👤 Rashmi Rana

Astroglia, often called as astrocytes, play a crucial role in protecting neurons and preserved the neurophysiological functions. Astrocytes' dysfunction contributes to numerous neurological disorders. Astrocytes are involved in the regulation of oxidative stress and inflammatory process within Central nervous system. Developments in specific transcriptomic and genomics have initiated the discovery of new mechanisms governing astrocyte during oxidative and inflammatory process. Despite the advancements in existing diagnostic and therapeutic methods like targeted ultrasound and NPs mediated administration, these methods still pose risks and have drawbacks. Aptamers, artificial single stranded oligonucleotides have the ability to specific target cells and exhibit strong binding affinity and enhance the administration of therapeutic agents. Research over the last few years has demonstrated that the ability to target specific molecules/intermediates such as reactive oxygen species, interleukins, tumor necrotic factor, vascular endothelial growth factor, brain-derived neurotrophic factor and penetrate the blood brain barrier makes aptamers ideal candidates for addressing the oxidative and inflammatory intermediaries within astrocytes. Present review explores the emerging applications of aptamers in cytoprotection specially focus on their potential to combat oxidative stress and inflammation in astrocytes. We also discuss the capability of aptamers as cell specific molecular probes for advancing tailored diagnostic and therapeutic interventions. Present article also addresses future directions and significant issues. Show less

The ability of neurons to communicate via synapses is called synaptic transmission, and it is an essential process of brain functioning and plasticity. Its interference has been discovered as a common molecular trait in a broad range of neurological and psychiatric ailments. Nevertheless, in spite of increasing evidence within the disease context, the existing knowledge is still rather disunified, and the molecular processes are poorly incorporated into coherent, cross-disorder models. This narrative review addresses this gap by concisely synthesising recent advances in molecular genetics, synaptic proteomics, neuroimaging, and systems neuroscience to provide an integrated overview of synaptic dysfunction across neurological and psychiatric disorders. It reviews the role of the changes in vesicle trafficking, calcium dynamics, neurotransmitter receptor signalling, brain-derived neurotrophic factor (BDNF) action, and glia-mediated synaptic plasticity in the pathophysiology of conditions like schizophrenia, autism spectrum disorder (ASD), Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), and Parkinson's disease (PD). The emerging tools that have translational relevance, as pointed out by the review, include single-cell RNA sequencing, spatial proteomics, and synaptic positron emission tomography (PET) imaging, with the capabilities of providing disease-specific and patient-level insights into the pathology of synapses. This review establishes the convergence of the dysfunction, as well as therapeutic potential, through the presentation of a systems-level, cross-diagnostic framework at the level of the synapse. It ends with a prospective report of where precision medicine, development of new biomarkers, and lifespan research efforts are required to incorporate synaptic biology in translational neuroscience. Show less

Several studies show that neurosteroids currently play a significant role in autism spectrum disorders (ASD). However, the pathway of neurosteroid synthesis involved in ASD remains unclear. This study aimed to investigate the crosstalk between autism and neurosteroids, focusing on the mechanism of allopregnanolone production. We used the BTBR T+ tf/J (BTBR) mouse, a well-established animal model of ASD that exhibits typical autism-like behaviors along with neuroinflammation. In the hippocampus of BTBR mice, we observed a marked overexpression of pregnenolone and a related reduction in allopregnanolone levels. This neurosteroid imbalance also appears to be associated with an inflammatory pattern and the manifestation of repetitive and asocial behaviors. The combination of low doses of ultramicronized palmitoylethanolamide (PEA-um) and docosahexaenoic acid (DHA) restores allopregnanolone production modulating neurosteroidogenesis. In association with neurosteroid modulation, this restoration reduces repetitive behaviors and improves social interactions in BTBR mice, also modulating the inflammatory profile with a significant reduction in proinflammatory cytokines and brain-derived neurotrophic factor (BDNF) levels in the hippocampus. These effects demonstrate an important role of the peroxisome proliferator-activated receptor alpha (PPAR-α), whose expression is particularly reduced in BTBR mice. In addition, the pivotal involvement of PPAR-α was further supported by administering a specific antagonist that abolished the advantageous effects of PEA-um ​+ ​DHA. Overall, our findings demonstrate the potential synergistic effect of the low-dose combination of PEA-um and DHA, confirming their therapeutic effect in ASD and the involvement of neurosteroids in their mechanism of action. Show less

