Biology subjects

Murugesan, S.

Publications and source records attributed to Murugesan, S..

7 recordsLinked to original sources

bioRxiv2026

TH1834-Mediated TIP60 Inhibition Protects Against Ischemia/Reperfusion Damage in Human iPSC-Derived Cardiomyocytes and Cardioids

Ischemia/reperfusion injury limits functional recovery after myocardial infarction through mitochondrial dysfunction, oxidative stress, energetic failure, impaired calcium handling, and contractile dysfunction. We previously identified the acetyltransferase TIP60/KAT5 as a maladaptive regulator of post-ischemic cardiac injury and showed that pharmacologic TIP60 inhibition with TH1834 mitigates myocardial infarction injury in mice. Here, we tested whether TH1834 promotes recovery in complementary 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) and cardioid (hiPSC-CO) models. Maturation-enhanced hiPSC-CMs subjected to hypoxia/reoxygenation (H/R) reproduced key features of ischemia/reperfusion injury, including mitochondrial loss, oxidative stress, cell death, impaired calcium handling, and contractile dysfunction. RNA sequencing further showed activation of stress programs and suppression of oxidative-metabolic pathways. At a non-arrhythmogenic dose, TH1834 inhibited TIP60 acetyltransferase activity, improved post-H/R survival and beating recovery, preserved mitochondrial and myofibrillar integrity, reduced reactive oxygen species, restored calcium transient kinetics, normalized sarcoplasmic reticulum calcium reserve, and improved contraction and relaxation. A central effect of TH1834 was enhancement of metabolic flexibility: following H/R, treatment restored mitochondrial respiratory capacity while simultaneously increasing glycolytic capacity and reserve. Because CM calcium cycling and mechanical work are highly dependent on energetic supply, this recovery of complementary oxidative and glycolytic capacity provides an energetic basis for improved calcium homeostasis and contractile recovery. Transcriptomic analysis supported this phenotype, showing preferential counter-regulation of H/R-induced stress programs and attenuation of persistent HIF1A-ARNT-PDK1 hypoxic metabolic signaling. In 3D hiPSC-COs, TH1834 similarly enhanced mitochondrial respiratory reserve and glycolytic capacity while improving calcium dynamics, contractile performance, beating recovery, and survival. Together, these findings identify enhanced metabolic flexibility as a central feature of TH1834-mediated protection against H/R, linking restoration of energetic capacity to preservation of calcium signaling and contractile function, supporting TIP60 as a therapeutic target for ischemic heart disease.

cell biology↗

bioRxiv2025

The SMARCA5-DMRT1 Pioneer Complex Establishes Epigenetic Priming to Direct Male Germline Development

The establishment of cell type-specific chromatin landscapes is essential for cellular identity, but how these landscapes are generated remains poorly understood. Here, we demonstrate that the chromatin remodeler SMARCA5 establishes epigenetic priming that is required for retinoic acid (RA)-induced differentiation in the male germline. Germ cell-specific deletion of Smarca5 results in a complete loss of differentiating spermatogonia, phenocopying vitamin A-deficient mice that lack RA signaling. During the perinatal transition from prospermatogonia to undifferentiated spermatogonia, SMARCA5 is recruited to binding sites of the pioneer transcription factor DMRT1, which are located at distal putative enhancers and promoters of germline genes. The SMARCA5-DMRT1 pioneer complex establishes chromatin accessibility at these loci, generating poised enhancers and promoters that serve as RA receptor (RAR)-binding sites. Thus, SMARCA5 licenses transcriptional responses to RA that enable spermatogenic differentiation. Our findings uncover a mechanism linking pioneer factor activity to external signal responsiveness. HighlightsSMARCA5 is required for spermatogonial differentiation The SMARCA5-DMRT1 pioneer complex establishes epigenetic priming for differentiation SMARCA5 remodels inaccessible DMRT1-binding sites to an accessible state SMARCA5 shapes chromatin states that enable retinoic acid responsiveness

developmental biology↗

bioRxiv2024

Decreased Extracellular Vesicle Vasorin in Severe Preeclampsia Plasma Mediates Endothelial Dysfunction

