👤 Prashant Kumar

The progressive neurodegenerative disease known as Parkinson's Disease (PD) is represented by deficits in both motor and non-motor functions. Levodopa and dopamine agonists are examples of pharmaceutical treatments that mainly reduce symptoms without having any discernible neuroprotective effects. The potential of exercise-based physical therapy to improve neuroplasticity and slow disease progression has drawn increasing attention. To provide awareness of their complementary roles in enhancing outcomes for people with PD, this narrative review examines the combined neuroprotective effects of pharmaceutical medicines and physical therapy. The aim of the review was to evaluate the effects of both physical and pharmaceutical therapies in the management of Parkinson's disease to enhance motor recovery and retard disease progression. The evidence from previous research is compiled in this review, which focuses on preclinical and clinical trials examining the neuroprotective benefits of medication and exercise-based physical therapy. We searched databases such as PubMed, Scopus, Embase, the Cochrane Library, and Web of Science to identify relevant peer-reviewed articles. The review discusses therapeutic synergies, underlying mechanisms, and how these affect clinical practice. Aerobic, resistance, and balance training are examples of exercise-based physiotherapy that reduce oxidative stress, increase brain-derived neurotrophic factor (BDNF) levels, and promote neuroplasticity. These effects enhance the ability of pharmacological drugs to relieve symptoms. Research indicates that, compared to stand-alone treatments, combined therapies produce superior outcomes in motor function, non-motor symptom management, and overall quality of life. The review also highlights important mechanisms of interaction between various medicines, including neuroprotective signaling pathways and improved dopamine utilization. Combined therapy in Parkinson's disease enhances neuroprotection by boosting BDNF and other neurotrophic factors, reducing oxidative stress and inflammation, and promoting neurogenesis. Exercise and medications work synergistically to improve neuronal survival, cognition, and motor function. However, challenges include poor patient adherence, limited access to structured programs, limited clinical integration, and the need to tailor treatment to disease stage. A possible method for improving neuroprotection in PD is the combination of pharmaceutical therapies and exercise-based physical therapy. Further research is needed to optimize therapy regimens and develop individualized approaches to enhance patient outcomes and slow disease progression. This combined method offers a multifaceted and comprehensive approach to managing Parkinson's disease. Show less

Anxiety is a common disorder characterized by excessive fear, tension, and physical symptoms, such as sweating and palpitations. There are approximately 16.6 % of patients worldwide affected by anxiety disorders, which have been classified as panic disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessivecompulsive disorder, and phobias. The amygdala plays a central role in regulating fear, anxiety, and aggression, particularly when influenced by trauma or heredity, which can contribute to the development of anxiety disorders. Another contributing factor is oxidative stress, characterized by reduced antioxidant levels and increased cellular damage. Neurotransmitters, such as serotonin, norepinephrine, and Gamma-Aminobutyric Acid, are critical in controlling anxiety. Anxiety also usually involves imbalances, in particular, low levels of serotonin and high norepinephrine. N-Methyl-D-aspartate and Cholecystokinin brain receptors are involved in long-term fear memory encoding, suggesting potential new targets for treating this condition. Although conventional pharmacological treatments such as benzodiazepines and selective serotonin reuptake inhibitors are effective, they are often associated with side effects, dependency, and limited long-term efficacy. In recent years, plant-based bioactive compounds have gained attention as potential alternatives or adjunct therapies for managing anxiety disorders, and they act in Gamma-Aminobutyric Acid modulation and monoamine regulation. Anxiety can be treated through herbal medicine using ethnopharmacology. Show less

Vicarious trauma, the psychological distress from witnessing others' suffering, is an increasingly recognized precursor to depression and anxiety. However, the underlying neurobiological mechanisms remain poorly understood and appear to be sex-dependent. This study investigated the behavioral, physiological, and molecular consequences of purely psychological stress using a novel rodent model of vicarious learned helplessness (VLH). Male and female C57BL/6J mice were used to establish VLH paradigm. Observer mice witnessed conspecifics receiving inescapable foot shocks through a partitioned chamber allowing multisensory interaction. Following 7 days of conditioning, behavioral assays assessed anxiety and depressive symptoms. Prefrontal cortex tissue was analyzed using RT-qPCR and immunoblotting to identify molecular alterations. Vicarious stress induced depression phenotype in both sexes, characterized by active avoidance deficits, anhedonia and anxiety, comparable to direct physical trauma. Physiological assessments revealed hypothalamic-pituitary-adrenal (HPA) axis hyperactivity with elevated plasma corticosterone in both sexes. While molecular analysis showed shared downregulation of metabotropic glutamate receptor 2 (mGluR2) and elevated Il6 mRNA in the prefrontal cortex, distinct sexual dimorphism emerged. Males displayed specific deficits in neurotrophic support ( Vicarious trauma is sufficient to drive depression-like pathology through distinct molecular trajectories in males and females. These findings are suggestive of the critical necessity for sex-specific therapeutic strategies when treating trauma-related psychiatric disorders. Show less

