Biology subjects

Chaudhary, M.

Publications and source records attributed to Chaudhary, M..

6 recordsLinked to original sources

bioRxiv2026

Aberrant microglial responses shape hypothalamic circuits in anorexia nervosa

Multimodal data indicates that microglia contribute to the pathophysiology of anorexia nervosa (AN). Here, we investigated microglial modulation of hypothalamic circuits, key regulators of energy balance, hypothesising an implication in the prolonged starvation and low body weight of AN. First, we generated microglia as well as hypothalamic and cortical neurons from patient-derived induced pluripotent stem cells (iPSCs) to discover upregulation of synapse-related genes in hypothalamic neurons, reduced microglial uptake of hypothalamic synaptic structures, and a microglial unresponsivness to the satiety hormone glucagon-like peptide-1. In an AN animal model (anx/anx mouse), spatial transcriptomics indicated hypothalamic microglial activation and disrupted microglia-synapse signaling. Despite an increased microglia density in both the arcuate nucleus (ARC) and the dorsomedial hypothalamus region (DMH), microglia displayed a decreased per cell uptake of synaptic material in Arc. Together, these data suggest that microglial responses shape hypothalamic circuits with possible implications for the maintained negative energy balance of AN.

neuroscience↗

bioRxiv2025

DRP1-mediated mitochondrial dynamics orchestrate EMT in glioblastoma cells

BackgroundEpithelial to mesenchymal transition (EMT), a differentiation process, frequently imparts invasive properties in Glioblastoma Multiforme (GBM), which leads to a poor prognosis. Cells lose apical-basal polarity, cell-cell connections, and/or chemo-resistance during EMT, which can result in the spread of cancer and the acquisition of additional stem cell-like traits. It is unclear how organelle dynamics influence EMT in this respect. The interaction between cytoskeletal and mitochondrial regulators governing GBM cell EMT is explored in this article. Results and DiscussionIn GBM cells, we observed that TGF-{beta}-induced EMT led to a proliferative arrest, which was accompanied by a fragmented mitochondrial morphology, elevated expression of fission markers such as DRP1, MFF, and FIS1, and most importantly, localization of mitochondria near the cell boundaries. An increase in mitochondrial ROS accompanied this, but their functional status was indicated by a higher oxygen consumption rate (OCR). Additionally, cytoskeleton re-distribution and EMT reversal were the outcomes of si-RNA-mediated elimination of the fission-marker DRP-1 or pharmacological inhibition of fission by Mdivi-1. On the other hand, drugs that disrupt the cytoskeleton, shifted the spatial distribution of mitochondria to the perinuclear area, which had an adverse effect on EMT. Notably, it was shown that RhoA, a protein that helps organize the actin cytoskeleton, co-immunoprecipitates with DRP1 and governs both cytoskeletal dynamics and mitochondrial fission in its presence. ConclusionOur research sheds substantial insight on the current interactions between the cytoskeleton and mitochondrial spatial dynamics that control EMT in GBM cells, which may have significant therapeutic implications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/694080v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@81b796org.highwire.dtl.DTLVardef@3bec9aorg.highwire.dtl.DTLVardef@2a79c3org.highwire.dtl.DTLVardef@9ff14a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Carnosinylation of Cardiac Antigens Attenuates Immunogenic Responses and Improves Function in Failing Hearts

ObjectiveTo investigate the effects of carnosine on heart failure and to examine whether this is associated with reduced immunogenicity of oxidatively-generated aldehyde modified proteins. BackgroundHeart failure is associated with the accumulation of lipid derived aldehydes that form immunogenic protein adducts. However, the pathological impact of these aldehydes and aldehyde-modified proteins in heart failure has not been assessed. Histidyl dipeptides, such as carnosine found in the heart, bind to aldehydes, and their protein adducts. However, the effects of carnosine on heart failure or the antigenicity of aldehyde modified proteins have not been studied. MethodsMale, wild type C57BL/6J mice were subjected to either sham or transverse aortic constriction (TAC) surgery. To increase carnosine levels, they were placed on drinking water with or without {beta}-alanine prior to surgery, and for the remainder of the study. Cardiac function was evaluated by echocardiography, and the levels of histidyl dipeptides, immune cell populations, and CD4+ T cell activation were assessed via LC-MS/MS and flow cytometry, respectively. ResultsMyocardial levels of histidyl dipeptides decreased at both 3- and 8-weeks post-TAC. Supplementation with {beta}-alanine increased myocardial histidyl dipeptide levels, attenuated adverse cardiac remodeling, and reduced aldehyde stress. Carnosine formed covalent bond with protein-bound aldehydes in the failing heart, reducing their antigenic potential and decreasing activation of dendritic cells and CD4+ T cells in vitro. {beta}-alanine supplementation decreased the population of CD11b+CD64-Ly6G+ neutrophils and CD4+ CD44+ effector T cells in the failing heart. ConclusionsIncreasing myocardial carnosine levels reduces aldehyde stress, dampens maladaptive immune responses, and preserves cardiac function during heart failure. HIGHLIGHTSO_LILevels of endogenous dipeptide carnosine are depleted in failing hearts, while supplementation of the carnosine precurson {beta}-alanine increases myocardial carnosine and preserves cardiac function during heart failure. C_LIO_LIHeart failure is associated with increased activation and infiltration of CD4+ T cells and generation of aldehyde modified protein adducts in failing hearts. C_LIO_LIThe free aldehyde moiety of aldehyde modified protein adducts activates CD4+ T cells through dendritic cell presentation and capping this moiety with carnosine diminishes their antigencity. C_LIO_LIIncreasing myocardial carnosine levels diminishes aldehyde stress and activation of CD4+ T cells during heart failure. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/671840v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@28fc7corg.highwire.dtl.DTLVardef@d851ccorg.highwire.dtl.DTLVardef@1e24a5dorg.highwire.dtl.DTLVardef@18023b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

