👤 Prashant Kapoor

India's escalating burden of obesity and metabolic disease is characterized by a distinctive "thin-fat" phenotype, in which individuals with normal or near-normal body mass index exhibit disproportionate visceral adiposity, reduced skeletal muscle mass, and heightened susceptibility to insulin resistance. Conventional obesity models centered primarily on caloric imbalance fail to adequately explain this pattern, underscoring the need for a more integrative pathophysiological framework. Emerging evidence implicates gut microbiome dysbiosis, impaired fermentation of dietary fibers, reduced short-chain fatty acid (SCFA) signaling, altered bile acid metabolism, metabolic endotoxemia, and dysregulated adipose tissue crosstalk as key contributors to metabolic vulnerability in South Asian populations. This commentary synthesizes mechanistic insights into the gut-metabolic axis and examines their relevance to India's phenotype-specific challenges. Key pathways, including SCFA-mediated incretin secretion, Toll-like receptor 4 (TLR4)-driven inflammatory signaling, angiopoietin-like protein 4 (ANGPTL4)-mediated lipid partitioning, and microbiota-dependent bile acid biotransformation, are discussed as interconnected drivers of metabolic dysfunction. Emerging clinical evidence from randomized controlled trials evaluating synbiotic and prebiotic-botanical formulations is also discussed, highlighting their potential benefits as adjuncts to lifestyle modification. Given India's dietary patterns and widespread deficiency of fermentable fiber intake, synbiotics may represent a scalable and biologically coherent strategy to support metabolic health. However, heterogeneity of formulations, interindividual microbiome variability, and limited long-term outcome data necessitate cautious interpretation. Advancing precision microbiome-targeted interventions will require population-specific research, multi-omics integration, and rigorous clinical evaluation. Show less

Systemic light chain amyloidosis (AL) arises from monoclonal immunoglobulin light chains, but determinants of progression from precursor states remain poorly defined. In a cross-sectional cohort comprising 1950 systemic AL patients diagnosed 2010-2024, 258 (13.2%) patients with a previously diagnosed plasma cell disorder (PCD) were compared to patients with no prior PCD diagnosis. Patients with monoclonal gammopathy of undetermined signficance (MGUS) and smoldering multiple myeloma (SMM) in the former group had lower difference between involved and uninvolved FLCs (dFLC), higher M-protein, and lower rates of t(11;14) at AL diagnosis. Patients developing AL from SMM had a shorter time to AL (median 34.2 versus 61.3 months) and higher dFLC (median 28.9 versus 11.0 mg/dl) compared to those from MGUS. Patients developing AL after known multiple myeloma (MM) or lymphoplasmacytic lymphoma (LPL) commonly lacked deep hematologic response before AL (≤ very good partial response in 78% of MM, 100% of LPL patients). We additionally studied longitudinally followed cohorts of 3,966 MGUS and 426 (SMM) patients with longitudinal FLC measurements and matched follow-up, in which 1.8% of MGUS and 7.2% of SMM patients developed AL. Those patients who developed AL showed markedly higher dFLC at MGUS/SMM diagnosis and more frequent λ restriction and rates of t(11;14). Higher dFLC was associated with progressively earlier AL development; a 10% cumulative risk occurred at 20 months for patients with a dFLC >80 mg/dL but was not reached if dFLC <10 mg/dL at an estimated median follow-up of 86 months. In multivariable analysis, dFLC >6.4 mg/dL (HR 11.3) and λ isotype (HR 3.6) independently predicted AL, whereas heavy chain secretion was associated with lower risk (HR 0.2 for IgG). These findings indicate that AL risk is primarily driven by cumulative light chain exposure, refining our knowledge of AL pathophysiology and providing guidance for follow-up of patients with elevated dFLC. Show less

