key words: Coronavirus-19, cytokine, antiviral, TRP channels, NF-κβ, STAT
... About 30-50% of the people hospitalized due to COVID-19 have hypertension and those hypertensive patients have a two-fold higher chance of dying from COVID-19 [116]. Treatments that target RAS, especially AT 1 R, have already been used to prevent infection-related tissue damage [117]. Notably, it has been suggested that the entry of SARS-CoV-2 into the cells via ACE2 binding is actually AT 1 R dependent [118]. ...
Hypertension is one of the most prevalent cardiovascular disorders worldwide, affecting 1.13 billion people, or 14% of the global population. Hypertension is the single biggest risk factor for cerebrovascular dysfunction. According to the American Heart Association, high blood pressure (BP), especially in middle-aged individuals (~ 40 to 60 years old), is associated with an increased risk of dementia, later in life. Alzheimer’s disease and cerebrovascular disease are the two leading causes of dementia, accounting for around 80% of the total cases and usually combining mixed pathologies from both. Little is known regarding how hypertension affects cognitive function, so the impact of its treatment on cognitive impairment has been difficult to assess. The brain renin-angiotensin system (RAS) is essential for BP regulation and overactivity of this system has been established to precede the development and maintenance of hypertension. Angiotensin II (Ang-II), the main peptide within this system, induces vasoconstriction and impairs neuro-vascular coupling by acting on brain Ang-II type 1 receptors (AT1R). In this review, we systemically analyzed the association between RAS and biological mechanisms of cognitive impairment, from the perspective of AT1R located in the central nervous system. Additionally, the possible contribution of brain AT1R to global cognition decline in COVID-19 cases will be discussed as well.
... On the basis of this information, Gurwitz introduced the use of accessible antagonists, such as angiotensin receptor 1 (AT1R), to suppress COVID-19 diseases [121]. ...
... It was hypothesized that excessive ACE2 may competitively bind with SARS-CoV-2 Spike protein and supplement cellular ACE2 activity, which negatively regulates the RAS to protect the lung from injury (Kuster et al., 2020). However, this plausible protective therapeutics against advanced stage COVID-19 remains clinically unproven until tried (Aronson and Ferner, 2020;Gurwitz, 2020). In this study, instead of ACE2, the other component genes of the RAS pathway, i.e., CMA1, CPA3, CTST, MME, PRCP and REN (Nehme et al., 2019), are predicted to be targeted by CHP bioactive compounds (Supplementary Table 4). ...
Network pharmacology analysis can act as a strategy to identify the pharmacological effect of plant-based bioactive compounds against coronavirus diseases. This study aimed to investigate the potential pharmacological mechanism of a local ethnomedicine (Costus speciosus, Hibiscus rosa-sinensis and Phyllanthus niruri) of Northern Borneo against coronaviruses known as CHP. Compounds in CHP were extracted from databases and screened for their oral bioavailability and drug-likeness before a compound-target network was built. Furthermore, the protein-protein interaction network and pathway enrichment were constructed and analyzed. A compound-target network consisting of 48 putative bioactive compounds targeting 587 candidate genes was identified. A total of 186 coronavirus-related genes were extracted and TP53, STAT3, HSP90AA1, STAT1, and EP300 were predicted to be the key targets. Notably, mapping of these target genes into the target-pathway network illustrated that functional enrichment was on viral infection and regulation of inflammation pathways. Urinatetralin is predicted, for the first time, as a bioactive compound that solely targets STAT3. The results from this study indicate that compounds present in CHP employ STAT3 and its connected pathways as the mechanism of action against coronaviruses. In conclusion, urinatetralin should be further investigated for its potential application against coronavirus infections.
... The virus makes use of a particular surface glycoprotein called a "spike" (peplomer) that connects to ACE2 and enters into the host cell [4]. The density of ACE2 in each tissue match up with the seriousness of the disease in that tissue and some have suggested decreasing ACE2 activity might be protective, [5] though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective [6]. As the alveolar disease progression, respiratory failure might evolve and death may occur [7]. ...
SARS-Cov-2 (severe acute respiratory syndrome coronavirus) that initially came to notice in December 2019 is the agent responsible for COVID-19 is still spreading rapidly worldwide and it is presently a potent danger to the world and also to the economy. Patients with COVID-19 are still at risk of Acute Respiratory Distress Syndrome (ARDS), respiratory failure, and death. Those patients whose aged more than sixty years with comorbidities, children, and healthcare workers are highly vulnerable to this virus patient shows various symptoms most commonly cough, fever, difficulty in breathing, fatigue, sore throat. The infection could be categorized into three stages: mild infection, the pulmonary stage, and the inflammatory stage. As the COVID-19 pandemic continues, it has been clear that infection caused due to SARS-Cov-2 might be responsible for the unpredicted long-term health consequences. In addition to this, it has acute respiratory manifestations, adversely SARS-Cov-2 also affects the other organ systems. However, there is limited to the management of COVID-19 related conditions of the extrapulmonary systems. After recovery, patients remain at risk for lung disease, heart disease, and mental ailment. There may be long-term consequences of adverse effects they observed in the course of COVID-19 and during its treatment. This review provided information about the extrapulmonary manifestations of COVID-19 that may impair the urinary, cardiovascular, gastrointestinal, hematological, hematopoietic, neurological, or reproductive systems. Also, the main purpose of this article is to describe the current concern of the extra pulmonary complications that were caused due to COVID-19 and also to improve the management and diagnosis of these patients.
... Obese people have more adipose tissue, which means they have a higher amount of ACE2 expressing cells. Angiotensin-converting enzyme (ACE) stimulation is critical in the pathophysiology of obesity and heart disease [45]. As a result, the connection between the ACE2-RAS system, adipose tissues, and SARS-CoV-2 could reflect, at least to some extent, why obese individuals have a higher morbidity risk from COVID-19. ...
Coronavirus disease -19 (COVID-19) pandemic has extended from late 2019 and continues to this day. The degree of the disease is related to some factors, including age and comorbidities. Obesity is now more widely considered as a main factor of infection, mainly because it has been shown that individuals who are obese have a more severe course of infection with COVID-19.
This review study summarized the relationship between the risk of obesity and COVID-19 and detected a difference in reporting from the period of the first pandemic in China to more recent studies. Obesity is a risk factor for developing signs and symptoms of patients with COVID-19 and this review will benefit clinicians by recognizing the role of obesity when giving COVID-19 diagnosis, follow-up, and treatment programs.
... This pathway increases the production of cytokines. Low levels of the conversion enzyme ACE-2 and high levels of angiotensin II result in the increased permeability of pulmonary veins and inflammatory damage to lung tissue (Gurwitz et al. 2020). The reason for lung damage during more severe SARS-CoV-2 infection stages is therefore currently thought to be from a cytokine storm resulting from a non-controlled immune response to lung damage (Shi et al. 2020, Al-Lami et al. 2020). ...
Recent molecular biology findings have shown that for the penetration of the SARS-CoV-2 coronavirus into host cells, a key role is played by protease serine 2, the activity of which is dependent on androgens. The important role of androgens is also evidenced by clinical observations that men in some age categories are infected by this novel coronavirus up to two times more frequently than women. In addition, men with androgenic alopecia tend to have more serious clinical courses, while men with androgen deprivation as a result of prostate cancer treatments tend to have milder courses. This is in line with the fact that preadolescent children are only rarely sickened with serious forms of SARS-CoV-2 infections. Even though these observations may be explained by other factors, many authors have hypothesized that lowered androgen levels and blocking their activity using anti-androgen medication may moderate the course of the viral infection in intermediately- to critically-affected cases. Clearly, it would be important for androgen deprivation to block not just gonadal androgens, but also adrenal androgens. On the other hand, low androgen levels are considered to be a risk factor for the course of SARS-CoV-2 infections, either because low androgen levels have a general effect on anabolic-catabolic equilibrium and energy metabolism, or because of the ability of testosterone to modify the immune system. It is not yet clear if infection with this novel coronavirus might induce hypogonadism, leading to undesirable side effects on male fertility.
... Вирус SARS-CoV-2 проникает в дыхательные пути и связывается с клеткой мишенью (альвеолярные клетки 2 типа), имеющие рецепторы ангиотензинпревращающего фермента II типа (ACE2) [1]. Гипотеза о причастности ренин-ангиотензиновой системы к воспалительному процессу, спровоцированному проникновением SARS-CoV-2 в ткани (в первую очередь в легкие), учитывает, что потеря функции ACE2 вызывает дисбаланс, повышая концентрацию ангиотензина II в тканях (провоспалительный эффект) и одновременно снижая уровень ангиотензина 1-7 (противовоспалительное действие) [2,3]. Это приводит к высвобождению провоспалительных цитокинов [4,5] и запускает каскад, приводящий к острому респираторному дистресс-синдрому (ОРДС). ...
Aim . To evaluate the potential of a fixed-dose combination of lisinopril+amlodipine+rosuvastatin (Equamer®) in achieving additional vascular protection in patients with hypertension and high pulse wave velocity (PWV) after severe and very severe coronavirus disease 2019 (COVID-19), complicated by bilateral multisegmental viral pneumonia, with the use of biological therapy, who had not previously received combination antihypertensive therapy.