Elevated atherogenic lipoproteins increase risk of atherosclerotic cardiovascular disease (ASCVD), though long-term risk for adults without ASCVD who have low-normal levels has not been well described. This study used pooled data from 16,384 individuals in 3 population-based prospective cohorts. At baseline all participants were without ASCVD and were not taking lipid-lowering therapy. We evaluated ASCVD events by baseline LDL-C, non-HDL-C and apoB, including low-normal values. ASCVD risk was assessed using multivariable Cox proportional hazards. The study cohort had a mean age of 52 (SD 18) years with 56.5% women, 64.7% of White race and 35.3% of Black race. Over a median follow-up of 18.8 years, unadjusted ASCVD event incidence was similar for adults with baseline LDL-C < 70 mg/dL and 70 to 99 mg/dL, and higher with LDL-C ≥ 100 mg/dL; trends were similar for non-HDL-C and apoB categories. Compared to having baseline LDL-C 70 to 99 mg/dL, LDL-C < 70 mg/dL was associated with similar ASCVD risk (adjusted HR 1.16 [95% Confidence Interval, 95% CI 0.90-1.50]) and LDL-C ≥ 130 mg/dL was associated with higher risk (adjusted HR 1.31 [95% CI 1.14-1.50]) after multivariable adjustment; adults with non-HDL-C ≥ 160 mg/dL or apoB ≥ 90 mg/dL also had higher risk after multivariable adjustment. Among adults without ASCVD not taking lipid-lowering therapy at baseline, ASCVD risk for adults with low-normal and high-normal LDL-C, non-HDL-C and apoB was similar, and their risk remained less than in adults with elevated lipoproteins. These findings emphasize the importance of achieving normal atherogenic lipoprotein levels for primary prevention of ASCVD from early adulthood through middle age. Show less

Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD. Show less

Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD) are severe psychiatric conditions that share overlapping clinical symptoms, yet they differ in their underlying molecular mechanisms. Despite extensive research, the biological foundations of these disorders remain incompletely understood. In this study, we performed a large-scale transcriptomic analysis by integrating 557 publicly available RNA-seq datasets from post-mortem brain tissues, spanning multiple regions, to better understand the shared and distinct molecular features of these disorders. Using systematic bioinformatic approaches, we identified differentially expressed genes (DEGs) and investigated associated biological pathways, regulatory transcription factors, and drug-gene interactions. Our analysis revealed notable overlap in gene expression profiles, particularly between SCZ and BD, suggesting common molecular pathways underlying these disorders. At the same time, each disorder also demonstrated unique transcriptional patterns, supporting the existence of disorder-specific mechanisms. Brain region-specific analyses further highlighted spatial heterogeneity in gene expression, with significant differences observed in regions such as the hippocampus and dorsolateral prefrontal cortex (DLPFC). The transcription factor enrichment analysis revealed distinct regulatory programs driving each disorder: MDD pathology appears regulated by ASCL3, MYOG, HNF1B, RUNX3, FOXA1 and STAT4; BD exhibited predominant control by immune-regulatory factors including FOSL1, FOSL2, PLSCR1, RELB, BATF3, IRF and NFKB1; while SCZ demonstrated unique regulation through ATF5, CREB3L3, SNAI1, NFIL3, CEBPB, RELB and IRF transcription factors. Moreover, our drug-gene interaction analysis uncovered promising therapeutic targets, with several differentially expressed genes showing potential for drug repurposing, particularly in relation to antipsychotics and immunomodulatory agents. Our comprehensive transcriptomic analysis reveals both shared molecular mechanisms and distinct immune signatures across schizophrenia, bipolar disorder, and major depressive disorder, advancing our understanding of psychiatric pathophysiology while highlighting the heterogeneous nature of these conditions. These findings establish a critical foundation for developing targeted, patient-specific therapeutic interventions that address the underlying biological complexity of major psychiatric disorders. Show less

Gallbladder cancer (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, the authors attempted to bridge this gap by revealing the mutational profile of GBC. To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 tumor and matched blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package. Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology. Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection. Show less

Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes. Show less

Anaphylaxis is a rapid and severe reaction to a trigger that is characterized by skin, mucosal, and cardiorespiratory changes. A minority of patients exhibit a biphasic anaphylactic reaction (BAR). Tirzepatide is a dual incretin receptor analog approved for the treatment of type 2 diabetes mellitus (T2DM). Allergic reactions to tirzepatide were reported during clinical trials, but none were severe enough to be characterized as an anaphylactic reaction. We describe a case of a BAR to tirzepatide. Show less

Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis. Show less

The studies investigating gene-gene and gene-environment (or gene-behavior) interactions provide valuable insight into the pathomechanisms underlying obese phenotypes. The Pakistani population due to its unique characteristics offers numerous advantages for conducting such studies. In this view, the current study was undertaken to examine the effects of gene-gene and gene-environment/behavior interactions on the risk of obesity in a sample of Pakistani population. A total of 578 adult participants including 290 overweight/obese cases and 288 normal-weight controls were involved. The five key obesity-associated genetic variants namely MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752 were genotyped using the TaqMan allelic discrimination assays. The data related to behavioral factors, such as eating pattern, diet consciousness, the tendency toward fat-dense food (TFDF), sleep duration, sleep-wake cycle (SWC), shift work (SW), and physical activity levels were collected via a questionnaire. Gene-gene and gene-behavior interactions were analyzed by multifactor dimensionality reduction and linear regression, respectively. In our study, only TMEM18 rs7561317 was found to be significantly associated with anthropometric traits with no significant effect of gene-gene interactions were observed on obesity-related phenotypes. However, the genetic variants were found to interact with the behavioral factors to significantly influence various obesity-related anthropometric traits including BMI, waist circumference, hip circumference, waist-to-hip ratio, waist-to-height ratio, and percentage of body fat. In conclusion, the interaction between genetic architecture and behavior/environment determines the outcome of obesity-related anthropometric phenotypes. Thus, gene-environment/behavior interaction studies should be promoted to explore the risk of complex and multifactorial disorders, such as obesity. Show less