In pancreatic ductal adenocarcinoma, hypoxia is a crucial component of the tumour microenvironment and is associated with worse clinical outcomes. Adaptation to extreme hypoxic settings is based on abnormal lipid metabolism, but insights into how hypoxia-regulated lipid changes link with aggressive migratory potential in pancreatic cancer are lacking. This study investigates the molecular processes, pathways, and critical proteins involved in hypoxia-induced lipidic and polyunsaturated fatty acid alterations in pancreatic cancer. Our findings elucidate increased multilayer unsaturation in FA chains of major lipid classes associated with greater migration and invasion, as well as higher abundances of particular desaturases. The expression of these proteins was verified in clinical tumour samples by unsaturated fatty acid biosynthesis-related gene enrichment score. High unsaturated fatty acid clusters were shown to be associated with a low survival rate. Pathway correlation and protein-protein interaction analysis indicated that the PPAR-hypoxia axis and SCD/FADS2/APOC3-HDLBP protein network are implicated in mediating the observed alterations in lipid pools and poly-unsaturation levels in pancreatic cancer under hypoxia. These results provide novel therapeutic targets in pancreatic cancer while improving our understanding of hypoxia-induced migratory potential in pancreatic cancer. Show less

Venetoclax showed promising activity in a small phase II trial in relapsed/refractory Waldenström macroglobulinemia (WM). To report the clinical activity of venetoclax and prognostic factors associated with outcomes in a larger cohort, we retrospectively identified 76 patients with relapsed/refractory lymphoplasmacytic lymphoma (LPL)/WM treated with venetoclax monotherapy at nine US medical centers. The median age at venetoclax treatment initiation was 66 years. MYD88, CXCR4, and TP53 mutations were detected in 65 (94%), 23 (40%), and 10 (22%) patients, respectively. The median number of prior lines of treatment was 3, including covalent BTK inhibitor in 82% and alkylating agent in 71% of patients. The overall and major response rates to venetoclax were 70% and 63%, respectively. The median and 2-year progression-free survival (PFS) were 28.5 months and 57%, respectively. The median and 2-year overall survival were not reached and 82%, respectively. Prior treatment with BTK inhibitor was the only factor associated with PFS in multivariate analysis (hazard ratio 2.97, p = 0.012). Venetoclax dose interruptions and/or reductions occurred in 27 patients (41%). Five patients (7%) developed laboratory tumor lysis syndrome (TLS), including 3 (4%) with clinical TLS. Venetoclax resulted in a high response rate and a prolonged PFS in patients with heavily pretreated LPL/WM. Show less

Benign prostatic hyperplasia (BPH) is a commonly occurring disease in aging men. It involves cellular proliferation of stromal and glandular tissues leading to prostate enlargement. Current drug therapies show several adverse effects such as sexual dysfunctions and cardiovascular side effects. Therefore, there is a need to develop more effective medical treatment for BPH. In this regard, we aimed to identify genes which play a critical role in BPH. We have obtained the dataset of differentially expressed genes (DEGs) of BPH from NCBI GEO. DEGs were investigated in the context of their protein-protein interactions (PPI). Hub genes i.e. genes associated with BPH were scrutinized based on the topological parameters of the PPI network. These were analyzed for functional annotations, pathway enrichment analysis and transcriptional regulation. In total, 38 hub genes were identified. Hub genes such as transcription factor activator protein-1 and adiponectin were found to play key roles in cellular proliferation and inflammation. Another gene peroxisome proliferator activated receptor gamma was suggested to cause obesity, a common comorbidity of BPH. Moreover, our results indicated an important role of transforming growth factor-beta (TGF-β) signaling and smooth muscle cell proliferation which may be responsible for prostate overgrowth and associated lower urinary tract symptoms frequently encountered in BPH patients. Zinc finger protein Snai1 was the most prominent transcription factor regulating the expression of hub genes that participate in TGF-β signaling. Overall, our study has revealed significant hub genes that can be employed as drug targets to develop potential therapeutic interventions to treat BPH. Show less

