👤 Garima Dwivedi

Epilepsy is generally described as a pathology resulting from an imbalance between excitatory and inhibitory activities. In recent years, neurotrophins have been recognized as key players in the pathophysiology of nervous system diseases. One such neurotrophin, BDNF, and its receptor, TrkB, play critical roles as epileptogenic factors that regulate neuronal hyperexcitability and synaptic plasticity. In this study, we sought to elucidate the exact mechanisms underlying the neuroprotective and antiepileptic effects of pantoprazole. The molecular docking study indicated key interactions of pantoprazole with the TrkB receptor (PDB ID: 4AT3). Furthermore, pantoprazole exhibited notable in vitro TrkB kinase inhibitory activity (IC Show less

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder characterized by hyperandrogenism, has been increasingly associated with a high risk of autism spectrum disorder (ASD) in offspring. The emerging interaction between reproductive endocrinology and neurodevelopmental biology suggests that excessive androgen exposure during gestation may perturb neurotrophic signaling and impair neural circuit formation. Brain-derived neurotrophic factor (BDNF) acts through tropomyosin receptor kinase B receptor to activate downstream phosphoinositide 3-kinase/protein kinase B and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways, both of which are fundamental to neuronal survival and synaptogenesis. Disruption of these signaling cascades under hyperandrogenic conditions may lead to altered neuroarchitecture, impaired synaptic connectivity, and ASD-like behavioral phenotypes. Clinical and experimental studies also implicate aberrant BDNF expression in ovarian dysfunction, oocyte maturation deficits, and placental steroidogenic imbalance, highlighting a shared endocrine-neurodevelopmental axis in PCOS. Moreover, androgen excess may induce epigenetic modifications and post translational alterations of BDNF or tropomyosin receptor kinases B receptors, further compromising downstream signaling. These molecular events can dysregulate the transcriptional control of multiple synaptic and neurodevelopmental genes, thereby promoting atypical neuronal circuit formation. Understanding the interaction between BDNF signaling and androgen excess provides a mechanistic framework to explain how maternal endocrine imbalance influences neurodevelopment of offspring. This review integrates multidisciplinary findings spanning clinical cohorts, animal models, and molecular studies to delineate how androgen-BDNF interactions amplified by epigenetic, transcriptional, and post translational dysregulation underpin key neurodevelopmental disruptions observed in ASD. Furthermore, it emphasizes the translational potential of targeting BDNF-related pathways as early biomarkers or therapeutic entry points to mitigate the intergenerational neurodevelopmental consequences of PCOS. Show less

Women are susceptible to hormonal imbalances and endocrine-related disorders such as Polycystic Ovary Syndrome (PCOS), Ovarian Cancer (OC), and Major Depressive Disorder (MDD). This study aims to identify gene-level interconnections among these conditions using omics-based bioinformatic approaches. Publicly available GEO datasets, viz., GSE226146 (PCOS), GSE18520 (OC), and GSE125664 (MDD), were analyzed, which in total resulted in 21,366 differentially expressed genes (DEGs), including 11,174 upregulated and 10,198 downregulated genes. Common genes PTTG1 and PID1 were identified using Venny 2.0. A protein-protein interaction (PPI) network was constructed using STRING, and 10 hub genes (ANAPC5, ANAPC2, PTTG1, FZR1, ANAPC4, CDC20, CDC27, ANAPC10, UBE2C, and BUB1) were identified using CytoHubba based on MCC scoring. Functional enrichment analysis showed significant involvement of these genes in oocyte meiosis, progesterone-mediated oocyte maturation, mitotic regulation, and metaphase-anaphase transition (p < 0.05). PTTG1, identified as both a common and hub gene, was downregulated in PCOS and upregulated in OC and MDD. Drug-gene interaction analysis using DSigDB via Enrichr identified Alvespimycin (for PCOS) and Gefitinib (for OC) as drugs targeting PTTG1. Molecular docking using AutoDock 4.2.6 showed that Alvespimycin and Ephedrone bind PTTG1 with a binding affinity of - 4.59 kcal/mol and - 5.81 kcal/mol, respectively, while Gefitinib showed - 4.92 kcal/mol, slightly less than Troglitazone (-5.3 kcal/mol) for OC. This study highlights PTTG1 as a shared molecular link among PCOS, OC, and MDD, suggesting its potential as a therapeutic target and providing insights into the genetic and physiological overlap of these conditions. Show less

