A computational study to target necroptosis via RIPK1 inhibition.

The human receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical necroptosis regulator implicated in cancer, psoriasis, ulcerative colitis, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis. Currently, there are no specific RIPK1 antagonists in clinical practice. In this study, we took a target-based computational approach to identify blood-brain-barrier-permeable potent RIPK1 ligands with novel chemotypes. Using molecular docking, we virtually screened the Marine Natural Products (MNP) library of 14,492 small molecules. Initial 18 hits were subjected to detailed ADMET profiling for bioavailability, brain penetration, druglikeness, and toxicities and eventually yielded 548773-66-6 as the best ligand. RIPK1 548773-66-6 binding was validated through duplicated molecular dynamics (MD) simulations where the co-crystallized ligand L8D served as a reference. Trajectory analysis indicated negligible Root-Mean-Square-Deviations (RMSDs) of the best ligand 548773-66-6 relative to the protein backbone: 0.156 ± 0.043 nm and 0.296 ± 0.044 nm (mean ± standard deviations) in two individual simulations. Visual inspection confirmed that 548773-66-6 occupied the RIPK1 ligand-binding pocket associated with the kinase activation loop. Further computations demonstrated consistent hydrogen bond interactions of the ligand with the residue ASP156. Binding free energy estimation also supported stable interactions of 548773-66-6 and RIPK1. Together, our in silico analysis predicted 548773-66-6 as a novel ligand for RIPK1. Therefore, 548773-66-6 could be a viable lead for inhibiting necroptosis in central nervous system inflammatory disorders.Communicated by Ramaswamy H. Sarma.

Hematological abnormalities and comorbidities are associated with COVID-19 severity among hospitalized patients: Experience from Bangladesh.

BACKGROUND: The hematological abnormalities are assumed to be involved in the disease progression of COVID-19. However, the actual associations between specific blood parameters and COVID-19 are not well understood. Here we aimed to assess the correlations between hematological parameters and the severity of COVID-19. METHODS: We included COVID-19 patients who were admitted to Evercare Hospital Ltd, Dhaka, Bangladesh, between November 10, 2020, to April 12, 2021, with a confirmed case of RT-PCR test. We recorded demographic information, clinical data, and routine hematological examination results of all COVID-19 patients. We performed statistical analyses and interpretation of data to compare severe COVID-19 patients (SCP) and non-severe COVID-19 patients (NSCP). RESULTS: The age and BMI of the admitted COVID-19 patients were 48.79±8.53 years and 25.82±3.75 kg/m2. This study included a total of 306 hospitalized COVID-19 patients. Among them, NSCP and SCP were 198 and 108, respectively. And we recorded 12 deaths from SCP. We observed the alterations of several hematological parameters between SCP and NSCP. Among them, we noticed the increased levels of C-reactive protein (CRP), d-dimer, and ferritin showed good indicative value to evaluate the severity of COVID-19. Also, there were positive correlations among these parameters. Moreover, we found correlations between the outcomes of COVID-19 patients with patient's demographics and comorbid diseases. CONCLUSION: Based on our results, CRP, d-dimer, and ferritin levels at admission to hospitals represent simple assessment factors for COVID-19 severity and the treatment decisions at the hospital setup. These blood parameters could serve as indicators for the prognosis and severity of COVID-19. Therefore, our study findings might help to develop a treatment protocol for COVID-19 patients at the hospital setup.

Therapeutic Potentials of Colocasia affinis Leaf Extract for the Alleviation of Streptozotocin-Induced Diabetes and Diabetic Complications: In vivo and in silico-Based Studies.

INTRODUCTION: Hypoglycemia in diabetes mellitus (DM) correlates with hepatic impairment, nephropathy, lipid abnormalities, and oxidative stress and subsequently complicates the disease pathogenesis. Medicinal plants have been used for the management of diabetes since ancient times. In this study, we explored the potentials of Colocasia affinis (CA), a plant known to possess anti-allergic and anti-inflammatory activities, as a remedy for diabetes and related complications. METHODS: We induced diabetes in rats using a single intraperitoneal dose (65 mg/kg) of streptozotocin (STZ). We next treated the rats with an ethanolic extract of leaves of CA to reveal its antidiabetic and organ-protective potentials. Biomarkers of diabetes, inflammation, and oxidative stress were measured using biochemical and histopathological analysis. We also performed molecular docking for three major phytochemicals (kaempferol, myricetin, and rosmarinic acid) of CA. RESULTS: Oral administration of the CA leaves extract at 250 mg/kg and 500 mg/kg doses decreased blood glucose level significantly (p<0.05) in STZ-induced diabetic rats. The extract also considerably attenuated plasma HbA1c levels and normalized blood lipids, glycogen, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Additionally, treatment with the extract improved kidney complications by decreasing serum creatinine and blood urea nitrogen (BUN) levels. Furthermore, CA leaves extract normalized nitric oxide (NO) and advance oxidative protein products (AOPP) in diabetic rats. The extract also showed significant improvement of the antioxidant enzymes glutathione dismutase (GSH) and superoxide dismutase (SOD) at a dose of 500 mg/kg. Besides, histological investigation demonstrated attenuation of inflammation of the vital organs, including the liver and the kidney. In silico studies revealed that three major phytochemicals (kaempferol, myricetin, and rosmarinic acid) of the ethanolic extract of leaves of CA can inhibit several molecular targets of diabetes and inflammation. CONCLUSION: Collectively, our results demonstrated the therapeutic potentials of CA for the mitigation of diabetes and diabetic complications.

C-MAF Expression in Adult Human Ocular Surface and its Implication in Pterygium Pathogenesis.

BACKGROUND: c-MAF, a transcription factor that belongs to the b-Zip Maf transcription factor family, was found to be critical for lens development in vertebrates. It is a well-known fact that the adult human ocular surface expresses c-MAF, however, its role in the limbus, cornea and conjunctiva remains unknown. Thus, the present study aimed to investigate c-MAF expression within the human ocular surface, and its potential role in pterygium pathogenesis. METHODS: We performed immunohistochemical staining to detect c-MAF expression in frozen adult human tissue sections, including the limbus, cornea and conjunctiva, and cultured cells from eye cadavers. We then compared c-MAF expression to the expression of a known protein, P63. Lastly, we performed RT-PCR, and immunohistochemistry for c-MAF expression in healthy adult human conjunctiva and pterygium. RESULTS: We found differential c-MAF expression between adult human limbus, cornea and conjunctiva tissues. Further, we observed that c-MAF is downregulated in the pterygium compared to healthy conjunctiva. CONCLUSION: Overall, our results suggest that c-MAF may play a context-specific role in maintaining limbal, corneal and conjunctival homeostasis, and may be critical for preventing pterygium development in humans.