The polymorphic alleles of APOA5 (rs2266788 (C), rs3135506 (G)), LPA (rs10455872 (A), rs3798220 (G)) and 9p21.3 (rs1333049 (C), rs2383207(A)) have been reported in association with susceptibility of coronary artery disease (CAD) from genome wide association studies. We aimed to assess the association of genetic variants with coronary angiogram proven CAD, severity scored with modified Gensini score and association of risk for myocardial infraction (MI) in North Indian population. We recruited 512 angiographic proven CAD patients (mean age 58.1±10.2years) and 272 controls (mean age 50.3±11.1years) with normal coronaries from North Indian population. The genotyping technique polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed for rs2266788, rs3135506 and rs10455872. Amplified refractory mutation system-PCR (ARMS-PCR) was used for genotyping of rs1333049, rs2383207 and rs3798220 genetic variants. The polymorphic risk allele of variants rs2266788 (C), rs1333049 (C), rs2383207 (A) and heterozygous polymorphic alleles of rs2266788 (TC) were significantly associated with CAD. The homozygous alleles of rs22667788 (CC) and rs1333049 (CC) had also been significantly associated with CAD. The significance of association of rs2266788 (C, CC, TC) and rs1333049 (C, CC) increases with severity of CAD. The presence of mutant allele of rs2266788 (C) was associated with risk of MI and unstable angina (UA). Also, homozygous risk allele of rs2266788 (CC) significantly associated with risk of MI and UA in patients of chronic stable angina (CSA) patients. Whereas, the risk allele of rs1333049 (C) have shown the association with MI and UA compared to controls. The genetic variants of rs3135506 (G), rs10455872 (A) and rs3798220 (G) have low frequency in our population and reflected no association with CAD. The polymorphic variants of Apo-A5; rs2266788 (C), 9p21.3; rs1333049 (C) rs2383207 (A) are associated with CAD, its severity and exerts the risk of MI in North Indian population. Show less

MicroRNAs (miRNAs) down-regulate their target genes. The intronic miR-140, present in the WW domain containing E3 ubiquitin protein ligase 2 (WWP2) gene, decreases the expression of genes that play detrimental roles in osteoarthritis (OA). As the expression level of miR-140 is significantly decreased in human OA chondrocytes, we investigated its regulation in those cells. Gene expression in human chondrocytes was determined by quantitative polymerase chain reaction (qPCR) and gene silencing was done in OA chondrocytes by transient transfection with specific small interfering RNAs (siRNAs). Binding sites of the miR-140 regulatory sequence (rsmiR-140) were identified by mutagenesis and chromatin immunoprecipitation (ChIP) in OA chondrocytes. The effects of translocation on OA chondrocytes were determined by immunocytochemistry and qPCR. In contrast to miR-140, the expression of WWP2 was similar in both normal and OA cells, suggesting that miR-140 has an additional level of regulation. rsmiR-140 showed activity and predicted binding sites for nuclear matrix transcription factor 4 (NMP4), myc-associated zinc (MAZ), nuclear factor of activated T-cells (NFAT), and mothers against decapentaplegic homolog 3 (SMAD3). Silencing NFAT3 (P ≤0.01) and SMAD3 (P ≤0.05) differentially regulated miR-140 independently of WWP2. Silencing NFAT5 decreased both miR-140 and WWP2 (P ≤0.003 and P ≤0.05, respectively). NFAT3 activation increased and transforming growth factor-β (TGF-β) decreased rsmiR-140 activity. Mutagenesis of rsmiR-140 and ChIP assays identified binding sites at which NFAT3 (activator) and SMAD3 (repressor) directly regulated miR-140. TGF-β interfered with NFAT3 translocation, and subsequently with miR-140 expression. This is the first study to provide evidence of a regulatory mechanism of miR-140 independent of WWP2, and new and differential roles for NFAT3 and SMAD3 in the OA process in the regulation of miR-140 transcription. Such knowledge could advance therapeutic strategies targeting OA. Show less

The synaptic protein PSD-95/SAP90 binds to and clusters a variety of membrane proteins via its two N-terminal PDZ domains. We report a novel protein, CRIPT, which is highly conserved from mammals to plants and binds selectively to the third PDZ domain (PDZ3) of PSD-95 via its C terminus. While conforming to the consensus PDZ-binding C-terminal sequence (X-S/T-X-V-COOH), residues at the -1 position and upstream of the last four amino acids of CRIPT determine its specificity for PDZ3. In heterologous cells, CRIPT causes a redistribution of PSD-95 to microtubules. In brain, CRIPT colocalizes with PSD-95 in the postsynaptic density and can be coimmunoprecipitated with PSD-95 and tubulin. These findings suggest that CRIPT may regulate PSD-95 interaction with a tubulin-based cytoskeleton in excitatory synapses. Show less