Material and methods . This 12-week open-label observational study included 30 patients with or without antihypertensive therapy. The patients underwent 24-hour blood pressure monitoring, applanation tonometry (determination of the augmentation index (AI) and central blood pressure (CBP)), PWV measurement, blood laboratory tests (lipid profile, fasting glucose, C-reactive protein, complete blood count, ferritin, fibrinogen, D-dimer, alanine aminotransferase, aspartate aminotransferase, creatinine, uric acid) before and after switch to a fixed-dose combination of lisinopril+amlodipine+rosuvastatin.
Results . At baseline, the patients had an increase in office blood pressure (BP) up to 152,6/89,1 mm Hg. After prescribing a fixed-dose combination of lisinopril+amlodipine+rosuvastatin, there was a decrease in systolic blood pressure (SBP) by 15,8% and diastolic blood pressure (DBP) by 12,2%. According to 24-hour blood pressure monitoring, the decrease in SBP was 15%, DBP — by 9%, PWV — by 23,8%, AI — by 9%, CBP — by 12,4% (p<0,05 for all compared to baseline values). Vascular age (VA) was initially increased to 41,9 years with a chronological age of 35,03 years. After the end of therapy, there was a significant decrease in VA to 36,5 years, low-density lipoproteins by 46,8%, triglycerides by 16,8% and an increase in high-density lipoproteins by 10,7% (p<0,05 for all compared to baseline values). In addition, the levels of C-reactive protein, fibrinogen, D-dimer, glucose, and uric acid significantly decreased.
Conclusion . The fixed-dosed combination of lisinopril+amlodipine+rosuvastatin provides better blood pressure control, improved vascular elasticity parameters (AI, PWV, CBP, decrease in VA), and also improves lipid and carbohydrate metabolism, reduces inflammation in patients with hypertension and hyperlipidemia after severe COVID-19.
... З огляду на те, що АПФ2 є функціональним рецептором для SARS-CoV-2 і його експресійні рівні можуть бути підвищені, деякі автори раніше стверджували, що препарати іАПФ і БРА можуть спричиняти негативний вплив на перебіг і наслідок захворювання в пацієнтів із COVID-19 [32]. На противагу цьому твердженню, інші дослідники стверджують, що іАПФ і БРА можуть бути досить ефективними в терапії коронавірусної інфекції [33], оскільки SARS-CoV і його вірусний Spike білок після з'єднання з функціональним рецептором для SARS-CoV-2 -АПФ2, знижують експресію АПФ2 в наступні стадії захворювання після досягнення вкрай високого рівня вірусемії [34]. ...
Пацієнти з цукровим діабетом (ЦД) знаходяться в центрі уваги з ранніх стадій пандемії COVID‑19, оскільки епідеміологічні дані показують, що вони схильні до підвищеного ризику важких клінічних наслідків. Водночас як глобальна пандемія COVID‑19 продовжує розвиватися, стає все більш очевидним, що зв’язок між COVID‑19 і ЦД є складною патофізіологічною взаємодією. Наслідки COVID‑19 важчі в пацієнтів із ЦД, який здатний прискорити виникнення гострих метаболічних ускладнень, таких як діабетичний кетоацидоз і гіперглікемія. Механізми, які лежать в основі цих зв’язків залишаються нез’ясованими, але вони, очевидно, включають рецептор ангіотензинперетворюючого ферменту 2 (АПФ2), сайт зв’язування для коронавірусу 2 важкого гострого респіраторного синдрому (SARS-CoV‑2), що експресується в ключових метаболічних органах, зокрема, у β-клітинах підшлункової залози (ПШЗ). Потенційно тропізм SARS-CoV‑2 до β-клітин може призвести до пошкодження клітин і порушення секреції інсуліну, викликаючи гіперглікемію і кетоацидоз. Розуміння двонапрямної взаємодії між ЦД і COVID‑19 буде мати вирішальне значення для профілактики та лікування пацієнтів із ЦД. Наявні епідеміологічні дані про COVID‑19 не підтверджують гіпотезу про те, що пацієнти з ЦД схильні до підвищеного ризику інфікування порівняно із загальною популяцією. На сьогодні встановлено, що декомпенсований ЦД є незалежним чинником, який обтяжує перебіг коронавірусної інфекції та вірогідно підвищує ризики фатального наслідку захворювання. В огляді представлена квінтесенція еволюції поглядів патогенетичних і клінічних аспектів розуміння механізмів цього патологічного тандему, а також терапевтичних стратегій лікування пацієнтів із COVID‑19 і ЦД. Оскільки захворюваність на ЦД продовжує зростати в усьому світі, наразі, більш ніж коли-небудь, профілактика ЦД та боротьба з ним повинні стати пріоритетом систем охорони здоров’я всіх країн світу.
... " and stress that before chelation is applied " . . . it must be determined whether COVID-19 leads to elevated iron levels or AI" [58] (p. 1). Other potential therapies are targeted at the use of the bradykinin (BK) system blockers [40] and angiotensin receptor 1 (AT1R) antagonists [43]. Monoclonal antibodies (mAbs) and interferons (IFNs) should also be mentioned as specific forms of therapy against COVID-19 [32,50]. ...
The current report provides a brief overview of the clinical features, hematological/biochemical abnormalities, biomarkers, and AI-related strategies in COVID-19; presents in a nutshell the pharmacological and non-pharmacological therapeutic options; and concisely summarizes the most important aspects related to sociodemographic and behavioral factors as well as comorbidities having an impact on this disease. It also gives a brief outline of the effect of selected elements on immune response and collects data on the levels of micro-/macro-elements and toxic metals in the blood/urine of SARS-CoV-2 infected patients and on supplementation with minerals in COVID-19 subjects. Moreover, this review provides an overview of clinical trials based on the use of minerals alone or in combination with other agents that can provide effective responses toward SARS-CoV-2 infection. The knowledge compiled in this report lays the groundwork for new therapeutic treatments and further research on biomarkers that should be as informative as possible about the patient’s condition and can provide more reliable information on COVID-19 course and prognosis. The collected results point to the need for clarification of the importance of mineral supplementation in COVID-19 and the relationships of the levels of some minerals with clinical improvement.
... [129][130][131] Human studies of RAS blockade or recombinant ACE2 to prevent respiratory decompensation in COVID-19-infected patients have been suggested, planned, or are ongoing. 132,133 In summary, there is currently no evidence to suggest that ACEIs or ARBs increase the risk associated with COVID-19 and there is no reason why these drugs should be discontinued due to concern about COVID-19. Treatment of hypertension, when indicated, should continue to follow the existing ESC-ESH guideline recommendations. ...
Aims
Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular (CV) disease in association with COVID-19.
Methods and results
A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, which was reported previously, focused on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19. This second part addresses the topics of: care pathways and triage systems and management and treatment pathways, both of the most commonly encountered CV conditions and of COVID-19; and information that may be considered useful to help patients with CV disease (CVD) to avoid exposure to COVID-19.
Conclusion
This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.
... The angiotensin-converting enzyme 2 (ACE2) receptor plays a basic role in the infectivity of SARS-CoV-2, and also has a key role in the cardiovascular system and blood circulation (Gurwitz, 2020a). The virus enters the host cells via an ACE2-mediated endocytosisdependent manner (Hoffmann et al., 2020). ...
The causative agent of coronavirus disease-2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters the host cells via an angiotensin-converting enzyme 2 (ACE2)-mediated endocytosis-dependent manner. Because ACE2 is highly expressed in the heart, SARS-CoV-2 can severely infect heart tissue and arteries, causing acute and chronic damage to the cardiovascular system. Therefore, special attention should be paid to finding appropriate agents to protect this vital system during COVID-19 treatment. Papaverine is a unique vasodilator alkaloid that is clinically used in the treatment of vasospasm. Interestingly, this compound has potent and direct effects on a wide range of viruses, and could also prevent viral exploitation mechanisms of the host cell facilities by inhibiting some cellular signaling pathways such as p38 MAPK. This pathway was recently introduced as a promising target for the treatment of COVID-19. Papaverine also has anti-inflammatory effects which is useful in combating the hyper-inflammatory phase of the COVID-19. Unlike some medications that have severe dosage-restrictions in the treatment of COVID-19 due to cardiac side effects, papaverine is recommended for use in many heart disorders. The ability of papaverine to treat COVID-19 has become more promising when the results of some extensive screenings showed the strong ability of this compound to inhibit the cytopathic effects of SARS-CoV-2 with EC50 of 1.1 μM. Having several therapeutic effects along with desired safety profile raises this hypothesis that papaverine could be a promising compound for the suppression of SARS-CoV-2 and prevention of ischemia/vasoconstriction-related complications in COVID-19 disease, especially in patients with underlying cardiovascular diseases (CVDs).
... Pituitary gland, substantia nigra [324][325][326] mucosa, olfactory bulb, trigeminal ganglion, and cerebellum were assessed by means of RT-qPCR. 139 The human ACE2 transgenic mice were intranasally administered with SARS-CoV-1, and the related antibodies evaluated in OB, parts of cortical areas, as well as the basal ganglia~60-66 h later. ...