BackgroundPreeclampsia (PE) is a serious pregnancy complication affecting 5-8% of pregnancies globally. It is a leading cause of maternal and neonatal morbidity and mortality. Despite its prevalence, the underlying mechanisms of PE remain unclear. This study aimed to determine the potential role of vasorin (VASN) in PE pathogenesis by investigating its levels in extracellular vesicles (EV) and its effects on vascular function. Methods & ResultsWe conducted unbiased proteomics on urine-derived EV from severe PE (sPE) and normotensive pregnant women (NTP), identifying differential protein abundances. Out of one hundred and twenty proteins with [≥] {+/-}1.5-fold regulation at P<0.05 between sPE and NTP, we focused on Vasorin (VASN), which is downregulated in sPE in urinary EV, in plasma EV and in the placenta and is a known regulator of vascular function. We generated EV with high VASN content from both human and murine placenta explants (Plex EV), which recapitulated disease-state-dependent effects on vascular function observed when treating murine aorta rings (MAR) or human aortic endothelial cells (HAEC) with murine or human plasma-derived EV. In normal murine pregnancy, VASN increases with gestational age (GA), and VASN is decreased in plasma EV, in placenta tissue and in Plex EV after intravenous administration of adenovirus encoding short FMS-like tyrosine kinase 1 (sFLT-1), a murine model of PE (murine-PE). VASN is decreased in plasma EV, in placenta tissue and in EV isolated from conditioned media collected from placenta explants (Plex EV) in patients with sPE as compared to NTP. Human sPE and murine-PE plasma EV and Plex EV impair migration, tube formation, and induces apoptosis in human aortic endothelial cells (HAEC) and inhibit acetylcholine-induced vasorelaxation in murine vascular rings (MAR). VASN over-expression counteracts the effects of sPE EV treatment in HAEC and MAR. RNA sequencing revealed that over-expression or knock down of VASN in HAEC results in contrasting effects on transcript levels of hundreds of genes associated with vasculogenesis, endothelial cell proliferation, migration and apoptosis. ConclusionsThe data suggest that VASN, delivered to the endothelium via EV, regulates vascular function and that the loss of EV VASN may be one of the mechanistic drivers of PE. CLINICAL PERSPECTIVEWhat is New O_LIVASN in circulating plasma EV in sPE is reduced compared with VASN content in plasma EV of gestational age-matched pregnant women. C_LIO_LIVASN is encapsulated and transported in EV and plays a pro-angiogenic role during pregnancy. C_LIO_LIVASN should be explored both for its pro-angiogenic mechanistic role and as a novel biomarker and potential predictive diagnostic marker for the onset and severity of PE. C_LI What Are the Clinical Implications? O_LIVASN plays a role in maintaining vascular health and the normal adaptive cardiovascular response in pregnancy. A decrease of VASN is observed in sPE patients contributing to cardiovascular maladaptation. C_LIO_LIStrategies to boost diminished VASN levels and/or to pharmacologically manipulate mechanisms downstream of VASN may be explored for potential therapeutic benefit in PE. C_LIO_LIThe decrease in EV-associated VASN could potentially be used as a (predictive) biomarker for PE. C_LI

molecular biology↗

bioRxiv2024

History of recurrent short and long-term coral bleaching events in Indian coral reefs: a a systematic review of contrasting bleaching patterns, lessons learned, and future directions

Climate change has intensified coral bleaching events, leading to widespread coral mortality and threatening the coral reef survival worldwide. However, species susceptibility patterns to bleaching differ spatially and temporally, making it crucial to understand bleaching impact and species susceptibility patterns across latitudinal ranges, particularly from understudied locations. We critically reviewed 23 years of bleaching episodes on Indian coral reefs (four major reefs and other patch reefs) reported from 1998 to 2020 to understand the geographical footprint of bleaching patterns, species susceptibility differences, and their impact. We found that all four major Indian reef systems (Gulf of Kachchh, Gulf of Mannar, Lakshadweep, and the Andaman Islands) have experienced three major bleaching episodes (1998, 2010, and 2016) and multiple short-term bleaching events. Short-term bleaching events (DHWs> four weeks) created differences in species susceptibility, but the disparity among species diminished to long-term bleaching events (DHWs <4 weeks) in all reef sites. Acropora, Porites, Pocillopora, Montipora, and Turninaria in the Gulf of Mannar, Porites, and Favia in the Gulf of Kachchh, and Acropora in the Andaman and Lakshadweep were the most vulnerable genera during all the bleaching events. In terms of recovery, Porites and other massive forms recovered better than branching forms. Furthermore, species susceptibility pattern analysis (winners vs. losers) to 2016 long-term bleaching events found conflicting results from studies (one-time surveys) in the same area. This result indicates that a one-time survey (survey timing) influences results as bleaching events lengthen, necessitating repeated surveys to determine winners and losers. Although inconsistent data from different study sites makes it difficult to create predictive models, data collected over the past 23 years provides critical insight into coral community susceptibility patterns and bleaching impacts, underscoring the need for systematic, uniform surveys in the future.

