👤 Rajendra Awasthi

Artemisinin and its derivatives, used as front-line anti-malarial drugs, exhibit anti-inflammatory properties. They were found to suppress the generation and function of Th1 and Th17 cells while promoting the generation of Foxp3 + regulatory T cells (Tregs). However, the specific role of Artemotil (β-arteether) in modulating the generation and functions of CD4 + T cells, particularly Type 1 regulatory T cells (Tr1), remains to be explored. Tr1 cells are one of the key cell types that are essential for regulating inflammatory response through IL-10. In this study, we report that Artemotil selectively promotes generation of Tr1 cells induced by IL-27 by upregulating signature genes of Tr1 cells, such as c-Maf, AhR, prdm1, IRF-1, and Batf, while inhibiting the Th1, Th2, and Th17 cells generation. We found that co-administration of Artemotil with anti-CD3 antibody increases the induction of IL-10 and frequency of Tr1 cells while suppressing Th1 and Th17 cells in vivo. Artemotil suppresses T-cell-induced enteropathy and alleviates the signs of colitis associated with the increased frequencies of Tr1 cells. Taken together, our data suggest that Artemotil provides protection in T-cell-mediated colitis by increasing the expansion of Tr1 cells and inhibiting the generation of Th1 and Th17 cells. Show less

Many drug targets in ongoing Parkinson's disease (PD) clinical trials have strong genetic links. While genome-wide association studies (GWAS) nominate regions associated with disease, pinpointing causal genes is challenging. Our aim was to prioritize additional druggable genes underlying PD GWAS signals. The polygenic priority score (PoPS) integrates genome-wide information from MAGMA gene-level associations and over 57,000 gene-level features. We applied PoPS to East Asian and European PD GWAS data and prioritized genes based on PoPS, distance to the GWAS signal, and non-synonymous credible set variants. We prioritized 46 genes, including well-established PD genes (SNCA, LRRK2, GBA1, TMEM175, VPS13C), genes with strong literature evidence supporting a mechanistic link to PD (RIT2, BAG3, SCARB2, FYN, DYRK1A, NOD2, CTSB, SV2C, ITPKB), and genes relatively unexplored in PD. Many hold potential for drug repurposing or development. We prioritized high-confidence genes with strong links to PD pathogenesis that may represent our next-best candidates for developing disease-modifying therapeutics. Show less

Gallbladder cancer (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, the authors attempted to bridge this gap by revealing the mutational profile of GBC. To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 tumor and matched blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package. Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology. Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection. Show less

Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the β-catenin destruction complex, reinforcing β-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced β-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation. Show less

Recent advancements in Parkinson's disease (PD) drug development have been significantly driven by genetic research. Importantly, drugs supported by genetic evidence are more likely to be approved. While genome-wide association studies (GWAS) are a powerful tool to nominate genomic regions associated with certain traits or diseases, pinpointing the causal biologically relevant gene is often challenging. Our aim was to prioritize genes underlying PD GWAS signals. The polygenic priority score (PoPS) is a similarity-based gene prioritization method that integrates genome-wide information from MAGMA gene-level association tests and more than 57,000 gene-level features, including gene expression, biological pathways, and protein-protein interactions. We applied PoPS to data from the largest published PD GWAS in East Asian- and European-ancestries. We identified 120 independent associations with Show less

Dementia is a global health concern owing to its complexity, which also poses a great challenge to pharmaceutical scientists and neuroscientists. The global prevalence of dementia is approximately 47 million, which may increase by three times by 2050. Alzheimer's disease (AD) is the most common cause of dementia. AD is a severe age-related neurodegenerative disorder characterized by short-term memory loss, aphasia, mood imbalance, and executive function. The etiology of AD is still unknown, and the exact origin of the disease is still under investigation. Aggregation of amyloid β (Aβ) plaques or neurotoxic Aβo oligomers outside the neuron is the most common cause of AD development. Amyloid precursor protein (APP) processing by β secretase and γ secretase produces abnormal Aβ monomers. This aggregation of Aβ and NFT is promoted by various genes like BACE1, ADAM10, PIN1, GSK-3, APOE, PPARα, etc. Identification of these genes can discover several therapeutic targets that can be useful in studying pathogenesis and underlying treatments. Melatonin modulates the activities of these genes, thereby reducing Aβ production and increasing its clearance. Melatonin also reduces the expression of APP by attenuating cAMP, thereby enhancing the nonamyloidogenic process. Present communication explored and discussed the neuroprotective role of melatonin against Aβ-dependent AD pathogenesis. The manuscript also discussed potential molecular and genetic mechanisms of melatonin in the production and clearance of Aβ that could ameliorate neurotoxicity. Show less

Selective permeability of the blood-brain barrier restricts the treatment efficacy of neurologic diseases. Berberine (BBR) and curcumin (CUR)-loaded transferosomes (TRANS) were prepared for the effective management of Alzheimer's disease (AD). The study involved the syntheses of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS by the film hydration method. Vesicles were characterized to ensure the formation of drug-loaded vesicles and their in vivo performance. The particle sizes of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS were 139.2 ± 7, 143.4 ± 8, and 165.3 ± 6.5 nm, respectively. The presence of diffused rings in the SED image indicates the crystalline nature of the payload. Low surface roughness in an AFM image could be associated with the presence of a surface lipid. BBR-CUR-TRANS showed 41.03 ± 1.22 and 47.79 ± 3.67% release of BBR and 19.22 ± 1.47 and 24.67 ± 1.94% release of CUR, respectively, in phosphate buffer saline (pH 7.4) and acetate buffer (pH 4.0). Formulations showed sustained release of both loaded drugs. BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS exhibited a lower percentage of hemolysis than pure BBR and CUR, indicating the safety of the payload from delivery vesicles. Lower percentages of binding were recorded from BBR-CUR-TRANS than BBR-TRANS and CUR-TRANS. Acetylcholinesterase inhibition activity of the prepared transferosomes was greater than that of pure drugs, which are thought to have good cellular penetration. The spatial memory was improved in treated mice models. The level of malondialdehyde decreased in AD animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS, respectively, as compared to the scopolamine-induced AD animals. BBR-CUR-TRANS-treated animals showed the highest decrease in the NO level. The catalase level was significantly restored in scopolamine-intoxicated animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS. The immunohistochemistry result suggested that the BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS have significantly decreased the regulation of expression of BACE-1 through antioxidant activity. In conclusion, the study highlights the utility of formulated transferosomes as promising carriers for the co-delivery of drugs to the brain. Show less

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3 Show less