OBJECTIVE: The aim of the present review was to highlight natural product investigations in silico and in vitro to find plants and chemicals that inhibit or stimulate angiotensin-converting enzyme 2 (ACE-2).
BACKGROUND: The global reduction of incidents and fatalities attributable to infections with SARS-CoV-2 is one of the most public health problems. In the absence of specific therapy for coronavirus disease 2019 (COVID-19), phytocompounds generated from plant extracts may be a promising strategy worth further investigation, motivating researchers to evaluate the safety and anti-SARS-CoV-2 effectiveness of these ingredients.
OBJECTIVE: To review phytochemicals in silico for anti-SARS-CoV-2 activity and to assess their safety and effectiveness in vitro and in vivo.
METHODS: The present review was conducted using various scientific databases and studies on anti-SARS-CoV-2 phytochemicals were analyzed and summarized. The results obtained from the in silico screening were subjected to extraction, isolation, and purification. The in vitro studies on anti-SarcoV-2 were also included in this review. In addition, the results of this research were interpreted, analyzed, and documented on the basis of the bibliographic information obtained.
RESULTS: This review discusses recent research on using natural remedies to cure or prevent COVID-19 infection. The literature analysis shows that the various herbal preparations (extracts) and purified compounds can block the replication or entrance of the virus directly to carry out their anti-SARS-CoV-2 effects. It is interesting to note that certain items can prevent SARS-CoV-2 from infecting human cells by blocking the ACE-2 receptor or the serine protease TMPRRS2. Moreover, natural substances have been demonstrated to block proteins involved in the SARS-CoV-2 life cycle, such as papain- or chymotrypsin-like proteases.
CONCLUSIONS: The natural products may have the potential for use singly or in combination as alternative drugs to treat/prevent COVID-19 infection, including blocking or stimulating ACE-2. In addition, their structures may provide indications for the development of anti-SARS-CoV-2 drugs.

BACKGROUND: Sepsis is a life-threatening condition responsible for up to 20% of all global deaths. Kidneys are among the most common organs implicated, yet the pathogenesis of sepsis-induced acute kidney injury (S-AKI) is not completely understood, resulting in the treatment being nonspecific and responsive. In situations of stress, the renin angiotensin aldosterone system (RAAS) may play a role. This systematic review focuses on analyzing the impact of the RAAS on the development of S-AKI and discussing the use of RAAS antagonists as an emerging therapeutic option to minimize complications of sepsis.
METHODS: Studies were identified using electronic databases (Medline via PubMed, Google Scholar) published within the past decade, comprised from 2014 to 2023. The search strategy was conducted using the following keywords: sepsis, S-AKI, RAAS, Angiotensin II, and RAAS inhibitors. Studies on human and animal subjects were included if relevant to the keywords.
RESULTS: Our search identified 22 eligible references pertaining to the inclusion criteria. Treatment of sepsis with RAAS inhibitor medications is observed to decrease rates of S-AKI, reduce the severity of S-AKI, and offer an improved prognosis for septic patients.
CONCLUSIONS: The use of RAAS antagonists as a treatment after the onset of sepsis has promising findings, with evidence of decreased renal tissue damage and rates of S-AKI and improved survival outcomes.
BACKGROUND: INPLASY202360098.

In recent years, catheter-based renal denervation (RDN) has emerged as a promising instrumental therapy for hypertension. The interruption of sympathetic nervous system was regarded as a possible mechanism for RDN regulating blood pressure. While the results reflected by renin-angiotensin-aldosterone system (RAAS), catecholamines and electrolytes remained inconsistent and was never systematically assessed. Pubmed, Embase, and Web of Science were comprehensively searched from inception to September 5, 2021. Studies that evaluated the effects of RDN on RAAS, catecholamines, and electrolytes were identified. Primary outcomes were changes in RAAS hormones after RDN, and secondary outcomes involved changes in plasma norepinephrine, serum, and urinary sodium and potassium. Out of 6391 retrieved studies, 20 studies (two randomized controlled studies and 18 observational studies) involving 771 persons were eventually included. Plasma renin activity had a statistically significant reduction after RDN (0.24 ng/mL/h, 95% CI 0.04 to 0.44, P = .02). While no significant change was found regarding plasma aldosterone (1.53 ng/dL, 95% CI -0.61 to 3.67, P = .16), norepinephrine (0.42 nmol/L, 95% -0.51 to 1.35, P = 0.38), serum sodium and potassium (0.16 mmol/L, 95% CI -0.17 to 0.49, P = .34; -0.02 mmol/L, 95% CI -0.09 to 0.04, P = .48, respectively), and urinary sodium and potassium (3.95 mmol/24 h, 95% CI -29.36 to 37.26, P = .82; 10.22 mmol/24 h, 95% CI -12.11 to 32.54, P = .37, respectively). In conclusion, plasma renin activity significantly decreased after RDN, while no significant change was observed in plasma aldosterone, plasma norepinephrine, and serum and urinary electrolytes.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is typically presented with acute symptoms affecting upper and lower respiratory systems. As the current pandemic progresses, COVID-19 patients are experiencing a series of nonspecific or atypical extra-pulmonary complications such as systemic inflammation, hypercoagulability state, and dysregulation of the renin-angiotensin-aldosterone system (RAAS). These manifestations often delay testing, diagnosis, and the urge to seek effective treatment. Although the pathophysiology of these complications is not clearly understood, the incidence of COVID-19 increases with age and the presence of pre-existing conditions. This review article outlines the pathophysiology and clinical impact of SARS-CoV-2 infection on extra-pulmonary systems. Understanding the broad spectrum of atypical extra-pulmonary manifestations of COVID-19 should increase disease surveillance, restrict transmission, and most importantly prevent multiple organ-system complications.