ecology↗

bioRxiv2023

Computational study of Piper betle L. phytocompounds by insilico and ADMET analysis for prediction of potential xanthine oxidase inhibitory activity

BackgroundXanthine oxidase (XO) enzyme is directly associated with pathogenesis of gout and indirectly with cancer, diabetes and metabolic syndromes. Allopurinol is a xanthine oxidase inhibitor which is useful in the treatment of gout but it causes side effects in humans and birds. Therefore, this study sought to identify the alternative compound from the natural resources with fewer side effects than the conventional ones. ObjectivesThe present study was designed to findout the xanthine oxidase inhibitory activity of Piper betle phytocompounds in comparison with Allopurinol. MethodsThe detection of phytocompounds present in the P. betle L. extract was identified through Gas Chromatography Mass Spectrometry (GC-MS) analysis. The insilico analysis and ADMET properties were evaluated for the GC-MS derived P.betle phytocompounds. Among the 32 phyto compounds of P.betle, 18 were showed favourable affinity with xanthine oxidase and their different conformational structures were docked in schrodinger module with xanthine oxidase enzyme structure. The interpretation of results was carried out through GLIDE XP Scoring, GLIDE Energy, MM-GBSA energy and hydrogen bond and Pi-Pi interactions. Further the absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis were also carriedout using QIKPRO programme. ResultsThe results revealed that, the twelve phytocompounds of P.betle showed GLIDE XP docking score (-6.881 to - 4.766 Kcal/mol) higher than allopurinol (-4.535 Kcal/mol) and 11 phytocompounds showed higher GLIDE energy (-42.822 Kcal/mol to - 36.706 Kcal/mol) than allopurinol (-32.676 Kcal/mol). Chromonol and eugenol were the most potential compounds of P.betle which showed both hydrogen bond and Pi-Pi interactions with the target xanthine oxidase as that of standard drug allopurinol. The selected phytocompounds satisfied the ADME descriptors and have no violation of Lipinskis rule of five. ConclusionsThe insilico and ADMET profile study on the phytocompounds of P.betle predicted their promising potential xanthine oxidase inhibition activity and they could be developed as alternate molecules against synthetic agents by invivo experiments for the treatment of xanthine oxidase associated diseases like hyperuricimia and cardiovascular disorders.

bioinformatics↗

bioRxiv2022

Effect of tempol on post-thaw semen parameters and fertility during chicken semen cryopreservation

The present study evaluated addition of tempol during chicken semen cryopreservation on post-thaw semen parameters and fertility. Adult PD-1 line semen was cryopreserved using 4% dimethyl sulfoxide (DMSO) in Sasaki diluent (SD). In the semen cryomixture tempol (1 and 5 mM) was added at final concentrations. The semen with additives were filled in 0.5 ml French straws and exposed to liquid nitrogen vapours for 30 min and then stored in liquid nitrogen. The semen straw was thawed at 5{degrees}C for 100 sec and evaluated for sperm motility, live, abnormal and acrosome intact sperm. The seminal plasma was evaluated for lipid peroxidation. Fertilizing potential of the cryopreserved sperm was evaluated after insemination in the PD-1 line hens. The post-thaw sperm parameters were significantly (P<0.05) lower in the cryopreserved groups. The lipid peroxidation was significantly (P<0.05) higher in cryopreserved groups. The fertility was significantly (P<0.05) lower in all the cryopreserved groups. In conclusion, addition of tempol to cryopreservation mixture did not improve the post-thaw semen parameters or fertility.

physiology↗

bioRxiv2019

Elevation of FAM129A in neutrophils exposed to serum of patients with severe sepsis: in silico investigations during a hands on training workshop and follow on validation of protein expression in neutrophils

Steps involved in reductionist investigation approaches can be imitated using public transcriptome datasets as source of training material. In the present report trainees explored an apparent gap in biological knowledge for FAM129A (family with sequence similarity 129 member A). Elevated abundance of FAM129A transcripts were observed in a transcriptome dataset where neutrophils were exposed in vitro to plasma of patients with sepsis. However, no literature linking FAM129A and either neutrophils, sepsis or inflammation could be identified. Additional datasets were selected to independently validate this initial observation and further explore differential expression of FAM129A in the context of sepsis studies. Follow on investigations carried out at the bench confirmed restriction of the expression of FAM129A protein at the surface of circulating blood neutrophils and monocytes. A potential role for FAM129A in neutrophil survival was inferred from profiling of literature associated with FAM129A, which remains to be investigated in further follow on investigations.

immunology↗