Angiotensin II Exaggerates SARS-CoV-2 Specific T-Cell Response in Convalescent Individuals following COVID-19

Dysregulation of renin−angiotensin systems during coronavirus disease 2019 (COVID-19) infection worsens the symptoms and contributes to COVID-19 severity and mortality. This study sought to investigate the effect of exogenous angiotensin II (Ang-II) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cells response in recovered COVID-19 patients. Human peripheral blood mononuclear cells (PBMCs) were treated with Ang II and then stimulated with a SARS-CoV-2 peptide pool. T-cell responses were measured using flow cytometry, while enzyme-linked immunosorbent assay (ELISA) and intracellular cytokine staining (ICS) assays determined functional capability and polarization. Additionally, the relative level of protein phosphorylation was measured using a phosphokinase array. Our results showed that Ang II treatment significantly increased the magnitude of SARS-CoV-2-specific T-cell response in stimulated PBMCs with a SARS-CoV-2 peptide pool. Moreover, the phosphorylation levels of numerous proteins implicated in cardiovascular diseases, inflammation, and viral infection showed significant increases in the presence of Ang II. The mitogenic stimulation of PBMCs after Ang II and SARS-CoV-2 peptide pool stimulation showed functional polarization of T-cells toward Th1/Th17 and Th17 phenotypes, respectively. Meanwhile, ELISA showed increased productions of IL-1β and IL-6 in Ang II-stimulated PBMCs without affecting the IL-10 level. To our knowledge, this study is the first to demonstrate that Ang II exaggerates SARS-CoV-2-specific T-cells response. Therefore, during COVID-19 infection, Ang II may aggravate the inflammatory response and change the immune response toward a more inflammatory profile against SARS-CoV-2 infection

Achillea fragrantissima (Forssk.) Sch.Bip Flower Dichloromethane Extract Exerts Anti-Proliferative and Pro-Apoptotic Properties in Human Triple-Negative Breast Cancer (MDA-MB-231) Cells: In Vitro and In Silico Studies

The aggressive triple-negative breast cancer (TNBC) is a challenging disease due to the absence of tailored therapy. The search for new therapies involves intensive research focusing on natural sources. Achillea fragrantissima (A. fragrantissima) is a traditional medicine from the Middle East region. Various solvent extracts from different A. fragrantissima plant parts, including flowers, leaves, and roots, were tested on TNBC MDA-MB-231 cells. Using liquid chromatography, the fingerprinting revealed rich and diverse compositions for A. fragrantissima plant parts using polar to non-polar solvent extracts indicating possible differences in bioactivities. Using the CellTiter-Glo™ viability assay, the half-maximal inhibitory concentration (IC50) values were determined for each extract and ranged from 32.4 to 161.7 µg/mL. The A. fragrantissima flower dichloromethane extract had the lowest mean IC50 value and was chosen for further investigation. Upon treatment with increasing A. fragrantissima flower dichloromethane extract concentrations, the MDA-MB-231 cells displayed, in a dose-dependent manner, enhanced morphological and biochemical hallmarks of apoptosis, including cell shrinkage, phosphatidylserine exposure, caspase activity, and mitochondrial outer membrane permeabilization, assessed using phase-contrast microscopy, fluorescence-activated single-cell sorting analysis, Image-iT™ live caspase, and mitochondrial transition pore opening activity, respectively. Anticancer target prediction and molecular docking studies revealed the inhibitory activity of a few A. fragrantissima flower dichloromethane extract-derived metabolites against carbonic anhydrase IX, an enzyme reported for its anti-apoptotic properties. In conclusion, these findings suggest promising therapeutic values of the A. fragrantissima flower dichloromethane extract against TNBC development

Oleuropein protects against cerebral ischemia injury in rats : molecular docking, biochemical and histological findings

This study was designed to evaluate the underlying protective mechanisms of oleuropein involved in alleviating brain damage in a rat model of ischemic stroke. Male Wistar rats were divided into four groups; Control, stroke (MCAO), MCAO + clopidogrel (Clop) and MCAO + oleuropein (Ole). Results showed that the MCAO group evidenced significant brain edema (+ 9%) as well as increases of plasma cardiac markers such as lactate deshydrogenase (LDH), creatine kinase (CK-MB), fibrinogen and Trop-T by 11 %, 43%, 168 and 590%, respectively, as compared to the control group. Moreover, infarcted rats exhibited remarkable elevated levels of angiotensin converting enzyme (ACE), both in plasma and brain tissue, with astrocyte swelling and necrotic neurons in the infarct zone, hyponatremia, and increased rate of thiobarbituric acid-reactive substances (TBARS) by 89% associated with decreases in the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (Cat) by 51%, 44 and 42%, respectively, compared to normal control rats. However, MCAO rats treated with oleuropein underwent mitigation of cerebral edema, correction of hyponatremia, remarkable decrease of plasma fibrinogen and cardiac dysfunctional enzymes, inhibition of ACE activity and improvement of oxidative stress status in brain tissue. Furthermore, in silico analysis showed considerable inhibitions of ACE, protein disulfide isomerase (PDI) and TGF-β1, an indicative of potent anti-embolic properties. Overall, oleuropein offers a neuroprotective effect against ischemic stroke through its antioxidative and antithrombotic activities