The Pathophysiology of Long COVID throughout the Renin-Angiotensin System.

COVID-19 has expanded across the world since its discovery in Wuhan (China) and has had a significant impact on people's lives and health. Long COVID is a term coined by the World Health Organization (WHO) to describe a variety of persistent symptoms after acute SARS-CoV-2 infection. Long COVID has been demonstrated to affect various SARS-CoV-2-infected persons, independently of the acute disease severity. The symptoms of long COVID, like acute COVID-19, consist in the set of damage to various organs and systems such as the respiratory, cardiovascular, neurological, endocrine, urinary, and immune systems. Fatigue, dyspnea, cardiac abnormalities, cognitive and attention impairments, sleep disturbances, post-traumatic stress disorder, muscle pain, concentration problems, and headache were all reported as symptoms of long COVID. At the molecular level, the renin-angiotensin system (RAS) is heavily involved in the pathogenesis of this illness, much as it is in the acute phase of the viral infection. In this review, we summarize the impact of long COVID on several organs and tissues, with a special focus on the significance of the RAS in the disease pathogenesis. Long COVID risk factors and potential therapy approaches are also explored.

Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases.

The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.

The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

Phenolic Profile of Herbal Infusion and Polyphenol-Rich Extract from Leaves of the Medicinal Plant Antirhea borbonica: Toxicity Assay Determination in Zebrafish Embryos and Larvae.

Antirhea borbonica (A. borbonica) is an endemic plant from the Mascarene archipelago in the Indian Ocean commonly used in traditional medicine for its health benefits. This study aims (1) at exploring polyphenols profiles from two types of extracts-aqueous (herbal infusion) and acetonic (polyphenol rich) extracts from A. borbonica leaves-and (2) at evaluating their potential toxicity in vivo for the first time. We first demonstrated that, whatever type of extraction is used, both extracts displayed significant antioxidant properties and acid phenolic and flavonoid contents. By using selective liquid chromatography-tandem mass spectrometry, we performed polyphenol identification and quantification. Among the 19 identified polyphenols, we reported that the main ones were caffeic acid derivatives and quercetin-3-O-rutinoside. Then, we performed a Fish Embryo Acute Toxicity test to assess the toxicity of both extracts following the Organisation for Economic Cooperation and Development (OECD) guidelines. In both zebrafish embryos and larvae, the polyphenols-rich extract obtained by acetonic extraction followed by evaporation and resuspension in water exhibits a higher toxic effect with a median lethal concentration (LC50: 5.6 g/L) compared to the aqueous extract (LC50: 20.3 g/L). Our data also reveal that at non-lethal concentrations of 2.3 and 7.2 g/L for the polyphenol-rich extract and herbal infusion, respectively, morphological malformations such as spinal curvature, pericardial edema, and developmental delay may occur. In conclusion, our study strongly suggests that the evaluation of the toxicity of medicinal plants should be systematically carried out and considered when studying therapeutic effects on living organisms.

Hesperidin Loaded on Gold Nanoparticles as a Drug Delivery System for a Successful Biocompatible, Anti-Cancer, Anti-Inflammatory and Phagocytosis Inducer Model.

Hesperidin is a flavonoid glycoside with proven therapeutic activities for various diseases, including cancer. However, its poor solubility and bioavailability render it only slightly absorbed, requiring a delivery system to reach its therapeutic target. Hesperidin loaded on gold nanoparticles (Hsp-AuNPs) was prepared by a chemical synthesis method. Various characterization techniques such as UV-VIS spectroscopy, FTIR, XRD, FESEM, TEM and EDX, Zeta potential analysis, particle size analysis, were used to confirm the synthesis of Hsp-AuNPs. The cytotoxic effect of Hsp-AuNPs on human breast cancer cell line (MDA-MB-231) was assessed using MTT and crystal violet assays. The results revealed significant decrease in proliferation and inhibition of growth of the treated cells when compared with human normal breast epithelial cell line (HBL-100). Determination of apoptosis by fluorescence microscope was also performed using acridine orange-propidium iodide dual staining assay. The in vivo study was designed to evaluate the toxicity of Hsp-AuNPs in mice. The levels of hepatic and kidney functionality markers were assessed. No significant statistical differences were found for the tested indicators. Histological images of liver, spleen, lung and kidney showed no apparent damages and histopathological abnormalities after treatment with Hsp-AuNPs. Hsp-AuNPs ameliorated the functional activity of macrophages against Ehrlich ascites tumor cells-bearing mice. The production of the pro-inflammatory cytokines was also assessed in bone marrow-derived macrophage cells treated with Hsp-AuNPs. The results obviously demonstrated that Hsp-AuNPs treatment significantly inhibited the secretion of IL-1ß, IL-6 and TNF.