Lipoprotein(a) [Lp(a)] and PCSK9 are emerging lipid biomarkers implicated in atherogenesis and residual cardiovascular risk, but their relationship with coronary disease complexity in acute coronary syndrome (ACS) is unclear. This study evaluates their serum levels in first-episode ACS patients versus controls and explores their relationship with SYNTAX score-defined coronary severity. This single-centre observational study enrolled 160 patients presenting with their first episode of ACS (aged 18-75) and 40 age-matched healthy controls. All participants were free from lipid-lowering therapy and major comorbidities. Fasting serum samples were collected to measure the standard lipid profile, Lp(a), and PCSK9 levels. The severity of coronary artery disease was quantified using the SYNTAX score after coronary angiography. The ACS cohort (mean age 55.7 years; 73.1 % male) most frequently presented with STEMI (53.7 %). Traditional risk factors included smoking/tobacco use (48.8 %), diabetes (40.0 %), and hypertension (38.1 %). Median SYNTAX score was 19.4. Compared with controls, ACS patients had significantly lower HDL-C and higher LDL/HDL and cholesterol/HDL ratios. Lp(a) (38.9 vs. 15.9 mg/dL, p < 0.001) and PCSK9 (272.3 vs. 169.6 ng/mL, p < 0.001) were markedly elevated in ACS patients. Neither Lp(a) nor PCSK9 correlated with SYNTAX score. LDL-C showed a modest positive correlation with Lp(a) (r = 0.163, p = 0.040). Higher SYNTAX scores were associated with more extensive multivessel disease. Patients with ACS exhibited significantly higher Lp(a) and PCSK9 levels compared with healthy controls, but these biomarkers did not reflect angiographic disease complexity. Their role may lie more in underlying cardiovascular risk assessment than in predicting anatomical severity. Show less

Depression involves maladaptive processes impairing an individual's ability to interface with the environment appropriately. Long noncoding RNAs (lncRNAs) are gaining traction for their role in higher-order brain functioning. Recently, we reported that lncRNA coexpression modules may underlie abnormal responses to stress in rats showing depression-like behavior. The current study explored the global expression regulation of lncRNAs and messenger RNAs (mRNAs) in the hippocampus of rats showing susceptibility (learned helplessness [LH]) or resiliency (non-LH) to depression and fluoxetine response to LH (LH+FLX). Multiple comparison analysis was performed with an analysis of variance via the Multiple comparison analyses revealed differentially expressed mRNAs and lncRNAs with each phenotype. Integrated bioinformatics analysis identified novel transcripts, specific modules, and regulatory pairs of mRNA-lncRNA in each phenotype. In addition, the machine learning approach predicted lncRNA-regulated The study shows a novel role for lncRNAs in the development of specific depression phenotypes and in identifying newer targets for therapeutic development. Show less