Integration of the hepatitis B virus (HBV) genome into the host chromosome of infected patients poses a threat to those with HBV-associated hepatocellular carcinoma (HBV-HCC) due to challenges in early diagnosis and poor prognosis. CircRNAs are known for their oncogenic and biomarker potential in various cancers, including HBV-HCC, by sequestering tumor suppressive miRNAs, which, when free, can silence the expression of oncogenic mRNAs. Therefore, we aimed to develop a bioinformatic model to identify the circRNA-miRNA-mRNA axis in HBV-integrated HCC cell lines and to identify prognostic biomarkers specific to HBV-HCC patients. We identified dysregulated host circRNAs and mRNAs in HBV-negative and HBV-integrated cells using RNA-seq, followed by differential gene expression analysis with DESeq, and performed pathway analysis using Gene Set Enrichment Analysis (GSEA). Junctional sequences of the circRNAs were validated by Sanger sequencing of the amplified products. RT-qPCR further confirmed the dysregulation of 9 randomly selected circRNAs chosen from those with the highest fold-change and adjusted p-values. The miRNA partners for each circRNA were identified using mirDB. miRNA expression validation was performed using the publicly available Gene Expression Omnibus (GEO) database of the same cells, and Empirical Cumulative Distribution Function (ECDF) plots were generated to assess the fold change of mRNAs in potential binding miRNA partners. The mRNA targets for 10 miRNA ECDF plots were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and hub genes were identified using Search Tool for the Retrieval of Interacting Genes (STRING) Cytohubba protein-protein interaction (PPI) analysis. Survival analysis of hub genes was plotted, and a competitive endogenous RNA (ceRNA) network was constructed using Cytoscape. We identified 494 dysregulated circRNAs, 346 dysregulated miRNAs, and 10,419 dysregulated mRNA in HBV-integrated cells through a comprehensive bioinformatic model. circADGRL2 (~ 25-fold) showed the highest upregulation and miR-361-5p acted as a central node of multiple circRNAs: circADGRL2, circPROX1 and circPALS2. BDNF, a target mRNA of miR-361-5p, was identified as the highest risk ratio in HBV-HCC patients, suggesting a possible circADGRL2-miR-361-5p-BDNF axis involved in HBV-HCC. The target mRNAs of miRNAs were predicted to be associated with several cancer pathways, such as MAPK and RAS. Our data suggest a potential dysregulated circRNA-miRNA-mRNA axis in HBV-integrated hepatocytes, which may indicate a poor prognosis for HBV-HCC patients. Show less

Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice. Show less

Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders. Show less

Studies suggest that obesity is linked to both autonomic nervous system dysfunction and cognitive impairment, but the specific quantitative associations are not well explored. This study was proposed to explore the quantification of different neurocognitive signatures and heart rate variability (HRV) parameters with increasing body weight among metabolically healthy obese participants for better analytical predictors. The present research is a cross-sectional study, including a total of 101 ( Significant changes were observed for neurocognitive performances and HRV indices for the metabolically healthy obese group compared with the control group. With the association heatmaps, BMI was found to be significantly negatively associated with the BDNF and high-frequency band (HF band, ms The findings of the present study support that HRV could be a valuable early non-invasive tool for future cognitive decline in a population with metabolically healthy obesity. The study was registered at Clinical Trial Registry of India (CTRI/2022/10/046935). Show less

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and obesity, show promising potential as a novel treatment for depression, particularly in patients with comorbid metabolic disorders. This narrative review examines the bidirectional relationship between obesity and depression, driven by shared mechanisms such as chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and impaired neuroplasticity. GLP-1 RAs, including liraglutide and exenatide, demonstrate neuroprotective effects by enhancing brain-derived neurotrophic factor expression and synaptic plasticity, alongside anti-inflammatory properties that reduce proinflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6). They also modulate serotonin turnover in mood-regulating brain regions, mirroring selective serotonin reuptake inhibitors. Preclinical studies in animal models reveal improved behavioral outcomes, while human observational studies and limited clinical trials, such as the LEAD-3 trial, report enhanced mood and quality of life in T2DM and obesity patients. However, challenges, including high treatment costs ($800-$1000/month), injectable administration, and needle-related anxiety, limit patient adherence, and clinical adoption. The lack of large-scale randomized controlled trials targeting depression as a primary outcome further hinders definitive conclusions. This review highlights GLP-1 RAs' potential to address both metabolic and depressive symptoms, offering a holistic approach to managing these interconnected conditions. Future research should focus on long-term efficacy, optimal dosing, and overcoming adherence barriers to establish GLP-1 RAs as a viable psychiatric treatment. Show less

