Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19.

The family of coronaviruses (CoVs) uses the autophagy machinery of host cells to promote their growth and replication; thus, this process stands out as a potential target to combat COVID-19. Considering the different roles of autophagy during viral infection, including SARS-CoV-2 infection, in this review, we discuss several clinically used drugs that have effects at different stages of autophagy. Among them, we mention (1) lysosomotropic agents, which can prevent CoVs infection by alkalinizing the acid pH in the endolysosomal system, such as chloroquine and hydroxychloroquine, azithromycin, artemisinins, two-pore channel modulators and imatinib; (2) protease inhibitors that can inhibit the proteolytic cleavage of the spike CoVs protein, which is necessary for viral entry into host cells, such as camostat mesylate, lopinavir, umifenovir and teicoplanin and (3) modulators of PI3K/AKT/mTOR signaling pathways, such as rapamycin, heparin, glucocorticoids, angiotensin-converting enzyme inhibitors (IECAs) and cannabidiol. Thus, this review aims to highlight and discuss autophagy-related drugs for COVID-19, from in vitro to in vivo studies. We identified specific compounds that may modulate autophagy and exhibit antiviral properties. We hope that research initiatives and efforts will identify novel or "off-label" drugs that can be used to effectively treat patients infected with SARS-CoV-2, reducing the risk of mortality.

Hypotensive activity of Campomanesia xanthocarpa leaf extract: beyond angiotensin II type 1 receptor blockage.

The ability of Campomanesia xanthocarpa leaf extract (CXLE) to alter blood pressure and heart rate was evaluated in anesthetized rats. The CXLE-induced hypotension was evaluated before and after losartan, methylatropine, L-N(ω)-nitro-L-arginine methyl ester (L-NAME), hexamethonium, indomethacin, glibenclamide, or nifedipine administration. The constituents of CXLE were identified by LC-DAD-MS. CXLE decreased blood pressure in a dose-dependent manner; only the highest dose decreased heart rate. The hypotension induced by CXLE was sensitive only to losartan, nifedipine, and glibenclamide. L-NAME decreased the time to recover 50% of the hypotensive effect of CXLE without altering its magnitude. Flavan-3-ols, proanthocyanidins (dimers and trimers), and glycosylated flavonols were identified from CXLE. The chemical constituents of CXLE seem to induce not only angiotensin II type 1 receptor blockage, but also ATP-sensitive potassium channels activation and L-type voltage-dependent Ca2+ channels inactivation. Nitric oxide is involved in the maintenance of the hypotensive effect of CXLE.

Hypotensive effect of Eugenia dysenterica leaf extract is primarily related to its vascular action: The possible underlying mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Eugenia dysenterica (ED) leaves are used in Brazil to treat cardiac diseases; however, there are no scientific data describing the effects of this species on cardiac activity. AIM OF THE STUDY: To investigate the effect of ED aqueous leaf extract (EDLE) on hear rate (HR) and mean arterial pressure (MAP) of anaesthetised rats and its underlying mechanism of action. MATERIAL AND METHODS: EDLE was analysed, and its proanthocyanidin composition was determined. After performing dose-effect curves for EDLE on HR and MAP, EDLE-induced hypotension was evaluated before and after atropine (AT), L-N(ω)-nitro-L-arginine methyl ester (L-NAME), hexamethonium (HXT), indomethacin (IND), carbenoxolone (CBX), or nifedipine (NFD) administration. The effect of proanthocyanidin-depleted extract (EDLE/P-) was also determined and compared to that of the EDLE with proanthocyanidins. RESULTS: EDLE decreased the MAP in a dose-dependent manner; HR was decreased only with the highest and most toxic dose. Only CBX and NFD decreased EDLE-induced hypotension. Five polymeric series of proanthocyanidins were identified, which were mainly constituted by procyanidin and prodelphinidin units with B-type linkage and up to 12 flavan-3-ol units. EDLE/P- induced hypotension did not differ from that induced by EDLE. CONCLUSIONS: The cardiovascular effects of EDLE were primarily related to its vascular action. EDLE-induced hypotensive effect appeared to involve L-type calcium channel blockage as well as myoendothelial gap junction signalling. The higher molecular weight proanthocyanidins from EDLE are unlikely to contribute to its cardiovascular effect.

Testosterone and Mast Cell Interactions in the Development of Kidney Fibrosis after Unilateral Ureteral Obstruction in Rats.

Mast cell and testosterone interactions involved in renal fibrosis in rats subjected to unilateral ureteral obstruction (UUO) were investigated. Orchiectomized (ORX) and nonorchiectomized Wistar rats were subjected to UUO, and a nonorchiectomized group was sham-operated (control: SO). Animals from the UUO group were treated with saline or sodium cromoglycate (CG). Some ORX rats from the saline or CG groups also received testosterone propionate replacement (TR). Kidneys and blood were collected 14 d after UUO or SO. Kidney sections were stained with toluidine blue to quantify mast cells, and picrosirius red was used for collagen analysis. Immunohistochemistry for α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) expression was also performed. Plasma testosterone levels (PTLs) were measured. ORX decreased and TR normalized PTLs. UUO increased mast cell density in the kidney pelvis, but not in the kidney parenchyma. UUO increased mast cell degranulation, and CG or ORX inhibited this effect. TR partially reversed the effect of ORX on mast cell degranulation, and CG partially inhibited that effect of TR. UUO increased the collagen areas of the renal parenchyma, whereas CG or ORX abolished that alteration; TR reversed the effects of ORX, and CG partially inhibited that effect of TR. UUO increased tubulointerstitial α-SMA expression and PCNA-positive cells, and these changes were sensitive to ORX or CG to the same degree, while TR again reversed the effect of ORX. Renal fibrosis after UUO appears to be determined by interactions between testosterone and mast cells.