Currently, SARS-CoV-2 has caused a global pandemic and threatened many lives. Although SARS-CoV-2 mainly causes respiratory diseases, growing data indicate that SARS-CoV-2 can also invade the central nervous system (CNS) and peripheral nervous system (PNS) causing multiple neurological diseases, such as encephalitis, encephalopathy, Guillain-Barré syndrome, meningitis, and skeletal muscular symptoms. Despite the increasing incidences of clinical neurological complications of SARS-CoV-2, the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established. In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.
... Snake venoms are a complex combination of proteins and peptides. Venom serine proteases (SVSPs), snake venom metalloproteinases (SVMPs), secreted phospholipases A2 (SV-PLA2s), C-type lectins, and disintegrins are the major groups of snake venom components, while the minor group includes nucleotidases (Ntases), phosphodiesterases (PDEs), cysteinerich secretory proteins, L-amino acid oxidases, Kunitz peptides, three-finger peptides (3FTX), and natriuretic peptides [44][45][46][47][48]. Bradykinin-potentiating peptide 10C (BPP-10C) isolated from Bothrops jararaca can decrease angiotensin II by inhibiting the ACE and increase bradykinin 2-receptor [49][50][51] that both have a role in the pathogenesis of SARS-CoV-2 [52][53][54][55], and it can be considered as an anti-SARS-CoV-2 agent [56]. Kunitz-type peptides ((also called bovine pancreatic trypsin inhibitors) (BPTIs)) are 50 to 60 amino acid components found in the snake venoms that inhibit the catalytic site of serine proteases [57]; so, they are potential antiviral agents because transmembrane protease serine-2 (TMPRSS2) activity is required for SARS-CoV-2 entry [58,59]. ...
SARS-CoV-2 is a novel coronavirus and the cause of the recent pandemic; it is an enveloped β-coronavirus. SARS-CoV-2 appear in the Wuhan City of China for the first time and outspread worldwide quickly. Due to its person-to-person fast transmission, COVID-19 is becoming a global problem. SARS-CoV-2 enter into cells by using ACE2 receptors that are numerous in the lungs and finally can cause acute respiratory distress syndrome (ARDS). Dry cough, sore throat, fever, body pain, headache, GIT discomfort, diarrhoea, and fatigue are some of the COVID-19 symptoms. There is no definite and certain treatment for disease caused by SARS-CoV-2 till now. Some pharmacological effects of toxins, toxoids, and venoms have been proven, and their effects on some diseases have been evaluated. This study aimed to investigate the role of toxins, toxoids, and venom in the pathophysiology of COVID-19 disease.
... Поражение вегетативной нервной системы может являться причиной длительных постковидных нарушений [22,23]. Гиперстимуляции симпатической нервной системы при COVID-19 способствует высокий уровень ангиотензина II, который возникает в результате дисбаланса между ангиотензинпревращаю щим ферментом 2 (АПФ-2) и ангиотензинпревращаю щим ферментом (АПФ) [24][25][26][27][28][29][30]. Подавление АПФ-2 вирусом SARS-CoV-2 в ядре солитарного тракта из-за нейроинвазивного эффекта SARS-CoV-2 может еще больше увеличить продукцию ангиотен-зина II и симпатическую стимуляцию [31,32]. ...
Introduction. Asthenia, vegetative manifestations, sleep disturbances and psycho-emotional background are companions of the coronavirus infection, the issue of drug correction of which is especially relevant. These symptoms disrupt the habitual way of life of patients for a long time, and in special cases lead to disability. Aim . To study the mental, somatoform and cognitive aspects of anxiety disorders after coronavirus infection during treatment with tofisopam (Grandaxin®) 150 mg/day. Materials and methods . The study included patients who had experienced a new coronavirus infection, who, after the end of treatment for the underlying disease, had complaints suggesting the presence of an anxiety disorder. The Hamilton scale was used to assess the level of anxiety. Examination of patients was carried out before the start of treatment, after 2, 4 and 6 weeks of therapy. Results and discussion . Prior to the start of therapy, all patients had an overall high level of anxiety: the average HAM-A score was 31.4 ± 2.92 points. At the end of Grandaxin® therapy, all patients showed a decrease in the level of anxiety: the average HAM-A score was 12.08 ± 2.27 points (p < 0.001). The maximum decrease in the severity of vegetative disorders was noted by the end of the 6th week of therapy with Grandaxin®. Thus, the indicator of this subscale decreased by more than 2 times – from 2.46 ± 0.54 to 1.05 ± 0.28 points (p < 0.001). The severity of insomnia during six weeks of therapy with Grandaxin® decreased from 2.56 ± 0.54 to 0.96 ± 0.45 points (p < 0.001). Conclusion . Psycho-emotional disorders (more often in the form of increased personal anxiety), sleep disorders, vegetative disorders, asthenic syndrome significantly affect the quality of life of patients who have had a new coronavirus infection. Involvement of the structures of the autonomic nervous system and central structures that regulate GABAergic transmission leads to significant vegetative failures, which requires pathogenetically substantiated drug correction of these disorders.
... 5 Modeling and hypothesis development studies also indicated a potential link between influenza vaccination and reduced rates of COVID-19 infection. [11][12][13][14] In a study based in Italy, it was found that the higher influenza vaccination rates, the fewer the deaths from COVID-19. With a 1% increase of influenza vaccination among adults aged >65 years, the regional death rate due to COVID-19 decreased 0.3450. ...
Introduction
The association between influenza vaccination and coronavirus disease 2019 (COVID-19) remains controversial. This meta-analysis aimed to investigate whether influenza vaccination reduces the susceptibility and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Methods
A systematic literature search of PubMed, Web of Science, the Cochrane Library, Embase, China National Knowledge Infrastructure, SinoMed, Wanfang Data Knowledge Service Platform, and China Science and Technology Journal VIP Database was conducted from database inception to August 2021. The pooled relative risk (RR) with 95% CI was used to estimate the effect of influenza vaccination on COVID-19. The I² value was used to assess heterogeneity. If I² >50%, the random effects model was used as the pooling method.
Results
Twenty-three published articles with 1,037,445 participants were identified. This meta-analysis showed that influenza vaccination was associated with reduced risk of COVID-19 infection (RR=0.83, 95% CI=0.76, 0.90) and hospitalization (RR=0.71, 95% CI=0.59, 0.84), though not significantly associated with intensive care unit admission and death (risk of intensive care unit admission: RR=0.93, 95% CI=0.64, 1.36; risk of death: RR=0.83, 95% CI=0.68, 1.01). Further analysis suggested that the tetravalent influenza vaccine may be associated with a reduced risk of COVID-19 infection (RR=0.74, 95% CI=0.65, 0.84).
Conclusions
The results suggest that that influenza vaccination is associated with reduced susceptibility to or disease severity of COVID-19, and influenza vaccination may reduce the risk of COVID-19 and improve clinical outcomes.
... Nevertheless, ACE2 plays an important physiological role by downregulating the pro-inflammatory peptides Ang II and bradykinin and through this action, it protects the lungs from acute inflammation (27). Therefore, it was proposed by several authors that higher levels of ACE2 may alleviate the severity of SARS-CoV-2 infection (28,29). Furthermore, although it is generally expected that an increase of membrane bound ACE2 levels (mACE2) may favor the virus propagation, mathematical models show that this not need necessarily be the case (14). ...
BackgroundCOVID‐19 can generate a broad spectrum of severity and symptoms. Many studies analysed the determinants of severity but not among some types of symptoms. More importantly, very few studies analysed patients highly exposed to the virus that nonetheless remain uninfected.Methods
We analysed serum levels of ACE2, Angiotensin II and anti-Spike antibodies in 2 different cohorts at high risk of viral exposure, highly exposed but uninfected subjects, either high risk health care workers or persons cohabiting with infected close relatives and seropositive patients with symptoms. We tested the ability of the sera of these subjects to neutralize lentivirus pseudotyped with the Spike-protein.ResultsWe found that the serum levels of ACE2 are significantly higher in highly exposed but uninfected subjects. Moreover, sera from this seronegative persons can neutralize SARS-CoV-2 infection in cellular assays more strongly that sera from non-exposed negative controls eventhough they do not have anti-CoV-2 IgG antibodies suggesting that high levels of ACE2 in serum may somewhat protect against an active infection without generating a conventional antibody response. Finally, we show that among patients with symptoms, ACE2 levels were significantly higher in infected patients who developed cutaneous as compared with respiratory symptoms and ACE2 was also higher in those with milder symptoms.Conclusions
These findings suggest that soluble ACE2 could be used as a potential biomarker to predict SARS-CoV-2 infection risk and to discriminate COVID-19 disease subtypes.
... In addition, since ARB upregulates ACE-2, which can degrade DABK, the agonist of the B1R, this might decease the inflammatory response as well. However, this higher ACE2 level will also help shedding circulating angiotensin II, thereby protecting from pulmonary hypertension and also block angiotensin II-AT1-receptor mediated interleukin 6 release (see also Figure 1) [41][42][43]. This hypothesis is supported by Dimitrov who reported that SARS-CoV-2 targets ACE2 as the receptor binding domain for its Sprotein [44]. ...