The Central nervous system is blemished by the high incidence of neurodegenerative diseases, which is known to cause disfiguration of regeneration and repair of axonal growth. Recognition of proteins that act as agents of repressing such repair has become the norm to tackle these abominable conditions. One such protein is LINGO1 that act as a repressor for axonal growth. Being one of the critical causative agents of several neurodegenerative pathways. Consequently, its inhibition may tend to help the outcomes of regenerative technologies aiming to outweigh the symptoms of neurodegenerative diseases. For this objective, LINGO1 was targeted with pharmacophore analogs of Fasudil and Ibuprofen, as they are known to have a deterring effect against the concerned protein. 1-Tosyl-2-(chloromethyl)-2,3-dihydro-1H-indole was found showing the least binding score of - 6.8, with verified ADMET admissibility. The pharmacological activity of the said ligand was estimated with QSAR tool showing favourable electro-steric model. All this was finally collaborated with a molecular dynamics simulation study which exhibited a stable structure compatibility of the ligand with LINGO-1. Further, the efficacy of the compound can be evaluated through experimental studies for inferring its future potential and utilization as an effective means to tackle neuronal regeneration and remyleination. The online version contains supplementary material available at 10.1007/s13205-023-03789-4. Show less

(1) Abnormally increased expression of claudin-6 in gastric cancer is considered a prognostic marker of the chromosomal unstable molecular subtype. However, a detailed molecular profile analysis of differentially expressed genes and affected pathways associated with claudin-6 increased (Cldn6 Show less

Recent studies suggest that microRNAs (miRNAs) can participate in depression pathogenesis by altering a host of genes that are critical in corticolimbic functioning. The present study focuses on examining whether alterations in the miRNA network in the amygdala are associated with susceptibility or resiliency to develop depression-like behavior in rats. Amygdala-specific altered miRNA transcriptomics were determined in a rat depression model following next-generation sequencing method. Target prediction analyses (cis- and trans) and qPCR-based assays were performed to decipher the functional role of altered miRNAs. miRNA-specific target interaction was determined using in vitro transfection assay in neuroblastoma cell line. miRNA-specific findings from the rat in vivo model were further replicated in postmortem amygdala of major depressive disorder (MDD) subjects. Changes in miRNome identified 17 significantly upregulated and 8 significantly downregulated miRNAs in amygdala of learned helpless (LH) compared with nonlearned helpless rats. Prediction analysis showed that the majority of the upregulated miRNAs had target genes enriched for the Wnt signaling pathway. Among altered miRNAs, upregulated miR-128-3p was identified as a top hit based on statistical significance and magnitude of change in LH rats. Target validation showed significant downregulation of Wnt signaling genes in amygdala of LH rats. A discernable increase in expression of amygdalar miR-128-3p along with significant downregulation of key target genes from Wnt signaling (WNT5B, DVL, and LEF1) was noted in MDD subjects. Overexpression of miR-128-3p in a cellular model lead to a marked decrease in the expression of Dvl1 and Lef1 genes, confirming them as validated targets of miR-128-3p. Additional evidence suggested that the amygdala-specific diminished expression of transcriptional repressor Snai1 could be potentially linked to induced miR-128-2 expression in LH rats. Furthermore, an amygdala-specific posttranscriptional switching mechanism could be active between miR-128-3p and RNA binding protein Arpp21 to gain control over their target genes such as Lef1. Our study suggests that in amygdala a specific set of miRNAs may play an important role in depression susceptibility, which could potentially be mediated through Wnt signaling. Show less