Western diet-induced cognitive dysfunction is a rapidly emerging health challenge driven by excessive intake of high-fat, high-sugar, and ultra-processed foods. These dietary patterns promote neuroinflammation, oxidative stress, insulin resistance, gut dysbiosis, and blood-brain barrier (BBB) disruption, ultimately leading to synaptic dysfunction and cognitive decline. Crocetin, an apocarotenoid derived from saffron and Show less

Melanocortin-4 receptor (MC4R) deficiency is the most common cause of monogenic obesity; yet treatment options for children with MC4R mutations are limited. We describe significant improvement in weight in three patients with pathogenic or likely pathogenic MC4R mutations; two adolescents treated with semaglutide, and a younger child treated with metformin and topiramate. These findings indicate GLP-1 receptor agonists, topiramate and metformin can be helpful in managing obesity associated with MC4R deficiency. Show less

Drug chemoresistance remains a major reason of treatment failure in cancer patients. In head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer worldwide, cisplatin chemotherapy remains the gold standard for advanced tumors but often faces loss of responsiveness and the drawback of relapse. We previously showed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is a molecular biomarker of oral dysplasia and HNSCC. We also found that through interaction with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratory pathways that contribute to HNSCC development. Using HNSCC xenografts, patient tumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13, and HN4, here we provide evidence of the role of ANGPTL4 in the development of platinum-based chemoresistance in HNSCC through the promotion of DNA damage response (DDR) and homologous recombination (HR). ANGPTL4 enhanced these mechanisms by promoting phosphorylation of RAD51 recombinase in Tyr Show less

The rising demand for high-quality pork among consumers has driven interest in genetic improvement strategies. Crossbreeding is well known to influence carcass performance and meat quality; however, the molecular mechanisms underlying these effects are still poorly understood. In this study, the F1 generation of the Songlei Crossbred Pig (SL) was developed through crossing the Songliao Black Pig (male) (SS) and the Leixiang Pig (female) (LL). We integrated the transcriptomes and metabolomes of the longissimus dorsi (LD) muscle of SS and SL under identical conditions to identify key mechanisms regulating the quality of crossbred meat. Compared with those of SS, the slaughter weight, carcass weight, and dressing percentage of SL were significantly lower, but the backfat thickness was greater; however, meat quality traits, including intramuscular fat (IMF), colour, and pH The meat quality of SL was better than that of their male parents, but not the carcass traits were not. Additionally, several critical genes and pathways related to lipid metabolism were identified. These findings provide new insights into how meat quality can be improved by hybridization. Show less

T2D mellitus (T2DM) is increasingly prevalent in South Asia, often affecting individuals with normal BMI, a phenotype described as metabolically obese but normal weight (MONW). While randomized trials demonstrate that low-carbohydrate diets can induce remission, long-term, real-world evidence in non-obese, predominantly vegetarian South Asian populations remains scarce. To evaluate the long-term efficacy and safety of a culturally adapted low-carbohydrate diet in an N-of-1 longitudinal study with systematic, multi-domain follow-up. A 49-year-old male with new-onset T2D (HbA1c 7.2%) began a phased initiation (~100 g/day carbohydrate), nutritional ketosis (<30 g/day carbohydrate), and long-term stabilization (~100 g/day). Assessments included continuous glucose monitoring (CGM) periodically, standardized mixed-meal challenges, advanced lipid and apolipoprotein panels including ApoB and lipoprotein(a) [Lp(a)], hs-CRP, liver and renal function, and serial cardiovascular, skeletal, and ophthalmic imaging over 10-years. The study was monitored through regular physician assessments and follow-up. HbA1c remained between 4.7 and 5.3% without medication for a decade. CGM showed >90% time-in-range with reduced variability (CV decreased from approximately 18-12%), Lp(a) decreased (43.4 → 25.3 mg/dL), and hs-CRP remained <1 mg/L. Coronary artery calcium (CAC) remained 0 across three scans, with CT angiography confirming CAD-RADS 0. CIMT showed no stenosis. Bone mineral density and ophthalmic imaging showed no deterioration. This report offers a detailed N-of-1 longitudinal characterization of decade-long, medication-free remission of T2D in a metabolically obese normal weight South Asian male. Observations at approximately 100 g per day carbohydrate intake suggest that moderate carbohydrate restriction may represent a physiologically plausible and culturally compatible approach for long-term metabolic management in similar phenotypes. While broader applicability requires validation in larger cohorts, these findings provide a rationale for further evaluation of moderate carbohydrate restriction as a feasible dietary strategy in South Asian and comparable settings. Show less