The SARS-CoV-2 virus is spreading around the world, and its clinical manifestation COVID-19 is challenging medical, economic, and social systems. With more and more scientific and social media reports on the COVID-19 pandemic appearing, differences in geographical presentations and clinical management occur. Since ACE2 (angiotensin-converting enzyme 2) is the gatekeeper receptor for the SARS-CoV-2 virus in the upper bronchial system, we here focus on the central role of the renin-angiotensin aldosterone system (RAAS) in the SARS-CoV-2 virus infection, the role of pharmacological RAAS inhibitors, and specific genetic aspects, i.e., single nucleotide polymorphisms (SNP) for the clinical outcome of COVID-19. We aimed to bring together clinical, epidemiological, molecular, and pathophysiological and pharmacological data/observations on cardiovascular aspects in the actual SARS-CoV-2 virus pandemic. In detail, we will report controversies about the Yin-Yan between ACE2 and ACE1 and potential implications for the treatment of hypertension, coronary artery disease, and heart failure. Here, we summarize the encouraging and dynamic global effort of multiple biomedical disciplines resulted in astonishing fight against COVID-19 targeting the renin-angiotensin-aldosterone system, yet the race for ACE just begun.
... However, few studies contradict the idea of the role of ACE2 in higher COVID-19 infections in males, and rather consider ACE2 a blessing in disguise that protects organ failure in severe COVID-19 cases. 16 Therefore, a thorough evaluation of ACE2 regarding its expression and role in COVID-19 needs to be conducted based on histological and clinical studies before arriving at any conclusion. ...
Due to a lack of data on various parameters with COVID-19 in the Indian population, this study was carried out to understand the relation among gender, age and comorbidities in Indian population. The data was collected using a questionnaire-based survey form that included questions on demographic characteristics, infection and any pre-underlying conditions (n=1146). The data showed that the male patients had suffered more from COVID-19 (58.6%). Also, the patients suffering from comorbidity are more likely to suffer from a severe form of COVID-19 and obesity/overweight was identified as the most prevalent (n=69) comorbid condition, followed by diabetes (n=35), thyroid (n=19) and hypertension (n=11). In severe COVID-19 cases, 85% of patients had a comorbid condition. In another study of COVID-19 hospitalized-cases, about 97% of patients were found to have an underlying medical condition. Among these, diabetes (55.9%) was identified as the most prevalent comorbidity. Males and older people are at a higher risk of developing COVID-19 infection in Indian population. The comorbid conditions also predisposed individuals to COVID-19 and aggravated the infection.
... В 2020г Gurwitz D предложил использовать лозартан и телмисартан в качестве превентивного альтернативного варианта лечения пациентов с COVID-19 на ранних этапах заболевания и до развития ОРДС [30]. ...
Patients at high cardiovascular risk, older people with cardiovascular comorbidities, as well as those with hypertension and familial hypercholesterolemia are more susceptible to severe coronavirus disease 2019 (COVID-19). Such patients are likely to be at increased long-term atherothrombotic risk after COVID-19. The renin-angiotensinaldosterone system (RAAS) not only plays a key role in the development and progression of cardiovascular diseases, but is also responsible for the penetration of the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) into the cells of target organs and the development of infection. Given that RAAS inhibitors and statins increase the expression of angiotensin-converting enzyme type 2 receptors, concerns were initially raised about their possible adverse effect on COVID-19 course. However, at present, we have data from large-scale, including randomized clinical trials and meta-analyses, confirming the organ protective effects of RAAS inhibitors and statins by reducing the inflammation severity and fibrosis in tissues. The review attempted to assess the potential role of these drugs in the management of SARS-CoV-2-infected patients and their impact on the development of complications.
... Further, ARBs possess inverse agonist properties that give them an additional pharmacological effect and improve drug efficacy [26]. Given the hypothesis that the severity of inflammation in COVID-19 depends on AT1 receptor stimulation by AngII, drugs that act on AT1R have been proposed as a treatment for COVID-19 [27]. Zhang et al. [28] found that among COVID-19 patients hospitalised with hypertension, patient treatment with ACEI/ARB was related to a lower risk of all-cause mortality. ...
SARS-CoV-2 is a virus that causes severe respiratory distress syndrome. The pathophysiology of COVID-19 is related to the renin–angiotensin system (RAS). SARS-CoV-2, a vector of COVID-19, uses angiotensin-converting enzyme 2 (ACE-2), which is highly expressed in human lung tissue, nasal cavity, and oral mucosa, to gain access into human cells. After entering the cell, SARS-CoV-2 inhibits ACE-2, thus favouring the ACE/Ang II/angiotensin II type 1 receptor (AT1R) axis, which plays a role in the development of acute lung injury (ALI). This study aimed to analyse the influence of angiotensin 1 receptor (AT1R) levels in the serum on the course of the severity of symptoms in healthcare professionals who had a SARS-CoV-2 infection. This prospective observational study was conducted on a group of 82 participants. The study group included physicians and nurses who had a COVID-19 infection confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2. The control group consisted of healthy medical professionals who had not had a SARS-CoV-2 infection or who had no symptoms of COVID-19 and who tested negative for SARS-CoV-2 on the day of examination. We analysed the correlation between AT1R concentration and the severity of COVID-19, as well as with sex, age, blood group, and comorbidities. There were no statistically significant differences in the mean values of AT1R concentration in the recovered individuals and the non-COVID-19 subjects (3.29 vs. 3.76 ng/mL; p = 0.32). The ROC curve for the AT1R assay showed an optimal cut-off point of 1.33 (AUC = 0.44; 95% CI = 0.32–0.57; p = 0.37). There was also no correlation between AT1R concentration and the severity of symptoms associated with COVID-19. Blood type analysis showed statistically significantly lower levels of AT1R in COVID-19-recovered participants with blood group A than in those with blood group O. In conclusion, AT1R concentration does not affect the severity of symptoms associated with COVID-19 among healthcare professionals.
... Studies show that there is a negative correlation between molecular ACE2 levels and a higher fatality from SARS-CoV-2 [59]. In summary, after the initial entry of SARS-CoV-2 through ACE2, a consecutive reduction in ACE2 expression occurs, followed by the overactivation of the Ang II/AT1 Receptor axis, thus generating damage and disorders in multiple organs. ...
Aerobic exercise training (ET) produces beneficial adaptations in skeletal muscles, including angiogenesis. The renin–angiotensin system (RAS) is highly involved in angiogenesis stimuli. However, the molecular mechanisms underlying capillary growth in skeletal muscle induced by aerobic ET are not completely understood. This study aimed to investigate the effects of volume-dependent aerobic ET on skeletal muscle angiogenesis involving the expression of miRNAs-27a and 27b on RAS and oxidant–antioxidant balance. Eight-week-old female Wistar rats were divided into three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5×/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week, but in the 9th week, rats trained 2×/day, and in the 10th week, trained 3×/day. Angiogenesis and molecular analyses were performed in soleus muscle samples. Furthermore, to establish ET-induced angiogenesis through RAS, animals were treated with an AT1 receptor blocker (losartan). Aerobic ET promoted higher VO2 peak and exercise tolerance values. In contrast, miRNA-27a and -27b levels were reduced in both trained groups, compared with the SC group. This was in parallel with an increase in the ACE1/Ang II/VEGF axis, which led to a higher capillary-to-fiber ratio. Moreover, aerobic ET induced an antioxidant profile increasing skeletal muscle SOD2 and catalase gene expression, which was accompanied by high nitrite levels and reduced nitrotyrosine concentrations in the circulation. Additionally, losartan treatment partially re-established the miRNAs expression and the capillary-to-fiber ratio in the trained groups. In summary, aerobic ET promoted angiogenesis through the miRNA-27a/b–ACE1/Ang II/VEGF axis and improved the redox balance. Losartan treatment demonstrates the participation of RAS in ET-induced vascular growth. miRNAs and RAS components are promising potential targets to modulate angiogenesis for combating vascular diseases, as well as potential biomarkers to monitor training interventions and physical performance.
... The benefit of using angiotensine converting enzyme (ACE) inhibitors or angiotensine II (Ang II) receptor blockers is a matter of controversy between authors. Some have proposed that using of ACE inhibitors or Ang II blockers, prescribed for patients with cardiovascular and nephropathy condition, is correlated to a lower mortality rate [103,[378][379][380][381], thus, recommending their use [382] for their renal/cardiovascular protective, anti-inflammatory insulin sensitivity maintenance influences besides the (Ang II) receptor blockers normal coagulation functions maintenance [383,384].While, the others not agree with that speculation [379,380] as the utilization of these two classes of the antihypertension drugs for diabetic individuals are co-related to the up regulation of ACE2 receptor compensation to the inclined levels of angiotensines, thus enhancing viral tissues tropism [4,121,385] particularly the lungs, heart, intestine, kidney and vascular endothelium leading to poor prognosis and elevated mortality rate [4].Losartan for example inhibits the internalization/cytosolic catabolism of ACE2 receptors via inhibiting angiotensin II interaction with the AT1 receptor [4,386].It is reported that ACE inhibitor use in diabetic individuals infected with SARS-COV2 inclines the disease severity [14,33].However, a third group of author have reported a neutral impact on SARS-COV2 infection severity, prognosis or mortality rate [282].It is believed that this paradoxical influences to the ACE2 receptor polymorphism caused by diabetes and SARS-COV2 infection. However, some reported that no valuable evidences have been presented for the involvement of these two classes of drugs in the up regulation of ACE2 receptor [183,387]. ...