(1) Background: The objective of this rapid review is to assess whether new potassium binders (NPBs) could enable the optimization of RAASi therapy more than usual care or placebo in patients with or at risk of heart failure and hyperkalemia. (2) Methods: We searched for RCTs that included patients with or at risk of hyperkalemia and patients treated with Patiromer or sodium zirconium cyclosilicate (ZSC). The comparators were placebo, usual care, and potassium binders with different doses or different treatment protocols. We searched the Cochrane CENTRAL, MEDLINE, and ClinicalTrials.gov databases. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs. Data were pooled using the random effects model, and the fixed effects model was used for sensitivity analysis. (3) Results: We included 12 studies with 2800 enrolled patients. Only three of these trials (412 patients) were included in the meta-analysis. NPBs seemed to have an effect on the optimization of MRA therapy, with an RR (95% CI) of 1.24 (1.09, 1.42) (moderate certainty evidence); Patiromer seemed to have an effect on MRA optimization, with an RR (95% CI) or 1.25 (1.08, 1.45) (high certainty evidence). ZSC seemed to have no effect on enabling MRA therapy, with an RR (95% CI) of 1.19 (0.89, 1.59) (low certainty evidence). The AEs in HF patients with hyperkalemia treated with Patiromer were GI disorders and hypomagnesemia. ZSC The AEs included chronic cardiac failure, hypokalemia, and edema. (4) Conclusions: This meta-analysis included three studies with a small number of patients and a short follow-up period (1-3 months). The evidence of the effect of NPBs on MRA optimization had a moderate certainty for imprecision. Data on the effect on MRA optimization and less severe AEs in long-term treatment seem to suggest the use of Patiromer for the optimization of MRA therapy in patients with or at risk of heart failure and hyperkalemia. Future adequately powered RCTs are needed to assess the benefits and potential harms of potassium binders.

