Biology subjects

SHARMA, N.

Publications and source records attributed to SHARMA, N..

3 recordsLinked to original sources

bioRxiv2026

Distinct Regulation of Host Defences by CRISPR-Cas in Typhoidal and Non-Typhoidal Salmonella serovars

CRISPR-Cas systems are best known for their role in adaptive immunity, but emerging evidence suggests broader regulatory functions. Here, we show that the CRISPR-Cas system acts as a serovar-specific regulator of stress adaptation in Salmonella enterica, exerting opposing effects in host-restricted (S. Typhi) and broad-host-range (S. Typhimurium) serovars. In S. Typhi, CRISPR-Cas system deletion reduces acid and bile tolerance by impairing envelope integrity and repressing key stress-response regulators (envZ, cadB, phoPQ, lexA, ruvB, wecD), while increasing resistance to cationic antimicrobial peptides via pmr activation and reduced oxidative damage. Conversely, CRISPR-Cas system loss in S. Typhimurium enhances acid survival-partly through speF upregulation but increases sensitivity to antimicrobial peptides. Spacer-1 of S. Typhi CRISPR-I array as the main regulator of gene expression, and its reintroduction partially restored stress tolerance, supporting spacer-dependent control of physiological pathways. These findings establish the CRISPR-Cas system as a non-canonical, spacer-dependent regulator of stress response networks in S. enterica, revealing its contribution to the evolutionary divergence of survival strategies between S. Typhi and S. Typhimurium.

microbiology↗

bioRxiv2025

Liver Kinome Profiling Identifies PS1145 as a Potential Therapeutic molecule for amelioration of Systemic Inflammation in Alcohol-related Liver Disease

Background and aimsAlcohol-related liver disease (ALD) has high mortality due to systemic inflammation. We analysed liver and monocyte kinome profiles in a chronic ethanol-fed pre-clinical rat model to identify therapeutic targets that could mitigate inflammation in ALD. MethodKinome profile was performed in liver and circulating monocytes at baseline, and after 8,12,16,20 and 24-weeks of 40% ethanol administration. Pathway-specific inhibitors, including PS1145 (IKK-phosphorylation inhibitor), PH-797804 (MAPK14 inhibitor), resveratrol and prednisolone were tested for their anti-inflammatory effects in ALD-rats, PBMC from patients and NIAAA mouse model. ResultsKinome profiling identified 497 liver and 345 monocyte kinases in ALD rats (FDR<0.01). A time-dependent increase in MAPK14-associated kinases was observed in both tissues (FC>1.5, p<0.05). By 24 weeks, 172 liver and 48 monocyte kinases were significantly upregulated, particularly those linked to MyD88-TLR4, PI3K-Akt, TNF, TGF{beta}, and cellular senescence pathways. Key contributors included TGF{beta}R1, ROS-generating kinases, and IL-1-driven MAPK14 and IKK phosphorylation. Targeting this axis, PS1145 (an IKK inhibitor) suppressed NF{kappa}B activation and inflammation in THP1 and HepG2 cells, as well as PBMCs from healthy and SAH patients, outperforming PH797804, resveratrol, and prednisolone (p<0.05, FC>1.5). PS1145 significantly reduced IL-6, TNF, and NF{kappa}B, while increasing IL-10. In vivo, PS1145 treatment in the NIAAA mouse model markedly reduced hepatic steatosis, cellular stress and inflammatory pathways (cytokine signalling, IL-36 signalling and others) more effectively than standard therapies, Notably, it also downregulated IL36R, impairing TLR receptor dimerization, suggesting a dual mechanism of action (p<0.05) highlighting its therapeutic potential in ameliorating systemic inflammation in ALD. ConclusionOur study highlights the key role of MAPK14 and MYD88-TLR4 pathway kinases in driving systemic inflammation in SAH. The IKK inhibitor PS1145, by blocking both IKK phosphorylation and TLR dimerization, effectively suppresses inflammatory signalling and improves liver pathology, positioning it as a promising targeted therapy for ALD.

pharmacology and toxicology↗

bioRxiv2025

R allele of ACTN3 R577X gene polymorphism is associated with Elite Indian Boxer Status

Genetic variations are considered important for athletic performance. In this regard, polymorphisms in angiotensin I-converting enzyme (ACE) and -actinin-3 genes are widely studied for their association with elite athlete status. The ACE gene regulates circulatory homeostasis, with the I variant of the ACE insertion/deletion (ACE I/D) gene polymorphism being associated with endurance performance, while the R allele of the R577X polymorphism of the ACTN3 gene, crucial for fast glycolytic muscle fibers, has been associated with speed and power performances. The present study investigated the association of these genetic variants with elite boxer (N=57) status and compared it with elite power/speed athletes (N=40), endurance athletes (N=44) and nonathletes (N=98) in the Indian population. The R allele frequency was found significantly higher in boxers than the nonathletes (p < 0.05). The allele and genotype frequencies of boxers, endurance and power/speed athletes did not differ significantly (p > 0.05). After analyzing overall athletic cohort on the basis of their level of performance, the frequency of RR genotype (24.1%) and R allele (47.7%) in national level athletes was found significantly higher than in nonathletes (8.7% and 34.2%, respectively), with the significant difference (p < 0.05) between national level endurance athletes and nonathletes only. The ACE I/D gene polymorphism was not found associated with any of the athletic cohorts (p > 0.05). Taken altogether, our study showed that the R allele of ACTN3 gene polymorphism is associated with elite boxer status as compared to the nonathletes. HighlightsO_LIBoxers had a higher ACTN3 gene R allele frequency than nonathletes; genotype did not differ. C_LIO_LIBoxers with RR genotype had more than 3x higher odds versus nonathletes (p = 0.02) in the X dominant model (RR vs RX+XX). C_LIO_LIACTN3 gene allele and genotype frequencies differed between overall athletic cohort and nonathletes. C_LIO_LIACE gene frequencies showed no difference or association across athletic cohorts. C_LI

genetics↗