👤 Sabarinath V Radhakrishnan

Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation. Show less

Three-dimensional (3D) spheroid models are increasingly used to emulate the tumour microenvironment for preclinical drug screening. This study aimed to optimise and assess spheroid formation from MDA-MB-468 triple-negative breast cancer (TNBC) cells using hanging drop, liquid overlay, and rigid scaffold methods under normal oxygen (NOC) and low oxygen (LOC) culture conditions. Spheroids were generated and characterised using bright-field microscopy with AnaSP morphometrics (sphericity, solidity, and perimeter). Gene expression of Epithelial-Mesenchymal Transition (EMT), stemness, and hypoxia/angiogenesis markers (CD44, HIF1A, VEGFA, TWIST1, SNAI1, and NES) was quantified using qPCR. The optimised model was further evaluated using field-emission scanning electron microscopy (FE-SEM) and Hoechst fluorescence. A workflow combining hanging-drop pre-aggregation with ultra-low attachment (ULA) or agarose-coated plates under NOC produced consistent, compact spheroids. Scaffold cultures formed rapidly but showed size variability under NOC and LOC. Across methods, spheroids were less compact, and gene expression patterns deviated from expected hypoxic responses. Spheroids cultivated under normoxic conditions demonstrated enhanced structural integrity and transcriptional fidelity. Nonetheless, the study identified that the most compact and resilient spheroids were achieved through the use of hanging-drop pre-aggregation combined with ULA-plates under NOC. The enhanced structural integrity and transcriptional fidelity observed in these spheroids make them valuable models for studying cancer biology and drug responses. The online version contains supplementary material available at 10.1007/s11033-026-11451-4. Show less

Background & objectives Central TB division facilitated development of a line probe assay (LPA) artificial intelligence (AI) tool. The tool was developed, trained, and validated for performance by collecting more than 18,000 LPA strips across culture and drug susceptibility Testing (C&DST) laboratories. The Indian Council of Medical Research (ICMR)-National Institute for Research in Tuberculosis (NIRT) evaluated the LPAAI tool independently. The objective was to establish and verify an AI-driven system for automatically interpreting LPA strips, which are employed in tuberculosis drug resistance screening, to improve accuracy, consistency, and scalability across diverse laboratory settings. Methods The AI system integrates faster regions convolutional neural network (FR-CNN) for strip detection, detection transformer (DETR) for band localisation, and a hierarchical neural network (HNN) for classification of bands, loci, and drug labels. Independent validation was conducted by ICMR-NIRT using 2810 first-line (FL)-LPA and 241 reflex second-line (SL-LPA) across ten intermediate reference laboratories (IRLs). Results AI comparative models demonstrated an accuracy range of 92-100 per cent, with sensitivity between 80-100 per cent and specificity from 86-100 per cent for the tub, rpoB, katG, InhA, gyrA/gyrB,rrs, and eisgenes. The overall F1 score varies from 0.81 to 1.00, indicating perfect precision and recall. Interpretation & conclusions This AI system offers a novel, modular architecture capable of expert-level interpretation of LPA strips. The AI tool performs at par with expert readers and offers a reliable, scalable solution for LPA interpretation.AI tool adoption can reduce interpretation time, enhance result uniformity, and improve treatment delivery across India's TB programme, supporting national goals for TB elimination. Show less

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α Show less

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized as rapid and progressive cognitive decline affecting 26 million people worldwide. Although immunotherapies are ideal, its clinical safety and effectiveness are controversial, hence, treatments are still reliant on symptomatic medications. Concurrently, the To present secondary metabolites from Research articles published between 2010 and 2021 were collected from five databases and 83 relevant research articles were identified. Post-screening, only 12 research articles on AD-related proteins were selected for further review. Bioinformatics analyses were performed through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) network, PANTHER Go-Slim classification system (PANTHER17.0), and Kyoto Encyclopedia of Genes and Genomes (KEGG) Mapper. A total of 20 target proteins were identified from the 12 shortlisted articles. Amyloid-β, BACE1, Nrf-2, Beclin-1, and ATG5 were identified as the potential target proteins, given their role in initiating AD, mitigating neuroinflammation, and autophagy. Besides, 10 compounds from The review highlights several prospective target proteins that can be regulated through treatments with Show less

Glioblastoma (GBM) mesenchymal (MES) transition can be regulated by long non-coding RNAs (lncRNAs) via modulation of various factors (Epithelial-to-Mesenchymal (EMT) markers, biological signalling, and the extracellular matrix (ECM)). However, understanding of these mechanisms in terms of lncRNAs is largely sparse. This review systematically analysed the mechanisms by which lncRNAs influence MES transition in GBM from a systematic search of the literature (using PRISMA) performed in five databases (PubMed, MEDLINE, EMBASE, Scopus, and Web of Science). We identified a total of 62 lncRNAs affiliated with GBM MES transition, of which 52 were upregulated and 10 were downregulated in GBM cells, where 55 lncRNAs were identified to regulate classical EMT markers in GBM (E-cadherin, N-cadherin, and vimentin) and 25 lncRNAs were reported to regulate EMT transcription factors (ZEB1, Snai1, Slug, Twist, and Notch); a total of 16 lncRNAs were found to regulate the associated signalling pathways (Wnt/β-catenin, PI3k/Akt/mTOR, TGFβ, and NF-κB) and 14 lncRNAs were reported to regulate ECM components (MMP2/9, fibronectin, CD44, and integrin-β1). A total of 25 lncRNAs were found dysregulated in clinical samples (TCGA vs. GTEx), of which 17 were upregulated and 8 were downregulated. Gene set enrichment analysis predicted the functions of HOXAS3, H19, HOTTIP, MEG3, DGCR5, and XIST at the transcriptional and translational levels based on their interacting target proteins. Our analysis observed that the MES transition is regulated by complex interplays between the signalling pathways and EMT factors. Nevertheless, further empirical studies are required to elucidate the complexity in this process between these EMT factors and the signalling involved in the GBM MES transition. Show less