Previous genome-wide association analyses for obesity related genes demonstrated the association of BDNF gene variant rs6265 and MC4R gene variant rs17782313 with body mass index (BMI). However, the associated metabolite pathways are still behind the curtain. The aim of the current study is to investigate the associations of metabolic changes in obesity with MC4R gene variant rs17782313 and BDNF variant rs6265. Gas chromatography-mass spectrometry based untargeted metabolomics approach was used and 42 identified serum metabolites were selected for statistical analyses. Significant association of seven metabolites with MC4R gene variant rs17782313 based on obesity and thirty metabolites with obesity dependent BDNF variant rs6265 using additive model (adjusted p < 0.05) was observed. This study highlights the importance of alteration of fatty acid biosynthesis, probably due to high consumption of fats may cause to develop obesity. But obesity is a complex disorder and the full clarification of this complex machinery is still distant. To understand the obesity in a better way, more studies are required to identify remaining metabolites and also mechanism of these metabolic entities. Show less

Obesity is an outcome of multiple factors including environmental and genetic influences. Common obesity is a polygenic trait indicating that multiple genetic variants act synergistically to influence its expression. We constructed a genetic risk score (GRS) based on five genetic variants (MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752) and examined its association with obesity-related traits in a sample of Pakistanis. The study involved 306 overweight/obese (OW/OB) and 300 normal-weight (NW) individuals. The age range of the study participants was 12-63 years. All anthropometric and metabolic parameters were measured for each participant via standard procedures and biochemical assays, respectively. The genetic variants were genotyped by allelic discrimination assays. The age- and gender-adjusted associations between the GRS and obesity-related anthropometric and metabolic measures were determined using linear regression analyses. The results showed that OW/OB individuals had significantly higher mean ranks of GRS than NW individuals. Moreover, a significant association of the GRS with obesity-related anthropometric traits was seen. However, the GRS did not appear to affect any obesity-related metabolic parameter. In conclusion, our findings indicate the combined effect of multiple genetic variants on the obesity-related anthropometric phenotypes in Pakistanis. Show less

The current case-control study sought the association of BDNF rs6265 and MC4R rs17782313 with metabolic syndrome (MetS), MetS components and other related metabolic parameters in a sample of Pakistani subjects. Fasting high-density lipoprotein cholesterol (HDL-C) and homeostatic model assessment of insulin sensitivity showed a significantly lower mean whereas body mass index (BMI), waist circumference, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, insulin, total cholesterol (TC), low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, triglycerides (TG), cholesterol to HDL-C ratio, TG to HDL-C ratio, homeostatic model assessment of insulin resistance, visceral adiposity index, lipid accumulation product and the product of TG and glucose showed a significantly higher mean in the presence of MetS. Reduced HDL-C appeared as the most frequent and hypertriglyceridemia as the least frequent component of MetS whereas clustering of reduced HDL-C + abdominal obesity (AO) + hyperglycemia appeared as the most prevalent combination of MetS components. Moreover, BDNF rs6265 showed BMI and gender independent association with increased risk of MetS in Pakistani individuals whereas MC4R rs17782313 showed BMI and gender dependent association with increased risk of MetS in Pakistani females. In addition, BDNF rs6265 and MC4R rs17782313 showed gender-dependent associations with decreased risk of having low HDL-C in males and increased risk of having abdominal obesity in females, respectively. However, no association was observed for metabolic variables other than components of MetS across genotypes of both BDNF rs6265 and MC4R rs17782313. Show less

MC4R represents a key player involved in melanocortin-mediated control of energy balance. Recently identified near MC4R variant rs17782313 (T > C) can serve as a contributing factor for obese phenotype but its association with obesity has never been sought in a sample of the Pakistani population. The role of genetic variants as causal factors varies across populations. Association studies in a specific population can help us to distinguish global from local gene-gene and gene-environment interactions. This is the first study that investigated the association of rs17782313 with obesity and various obesity-linked anthropometric, metabolic, physical, and behavioural traits in Pakistani subjects including 306 OW/OB (overweight and obese) and 300 NW (normal weight) individuals. The comparison of various aforementioned obesity-linked continuous and categorical variables between OW/OB and NW subjects revealed that almost all variables were found significantly aberrant ( 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