Biology subjects

Palanisamy, A.

Publications and source records attributed to Palanisamy, A..

4 recordsLinked to original sources

bioRxiv2026

Lactational transfer of synthetic oxytocin and sex-specific suppression of neurodevelopmental risk gene networks in the rat prefrontal cortex

Autism spectrum disorder and related neurodevelopmental disorders (NDDs) affect males at two-to-four times the rate of females, yet the environmental contributors to this sex-differentiated vulnerability remain poorly understood. Here, using a clinically translatable postpartum rat model, we show that synthetic oxytocin (OT) administered for postpartum hemorrhage (PPH) prophylaxis ( PPH-OT), a universally administered obstetric medication, undergoes lactational transfer, confirmed by stable isotope-labeled OT and LC-MS/MS, without altering maternal behavior or neonatal cortical OT receptor expression. In offspring, PPH-OT altered ultrasonic vocalizations during dyadic interaction and caused a male-specific reduction in social approach, without affecting other behavioral domains. Sex-stratified RNA-sequencing of the medial prefrontal cortex (mPFC) revealed pronounced transcriptional dimorphism: males showed 1,732 differentially expressed genes versus 693 in females, and a sex-by-treatment interaction contrast identified 1,229 formally sex-differentiated genes. Male mPFC downregulated genes were significantly enriched for high-confidence NDD risk genes across three independent databases -- SFARI score-1 (highest confidence autism genes; OR = 4.56, p = 0.015), DBD autism (OR = 10.34, p = 7.3x10-{superscript 1}{superscript 2}), and SysNDD autosomal dominant (OR = 9.78, p = 8.4x10-) -- including core regulators of cortical circuit assembly (Grin2a, Grin2b, Reln, Tbr1, Mef2c, and Tcf4), an enrichment pattern largely restricted to males. Hypothalamic transcriptional changes were pronounced but showed no enrichment for NDD risk genes, establishing mPFC specificity. These findings identify PPH-OT as a candidate environmental modifier of male neurodevelopmental vulnerability and provide a pressing rationale for prospective investigation of neurodevelopmental outcomes in PPH-OT-exposed children.

neuroscience↗

bioRxiv2025

Comprehensive Network of Signaling Pathways in Hepatocellular Carcinoma and Network Analysis Reveals PTK2, GSK3β, and β-catenin to be Crucial for Cancer Progression

Hepatocellular carcinoma (HCC) is a highly aggressive primary liver cancer with significant morbidity and mortality. The development and progression of HCC involves several genetic mutations, alterations in signaling pathways leading to dysregulation of cellular processes. Several investigations have demonstrated the involvement of diverse regulators and their complex signaling cascades in progression of HCC. Understanding these crucial signaling pathways, including receptor tyrosine pathways, PI3K/AKT/mTOR, Wnt/{beta}-catenin, Ras/Raf/MAPK, TGF-{beta}, Hedgehog, JAK/STAT, and Hippo signaling, offers potential avenues for further experimental explorations and system level studies. The present study aims to construct a comprehensive molecular map of the signaling pathways involved in the development and progression of HCC using network editor Cell Designer. The assembled network, consisting of 193 distinct regulators and 362 reactions, provides a holistic representation of HCC associated pathways and adheres to Systems Biology Graphical Notation (SBGN) format. Through subsequent analysis the crucial regulators such as PTK2, GSK3{beta}, {beta}-catenin, and their pivotal roles in driving HCC progression were illuminated. These findings underscore the potential prognostic and clinical significance of regulators influencing the patient outcomes in HCC. Similar workflow can provide further insights and comprehensive understanding of the disease mechanisms. HighlightsO_LIA detailed molecular interaction map of pathways and regulators involved in HCC was developed. C_LIO_LITo illustrate one of the applications of the map developed, topological analysis using Cytoscape was performed to identify the significant hubs. Subsequently, the prognostic relevance of these identified hubs was evaluated using the transcriptome-based analysis. C_LIO_LIThese analysis revealed the crucial roles of regulators like PTK2, GSK3{beta}, and {beta}-catenin offering new prospects for potential prognostic and clinical significance of regulators in influencing HCC. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/666714v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@a0714forg.highwire.dtl.DTLVardef@16f18a1org.highwire.dtl.DTLVardef@ba17b1org.highwire.dtl.DTLVardef@1697432_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2021

A NOVEL PREGNANT RAT MODEL FOR LABOR INDUCTION AND AUGMENTATION WITH OXYTOCIN

BackgroundDespite the widespread use of oxytocin for induction of labor, mechanistic insights into maternal and neonatal wellbeing are lacking because of the absence of an animal model that recapitulates modern obstetric practice. ObjectiveThe objectives of this research were to create and validate a hi-fidelity animal model that mirrors labor induction with oxytocin in parturients and to assess its translational utility. Study DesignThe study was performed in timed-pregnant Sprague Dawley dams. The model consisted of a subcutaneously implanted microprocessor-controlled infusion pump on gestational day 18 that was pre-programmed to deliver an escalating dose of intravenous oxytocin on gestational day 21 to induce birth. Once predictable delivery of healthy pups was achieved, we validated the model with molecular biological experiments on the uterine myometrium and telemetry-supported assessment of changes in intrauterine pressure. Finally, we applied this model to test the hypothesis that labor induction with oxytocin was associated with oxidative stress in the newborn brain with a comprehensive array of biomarker assays and oxidative stress gene expression studies. ResultsDuring the iterative model development phase, we confirmed the optimal gestational age for pump implantation, the concentration of oxytocin, and the rate of oxytocin administration. Exposure to anesthesia and surgery during pump implantation was not associated with significant changes in the cortical transcriptome. Activation of pump with oxytocin on gestational day 21 resulted in predictable delivery of pups within 8-12 hours. Increased frequency of change of oxytocin infusion rate was associated with dystocic labor. Labor induction and augmentation with oxytocin was associated with increased expression of the oxytocin receptor gene in the uterine myometrium, decreased expression of the oxytocin receptor protein on the myometrial cell membrane, and cyclical increases in intrauterine pressure. Examination of the frontal cortex of vaginally delivered newborn pups born after oxytocin-induced labor did not reveal an increase in oxidative stress compared to saline-treated control pups. Specifically, there were no significant changes in oxidative stress biomarkers involving both the oxidative stress (reactive oxygen/nitrogen species, 4-hydroxynonenal, protein carbonyl) and the antioxidant response (total glutathione, total antioxidant capacity). In addition, there were no significant differences in the expression of 16 genes emblematic of the oxidative stress response pathway. ConclusionsCollectively, we provide a viable and realistic animal model for labor induction and augmentation with oxytocin. We demonstrate its utility in addressing clinically relevant questions in obstetric practice that could not be mechanistically ascertained otherwise. Based on our findings, labor induction with oxytocin is not likely to cause oxidative stress in the fetal brain. Adoption of our model by other researchers would enable new lines of investigation related to the impact of perinatal oxytocin exposure on the mother-infant dyad.

pharmacology and toxicology↗

bioRxiv2019

Transient uterine hypercontractility causes oxidative stress in the fetal brain, sex-dependent mitochondrial abnormalities, and altered social behavior of adolescent male rat offspring

The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI imaging, we confirmed that oxytocin-induced aberrant uterine hypercontractility significantly compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 h after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.

neuroscience↗