A paradigm shift in preclinical evaluations of new anticancer GBM drugs should occur in favour of 3D cultures. This study leveraged the vast genomic data banks to investigate the suitability of 3D cultures as cell-based models for GBM. We hypothesised that correlating genes that are highly upregulated in 3D GBM models will have an impact in GBM patients, which will support 3D cultures as more reliable preclinical models for GBM. Using clinical samples of brain tissue from healthy individuals and GBM patients from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Chinese Glioma Genome Atlas (CGGA), and Genotype-Tissue Expression (GTEx) databases, several genes related to pathways such as epithelial-to-mesenchymal transition (EMT)-related genes ( Show less

Fetal akinesia deformation sequence (FADS) is a clinically and genetically heterogeneous condition. Pathogenic variants in DOK7 are known to cause myasthenic syndrome, congenital, 10 (MIM#254300) and, rarely (reported in a single family) lethal FADS. Herein, we describe a biallelic variant c.1263dupC in DOK7, known to cause congenital myasthenic syndrome 10, causing lethal FADS in a consanguineous family. The present report illustrates wide phenotypic variability caused by biallelic pathogenic variants in DOK7. We also describe the second family with FADS due to pathogenic variants in DOK7. Show less

Snail transcription factors mediate key cellular transitions in many developmental processes, including spermatogenesis, and their production can be regulated by TGF-β superfamily signalling. SNAI1 and SNAI2 support many cancers of epithelial origin. Their functional relevance and potential regulation by TGF-β superfamily ligands in germ cell neoplasia are unknown. SNAI1, SNAI2 and importin 5 (IPO5; nuclear transporter that selectively mediates BMP signalling) cellular localization was examined in fixed normal adult human and/or neoplastic testes using in situ hybridization and/or immunohistochemistry. SNAI1 and SNAI2 functions were assessed using the well-characterized human seminoma cell line, TCam-2. Cell migration, adhesion/proliferation and survival were measured by scratch assay, xCELLigence and flow cytometry following siRNA-induced reduction of SNAI1 and SNAI2 in TCam-2 cells. The potential regulation of SNAI1 and SNAI2 in TCam-2 cells by TGF-β signalling ligands, activin A and BMP4 was evaluated following 48 hours culture, including with siRNA regulation of IPO5 to selectively restrict BMP4 signalling. In normal testes, SNAI1 transcript was identified in some spermatogonia and in spermatocytes, and SNAI2 protein localized to nuclei of spermatogonia, spermatocytes and round spermatids. In neoplastic testes, both SNAI1 and SNAI2 were detected in GCNIS and in seminoma cells. SNAI1 and SNAI2 reduction in TCam-2 cells by siRNAs significantly inhibited migration and survival, respectively. Exposure to BMP4, but not activin A, significantly increased SNAI2 (~18-fold). IPO5 inhibition by siRNAs decreased BMP4-induced SNAI2 upregulation (~5-fold). Additionally, SNAI2 reduction using siRNAs inhibited BMP4-induced TCam-2 cell survival. This is the first evidence that SNAI1 and SNAI2 are involved in human spermatogenesis, with independent functions. These outcomes demonstrate that SNAI1 and SNAI2 inhibition leads to loss of migratory and viability capacities in seminoma cells. These findings show the potential for therapeutic treatments targeting SNAIL or BMP4 signalling for patients with metastatic testicular germ cell tumours. Show less

Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM₀₀₀₁₅₈₎. Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum. Show less

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10 Show less

Varicose veins of lower extremities are a heritable common disorder. Mechanisms underlying its pathogenesis are still vague. Structural failures such as valve weakness and wall dilatation in saphenous vein result in venous retrograde flow in lower extremities of body. Reflux of blood leads to distal high venous pressure resulting in distended veins. In an earlier study, we observed a positive association between c.-512C>T FoxC2 gene polymorphism and upregulated FoxC2 expression in varicose vein specimens. FoxC2 overexpression in vitro in venous endothelial cells resulted in the elevated mRNA expression of arterial endothelial markers such as Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2). We hypothesized that an altered FoxC2-Dll4 signaling underlies saphenous vein wall remodeling in patients with varicose veins. Saphenous veins specimens were collected from 22 patients with varicose veins and 20 control subjects who underwent coronary artery bypass grafting. Tissues were processed for paraffin embedding and sections were immunostained for Dll4, Hey2, EphrinB2, α-SMA, Vimentin, and CD31 antigens and examined under microscope. These observations were confirmed by quantitative real-time PCR and western blot analysis. An examination of varicose vein tissue specimens by immunohistochemistry indicated an elevated expression of Notch pathway components, such as Dll4, Hey2, and EphrinB2, and smooth muscle markers, which was further confirmed by gene and protein expression analyses. We conclude that the molecular alterations in Dll4-Hey2 signaling are associated with smooth muscle cell hypertrophy and hyperplasia in varicose veins. Our observations substantiate a significant role for altered FoxC2-Dll4 signaling in structural alterations of saphenous veins in patients with varicose veins. Show less