Viral infections deteriorates the infected diabetic individuals' glycemic state, hence developing hyperglycemia as frequently reported for SARS-COV2 viral infection. However, higher prevalence, poorer prognosis as well as higher mortality rates associated with SARS-COV2 infection among diabetic individuals. Consequently, it is strictly recommended good glycemic control for ensuring reducing disease severity as well as better survival rate. Uptodate, insulin seems to be the hypoglycemic agent of choice for treating hyperglycemia condition encountered during acute/severe microbial infection that requires hospitalization. Nevertheless, paradoxical spectulations are issued regarding the feasibility of considering oral hypoglycemic agents such as metformin,(GLP-1) Receptor Agonists, Sodium-Glucose-Transporter-2 (SGLT-2) Inhibitors, pioglitazone administration to SARS-COV2 infected diabetic patients' therapy. Although, several reports about various side effects associated with these drugs including dehydration, hypovolemia, gastrointestinal and perecipitating lactic acidosis side effects. Thus, this report surveys the paradoxical spectulations and recommendation are reported for these classes of hypoglycemic drugs beside some other drugs related to other comorbidities such as those acting on renine-angiotensine system and hydroxychloroquine.
Today, during the SARS-CoV-2 pandemic, when there are no clear therapeutic strategies for prevention and treatment, attention should be paid to alternative treatments, which may include the use of bacteriotherapeutic drugs based on probiotic microorganisms, i.e. representatives of the host normobiota. Experimental data show that changes in immune balance in patients with SARS-CoV-2 may be mediated by corresponding changes in the host intestinal microbiota. This statement is especially significant for the elderly, whose intestinal biota is less diverse. Especially the number of useful representative’s decreases, which leads to greater sensitivity of the older generation to SARS-CoV-2. The composition and function of the intestinal microbiota may be a potential biological mechanism responsible for the diversity of susceptibility of different groups of people to SARS-CoV-2. A bidirectional connection along the intestinelung axis due to soluble microbial metabolites transported by the bloodstream is shown. The intestinal microbiota produces many diffusing metabolites with immunomodulatory properties. Given the potential beneficial effects of bacteriotherapeutic drugs and functional foods enriched with probiotic microbiota during respiratory viral infection, their use as therapeutic agents during SARS-CoV-2 infection can be considered. Since the microbiota can be maintained using adequate, safe, and relatively inexpensive bacteriotherapeutic drugs (pro-, pre-, para-, post-, synbiotics, immunobiotics, functional foods enriched with probiotic microorganisms, etc.), their use should be considered as adjunctive therapy to limit SARS-CoV-2 progression in infected patients or as a prophylactic strategy for uninfected people at risk during the expansion of SARS-CoV-2.
The COVID-19 pandemic is associated with a global health crisis and the greatest challenge for scientists and doctors. The virus causes severe acute respiratory syndrome with an outcome that is fatal in more vulnerable populations. Due to the need to find an efficient treatment in a short time, there were several drugs that were repurposed or repositioned for COVID-19. There are many types of available COVID-19 therapies, including antiviral agents (remdesivir, lopinavir/ritonavir, oseltamivir), antibiotics (azithromycin), antiparasitics (chloroquine, hydroxychloroquine, ivermectin), and corticosteroids (dexamethasone). A combination of antivirals with various mechanisms of action may be more efficient. However, the use of some of these medicines can be related to the occurrence of adverse effects. Some promising drug candidates have been found to be ineffective in clinical trials. The knowledge of pharmacogenetic issues, which translate into variability in drug conversion from prodrug into drug, metabolism as well as transport, could help to predict treatment efficiency and the occurrence of adverse effects in patients. However, many drugs used for the treatment of COVID-19 have not undergone pharmacogenetic studies, perhaps as a result of the lack of time.
Disease-2019 (COVID-19) has been reported to be caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has endangered the health situation of many people globally. Moreover, almost 10 million cases have been reported worldwide, while 5 million mortality related to COVID-19 has been reported. Early and rapid laboratory identification of COVID-19 have been recognized as foremost focus of control and treatment. It has been discovered that point-of-care assessment entails diverse merits which include low cost, rapid, non-specific device requirements, accurate, portable which enable them to play numerous crucial role in the detection and diagnosis of diseases. Therefore, this chapter intends to provide a detailed information on numerous comprehensive techniques that are applied for the diagnosis of COVID-19. Molecular techniques applied in the detection and analysis of SARS CoV-2 were also highlighted.
Enormous amount of patient care is commonly obtained through manual means in hospitals through the application of standalone medical devices which entails vital signs. It has been observed that such data are sometimes stored in spreadsheets did not constitute parts of the patient’s electronic health records which makes it very problematic for caregivers to analyze and combine. Therefore, one of the reliable solutions to overawe these precincts is the interconnections of medical devices through the internet by applying a distributed platform, referred to as Internet of Things (IOT). The IoT revolution has played a crucial role toward the reshaping of modern healthcare systems through integration of social prospects, economic and technological. This entails the healthcare systems from unadventurous to more modified healthcare systems via which patients could be identified, managed, and examined more easily. These techniques enable data derived from numerous sources to be integrated for adequate identification of patient health status and prediction of possible anticipatory actions. The recent global problem of pandemic triggered by the novel severe respiratory syndrome coronavirus has been identified as the highest global public health crisis. Therefore, this chapter intends to provide a holistic information on how the concept of the Internet of Health Things (IoHT) could help in the management of COVID-19 diseases. Detailed information on the application of linked devices and IoT-enabled application that could be applied for reduction of COVID-19 others by quick identification, practicing defined protocols after patient recovery, monitoring patients. Moreover, detailed information on function of IoT-based technologies in COVID-19 management provides relevant information on the applications, platforms, state-of-the-art architectures, and industrial IoT-based resolutions for effective management of COVID-19 which entails quick diagnosis, after recovery and during quarantine time. Detailed information on the usage of IoHT for identification of quick treatment and identification of symptoms provides several usefulness of IoHT which has been adopted by several surgeons, physicians, patients, and hospital management systems in the treatment of COVID-19.
Several important sex and gender differences in the clinical manifestation of diseases have been known for a long time but are still underestimated. The infectious Coronavirus 2019 disease pandemic has provided evidence of the importance of a sex and gender-based approach; it mainly affected men with worse symptomatology due to a different immune system, which is stronger in women, and to the Angiotensin-converting enzyme 2 and Transmembrane protease serine 2 roles which are differently expressed among the sexes. Additionally, women are more inclined to maintain social distance and smoke less. Analysis of data on the infectious Coronavirus 2019 disease testing from people admitted to the Amedeo di Savoia Hospital, a regional referral center for infectious diseases, has been applied to the whole of 2020 data (254,640 records). A high percentage of data in the dataset was not suitable due to a lack of information or entering errors. Among the suitable samples, records have been analyzed for positive/negative outcomes, matching records for unique subjects (N = 123,542), to evaluate individual recurrence of testing. Data are presented in age and sex-disaggregated ways. Analyses of the suitable sample also concerned the relation between testing and hospital admission motivation and symptoms. Our analysis indicated that a sex and gender-based approach is mandatory for patients and the National Health System’s sustainability.
Although there are many hypotheses for the age-related difference in the severity of COVID-19, differences in innate, adaptive and heterolo-gous immunity, together with differences in endothelial and clotting function, are the most likely mechanisms underlying the marked age gradient. Children have a faster and stronger innate immune response to SARS-CoV-2, especially in the nasal mucosa, which rapidly controls the virus. In contrast, adults can have an overactive, dysregulated and less effective innate response that leads to uncontrolled pro-inflamma-tory cytokine production and tissue injury. More recent exposure to other viruses and routine vaccines in children might be associated with protective cross-reactive antibodies and T cells against SARS-CoV-2. There is less evidence to support other mechanisms that have been proposed to explain the age-related difference in outcome following SARS-CoV-2 infection, including pre-existing immunity from exposure to common circulating coronaviruses, differences in the distribution and expression of the entry receptors ACE2 and TMPRSS2, and difference in viral load.
Citation: Derruau, S.; Bouchet, J.; Nassif, A.; Baudet, A.; Yasukawa, K.; Lorimier, S.; Prêcheur, I.; Bloch-Zupan, A.; Pellat, B.; Chardin, H.; et al. COVID-19 and Dentistry in 72 Questions: An Overview of the Literature.
Background:
Individuals with chronic kidney disease are affected by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to multiple comorbidities and altered immune system. The first step of the infection process is the binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) receptor, followed by its priming by transmembrane protease serine 2 (TMPRSS2). We hypothesized that circulating soluble ACE2 levels, as well as the expressions of ACE2 and TMPRSS2 in the microvasculature, are increased in patients with end-stage kidney disease (ESKD).
