Biology subjects

Dogra, S.

Publications and source records attributed to Dogra, S..

8 recordsLinked to original sources

bioRxiv2026

Targeting Histamine H3 Receptors to Suppress NGF-Driven Hyperexcitability in Neuropathic Pain

Peripheral nerve injury induces long-lasting changes in sensory neurons that contribute to the development of neuropathic pain. Although the histamine H3 receptor (H3R) is best known for regulating neurotransmitter release in the central nervous system, its expression and role in dorsal root ganglia (DRG) remain poorly understood. In this study, we examined the expression, cellular distribution, and functional role of H3 R in DRG and implications in neuropathic pain. Sciatic nerve injury increased membrane-associated H3R protein expression in the DRG, suggesting enhanced receptor trafficking or stabilization at the neuronal membrane. Single-cell transcriptomic analysis revealed that H3R mRNA expression in DRG is predominantly restricted in peptidergic sensory neurons and C-LTMRs neurons. Fluorescence imaging and transcriptomic analysis also suggest that the majority of H3R co-express with TrkA (a NGF receptor) sensory neuron populations. These findings identify a subset of NGF-responsive nociceptors in which H3R may directly influence injury-induced sensitization. Pain behavior assessment demonstrated a paradoxical role of an H3R inverse agonist (GSK334429), which reduces mechanical hypersensitivity caused by chronic constriction injury (CCI) with no change in thermal pain. Patch-clamp recordings show that the GSK334429 attenuates NGF-induced hyperexcitability in DRG neuronal cultures. Overall, our work suggests a contributing role of H3R in modality-specific effects on sensory processing through its enrichment in specific neuronal populations in DRG.

neuroscience↗

bioRxiv2026

Machine Learning Ensemble Reveals Distinct Molecular Pathways of Retinal Damage in Spaceflown Mice

BackgroundSpaceflight-associated neuro-ocular syndrome (SANS) poses significant risks to astronaut visual health during long-duration missions, yet its underlying molecular mechanisms remain incompletely understood. Oxidative stress and apoptosis are candidate molecular drivers, but their transcriptomic signatures in spaceflight-exposed retinal tissue have not been systematically characterized. MethodsWe applied a machine learning ensemble of linear regression models to predict two ocular phenotypes: 4-hydroxynonenal (4-HNE) immunostaining as a marker of lipid peroxidation-mediated oxidative damage; and TUNEL positivity as a marker of apoptotic cell death. In this observational study, we use bulk retinal gene expression data obtained from a controlled experiment with ground control and spaceflown mice to predict these phenotypes. Gene Ontology pathway enrichment was performed on the most predictive gene sets for each phenotype. ResultsThe 4-HNE phenotype was predicted by genes that converge on membrane-associated pathways, photoreceptor protein modification, synaptic dysfunction, and extracellular matrix dysregulation, including B2m, Tf, Cnga1, mt-Nd1, Snap25, and Efemp1. The genes predicting the TUNEL phenotype revealed a distinct signature emphasizing stress-induced apoptosis, rod photoreceptor degeneration, and endoplasmic reticulum dysfunction, with Ddit4, Nrl, Rom1, Reep6, and Gabarapl1 emerging as central regulators. ConclusionsOxidative lipid peroxidation and apoptotic cell death represent complementary and molecularly distinct pathological mechanisms in spaceflight-exposed murine retinal tissue. The gene signatures provide a putative molecular framework for developing noninvasive biomarkers and therapeutic targets to monitor and protect astronaut visual health during long-duration and deep-space missions.

bioinformatics↗

bioRxiv2025

Reciprocal regulation of the H3 histamine receptor in Rett syndrome and MECP2 Duplication 1 syndrome: implications for therapeutic development

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2). We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the expression of the histamine H3 receptor (HRH3). In the current manuscript, we expanded this H3 receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of H3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H3 receptor expression across various brain areas, with Hrh3 expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H3 receptor, (R)--methylhistamine (RAMH), and the H3 receptor inverse agonist, pitolisant (Wakix(R)), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT (MecpNull/+), but pitolisant had no effect on the behaviors examined here in MDS animals (MECP2Tg1).

neuroscience↗

bioRxiv2024

Preferential Release of microRNAs via Extracellular Vesicles is Associated with Ductal Carcinoma In Situ to Invasive Breast Cancer Progression

Ductal carcinoma in situ (DCIS) is a benign "pre-cancer" that increases the risk of invasive breast cancer (IBC). Not all DCIS progress to IBC, and the primary factors driving progression remain unclear. Small extracellular vesicles (sEVs) or exosomes are known to play a role in advanced cancers, but their involvement in DCIS is poorly understood. This study examined the role of sEVs and their RNA content in DCIS progression. Rab27A, which regulates exosome release, is elevated in DCIS and IBC tissues compared with normal breast tissues. Inhibition of sEV release via Rab27A knockdown alters pro-invasive pathways and reduces invasion in a DCIS mouse model. Using the isogenic MCF10 breast cancer progression series, we found a significant increase in microRNAs (miRNAs) in sEVs from normal to malignant states, with the highest number of differentially expressed miRNAs in IBC sEVs compared with DCIS sEVs. In vivo, DCIS invasive progression elevated circulating sEV miRNA levels, which decreased upon Rab27A knockdown. Re-expression of miR-205, preferentially loaded into IBC sEVs, reduced proliferation, invasion, and EMT marker expression in DCIS cells. Combined Rab27A knockdown and miR-205 expression repressed TGF-{beta} signaling, activated p38, and induced cell cycle arrest and cell death. These findings illustrate that sEVs and their miRNAs promote DCIS progression, and the reintroduction of miR-205 in DCIS cells can inhibit invasive progression.

cancer biology↗

bioRxiv2020

Activating mGlu3 metabotropic glutamate receptors rescues schizophrenia-like cognitive deficits through metaplastic adaptations within the hippocampus.

BackgroundPolymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition. MethodsWe examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations. ResultsmGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through a mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. ConclusionsThese data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function - providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.

pharmacology and toxicology↗

bioRxiv2020

Fine-scale population structure and demographic history of British Pakistanis

Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genetic and questionnaire data from >4,000 British Pakistani individuals, mostly with roots in Azad Kashmir and Punjab. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low effective population sizes (Ne) over the last 50 generations, with some showing a decrease in Ne 15-20 generations ago that has resulted in extensive identity-by-descent sharing and increased homozygosity. Using new theory, we show that the footprint of regions of homozygosity in the two largest subgroups is about twice that expected naively based on the self-reported consanguinity rates and the inferred historical Ne trajectory. These results demonstrate the impact of the cultural practices of endogamy and consanguinity on population structure and genomic diversity in British Pakistanis, and have important implications for medical genetic studies.

genomics↗

bioRxiv2019

Hyperinsulinemia promotes HMGB1 release leading to inflammation induced systemic insulin resistance: An interplay between pancreatic beta-cell and peripheral organs

Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. Pancreatic {beta}-cells hypersecretion (hyperinsulinemia), is a central hallmark of peripheral insulin resistance. However, the underlying mechanism by which hyperinsulinemia perpetuates towards the development of insulin resistance remains unclear and is still a bigger therapeutic challenge. Here, we found hyperinsulinemia triggers inflammation and insulin resistance by stimulating TLR4-driven inflammatory cascades. We show that hyperinsulinemia activates the TLR4 signaling through HMGB1, an endogenous TLR4 ligand emanating from hyperinsulinemia exposed immune cells and peripheral organs like adipose tissue and liver. Further, our observation suggests hyperinsulinemia ensuring hyperacetylation, nuclear-to-cytoplasmic shuttling and release of HMGB1 into the extracellular space. HMGB1 was also found to be elevated in serum of T2DM patients. We found that extracellular HMGB1 plays a crucial role to promote proinflammatory responses and provokes systemic insulin resistance. Importantly, in-vitro and in-vivo treatment with naltrexone, a TLR4 antagonist led to an anti-inflammatory phenotype with protection from hyperinsulinemia mediated insulin resistance. In-vitro treatment with naltrexone directly enhanced SIRT1 activity, blocked the release of HMGB1 into extracellular milieu, suppressed release of proinflammatory cytokines and ultimately led to insulin-sensitizing effects. These observations elucidate a regulatory network between pancreatic {beta}-cells, macrophage and hepatocytes and assign an unexpected role of TLR4 - HMGB1 signaling axis in hyperinsulinemia mediated systemic insulin resistance.\n\nGraphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

physiology↗

bioRxiv2019

Correlates of resting and exertional dyspnea among older adults with obstructive lung disease: a cross-sectional analysis of the Canadian Longitudinal Study on Aging

IntroductionIn patients with chronic obstructive pulmonary disease (COPD), the perception of dyspnea is related to quality of life, and is a better predictor of mortality than the severity of airway obstruction. The purpose of the current study was to use population-level data from the Canadian Longitudinal Study on Aging (CLSA) to identify potential correlates of dyspnea in adults with obstructive lung disease.\n\nMethodsData from participants with a self-reported obstructive lung disease (asthma or COPD) were used for analysis (n=2,854). Four outcome variables were assessed: self-reported dyspnea at 1) rest, 2) walking on a flat surface, 3) walking uphill/climbing stairs, 4) following strenuous activity. Potential sociodemographic, health, and health behaviour correlates were entered in to logistic regression models.\n\nResultsHigher body fat percentage, and worse forced expiratory volume in one second were associated with higher odds of reporting dyspnea. Females with an anxiety disorder (OR=1.91, CI: 1.29, 2.83) and males with a mood disorder (OR=2.67, CI: 1.53, 4.68) reported higher odds of experiencing dyspnea walking on a flat surface, independent of lung function and other correlates. Dyspnea while walking uphill/climbing stairs was associated with a slower timed up and go time in females (e.g. OR=1.18, CI: 1.10) and males (OR=1.19, CI: 1.09, 1.30).\n\nConclusionsIn addition to traditional predictors such as lung function and body composition, we found that anxiety and mood disorders, as well as functional fitness were correlates of dyspnea. Further research is needed to understand whether targeting these correlates leads to improvements in perceptions of dyspnea.

epidemiology↗