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less

Essential oil components from turmeric (Curcuma longa L.) are documented for neuroprotective, anti-cancer, anti-thrombotic and antioxidant effects. The present study aimed to investigate the disease-modifying potential of curcuma oil (C. oil), a lipophilic component from C. longa L., in hyperlipidaemic hamsters. Male golden Syrian hamsters were fed a chow or high-cholesterol (HC) and fat-rich diet with or without C. oil (30, 100 and 300 mg/kg) for 28 d. In HC diet-fed hamsters, C. oil significantly reduced plasma total cholesterol, LDL-cholesterol and TAG, and increased HDL-cholesterol when compared with the HC group. Similar group comparisons showed that C. oil treatment reduced hepatic cholesterol and oxidative stress, and improved liver function. Hyperlipidaemia-induced platelet activation, vascular dysfunction and repressed eNOS mRNA expression were restored by the C. oil treatment. Furthermore, aortic cholesterol accumulation and CD68 expression were also reduced in the C. oil-treated group. The effect of C. oil at 300 mg/kg was comparable with the standard drug ezetimibe. Delving into the probable anti-hyperlipidaemic mechanism at the transcript level, the C. oil-treated groups fed the chow and HC diets were compared with the chow diet-fed group. The C. oil treatment significantly increased the hepatic expression of PPARa, LXRa, CYP7A1, ABCA1, ABCG5, ABCG8 and LPL accompanied by reduced SREBP-2 and HMGCR expression. C. oil also enhanced ABCA1, ABCG5 and ABCG8 expression and suppressed NPC1L1 expression in the jejunum. In the present study, C. oil demonstrated an anti-hyperlipidaemic effect and reduced lipid-induced oxidative stress, platelet activation and vascular dysfunction. The anti-hyperlipidaemic effect exhibited by C. oil seems to be mediated by the modulation of PPARa, LXRa and associated genes involved in lipid metabolism and transport. Show less

Despite the growing epidemic of the metabolic syndrome (MetS), few studies have evaluated genetic polymorphisms associated with the MetS phenotype. One candidate, APOC3, modulates lipid and lipoprotein metabolism and the promoter polymorphisms C-482T/T-455C are associated with loss of insulin downregulation. One hundred twenty two consecutive MetS cases were matched by age, sex and race in a 1:1 case-control design to evaluate the prevalence of common polymorphisms in the following candidate genes: APOC3, APOE, B3AR, FABP2, GNB3, LPL, and PPARalpha and PPARgamma. Compared to controls, MetS subjects exhibited a greater prevalence of APOC3 promoter polymorphisms. Specifically, the frequency of the variant C-482T and T-455C alleles was 70.5 and 81.9% of cases compared to 43.4 and 54.1% in controls, respectively (p <0.0001). Overall, APOC3 promoter variants were associated with a greater likelihood of MetS compared to wild type [C-482T (OR: 4.3; 95% CI: 2.2, 8.6 [p <0.0001]), T-455C (OR: 3.6; 95% CI: 2.0, 6.7 [p <0.0001])]. No material differences were identified between the other genetic variants tested and prevalence of MetS. These data, therefore, suggest that the APOC3 promoter polymorphisms C-482T and T-455C are associated with the MetS. Show less

Extracellular signal-regulated kinase 5 (ERK5), the newest member of the mitogen-activated protein (MAP) kinase family, is regulated differently than the other MAP kinases. Emerging evidence suggest the role of ERK5 signaling in promoting cell proliferation, differentiation, neuronal survival, and neuroprotection. The present study investigates whether suicide brain is associated with alterations in components of the ERK5 signaling cascade. In the prefrontal cortex (PFC) and hippocampus of suicide subjects (n=28) and nonpsychiatric control subjects (n=21), we examined the catalytic activities and protein levels of ERK5 and upstream MAP kinase kinase MEK5 in various subcellular fractions; mRNA levels of ERK5 in total RNA; and DNA-binding activity of myocyte enhancer factor (MEF)2C, a substrate of ERK5. In the hippocampus of suicide subjects, we observed that catalytic activity of ERK5 was decreased in cytosolic and nuclear fractions, whereas catalytic activity of MEK5 was decreased in the total fraction. Further, decreased mRNA and protein levels of ERK5, but no change in protein level of MEK5 were noted. A decrease in MEF2C-DNA-binding activity in the nuclear fraction was also observed. No significant alterations were noted in the PFC of suicide subjects. The observed changes were not related to a specific psychiatric diagnosis. Our findings of reduced activation and/or expression of ERK5 and MEK5, and reduced MEF2C-DNA-binding activity demonstrate abnormalities in ERK5 signaling in hippocampus of suicide subjects and suggest possible involvement of this aberrant signaling in pathogenic mechanisms of suicide. Show less