Recently, a new coronavirus (SARS-CoV-2) was discovered in China. Due to its high level of contagion, it has already reached most countries, quickly becoming a pandemic. Although the most common symptoms are related to breathing problems, SARS-CoV-2 infections also affect the gastrointestinal tract culminating in inflammation and diarrhea. However, the mechanisms related to these enteric manifestations are still not well understood. Evidence shows that the SARS-CoV-2 binds to the angiotensin-converting enzyme receptor 2 (ACE2) in host cells as a viral invasion mechanism and can infect the lungs and the gut. Other viruses have already been linked to intestinal symptoms through binding to ACE2. In turn, this medical hypothesis article conjectures that the ACE2 downregulation caused by the SARS-CoV-2 internalization could lead to decreased activation of the mechanistic target of mTOR with increased autophagy and lead to intestinal dysbiosis, resulting in diarrhea. Besides that, dysbiosis can directly affect the respiratory system through the lungs. Although there are clues to other viruses that modulate the ACE2/gut/lungs axis, including the participation of autophagy and dysbiosis in the development of gastrointestinal symptoms, there is still no evidence of the ACE2/mTOR/autophagy pathway in SARS-CoV-2 infections. Thus, we propose that the new coronavirus causes a change in the intestinal microbiota, which culminates in a diarrheal process through the ACE2/mTOR/autophagy pathway into enterocytes. Our assumption is supported by premises that unregulated intestinal microbiota increases the susceptibility to other diseases and extra-intestinal manifestations, which can even cause remote damage in lungs. These putative connections lead us to suggest and encourage future studies aiming at assessing the aforementioned hypothesis and regulating dysbiosis caused by SARS-CoV-2 infection, in order to confirm the decrease in lung injuries and the improvement in the prognosis of the disease.
Objectives/Hypothesis: The objectives of this study were to evaluate laryngeal inflammation and mucosal integrity in a murine model of reflux disease and to assess the protective effects of topical agents including alginate, hyaluronic acid, and cashew gum. Study Design: Animal study. Methods: A surgical murine model of reflux disease was evaluated at 3 or 7 days postsurgery, and laryngeal samples were collected to measure inflammation (wet weight and myeloperoxidase [MPO]) and mucosal integrity (transepithelial resistance [TER] and mucosal permeability to fluorescein). Additional groups of animals were administered one of several topical agents (alginate, hyaluronic acid, or cashew gum) daily, and laryngeal inflammation and mucosal integrity were evaluated at 3 days postsurgery. Results: At 3 days, and not 7 days postsurgery, we observed increased laryngeal wet weight and MPO, decreased laryngeal TER, and increased laryngeal mucosa permeability. Alginate partially decreased laryngeal inflammation (wet weight and not MPO) and dramatically improved laryngeal mucosal integrity. Conversely, hyaluronic acid eliminated the inflammation; however, it had no effect on laryngeal mucosal integrity impairment. Cashew gum eliminated laryngeal inflammation as well as the impairment in laryngeal mucosal integrity. Conclusions: This study shows that a surgical model of reflux disease induced laryngeal inflammation and impairment in laryngeal barrier function. These observed alterations were partially attenuated by alginate and hyaluronic acid and completely reversed by cashew gum.
Anacardic acid (AA), a compound extracted from cashew nut liquid, exhibits numerous pharmacological activities. The aim of the current investigation was to assess the anti-inflammatory, antinociceptive, and antioxidant activities of AA in mouse models. For this, Swiss albino mice were pretreated with AA (10, 25, 50 mg/kg, intraperitoneally, ip) 30 min prior to the administration of carrageenan, as well as 25 mg/kg of prostaglandin E2, dextran, histamine, and compound 48/80. The antinociceptive activity was evaluated by formalin, abdominal, and hot plate tests, using antagonist of opioid receptors (naloxene, 3 mg/kg, ip) to identify antinociceptive mechanisms. Results from this study revealed that AA at 25 mg/kg inhibits carrageenan-induced edema. In addition, AA at 25 mg/kg reduced edema and leukocyte and neutrophilic migration to the intraperitoneal cavity, diminished myeloperoxidase activity and malondialdehyde concentration, and increased the levels of reduced glutathione. In nociceptive tests, it also decreased licking, abdominal writhing, and latency to thermal stimulation, possibly via interaction with opioid receptors. Taken together, these results indicate that AA exhibits anti-inflammatory and antinociceptive actions and also reduces oxidative stress in acute experimental models, suggesting AA as a promising compound in the pharmaceutical arena.
Anadenanthera colubrina var. cebil (Griseb.) Altschul (Fabaceae family), commonly known as the red angico tree, is a medicinal plant found throughout Brazil’s semi-arid area. In this study, a chemical analysis was performed to investigate the antidiarrheal activity and safety profile of red angico gum (RAG), a biopolymer extracted from the trunk exudate of A. colubrina. Upon FT-IR spectroscopy, RAG showed bands in the regions of 1608 cm−1, 1368 cm−1, and 1029 cm−1, which relate to the vibration of O–H water molecules, deformation vibration of C-O bands, and vibration of the polysaccharide C-O band, respectively, all of which are relevant to glycosidic bonds. The peak molar mass of RAG was 1.89 × 105 g/mol, with the zeta potential indicating electronegativity. RAG demonstrated high yield and solubility with a low degree of impurity. Pre-treatment with RAG reduced the total diarrheal stool and enteropooling. RAG also enhanced Na+/K+-ATPase activity and reduced gastrointestinal transit, and thereby inhibited intestinal smooth muscle contractions. Enzyme-Linked Immunosorbent Assay (ELISA) demonstrated that RAG can interact with GM1 receptors and can also reduce E. coli-induced diarrhea in vivo. Moreover, RAG did not induce any signs of toxicity in mice. These results suggest that RAG is a possible candidate for the treatment of diarrheal diseases.
Loperamide is a synthetic opioid commonly used as an antidiarrheal due to its activation of u-opioid receptors in the myenteric plexus. In therapeutic doses, it inhibits peristalsis and has anti-secretory and anti-motility effects, until metabolized by intestinal and hepatic CYP3A4 and CYP2C8 into inactive metabolites. Furthermore, loperamide also inhibits L-type voltage-gated calcium (Ca2+) channels, increases action potential duration, and can induce arrhythmias and even cardiotoxicity, particularly when taken in extremely high doses. Thus, the aim of this study was to perform an integrative review of the available evidence in the recent literature on the cardiac risks of acute and chronic use of loperamide. In electrocardiogram (ECG) analysis, the most common finding was QTc prolongation in 27 cases, followed by QRS prolongation, first-degree atrioventricular (AV) block, torsades de pointes, ventricular tachycardia, and right bundle branch block. As for the symptoms encountered, syncope, weakness, palpitations, lightheadedness, shortness of breath, nausea, vomiting, bradycardia, and cardiac arrest were the most common. Loperamide can inhibit hERG voltage-gated potassium (K+) channels (Kv11.1), leading to the prolongation of repolarization, QTc interval prolongation, and increased risk of torsades de pointes. In addition, loperamide can inhibit voltage-gated sodium (Na+) channels (Nav1.5), impairing electrical cardiac conduction and potentiating QRS interval widening. Therefore, QTc prolongation, torsades de pointes, and other ECG alterations are of particular concern regarding loperamide toxicity, particularly when overdosed.
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