Calcifediol boosts efficacy of ChAdOx1 nCoV-19 vaccine by upregulating genes promoting memory T cell responses.

The ChAdOx1 nCoV-19 (COVISHIELD) vaccine has emerged as a pivotal tool in the global fight against the COVID-19 pandemic. In our previous study eligible subjects were supplemented with calcifediol, a direct precursor to the biologically active form of vitamin D, calcitriol with an objective to enhance the immunogenicity of the COVISHIELD vaccine. Herein we investigated the effects of calcifediol supplementation on gene expression profiles in individuals who received the COVISHIELD vaccine. Peripheral blood mononuclear cells were isolated from vaccinated individuals with and without calcifediol supplementation at baseline, 3rd and 6th month, and the gene expression profiles were analyzed using high-throughput sequencing. The results revealed distinct patterns of gene expression associated with calcifediol supplementation, suggesting potential molecular mechanisms underlying the beneficial effects of calcifediol in improving the efficacy of COVISHIELD vaccine via augmentation of T cell activation, proliferation and T cell memory responses. Additionally, there was upregulation of NOD like receptor, JAK/STAT and TGF beta signaling pathways. Calcifediol supplementation in vaccinated individuals also downregulated the pathways related to the Coronavirus disease. Taken together, our findings provide valuable insights into the interplay between vitamin D receptor (VDR) signaling and vaccine-induced immune responses and offer another approach in improving vaccination induced antiviral responses.

Target Specific Uptake of a Newly Synthesized Radiolabeled 5α-Reductase Inhibitor "Tc-99m-17-Oxo-17a-Aza-D-Homo-5-Androsten-3ß-yl Phenoxyacetate (Tc-99m-17a-Aza Steroid)" in Rat Prostatic Neoplastic Lesions.

Objective: Considering the 5α-reductase (5AR) inhibitory activity of the oximes and the importance of the ester group in increasing the anti-androgenic property, we reasoned to synthesize a compound having a lactam group in ring D and an ester group at the 3 ß position of the androsterone nucleus. The study aims to radiolabel 17-oxo-17a-aza-D-homo-5-androsten-3ß-yl phenoxyacetate (17a-aza steroid) with Tc-99m to evaluate its targeted uptake in experimentally induced prostate carcinogenesis in rats. Materials and Methods: The prediction of the optimal interaction and binding affinity of Tc-99m-17-oxo-17a-aza-D-homo-5-androsten-3 ß-ylphenoxyacetate (Tc-99m-17a-aza steroid) toward 5AR inhibitor was done using Biopredicta Vlife MDS tool. Tc-99m-17a-aza steroid was developed by direct radiolabeling protocol. The radio-pharmacological characteristics (serum stability, plasma protein-binding ability, and lipophilicity) of the complex were evaluated. Further, the bio-distribution studies of the complex were performed in rats with experimentally induced prostate carcinogenesis. Results: The in-silico analysis exhibits favorable binding of Tc-99m-17a-aza toward 5AR with D score-130.97. The radiochemical purity of Tc-99m-17a-aza was 96.79%. The radio-complex maintained stability in the rat serum for a period of 6 h (hours). Plasma protein binding and Log Po/w value were observed to be 86.23 ± 7.08% and 0.118 ± 0.045, respectively. A significantly enhanced percent-specific uptake was observed in the prostate of rats with induced prostate carcinogenesis. Conclusion: The study concludes that Tc-99m-17a-aza exhibits prostate specificity and can be explored further for its potential as a radionuclide imaging probe.

Understanding the epigenetic mechanisms in SARS CoV-2 infection and potential therapeutic approaches.

COVID-19 pandemic caused by the Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) has inflicted a global health challenge. Although the overwhelming escalation of mortality seen during the initial phase of the pandemic has reduced, emerging variants of SARS-CoV-2 continue to impact communities worldwide. Several studies have highlighted the association of gene specific epigenetic modifications in host cells with the pathogenesis and severity of the disease. Therefore, alongside the investigations into the virology and pathogenesis of SARS-CoV-2 infection, understanding the epigenetic mechanisms related to the disease is crucial for the rational design of effective targeted therapies. Here, we discuss the interaction of SARS-CoV-2 with the various epigenetic regulators and their subsequent contribution to the risk of disease severity and dysfunctional immune responses. Finally, we also highlight the use of epigenetically targeted drugs for the potential therapeutic interventions capable of eliminating viral infection and/or build effective immunity against it.

Sarm1 induction and accompanying inflammatory response mediates age-dependent susceptibility to rotenone-induced neurotoxicity.

Aging is a complex biological process and environmental risk factors like pesticide exposure have been implicated in the increased incidence of age-related neurodegenerative diseases like Parkinson's disease (PD) but the etiology remains unknown. There is also lack of a proper animal model system to study the progressive effect of these environmental toxins on age-associated neurodegeneration. In this study, we established a drosophila model of aging to study the age-dependent vulnerability to the environmental toxin rotenone that has been implicated in sporadic cases of PD. We demonstrate that age plays a determining role in the increased susceptibility to chronic rotenone exposure that is accompanied by severe locomotor deficits, decreased lifespan and loss of dopaminergic (DA) neurons. Chronic low dose exposure to rotenone results in the rapid induction of the neurodegenerative molecule SARM1/dSarm. Further, the age-dependent dSarm induction is accompanied by a heightened inflammatory response (increased expression of Eiger and Relish) that is independent of reactive oxygen species (ROS) generation in the observed rotenone-induced neurotoxicity. dSarm induction and subsequent locomotor deficits is reversed in the presence of the anti-inflammatory molecule resveratrol. Thus, dSarm and heightened inflammatory responses may play a crucial role in age-dependent vulnerability to the pesticide rotenone thus making it an attractive target to help develop cost-effective therapeutic strategies to prevent ongoing dopaminergic neuronal loss as seen in PD.