Methods:
A total of 210 participants were enrolled, representing 80 ESKD patients and 73 non-CKD controls for soluble ACE2, and 31 ESKD and 26 non-CKD controls for vasculature and fat tissue bioassays. We have assessed ACE2 expression in blood using ELISA and in tissue using immunofluorescence.
Results:
Soluble ACE2 levels were higher in ESKD patients compared to controls however, there is no sex difference observed. In ESKD and controls, soluble ACE2 positively correlated with IL-6 and hsCRP respectively. Similarly, ACE2 tissue expression in the vasculature was higher in ESKD patients, moreover, this higher ACE2 expression was observed only in male ESKD patients. In addition, TMPRSS2 expression was observed in vessels from males and females but showed no sex difference. The expression of ACE2 receptor was higher in ESKD patients on ACE-inhibitor/angiotensin blocker treatment.
Conclusion:
ESKD is associated with increased ACE2 levels in the circulation and pronounced in male vasculature, however further studies are warranted to assess possible sex differences on specific treatment regime(s) for different comorbidities present in ESKD.
The new SARS-CoV-2 coronavirus is responsible for the COVID-19 pandemic. A massive vaccination campaign, which is still ongoing, has averted most serious consequences worldwide; however, lines of research are continuing to identify the best drug therapies to treat COVID-19 infection. SARS-CoV-2 penetrates the cells of the host organism through ACE2. The ACE2 protein plays a key role in the renin–angiotensin system (RAS) and undergoes changes in expression during different stages of COVID-19 infection. It appears that an unregulated RAS is responsible for the severe lung damage that occurs in some cases of COVID-19. Pharmacologically modifying the expression of ACE2 could be an interesting line of research to follow in order to avoid the severe complications of COVID-19.
The microbiome is the indigenous microbial population (microbiota) and the host environment in which it lives, and it is revolutionising how doctors think about germs in human health and illness. The understanding that most microbes in human bodies perform vital ecosystem functions that benefit the whole microbial host system is perhaps the most basic development. The microbiome is a collection of varied and numerous bacteria that live in the gastrointestinal system. Generally, this ecosystem comprises billions of microbial cells that play a vital role in human health control. Immunity, nutrition absorption, digestion, and metabolism have all been linked to the microbiome. Researchers have discovered that changes in the microbiome are linked to the development of diseases including obesity, inflammatory lung disease, and CVS diseases, carcinoma in recent times. A change in the microbial population of the intestine has a big impact on human health and disease aetiology. These changes are caused by a combination of factors, including lifestyle and the existence of an underlying illness. Dysbiosis makes the host more susceptible to infection, the type of which varies depending on the anatomical location. The distinct metabolic processes and roles of these bacteria inside each bodily location are accounted for by the inherent variety of the human microbiota. As a result, it is critical to comprehend the human microbiome’s microbial makeup and behaviours as they relate to health and illness.
The study was to show fatal effects for the hypertension on the patients of COVID-19 pandemic. 150 patient records belong to the severely infected COVID-19 patients had been collected from two hospitals interested in this pandemic patients, some of them were hypertensive. The patients were 113 men and 37 women with ages 40 - 70 years. They visited the hospitals in a period extend from 1/2/2020 to 15/5/2020. All the patients were hospitalized for different periods and a number of the them admitted intensive care units. 46 patients died due to consequences of COVID-19. Death was significantly higher among the patients with hypertension. In the men, percentage of death among hypertensive was 33.33%. while it was 26.76% in the patient without hypertension. In women, the percentage was 43.75% with hypertension, and was 28.57% without hypertension.
Background:
Red blood cell distribution width (RDW) was frequently assessed in COVID-19 infection and reported to be associated with adverse outcomes. However, there was no consensus regarding the optimal cutoff value for RDW.
Methods:
Records of 98 patients with COVID-19 from the First People's Hospital of Jingzhou were reviewed. They were divided into two groups according to the cutoff value for RDW on admission by receiver operator characteristic curve analysis: ≤ 11.5% (n = 50) and > 11.5% (n = 48). The association of RDW with the severity and outcomes of COVID-19 was analyzed.
Results:
The receiver operating characteristic curve indicated that the RDW was a good discrimination factor for identifying COVID-19 severity (area under the curve= 0.728, 95% CI: 0.626-0.830, p < 0.001). Patients with RDW > 11.5% more frequently suffered from critical COVID-19 than those with RDW ≤ 11.5% (62.5% vs. 26.0%, p < 0.001). Multivariate logistic regression analysis showed RDW to be an independent predictor for critical illness due to COVID-19 (OR = 2.40, 95% CI: 1.27-4.55, p = 0.007). A similar result was obtained when we included RDW >11.5% into another model instead of RDW as a continuous variable (OR = 5.41, 95% CI: 1.53-19.10, p = 0.009).
Conclusion:
RDW, as an inexpensive and routinely measured parameter, was promising to be a predictor for critical illness in patients with COVID-19 infection. RDW > 11.5% could be the optimal cutoff to discriminate critical COVID-19 infection. This article is protected by copyright. All rights reserved.
This review discusses peptide epitopes used as antigens in the development of vaccines in clinical trials as well as future vaccine candidates. It covers peptides used in potential immunotherapies for infectious diseases including SARS-CoV-2, influenza, hepatitis B and C, HIV, malaria, and others. In addition, peptides for cancer vaccines that target examples of overexpressed proteins are summarized, including human epidermal growth factor receptor 2 (HER-2), mucin 1 (MUC1), folate receptor, and others. The uses of peptides to target cancers caused by infective agents, for example, cervical cancer caused by human papilloma virus (HPV), are also discussed. This review also provides an overview of model peptide epitopes used to stimulate non-specific immune responses, and of self-adjuvanting peptides, as well as the influence of other adjuvants on peptide formulations. As highlighted in this review, several peptide immunotherapies are in advanced clinical trials as vaccines, and there is great potential for future therapies due the specificity of the response that can be achieved using peptide epitopes.
There is a current worldwide outbreak of a new type of coronavirus (2019-nCoV), which originated from Wuhan in China and has now spread to 17 other countries. Governments are under increased pressure to stop the outbreak spiraling into a global health emergency. At this stage, preparedness, transparency, and sharing of information are crucial to risk assessments and beginning outbreak control activities. This information should include reports from outbreak sites and from laboratories supporting the investigation. This paper aggregates and consolidates the virology, epidemiology, clinical management strategies from both English and Chinese literature, official news channels, and other official government documents. In addition, by fitting the number of infections with a single-term exponential model, we report that the infection is spreading at an exponential rate, with a doubling period of 1.8 days.
2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.
Objective
Since December 2019, an outbreak of corona virus disease 2019 (COVID-19) occurred in Wuhan, and rapidly spread to almost all parts of China. This was followed by prevention programs recommending Chinese medicine (CM) for the prevention. In order to provide evidence for CM recommendations, we reviewed ancient classics and human studies.
Methods
Historical records on prevention and treatment of infections in CM classics, clinical evidence of CM on the prevention of severe acute respiratory syndrome (SARS) and H1N1 influenza, and CM prevention programs issued by health authorities in China since the COVID-19 outbreak were retrieved from different databases and websites till 12 February, 2020. Research evidence included data from clinical trials, cohort or other population studies using CM for preventing contagious respiratory virus diseases.
Results
The use of CM to prevent epidemics of infectious diseases was traced back to ancient Chinese practice cited in Huangdi’s Internal Classic (Huang Di Nei Jing) where preventive effects were recorded. There were 3 studies using CM for prevention of SARS and 4 studies for H1N1 influenza. None of the participants who took CM contracted SARS in the 3 studies. The infection rate of H1N1 influenza in the CM group was significantly lower than the non-CM group (relative risk 0.36, 95% confidence interval 0.24–0.52; n=4). For prevention of COVID-19, 23 provinces in China issued CM programs. The main principles of CM use were to tonify qi to protect from external pathogens, disperse wind and discharge heat, and resolve dampness. The most frequently used herbs included Radix astragali (Huangqi), Radix glycyrrhizae (Gancao), Radix saposhnikoviae (Fangfeng), Rhizoma Atractylodis Macrocephalae (Baizhu), Lonicerae Japonicae Flos (Jinyinhua), and Fructus forsythia (Lianqiao).
Conclusions
Based on historical records and human evidence of SARS and H1N1 influenza prevention, Chinese herbal formula could be an alternative approach for prevention of COVID-19 in high-risk population. Prospective, rigorous population studies are warranted to confirm the potential preventive effect of CM.
Therapeutic options in response to the 2019-nCoV outbreak are urgently needed. Here, we discuss the potential for repurposing existing antiviral agents to treat 2019-nCoV infection (now known as COVID-19), some of which are already moving into clinical trials. Therapeutic options in response to the 2019-nCoV outbreak are urgently needed. Here, we discuss the potential for repurposing existing antiviral agents to treat 2019-nCoV infection (now known as COVID-19), some of which are already moving into clinical trials.
