Integrated in-silico and in-vitro assessments of HDAC6 inhibitor efficacy in mitigating amyloid beta pathology in Alzheimer's disease.

Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aß) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aß degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aß build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aß load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aß accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.

A systematic review for the development of Alzheimer's disease in in vitro models: a focus on different inducing agents.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and is associated with dementia. Presently, various chemical and environmental agents are used to induce in-vitro models of Alzheimer disease to investigate the efficacy of different therapeutic drugs. We screened literature from databases such as PubMed, ScienceDirect, and Google scholar, emphasizing the diverse targeting mechanisms of neuro degeneration explored in in-vitro models. The results revealed studies in which different types of chemicals and environmental agents were used for in-vitro development of Alzheimer-targeting mechanisms of neurodegeneration. Studies using chemically induced in-vitro AD models included in this systematic review will contribute to a deeper understanding of AD. However, none of these models can reproduce all the characteristics of disease progression seen in the majority of Alzheimer's disease subtypes. Additional modifications would be required to replicate the complex conditions of human AD in an exact manner. In-vitro models of Alzheimer's disease developed using chemicals and environmental agents are instrumental in providing insights into the disease's pathophysiology; therefore, chemical-induced in-vitro AD models will continue to play vital role in future AD research. This systematic screening revealed the pivotal role of chemical-induced in-vitro AD models in advancing our understanding of AD pathophysiology and is therefore important to understand the potential of these chemicals in AD pathogenesis.

Update on omicron variant: What we know so far.

The new omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in South Africa in November 2021 has been declared as a Variant of Concern by the World Health Organization. This variant has been found to carry multifold mutations that have not been observed in any of the variants detected so far. The majority of these mutations are present in spike protein, contributing to its ability to escape the currently available neutralizing antibodies and vaccines, as well as increasing the chances of reinfection. This brief communication provides an insight into mutations detected in the omicron variant and their impact on currently available interventions against SARS-CoV-2 and the need for a booster dose. We also discuss the severity status of infection due to this variant. Additionally, we highlight the hypothesis supporting the association of high HIV prevalence and the appearance of the omicron variant of SARS-CoV-2 in immune-compromised individuals.

Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R).

INTRODUCTION: Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein. MATERIALS AND METHODS: Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). RESULTS AND DISCUSSION: Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better. CONCLUSION: We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.

Stem cell therapy in COVID-19: Pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review.

BACKGROUND: SARS-CoV-2, which majorly affects the lungs and respiratory tract is thought due to dysregulation of the immune system which causes an immense imbalance of the cytokines. However, till now no standard treatment has been developed in treating the disease. On the other hand, it becomes important to prevent the acute respiratory tract infection due to COVID-19 which is the most dangerous phase leading to increased mortality. Hence this systematic review has been framed by pooling the available data of the use of stem cells in SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS. METHODS: 6 literature databases (PubMed, EMBASE, Scopus, Google Scholar, Clinicaltrials.gov, and Clinical trial registry of India) were searched for relevant studies till 10th August 2020 using keywords stem cells, mesenchymal stem cells, cell therapy, SARS CoV-2, SARS Coronavirus, Coronavirus 2, COVID-19, nCoV-19, Novel Coronavirus, MERS CoV, ARDS, acute respiratory distress syndrome. RESULTS: The observations of this systematic review suggest capability of MSCs in reducing the systemic inflammation and protecting against SARS-CoV-2 as evidenced by the available clinical data. CONCLUSION: MSCs can overcome the clinical challenges currently faced by SARS-CoV-2 infected patients, specifically who are seriously ill and not responding to conventional therapies. Though the available clinical data is motivating, still predicting the therapeutic potential of MSCs will be too early in COVID-19. Hence, further studies in a larger cohort of patients becomes a prerequisite to validate their potential efficacy.

Pharmacological evaluation and antifertility activity of Jatropha gossypifolia in rats.

OBJECTIVES: Pharmacological and antifertility activity evaluation of Jatropha gossypifolia in rats. METHODS: The antifertility activity of the extracts of Jatropha gossypifolia in rats was evaluated using two experimental animal models. Estrogenic activity was evaluated in immature female rats using ethinyl estradiol as standard. Anti-implantation and early abortifacient activity was performed in female Wistar rats by determining the number of implantations and implantation resorptions. RESULTS: In estrogenic activity evaluations, the ethanolic and aqueous extracts offered significant estrogen-like activity at 400 mg kg⁻¹ p.o. by increasing the uterine weight compared to vehicle control group. Ethanolic extract (400 mg kg⁻¹, p.o.) treatment significantly decreased the number of implants and increased the number of resorptions compared to vehicle control group. CONCLUSION: The results of the present study provide the evidence of the anti-fertility activity of Jatropha gossypifolia as claimed in the traditional use. The results are consistent with the literature reports related to the antifertility effect of flower extracts of Jatropha gossypifolia.