Effects of Renin-Angiotensin System Inhibitors on Mortality and Disease Severity of COVID-19 Patients: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: There is controversy over the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on the prognosis in patients with coronavirus disease 2019 (COVID-19), therefore, we aim to further explore the effect of renin-angiotensin-aldosterone system inhibitors on COVID-19-associated disease severity and mortality. METHODS: We systematically searched PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv from inception to 6 September 2021. The primary outcome was all-cause mortality. Secondary outcome was severe disease which was defined as admission to the intensive care unit, the use of noninvasive or invasive mechanical ventilation, or death. RESULTS: A total of 7 randomized controlled trials involving 1,321 COVID-19 patients were included. Fixed-effects meta-analysis demonstrated that the use of ACEI/ARB was not associated with higher risk of mortality (risk ratio [RR] = 0.84, 95% confidence interval [CI] 0.57-1.22, P = 0.10, I2 = 43%) and disease severity (RR = 0.86, 95% CI 0.71-1.05, P = 0.11, I2 = 47%). However, the subgroup analysis showed that compared with no ACEI/ARB use, the use of ARB was associated with a significant reduction of mortality (RR = 0.23, CI 0.09-0.60, P = 0.55, I2 = 0%) and disease severity (RR = 0.38, CI 0.19-0.77, P = 0.007). CONCLUSIONS: In conclusion, based on the available data, ACEI/ARB is not associated with the risk of mortality and disease severity in COVID-19 patients. And ACEI/ARB medications, especially ARB, should not be discontinued for patients with COVID-19.

Using a System Pharmacology Method to Search for the Potential Targets and Pathways of Yinqiaosan against COVID-19.

The first reported case of coronavirus disease 2019 (COVID-19) occurred in Wuhan, Hubei, China. Thereafter, it spread through China and worldwide in only a few months, reaching a pandemic level. It can cause severe respiratory illnesses such as pneumonia and lung failure. Since the onset of the disease, the rapid response and intervention of traditional Chinese medicine (TCM) have played a significant role in the effective control of the epidemic. Yinqiaosan (YQS) was used to treat COVID-19 pneumonia, with good curative effects. However, a systematic overview of its active compounds and the therapeutic mechanisms underlying its action has yet to be performed. The purpose of the current study is to explore the compounds and mechanism of YQS in treating COVID-19 pneumonia using system pharmacology. A system pharmacology method involving drug-likeness assessment, oral bioavailability forecasting, virtual docking, and network analysis was applied to estimate the active compounds, hub targets, and key pathways of YQS in the treatment of COVID-19 pneumonia. With this method, 117 active compounds were successfully identified in YQS, and 77 potential targets were obtained from the targets of 95 compounds and COVID-19 pneumonia. The results show that YQS may act in treating COVID-19 pneumonia and its complications (atherosclerosis and nephropathy) through Kaposi sarcoma-related herpesvirus infection and the AGE-RAGE signaling pathway in diabetic complications and pathways in cancer. We distinguished the hub molecular targets within pathways such as TNF, GAPDH, MAPK3, MAPK1, EGFR, CASP3, MAPK8, mTOR, IL-2, and MAPK14. Five of the more highly active compounds (acacetin, kaempferol, luteolin, naringenin, and quercetin) have anti-inflammatory and antioxidative properties. In summary, by introducing a systematic network pharmacology method, our research perfectly forecasts the active compounds, potential targets, and key pathways of YQS applied to COVID-19 and helps to comprehensively clarify its mechanism of action.

A small molecule compound berberine as an orally active therapeutic candidate against COVID-19 and SARS: A computational and mechanistic study.

The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.