On December 31, 2019, Chinese health officials reported a cluster of cases of acute respiratory illness in persons associated with the Hunan seafood and animal market in the city of Wuhan, Hubei Province, in central China. On January 7, 2020, Chinese health officials confirmed that a novel coronavirus (2019-nCoV) was associated with this initial cluster (1). As of February 4, 2020, a total of 20,471 confirmed cases, including 2,788 (13.6%) with severe illness,* and 425 deaths (2.1%) had been reported by the National Health Commission of China (2). Cases have also been reported in 26 locations outside of mainland China, including documentation of some person-to-person transmission and one death (2). As of February 4, 11 cases had been reported in the United States. On January 30, the World Health Organization (WHO) Director-General declared that the 2019-nCoV outbreak constitutes a Public Health Emergency of International Concern.† On January 31, the U.S. Department of Health and Human Services (HHS) Secretary declared a U.S. public health emergency to respond to 2019-nCoV.§ Also on January 31, the president of the United States signed a "Proclamation on Suspension of Entry as Immigrants and Nonimmigrants of Persons who Pose a Risk of Transmitting 2019 Novel Coronavirus," which limits entry into the United States of persons who traveled to mainland China to U.S. citizens and lawful permanent residents and their families (3). CDC, multiple other federal agencies, state and local health departments, and other partners are implementing aggressive measures to slow transmission of 2019-nCoV in the United States (4,5). These measures require the identification of cases and their contacts in the United States and the appropriate assessment and care of travelers arriving from mainland China to the United States. These measures are being implemented in anticipation of additional 2019-nCoV cases in the United States. Although these measures might not prevent the eventual establishment of ongoing, widespread transmission of the virus in the United States, they are being implemented to 1) slow the spread of illness; 2) provide time to better prepare health care systems and the general public to be ready if widespread transmission with substantial associated illness occurs; and 3) better characterize 2019-nCoV infection to guide public health recommendations and the development of medical countermeasures including diagnostics, therapeutics, and vaccines. Public health authorities are monitoring the situation closely. As more is learned about this novel virus and this outbreak, CDC will rapidly incorporate new knowledge into guidance for action by CDC and state and local health departments.
Background
Chronic kidney disease (CKD) is defined by abnormalities in kidney structure and/or function present for more than 3 months. Worldwide, both the incidence and prevalence rates of CKD are increasing. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance through the kidney. RAAS activation is associated with hypertension, which is directly implicated in causation and progression of CKD. RAAS blockade, using drugs targeting individual RAAS mediators and receptors, has proven to be renoprotective.
Objectives
To assess genomic variants present within RAAS genes, ACE , ACE2 , AGT , AGTR1 , AGTR2 and REN , for association with CKD.
Design and data sources
A systematic review and meta-analysis of observational research was performed to evaluate the RAAS gene polymorphisms in CKD using both PubMed and Web of Science databases with publication date between the inception of each database and 31 December 2018. Eligible articles included case–control studies of a defined kidney disease and included genotype counts.
Eligibility criteria
Any paper was removed from the analysis if it was not written in English or Spanish, was a non-human study, was a paediatric study, was not a case–control study, did not have a renal disease phenotype, did not include data for the genes, was a gene expression-based study or had a pharmaceutical drug focus.
Results
A total of 3531 studies were identified, 114 of which met the inclusion criteria. Genetic variants reported in at least three independent publications for populations with the same ethnicity were determined and quantitative analyses performed. Three variants returned significant results in populations with different ethnicities at p<0.05: ACE insertion, AGT rs699-T allele and AGTR1 rs5186-A allele; each variant was associated with a reduced risk of CKD development.
Conclusions
Further biological pathway and functional analyses of the RAAS gene polymorphisms will help define how variation in components of the RAAS pathway contributes to CKD.
Introduction. Studies in the 1970s and 1980s signaled concern that repeated influenza vaccination could affect vaccine protection. The antigenic distance hypothesis provided a theoretical framework to explain variability in repeat vaccination effects based on antigenic similarity between successive vaccine components and the epidemic strain.
Areas covered. A meta-analysis of vaccine effectiveness studies from 2010-11 through 2014-15 shows substantial heterogeneity in repeat vaccination effects within and between seasons and subtypes. When negative effects were observed, they were most pronounced for H3N2, especially in 2014-15 when vaccine components were unchanged and antigenically distinct from the epidemic strain. Studies of repeated vaccination across multiple seasons suggest that vaccine effectiveness may be influenced by more than one prior season. In immunogenicity studies, repeated vaccination blunts the hemagglutinin antibody response, particularly for H3N2.
Expert commentary. Substantial heterogeneity in repeated vaccination effects is not surprising given the variation in study populations and seasons, and the variable effects of antigenic distance and immunological landscape in different age groups and populations. Caution is required in the interpretation of pooled results across multiple seasons, since this can mask important variation in repeat vaccination effects between seasons. Multi-season clinical studies are needed to understand repeat vaccination effects and guide recommendations.
Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Background:
Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and converts angiotensin (Ang) II to Ang-(1-7), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remain unclear.
Methods:
Of participants in the Tanno-Sobetsu cohort study in 2011 (n = 617), subjects on no medication (n = 101) and hypertensive patients treated with antihypertensive agents, including the calcium channel blockers amlodipine and long-acting nifedipine; the ACE inhibitor enalapril; and the Ang II receptor blockers losartan, candesartan, valsartan, telmisartan, and olmesartan, for more than 1 year (n = 100) were enrolled, and urinary ACE2 level was measured.
Results:
Glucose and hemoglobin A1c were significantly higher in patients treated with enalapril, telmisartan or olmesartan than in the control subjects. Urinary albumin-to-creatinine ratio (UACR) was significantly higher in patients treated with enalapril than in the control subjects. Urinary ACE2 level was higher in the olmesartan-treated group, but not the other treatment groups, than in the control group. Urinary ACE2 level was positively correlated with systolic blood pressure (r = 0.211; P = 0.003), UACR (r = 0.367; P < 0.001), and estimated salt intake (r = 0.260; P < 0.001). Multivariable regression analysis after adjustment of age, sex, and the correlated indices showed that the use of olmesartan was an independent predictor of urinary ACE2 level.
Conclusions:
In contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary ACE2 level, which could potentially offer additional renoprotective effects.
The 2002-3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.
Severe acute respiratory syndrome (SARS) emerged in China in 2002 and spread to other countries before brought under control. Because of a concern for reemergence or a deliberate release of the SARS coronavirus, vaccine development was initiated. Evaluations of an inactivated whole virus vaccine in ferrets and nonhuman primates and a virus-like-particle vaccine in mice induced protection against infection but challenged animals exhibited an immunopathologic-type lung disease.
Four candidate vaccines for humans with or without alum adjuvant were evaluated in a mouse model of SARS, a VLP vaccine, the vaccine given to ferrets and NHP, another whole virus vaccine and an rDNA-produced S protein. Balb/c or C57BL/6 mice were vaccinated i.m. on day 0 and 28 and sacrificed for serum antibody measurements or challenged with live virus on day 56. On day 58, challenged mice were sacrificed and lungs obtained for virus and histopathology.
All vaccines induced serum neutralizing antibody with increasing dosages and/or alum significantly increasing responses. Significant reductions of SARS-CoV two days after challenge was seen for all vaccines and prior live SARS-CoV. All mice exhibited histopathologic changes in lungs two days after challenge including all animals vaccinated (Balb/C and C57BL/6) or given live virus, influenza vaccine, or PBS suggesting infection occurred in all. Histopathology seen in animals given one of the SARS-CoV vaccines was uniformly a Th2-type immunopathology with prominent eosinophil infiltration, confirmed with special eosinophil stains. The pathologic changes seen in all control groups lacked the eosinophil prominence.
These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.
Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.
Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.
During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
Severe acute respiratory syndrome (SARS) is a virulent viral infection that affects a number of organs and systems. This study examined if SARS may result in cardiovascular complications.
121 patients (37.5 (SD13.2) years, 36% male) diagnosed to have SARS were assessed continuously for blood pressure, pulse, and temperature during their stay in hospital. Hypotension occurred in 61 (50.4%) patients in hospital, and was found in 28.1%, 21.5%, and 14.8% of patients during the first, second, and third week, respectively. Only one patient who had transient echocardiographic evidence of impaired left ventricular systolic function required temporary inotropic support. Tachycardia was present in 87 (71.9%) patients, and was found in 62.8%, 45.4%, and 35.5% of patients from the first to third week. It occurred independent of hypotension, and could not be explained by the presence of fever. Tachycardia was also present in 38.8% of patients at follow up. Bradycardia only occurred in 18 (14.9%) patients as a transient event. Reversible cardiomegaly was reported in 13 (10.7%) patients, but without clinical evidence of heart failure. Transient atrial fibrillation was present in one patient. Corticosteroid therapy was weakly associated with tachycardia during the second (chi(2) = 3.99, p = 0.046) and third week (chi(2) = 6.53, p = 0.01), although it could not explain tachycardia during follow up.
In patients with SARS, cardiovascular complications including hypotension and tachycardia were common but usually self limiting. Bradycardia and cardiomegaly were less common, while cardiac arrhythmia was rare. However, only tachycardia persisted even when corticosteroid therapy was withdrawn.
