👤 Sameer Trivedi

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the "trial and error" approach in choosing the most effective antidepressant treatment for each patient allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, cross the blood-brain-barrier, and be highly sensitive to changes in both synaptic activity and neuronal receptor signaling. Here we present evidence that expression of the brain-enriched circRNA, CDR1as, is associated with symptomatic response to SSRI treatment, and regulated by serotonin and Brain-Derived Neurotrophic Factor (BDNF) receptor activity. We present data using circRNA-specific PCR in baseline whole blood samples from two independent cohorts, drawn from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) and the Biomarkers of ANTidepressant RESponse (ANTARES) clinical studies, showing that before treatment CDR1as is differentially expressed between future symptomatic responders and non-responders to treatment with the SSRI sertraline. Additional data from naturalistic antidepressant response studies further highlight the association between CDR1as and antidepressant effects of SSRIs as a class. In addition, we show that CDR1as levels are altered following sertraline treatment in responders with the trajectory of change post-treatment associated with long-term remission. Furthermore, we report that levels of CDR1as in the blood can specifically predict remission with SSRI treatment, but not response/remission with Placebo or Bupropion treatments. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting mouse Cdr1as is strongly regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment. Show less

Chemical carcinogen induced mouse models closely mimic environmentally driven human cancers and provide platforms for studying tumor initiation and progression. However, the behavior and diagnostic value of cell-free DNA (cfDNA) in such models remain poorly understood, limiting their translational utility for biomarker development. Considering the increasing clinical relevance of cfDNA for early detection and treatment monitoring, this study aimed to systematically characterize cfDNA dynamics and genomic alterations in B(a)P induced lung cancer and DMH induced colon cancer mouse models. The aim was to evaluate cfDNA as a minimally invasive biomarker that reflects tumor burden and its potential use in preclinical diagnostic and therapeutic studies. Mouse lung and colon cancers were induced using B(a)P and DMH, respectively. Plasma was collected at defined time points, cfDNA was isolated, quantified, and analyzed for integrity profiles. Real time assessment was performed using liquid biopsies of cell free DNA using NGS-WGS platform for non-invasive tumor detection in live animals, reserving histopathology for post-mortem analysis. Our results reveal circulating cell-free DNA mutations similar to those found in humans (Lung cancer: ALK, NRAS, NF1, BRAF, FGFR1OP, FGFR1, STK11ip, AKT1 & AK1S1; Colon cancer: APC, MYC, KRAS). We have performed gene enrichment and protein-protein interactions and found various cancer related genes. The histopathological examination revealed neoplastic changes that corroborated with genomic studies. This study establishes cfDNA as a potential surrogate biomarker in chemical carcinogen induced lung and colon cancer models, supporting its utility for early detection, disease monitoring, and preclinical therapeutic assessment. Show less

Chronic alcohol exposure disrupts blood-brain barrier (BBB) integrity and promotes neuroinflammation, with P2X7 receptor (P2X7R) signaling playing a critical role. Our prior work in male mice linked P2X7R inhibition to reduced extracellular adenosine triphosphate (eATP) release, modulated extracellular vesicle (EV) cargo, and attenuated neuroinflammation in chronic intermittent ethanol (CIE)-exposed mice. However, sex-specific roles of P2X7R signaling and EV-mediated mechanisms in alcohol-induced neuroinflammation remain unclear. Male and female mice were exposed to ethanol vapor for three weeks and treated with Brilliant Blue G (BBG), a P2X7R inhibitor. Compared to their respective CIE-unexposed controls, brain gene expression of tumor necrosis factor-α ( Show less

The dysregulation of long-chain noncoding RNAs (lncRNAs) causes several complex human diseases including neurodegenerative disorders across the globe. This study aimed to investigate lncRNA expression profiles of Withania somnifera (WS)-treated human neuroblastoma SK-N-SH cells at different timepoints (3 & 9 h) and concentrations (50 & 100 µg/mL) using RNA sequencing. Differential gene expression analysis showed a total of 4772 differentially expressed lncRNAs, out of which 3971 were upregulated and 801 were downregulated compared to controls. Differential gene expression was observed in dose-dependent (30 upregulated, 25 downregulated, 100 µg/mL 3 h vs. 50 µg/mL 3 h; 36 upregulated, 247 downregulated, 100 µg/mL 9 h vs. 50 µg/mL 9 h) and temporal kinetics (79 upregulated, 64 downregulated, 50 µg/mL 9 h vs. 50 µg/mL 3 h; 22 upregulated, 200 downregulated, 100 µg/mL 9 h vs. 100 µg/mL 3 h). Enrichment analysis showed that modulated lncRNAs were mainly implicated in GPCR ligand binding, HDACs and HATs histones, cellular senescence, cell cycle and post-translational protein modifications. Dysregulated lncRNAs upon WS treatment included BACE1-AS, MALAT1, SNHG1, HOTAIR, MEG3, BDNF-AS, and SHANK2-AS1 which are potential biomarkers in several neurodegenerative diseases. Co-expression analysis revealed that genes such as HMOX1, CHGB, SLC7A11, NOS1, KCNJ and NPY2R may be important in neurodegenerative disorders. Taken together, our results indicated that WS treatment modulated several differentially expressed lncRNAs with putative regulatory potential in various neurodegenerative disorders. To the best of our knowledge, the lncRNA regulome that elicits the health-beneficial effects of WS has not been delineated thus far. Show less

Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of death. Although statins are the foundation of lipid-lowering therapy, many high-risk patients fail to achieve low-density lipoprotein cholesterol (LDL-C) targets due to intolerance or insufficient response. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent agents that address this residual risk. This review summarizes the clinical efficacy, safety, and mechanistic role of PCSK9 inhibitors in cardiovascular risk reduction. Relevant randomized trials, meta-analyses, and observational studies were analyzed, alongside emerging nonstatin therapies including bempedoic acid, inclisiran, and Angiopietin-like 3 inhibitors. PCSK9 inhibitors, such as alirocumab and evolocumab, have shown LDL-C reductions of up to 62% and significant decreases in major adverse cardiovascular events. Trials like Further cardiovascular outcomes research with PCSK9 inhibition in subjects With elevated risk (FOURIER) and Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab (ODYSSEY OUTCOMES) reported relative risk reductions of 15-24% in select populations. These agents also reduce lipoprotein(a) (Lp(a)) and stabilize atherosclerotic plaques. Additional therapies like inclisiran and bempedoic acid further expand treatment options, particularly for statin-intolerant patients. PCSK9 inhibitors offer a well-tolerated and effective approach to lowering LDL-C and mitigating cardiovascular risk. Their integration, along with emerging therapies, provides a comprehensive strategy to address residual ASCVD risk and improve patient outcomes. This review highlights the pivotal role of PCSK9 inhibitors in achieving significant LDL-C reduction and improving cardiovascular outcomes, especially in high-risk and statin-intolerant populations. By also targeting Lp(a) and promoting plaque stabilization, these agents address multiple contributors to residual ASCVD risk. Incorporating PCSK9 inhibitors and emerging nonstatin therapies into clinical practice offers a powerful strategy to enhance long-term cardiovascular prevention. Show less

To study peripheral blood DNA differential methylation in oligozoospermic infertile men in comparison with normozoospermic fertile controls. Case-control study. Reproductive biology laboratory. Azoospermic and oligozoospermic infertile patients (n = 6) and normozoospermic fertile controls (n = 6) in the discovery phase, and oligo/asthenozoospermic infertile men (n = 11) and normozoospermic fertile controls (n = 10) in the validation phase. Blood samples drawn from all participants, DNA isolation and methylation analysis. DNA methylation values analyzed using genomewide methylation 450K BeadChip array, followed by deep sequencing of selected regions for methylation analysis in the neighborhood regions of differentially methylated CpGs. We found 329 differentially methylated CpG spots, out of which 245 referred to the genes, representing 170 genes. Deep-sequencing analysis confirmed the methylation pattern suggested by 450K array. A thorough literature search suggested that 38 genes play roles in spermatogenesis (PDHA2, PARP12, FHIT, RPTOR, GSTM1, GSTM5, MAGI2, BCAN, DDB2, KDM4C, AGPAT3, CAMTA1, CCR6, CUX1, DNAH17, ELMO1, FNDC3B, GNRHR, HDAC4, IRS2, LIF, SMAD3, SOD3, TALDO1, TRIM27, GAA, PAX8, RNF39, HLA-C, HLA-DRB6), are testis enriched (NFATC1, NMNAT3, PIAS2, SRPK2, WDR36, WWP2), or show methylation differences between infertile cases and controls (PTPRN2, RPH3AL). We found a statistically significant correlation between peripheral blood DNA methylation and male infertility, raising the hope that epigenome-based blood markers can be used for screening male infertility risk. The study also identified new candidates for spermatogenesis and fertility. Show less

