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Coronavirus disease 2019 (COVID-19) is an infectious disease with fast spreading all over the world caused by the SARS-CoV-2 virus which can culminate in a severe acute respiratory syndrome by the injury caused in the lungs. However, other organs can be also damaged. SARS-CoV-2 enter into the host cells using the angiotensinconverting enzyme 2 (ACE2) as receptor, like its ancestor SARS-CoV. ACE2 is then downregulated in lung tissues with augmented serum levels of ACE2 in SARS-CoV-2 patients. Interestingly, ACE2 + organs reveal the symptomatic repercussions, which are signals of the infection such as dry cough, shortness of breath, heart failure, liver and kidney damage, anosmia or hyposmia, and diarrhea. ACE2 exerts a chief role in the renin-angiotensin system (RAS) by converting angiotensin II to angiotensin-(1-7) that activates Mas receptor, inhibits ACE1, and modulates bradykinin (BK) receptor sensitivity, especially the BK type 2 receptor (BKB2R). ACE2 also hydrolizes des-Arg 9-bradykinin (DABK), an active BK metabolite, agonist at BK type 1 receptors (BKB1R), which is upregulated by inflammation. In this opinion article, we conjecture a dialogue by the figure of Sérgio Ferreira which brought together basic science of classical pharmacology and clinical repercussions in COVID-19, then we propose that in the course of SARS-CoV-2 infection: i) downregulation of ACE2 impairs the angiotensin II and DABK inactivation; ii) BK and its metabolite DABK seems to be in elevated levels in tissues by interferences in kallikrein/kinin system; iii) BK1 receptor contributes to the outbreak and maintenance of the inflammatory response; iv) kallikrein/kinin system crosstalks to RAS and coagulation system, linking inflammation to thrombosis and organ injury. We hypothesize that targeting the kallikrein/kinin system and BKB1R pathway may be beneficial in SARS-CoV-2 infection, especially on early stages. This route of inference should be experimentally verified by SARS-CoV-2 infected mice.

Our objective was to evaluate the role of soluble guanylate cyclase (sGC) activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats. Rats were pretreated, once daily for 4 days, with saline, hemin (HO-1 inducer), or dimanganese decacarbonyl (DMDC, CO donor). Another group received zinc protoporphyrin IX (ZnPP IX, HO-1 antagonist) 1 h before hemin treatment or sGC inhibitor (ODQ) 30 min before hemin and DMDC treatment. After 30 min, gastric damage was induced by alendronate (30 mg/kg) by gavage. On the last day of treatment, 4 h after alendronate administration, the animals were killed. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β), myeloperoxidase (MPO), or bilirubin. Another group was used to measure gastric mucus. HO-1 expression was determined after saline or alendronate administration by immunohistochemistry. Alendronate induced gastric damage, produced neutrophil accumulation, increased MDA levels and MPO activity, and reduced GSH and mucus in the gastric tissue. Alendronate also increased HO-1 immunoreactivity and the level of bilirubin in gastric mucosa. Pretreatment with hemin or DMDC reduced neutrophil infiltration and TNF-α, IL-1β, and MDA formation, and increased the levels of GSH and mucus in the gastric tissue. ODQ completely abolished the gastroprotective effect of hemin and DMDC and increased alendronate gastric damage. Our results suggest that the HO-1/CO pathway plays a protective role against alendronate-induced gastric damage through mechanisms that can be dependent on sGC activation.

Long-term use nonsteroidal anti-inflammatory drug is associated with gastrointestinal (GI) lesion formation. The aim of this study was to investigate the protective activity of cashew gum (CG), a complex heteropolysaccharide extracted from Anacardium occidentale on naproxen (NAP)-induced GI damage. Male Wistar rats were pretreated with vehicle or CG (1, 3, 10, and 30 mg/kg, p.o.) twice daily for 2 days; after 1 h, NAP (80 mg/kg, p.o.) was administered. The rats were euthanized on the 2nd day of treatment, 4 h after NAP administration. Stomach lesions were measured using digital calipers. The medial small intestine was used for the evaluation of macroscopic lesion scores. Samples of the stomach and the intestine were used for histological evaluation, and assays for glutathione (GSH), malonyldialdehyde (MDA), and myeloperoxidase (MPO). Additional rats were used to measure gastric mucus and secretion. Pretreatment with CG reduced the macroscopic and microscopic damage induced by NAP. CG significantly attenuated NAP-induced alterations in MPO, GSH, and MDA levels. Furthermore, CG returned adherent mucus levels to normal values. These results suggest that CG has a protective effect against GI damage via mechanisms that involve the inhibition of inflammation and increasing the amount of adherent mucus in mucosa.