Biology subjects

Parihar, S. P.

Publications and source records attributed to Parihar, S. P..

4 recordsLinked to original sources

bioRxiv2025

Metabolomics of a Cysteinyl Leukotriene Receptor 1 (CysLTR1) Knockout Mouse Model by Analysis of Bronchoalveolar Lavage Fluid Using Gas Chromatography-time of Flight Mass Spectrometry.

Cysteinyl leukotriene receptor 1 (CysLTR1), a potent lipid mediator, is known for its critical role in regulating inflammatory responses, particularly in asthma and airway diseases. While its function in immune cell recruitment has been previously reported, its broader impact on pulmonary metabolism remains largely unexplored. In this study, we investigated the metabolic consequences of CysLTR1 deletion in mice using GC-TOFMS-based metabolomics analysis of bronchoalveolar lavage fluid (BALF) from both CysLTR1 knockout (KO) and wild-type (WT) mice. The BALF from CysLTR1 KO mice exhibited significantly reduced levels of glucose, gluconic acid, sedoheptulose, D-xylose, glucosamine, glyceric acid, and 1-methylinosine, indicating impaired glucose uptake and dysregulation of glycolysis and gluconeogenesis. Further disruption of glucose-associated pathways, including the pentose phosphate pathway and purine metabolism, alongside reduced 1-methylinosine levels, suggests altered RNA turnover. In addition, decreases in butanoic acid, decan-2-ol, and 1-hexadecanol point to dysregulated fatty acid metabolism, potentially as a compensatory response to glucose deficiency. Altered levels of mandelic acid, glutaric acid, tricarballylic acid, and decan-2-ol, some of which are derived from corn-based diets also indicate changes in the pulmonary microbiome. Overall, the deletion of CysLTR1 significantly disrupts pulmonary metabolic homeostasis, affecting the metabolism of carbohydrates, lipids, amino acids, nucleotides, and microbial-derived metabolites.

biochemistry↗

bioRxiv2025

Protein Kinase C δ: a critical hub regulating macrophage immunomodulatory functions during Mycobacterium tuberculosis infection

A host-modulating candidate gene involved in putative pathogen-killing pathways, with potential novel therapeutic intervention, Protein Kinase C - {delta} (PKC{delta}) has been recognized as a critical marker of inflammation with clinical and experimental evidence in recent years. Pulmonary microenvironment during Mtb infection is largely governed by lung resident macrophages, initiating innate and subsequent adaptive immune responses. We investigated the role of PKC{delta} in macrophages using a macrophage-specific PKC{delta} knockout mice model (LysMcrePKC{delta}flox/flox). PKC{delta} deficiency in macrophages triggers an early lymphocytic immune response, increases neutrophil recruitment, and reduces inflammatory macrophages in the lungs, leading to higher Mtb burden and exacerbated pathology. Experimental and omics analysis further revealed that dysregulation of antimicrobial effector functions is detrimental to macrophages ability to restrict bacterial growth in vitro. Importantly this defect was mitigated by exogenous GM-CSF supplementation and/or overexpressing PKC{delta} in macrophages. Thus, PKC{delta} plays a crucial role in immune modulation during Mtb infection with GM-CSF amongst several downstream pathways through which PKC{delta} exerts its regulatory effects. TeaserPKC{delta} is crucial for immune modulation during Mtb infection revealing macrophages as a potential axis of signaling.

immunology↗

bioRxiv2025

Targeting ALOX5/LTA4H driven granuloma caseation as a host-directed strategy for control of TB associated lung damage

Tuberculosis remains one of the major global health challenges with those previously exposed presenting persisting pulmonary dysfunction. Therefore, improved control measures are still required to prevent or reduce the TB-induced immunopathology in affected individuals. Host directed therapies that target host factors, have been suggested to improve on current treatments against TB. We previously reported a potential role for proteins which metabolize the arachidonic acids during TB immunopathogenesis. The study, therefore, sought to demonstrate the potential role of these proteins in TB-induced immunopathology. Using immune-histopathological assays, the association of macrophage driven ALOX5 signaling with severe pulmonary immunopathology during TB was demonstrated. Furthermore, using both in vitro and in vivo assays, the data demonstrated the contribution of ALOX5 signaling to TB-induced granulomatous inflammation. Interception of the signaling pathway through clinically approved pharmaceutical inhibitors, resulted in reduced lung damage during the disease. The resolution of TB-induced lung pathology further contributed to increased bactericidal activity. Taken together, our data strongly suggest a role for macrophage driven inflammation via ALOX5 signaling which can be targeted for the development of therapeutic treatment to prevent exacerbated TB-induced pulmonary immunopathology.

immunology↗

bioRxiv2017

Viral apoptosis evasion via the MAPK pathway by use of a host long noncoding RNA

An emerging realisation of infectious disease is the high incidence of genetic instability resulting from pathogen-induced DNA lesions, often leading to classical hallmarks of cancer such as evasion of apoptosis. The Human Immunodeficiency Virus type 1 (HIV-1) induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages, thereby leading to long-term dissemination of the pathogen specifically by these host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21, in a complex with its protein binding partners HuR and hnRNP-K. Here, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Notably, this pro-survival cascade is unavailable for similar viral manipulation in CD4+ T cells. The introduction of MAP2K1, ERK2 or HDM2 inhibitors in HIV-infected macrophages results in apoptosis providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and hnRNP-K. These results reveal pathogenic control of apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages.

molecular biology↗