Background: Acute kidney injury (AKI) may increase the risk of chronic kidney disease (CKD), development of end-stage renal disease (ESRD), and mortality. However, the impact of exposure to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEi/ARB) in patients experiencing AKI/acute kidney disease (AKD) is still unclear. Methods: In this systematic review, we searched all relevant studies from PubMed, Embase, Cochrane, Medline, Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, and ClinicalTrials.gov until July 21, 2020. We evaluated whether the exposure to ACEi/ARB after AKI onset alters recovery paths of AKD and impacts risks of all-cause mortality, recurrent AKI, or incident CKD. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. Results: A total of seven articles, involving 70,801 patients, were included in this meta-analysis. The overall patient mortality rate in this meta-analysis was 28.4%. Among AKI patients, all-cause mortality was lower in ACEi/ARB users than in ACEi/ARB nonusers (log odds ratio (OR) -0.37, 95% confidence interval (CI): -0.42--0.32, p < 0.01). The risk of recurrent adverse kidney events after AKI was lower in ACEi/ARB users than in nonusers (logOR -0.25, 95% CI: -0.33--0.18, p < 0.01). The risk of hyperkalemia was higher in ACEi/ARB users than in nonusers (logOR 0.43, 95% CI: 0.27-0.59, p < 0.01). Patients with continued use of ACEi/ARB after AKI also had lower mortality risk than those prior ACEi/ARB users but who did not resume ACEi/ARB during AKD (logOR -0.36, 95% CI: -0.4--0.31, p < 0.01). Conclusions: Exposure to ACEi/ARB after AKI is associated with lower risks of all-cause mortality, recurrent AKI, and progression to incident CKD. Patients with AKI may have a survival benefit by continued use of ACEi/ARB; however, a higher incidence of hyperkalemia associated with ACEi/ARB usage among these patients deserves close clinical monitoring.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has been observed to cause a high mortality in people with cardiometabolic diseases. Renin-angiotensin-aldosterone system (RAAS) blockers enhance the expression of ACE2, the binding receptor of SARS-CoV-2, and can enhance viral infectivity. We aim to provide a pooled estimate of the effect of RAAS blockers on COVID-19 outcomes.
METHODS: A literature search was performed using MEDLINE/PubMed, Google Scholar and preprint servers. All clinical studies analyzing the effect of RAAS blockers on clinical outcomes in COVID-19 patients were included in this study. Newcastle-Ottawa scale was used for quality assessment of studies. MOOSE checklist was followed. Mortality and severity outcomes were recorded as pooled odds ratio (OR) with 95% Confidence Intervals (CIs) and level of heterogeneity (I 2). Odds of mortality was the primary outcome. Odds of severity, hospitalization, intensive care unit (ICU) admission, mechanical ventilation (MV), steroid use and acute kidney injury were the secondary outcomes. Severity outcomes were chosen depending upon the definition used by respective authors. Country-specific variations and effects of individual class of RAAS blockers were also explored.
RESULTS: In total 47 published studies were included in the final analysis, with a total of 26,432 patients from 31 studies in mortality analysis and 20,127 patients from 23 studies in severity analysis. No increased risk of mortality [Pooled OR 0.91 (0.65-1.26), I 2 = 89%] or severity [Pooled OR 1.08 (0.79-1.46), I 2 = 88%] was seen with RAAS blockers. The drug class was protective in hypertension [pooled OR 0.63 (0.46-0.86), I 2 = 58%]. Severity of COVID-19 outcomes was high for Europeans [Pooled OR 2.08 (1.52-2.85), I 2 = 77%] and US patients [Pooled OR 1.87 (1.62-2.17)]. Nearly 4 times higher risk of hospitalization and 2 times higher risk of ICU admission and MV were observed in US patients. Class-wise, angiotensin receptor blocker use was associated with 1.6 times higher odds of severity, mainly in Europeans.
CONCLUSIONS: RAAS blockers are not associated with increased mortality in COVID-19 patients and should be continued in hypertensives. US and European patients are at higher risk of severe outcomes. Pharmacogenetic differences may explain the ethnicity-related variations.
CONCLUSIONS: Effect of RAAS-blocking medicines on COVID-19 Background and aims: Higher deaths have been observed in COVID-19 patients who have other long-term diseases such as heart disease, diabetes, and high blood pressure. Many of these patients are prescribed a class of medicines called RAAS blockers (ramipril, telmisartan, etc). We studied whether the use of these medicines worsens the course of COVID-19 disease in these patients or causes excess deaths.Methods: We conducted a pooled analysis of 47 observational studies on the use of RAAS blocker drugs in COVID-19 patients.Results: We found that RAAS blockers do not cause excess deaths in patients with COVID-19. On the contrary, they have benefits if prescribed to those with high blood pressure. We also found that whereas European and US patients of COVID-19 taking these medicines had higher disease severity, this was not the case for Chinese patients.Conclusion: Theremay be some genetic and other factors responsible for differences by ethnicity.

The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 28 million cases of COVID-19 (Corona virus disease-2019) and more than 900000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1-7) axes, that can be utilized against COVID-19 disease progression.

The COVID-19 pandemic is caused by the severe acute-respiratory-syndrome-coronavirus-2 that uses ACE2 as its receptor. Drugs that raise serum/tissue ACE2 levels include ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) that are commonly used in patients with hypertension, cardiovascular disease and/or diabetes. These comorbidities have adverse outcomes in COVID-19 patients that might result from pharmacotherapy. Increasing ACE2 could potentially increase the risk of infection, severity or mortality in COVID-19 or it might be protective as it forms angiotensin-(1-7) which exhibits anti-inflammatory/anti-oxidative effects and prevents diabetes- and/or hypertension-induced end-organ damage. Thus, there existed clinical uncertainty. Here, we review studies implicating 15 classes of drugs in increasing ACE2 levels in vivo and the available literature on the clinical safety of these drugs in COVID-19 patients. Further, in a re-analysis of clinical data from a meta-analysis of 9 studies, we show that ACEIs/ARBs usage was not associated with an increased risk of all-cause mortality. Literature suggests that ACEIs/ARBs usage generally appears to be clinically safe though their use in severe COVID-19 patients might increase the risk of acute renal injury. For definitive clarity, further clinical and mechanistic studies are needed in assessing the safety of all classes of ACE2 raising medications.

Merkel cell carcinoma (MCC) is a rare entity that most commonly arises from the skin. Angiosarcoma (AS) is a rare malignancy with a predilection for elderly males, has endothelial differentiation and a notoriously poor prognosis despite aggressive therapy. Herein, we report an angiosarcoma colliding with a MCC, in a patient with a past medical history of squamous cell carcinoma, status-post radiation therapy. More specifically, our case represents a collision tumor, a rare entity composed of two histologically distinct neoplasms which coincide together at the same location. This case represents the first documented report of such a presentation. With that being said, its clinical course, prognosis, pathogenesis, and molecular profile, currently remains unclear. Importantly, neoplasms are increasingly being found to be associated with radiation therapy, of which our patient had received. Ultimately, however, with the lack of c-MYC immunohistochemical staining, and a short duration between radiation exposure and presentation, the AS in our case was likely coincidental.