The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
The novel coronavirus 2019 (COVID-19) infected patients by binding human ACE2, leading to severe pneumonia and highly mortality rate in patients. At present, there is no definite and effective treatment for COVID-19. ACE2 plays an important role in the RAS, and the imbalance between ACE/Ang II/AT1R pathway and ACE2/Ang (1-7)/Mas receptor pathway in the RAS system will lead to multi-system inflammation. Increased ACE and Ang II are poor prognostic factors for severe pneumonia. Animal studies have shown that RAS inhibitors could effectively relieve symptoms of acute severe pneumonia and respiratory failure. The binding of COVID-19 and ACE2 resulted in the exhaustion of ACE2, and then ACE2/Ang (1-7)/Mas receptor pathway was inhibited. The balance of the RAS system was broken, and this would lead to the exacerbation of acute severe pneumonia. Therefore, we speculate that ACEI and AT1R inhibitors could be used in patients with COVID-19 pneumonia under the condition of controlling blood pressure, and might reduce the pulmonary inflammatory response and mortality.
An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA virus infection and we have found that general treatments, coronavirus‐specific treatments, and antiviral treatments should be useful in fighting COVID‐19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID‐19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID‐19 if the infection is uncontrollable. This article is protected by copyright. All rights reserved.
The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
Background:
In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed.
Methods:
We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus.
Findings:
The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.
Interpretation:
2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation.
Funding:
National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.
The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiology and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses.
Telmisartan belongs to the angiotensin II type 1 (AT1) receptor antagonizing class of antihypertensives, which are widely recognized and increasingly prescribed because of their good tolerability. Moreover, due to the results of the ONTARGET trial program, telmisartan was the first AT1 receptor antagonist to receive approval for the prevention of cardiovascular events in cardiovascular high risk patients, thereby, indicating that its clinical importance will further increase.
This article reviews the pharmacokinetic and pharmacodynamic properties of telmisartan with a special focus on novel pharmacokinetic characteristics of the drug.
An overview of the published data regarding the pharmacokinetic properties of telmisartan as well as a summary of the results from selected small exploratory and large clinical outcome trials involving telmisartan.
Telmisartan is a safe and effective alternative for the treatment of hypertension. Moreover, due to its good tolerability, an increasing use of telmisartan in cardiovascular high risk patients can be anticipated. This will grant further experimental and clinical research on AT1 receptor-independent pharmacodynamics of telmisartan as well as on telmisartan-related drug safety issues.
Losartan potassium, an angiotensin II receptor antagonist, is the first of a new class of agents to be introduced for the treatment of hypertension. In this review, we describe the clinical pharmacology of losartan, including its pharmacokinetics in healthy, male volunteers and special patient groups, such as the elderly, patients with liver disease and patients with renal impairment. We also review its pharmacodynamics, including safety and tolerability; specificity of action; and the effect of salt depletion. We then review the studies examining clinical efficacy and safety in hypertension.
The renin-angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2-8)], Ang IV [Ang-(3-8)], and Ang-(1-7) may also have important biological activities. Ang-(1-7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1-7) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1-7) after an acute water load. Ang-(1-7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1-7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1-7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.
The membrane-associated carboxypeptidase angiotensin-converting enzyme 2 (ACE2) is an essential regulator of heart function. Now, Li at al. identify and characterize an unexpected second function of ACE2 as a partner of the SARS-CoV spike glycoprotein in mediating virus entry and cell fusion.
The angiotensin-converting enzyme 2 (ACE2) is an important regulator of the renin-angiotensin system and was very recently identified as a functional receptor for the SARS virus. The ACE2 sequence is similar (sequence identities 43% and 35%, and similarities 61% and 55%, respectively) to those of the testis-specific form of ACE (tACE) and the Drosophila homolog of ACE (AnCE). The high level of sequence similarity allowed us to build a robust homology model of the ACE2 structure with a root-mean-square deviation from the aligned crystal structures of tACE and AnCE less than 0.5A. A prominent feature of the model is a deep channel on the top of the molecule that contains the catalytic site. Negatively charged ridges surrounding the channel may provide a possible binding site for the positively charged receptor-binding domain (RBD) of the S-glycoprotein, which we recently identified [Biochem. Biophys. Res. Commun. 312 (2003) 1159]. Several distinct patches of hydrophobic residues at the ACE2 surface were noted at close proximity to the charged ridges that could contribute to binding. These results suggest a possible binding region for the SARS-CoV S-glycoprotein on ACE2 and could help in the design of experiments to further elucidate the structure and function of ACE2.
The zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2) is the only known human homologue of the key regulator of blood pressure angiotensin-converting enzyme (ACE). Since its discovery in 2000, ACE2 has been implicated in heart function, hypertension and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin-(1-7). Unexpectedly, ACE2 also serves as the cellular entry point for the severe acute respiratory syndrome (SARS) virus and the enzyme is therefore a prime target for pharmacological intervention on several disease fronts.
Angiotensin-converting enzyme 2 (ACE2) is considered an important therapeutic target for controlling cardiovascular diseases and severe acute respiratory syndrome (SARS) outbreaks. Recently solved high-resolution crystal structures of the apo-bound and inhibitor-bound forms of ACE2 have provided the basis for a novel molecular docking approach in an attempt to identify ACE2 inhibitors and compounds that block SARS coronavirus spike protein-mediated cell fusion. In this study, approximately 140 000 small molecules were screened by in silico molecular docking. In this structure-activity relation study, the molecules with the highest predicted binding scores were identified and assayed for ACE2 enzymatic inhibitory activity and for their ability to inhibit SARS coronavirus spike protein-mediated cell fusion. This approach identified N-(2-aminoethyl)-1 aziridine-ethanamine as a novel ACE2 inhibitor that also is effective in blocking the SARS coronavirus spike protein-mediated cell fusion. Thus, the molecular docking approach resulting in the inhibitory capacity of N-(2-aminoethyl)-1 aziridine-ethanamine provides an attractive small molecule lead compound on which the development of more effective therapeutic agents could be developed to modulate hypertension and for controlling SARS infections.
Viruses frequently render cells refractory to subsequent infection with the same virus. This state of superinfection immunity counteracts potentially detrimental consequences for the infected cell and facilitates high-level replication and viral spread in the host.
Here, we show that human immunodeficiency virus (HIV) employs its early gene product Nef to efficiently interfere with superinfection at the viral-entry step. In this context, we identify the downregulation of cell-surface CCR5, the major HIV coreceptor, as a novel and highly conserved activity of Nef. Nef targets the CCR5 coreceptor and the HIV binding receptor CD4 via distinct cellular machineries to enhance the endocytosis rate of both HIV receptor components and to accelerate their degradation. Functionally, these genetically separable actions by Nef synergized to efficiently protect cells from HIV superinfection at the level of fusion of the viral envelope with the plasma membrane.
HIV has evolved two independent activities for Nef to downregulate the receptor complex and to facilitate its efficient replication and spread. This evasion strategy likely represents a mechanism by which the pathogenicity factor Nef elevates viral replication in vivo and thus promotes AIDS pathogenesis.
We investigated in Lewis normotensive rats the effect of coronary artery ligation on the expression of cardiac angiotensin-converting enzymes (ACE and ACE 2) and angiotensin II type-1 receptors (AT1a-R) 28 days after myocardial infarction. Losartan, olmesartan, or the vehicle (isotonic saline) was administered via osmotic minipumps for 28 days after coronary artery ligation or sham operation. Coronary artery ligation caused left ventricular dysfunction and cardiac hypertrophy. These changes were associated with increased plasma concentrations of angiotensin I, angiotensin II, angiotensin-(1-7), and serum aldosterone, and reduced AT1a-R mRNA. Cardiac ACE and ACE 2 mRNAs did not change. Both angiotensin II antagonists attenuated cardiac hypertrophy; olmesartan improved ventricular contractility. Blockade of the AT1a-R was accompanied by a further increase in plasma concentrations of the angiotensins and reduced serum aldosterone levels. Both losartan and olmesartan completely reversed the reduction in cardiac AT1a-R mRNA observed after coronary artery ligation while augmenting ACE 2 mRNA by approximately 3-fold. Coadministration of PD123319 did not abate the increase in ACE 2 mRNA induced by losartan. ACE 2 mRNA correlated significantly with angiotensin II, angiotensin-(1-7), and angiotensin I levels. These results provide evidence for an effect of angiotensin II blockade on cardiac ACE 2 mRNA that may be due to direct blockade of AT1a receptors or a modulatory effect of increased angiotensin-(1-7).
Rapid response: Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona Virus infections—Novel mode of treatment. Response to the emerging novel coronavirus outbreak
- Phadke M.
Phadke, M., & Saunik, S. (2020). Rapid response: Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona
Virus infections-Novel mode of treatment. Response to the emerging
novel coronavirus outbreak. BMJ 2020, 368, m406. https://doi.org/
10.1136/bmj.m406
The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell‐surface CCR5 and CD4
- N. Michel
- I. Allespach
- S. Venzke
- O. T. Fackfmicheller
- O. T. Keppler