Do methylation changes in sperm DNA correlate with infertility? Loss of spermatogenesis and fertility was correlated with 1680 differentially-methylated CpGs (DMCs) across 1052 genes. Methylation changes in a number of genes have been correlated with reduced sperm count and motility. This case-control study used spermatozoal DNA from 38 oligo-/oligoastheno-zoospermic infertile patients and 26 normozoospermic fertile men. Genome-wide methylation analysis was undertaken using 450 K BeadChip on spermatozoal DNA from six infertile and six fertile men to identify DMCs. This was followed by deep sequencing of spermatozoal DNA from 32 infertile patients and 20 fertile controls. A total of 1680 DMCs were identified, out of which 1436 were hypermethylated and 244 were hypomethylated. Classification of DMCs according to the genes identified BCAN, CTNNA3, DLGAP2, GATA3, MAGI2 and TP73 among imprinted genes, SPATA5, SPATA7, SPATA16 and SPATA22 among spermatogenesis-associated genes, KDM4C and JMJD1C, EZH2 and HDAC4 among genes which regulate methylation and gene expression, HLA-C, HLA-DRB6 and HLA-DQA1 among complementation and immune response genes, and CRISPLD1, LPHN3 and CPEB2 among other genes. Genes showing significant differential methylation in deep sequencing, i.e. HOXB1, GATA3, EBF3, BCAN and TCERG1L, are strong candidates for further investigations. The role of chance was ruled out by deep sequencing of select genes. N/A. Genome-wide analyses are fairly accurate, but may not be exactly validated in replication studies across all DMCs. We used the 't' test in the genome-wide methylation analysis, whereas other tests could provide a more robust and powerful analysis. DMCs can serve as markers for inclusion in infertility screening panels, particularly those in the genes showing differential methylation consistent with previous studies. The genes validated by deep sequencing are strong candidates for investigations of their roles in spermatogenesis. The study was funded by the Council of Scientific and Industrial Research (CSIR), Govt. of India with grant number BSC0101 awarded to Rajender Singh. None of the authors has any competing interest to declare. Show less

Cerebral vasospasm is a major contributor to delayed morbidity following aneurysmal subarachnoid hemorrhage. We sought to evaluate differential plasma protein levels across time in patients with aneurysmal subarachnoid hemorrhage to identify potential biomarkers and to better understand the pathogenesis of cerebral vasospasm. Nine female patients with aneurysmal subarachnoid hemorrhage underwent serial analysis of 239 different serum protein levels using quantitative, multiplexed immunoassays (DiscoveryMAP 250+ v2.0, Myriad RBM, Austin, TX, USA) on post-hemorrhage days 0 and 5. A repeated measures analysis of variance determined that mean protein concentration decreased significantly in patients who developed vasospasm versus those who did not for alpha-2-macroglobulin (F [1.00,7.00]=16.33, p=0.005), angiogenin (F [1.00,7.00]=7.65, p=0.028), apolipoprotein A-IV (F [1.00,7.00]=6.308, p=0.040), granulocyte colony-stimulating factor (F [1.00,7.00]=9.08, p=0.020), macrophage-stimulating protein (F [1.00,7.00]=24.21, p=0.002), tetranectin (F [1.00,7.00]=5.46, p<0.039), vascular endothelial growth factor receptor 3 (F [1.00,7.00]=6.94, p=0.034), and significantly increased for vitronectin (F [1.00,7.00]=5.79, p=0.047). These biomarkers may be of value in detecting cerebral vasospasm, possibly aiding in the identification of patients at high-risk prior to neurological deterioration. Show less

Stimulation of insulin secretion by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) has been found to be diminished in type 2 diabetes. We hypothesized that this impairment is due to a defect at the receptor level induced by the diabetic state, particularly hyperglycemia. Gene expression of incretin receptors, GLP-1R and GIPR, were significantly decreased in islets of 90% pancreatectomized (Px) hyperglycemic rats, with recovery when glucose levels were normalized by phlorizin. Perifused islets isolated from hyperglycemic Px rats showed reduced insulin responses to GLP-1 and GIP. To examine the acute effect of hyperglycemia on incretin receptor expression, a hyperglycemic clamp study was performed for 96 h with reduction of GLP-1 receptor expression but increase in GIP receptor expression. Similar findings were found when islets were cultured at high glucose concentrations for 48 h. The reduction of GLP-1 receptor expression by high glucose was prevented by dominant-negative protein kinase C (PKC)alpha overexpression, whereas GLP-1 receptor expression was reduced with wild-type PKCalpha overexpression. Taken together, GLP-1 and GIP receptor expression is decreased with chronic hyperglycemia, and this decrease likely contributes to the impaired incretin effects found in diabetes. Show less