YY1 protein is essential for the promotion of Muller glia reprogramming and retina regeneration

Unlike mammals, the Muller glia reprogramming in zebrafish retina restores vision after an acute retinal injury. Here, we explored the Ying yang (Yy1) protein and its multi-faceted roles in different phases of retina regeneration. We show that the acetylation and deacetylation status of Yy1 contribute to its transcriptional activation and repression functions on various target genes, including regeneration-associated genes (RAGs). Yy1 is regulated positively by TGF-{beta} and negatively through Delta-Notch signaling in the injured retina. Yy1-knockdown caused reduced retinal progenitor induction and regeneration, while the opposite was seen in its overexpression. Yy1 collaborates with histone deacetylases, BAF complex, and the effector of TGF-{beta} signaling, pSMAD3, to target the genome differentially. Lastly, the whole transcriptome analysis of the Yy1-debilitated retina revealed differential expression of various RAGs and BMP-signaling. Yy1 facilitates the BMP pathways genes through the downregulation of noggin3. Our study unravels how a single transcription factor, Yy1, could influence many important regulatory steps of retina regeneration.

cell biology↗

bioRxiv2024

Reciprocal regulation of autophagy and exosome pathway is mediated by GABARAPL2 and Alix to facilitate cellular homeostasis

The continuous reliance of cancer cells to acquire energy and communicate their nutrient needs makes them resilient and vulnerable. It provides an opportunity to stifle cancer cells by restricting their energy generation and communication ability. Autophagy and exosome biogenesis are two such pathways that are essential in maintaining the robust growth and survival of cancer cells. In this study we observed that inhibition of one pathway altered the expression of genes in other pathway. Exosome biogenesis, when blocked, led to an increase in breast cancer cell proliferation, while inhibition of autophagy did not significantly affect cancer cell proliferation. Therefore, the two pathways, when independently inhibited, did not present any significant effect on restricting cancer cell growth. However, we observed a substantial reduction in cancer cell proliferation upon combined inhibition of two pathways. To evaluate the reciprocal regulation of two pathways, we blocked the autophagy pathway and observed increase in the secretion of exosomes from MDA-MB-231 cells, along with decreased expression of Alix and CD63. On contrary, inhibition of exosome biogenesis led to an increase in the expression of ATG5 and ATG16L1, which caused a significant decrease in expression of GABARAPL2. Interestingly, the knockdown of GABARAPL2 abrogated the decrease in Alix expression upon autophagy inhibition, thus highlighting the essential role of GABARAPL2 in Alix secretion. Thus, our study highlights for the first time the synergistic effects of autophagy and exosome pathway inhibition in restricting cancer cell growth as well as the involvement of GABARAPL2 in the regulation of exosome secretion via modulating Alix expression.

cancer biology↗

bioRxiv2022

Men in menopause? Experimental verification of the mate choice theory of menopause with Drosophila melanogaster

Various hypotheses regarding the origin of menopause have been proposed, and although the kin-selection-based theory appears promising, it involves population genetic processes that are insufficient to compensate for loss of fitness. The grandmother hypothesis and its variation the live long hypothesis are untenable; the former requires "climbing a steep fitness hill", as grandmothers share only 25% of their genes with their grandchildren, compared to 50% with their direct offspring, while the latter proposes a prolongation of the post-menopausal lifespan through selection, which is impossible in a population of non-reproducing females. The mate choice theory explains menopause as the result of asymmetric mating involving younger females and older males that leads to an accumulation of infertility mutations and the evolution of menopause in older females. In this study, we investigated the mate choice theory using an infertility mutation accumulation experiment with Drosophila melanogaster that involved mating between individuals of different age groups. After 70 generations of asymmetric mating, the results showed that younger females who were paired with older males showed declining fertility in old age. The same trend was noted with younger males when mated with older females; the fertility of the males declined in old age. These results support the mate choice theory and indicate that menopause is not a life history trait of females but of the sex of the younger mate. Mate choice theory treats the evolution of menopause and post-menopausal lifespan as independent traits that are driven by the mate choices exercised by older males. Menopause may be an atypical process because the evolutionary mechanism (age-restricted asymmetric mating) involved is rarely observed.

evolutionary biology↗