Apolipoprotein E (APOE) regulates lipid metabolism and neuronal repair, yet its alleles show contrasting effects on hemorrhagic stroke (HS) risk. While some variants increase susceptibility, others appear protective, leading to inconsistent findings. This meta-analysis systematically evaluates the APOE-HS association to clarify its role in stroke pathophysiology. A comprehensive literature search was conducted across multiple databases up to January 31, 2025, using the keywords: ("Apolipoprotein E" OR "APOE" OR "APOE genotype") AND ("Single Nucleotide Polymorphisms" OR "SNP") AND ("Hemorrhagic stroke" OR "HS" OR "Intracerebral Hemorrhage" OR "ICH"). The APOE ε3/ε3 genotype served as the reference genotype in all studies, and only those studies with ε3/ε3 genotype were included in the analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and statistical analyses were performed using STATA version 13.0 (StataCorp LLC, College Station, Texas, United States). A total of 24 studies comprising 8,269 HS patients and 26,321 controls were included. Meta-analysis revealed a significant association of APOE ε2/ε2 (OR = 1.93, 95% CI = 1.32-2.81), ε4/ε4 (OR = 1.60, 95% CI = 1.21-2.13), ε2/ε4 (OR = 1.81, 95% CI = 1.34-2.44), ε2 (OR = 1.23, 95% CI = 1.12-1.35), and ε4 (OR = 1.31, 95% CI = 1.14-1.51) with an increased risk of HS. Our findings suggest that APOE ε2/ε2, ε2/ε4, ε2, and ε4/ε4 genotypes and the ε4 allele are associated with an elevated risk of HS. These results highlight the potential role of APOE genotypes in HS susceptibility and warrant further investigation. Show less

Millions of individuals worldwide are affected by Alzheimer's disease dementia (ADD) and frontotemporal dementia (FTD), with FTD characterized by degeneration of the frontal and temporal lobes leading to cognitive and behavioral impairments. A subset of Alzheimer's cases exhibits familial inheritance, with the PAISA mutation, a glutamic acid to alanine substitution at codon 280 (E280A) in the PSEN1 gene, being a primary cause of early-onset dementia. PSEN1 encodes a key component of the γ-secretase complex, which cleaves amyloid precursor protein (APP) to generate beta-amyloid (Aβ) peptides. The PAISA mutation disrupts normal Aβ processing, leading to overproduction or accumulation of Aβ, formation of amyloid plaques, and accelerated progression of dementia. Its prevalence is particularly high in Colombian families, giving rise to the term "PAISA mutation." The APOE genotype further modulates the clinical manifestation in PAISA carriers, with APOE2 potentially delaying disease onset, whereas APOE4 is associated with earlier onset. Recent research highlights TAF2N (also known as RBP56, encoded by TAF15) as a promising therapeutic target, as its modulation may regulate AD-associated genes, reduce toxic Aβ isoforms, modulate tau and APP pathways, protect neurons, and enhance synaptic function. Overall, understanding the molecular effects of PAISA mutations and exploring TAF2N-targeted therapies offers novel avenues for addressing early-onset familial AD, providing insights into broader mechanisms of disease pathogenesis. Show less

Heterozygous familial hypercholesterolemia (FH), a monogenic cause for premature coronary artery disease (CAD) is often underdiagnosed. In individuals who meet the FH diagnostic criteria and lack pathogenic variants, polygenic factors are recognized as potential contributors. This study aimed to characterize the spectrum of genetic variants and determine the low-density lipoprotein polygenic risk score (LDL-PRS) among clinically diagnosed FH participants from South India. We recruited 116 unrelated participants with a pretreatment LDL- C concentration ≥ 190 mg/dl and a DLCN (Dutch Lipid Clinic Network) score ≥ 3. Targeted next-generation sequencing (NGS) of 23 lipid related genes and 12-SNP (Single nucleotide polymorphism) genotyping were performed. NGS identified 39 variants including 13 pathogenic and 26 variants of unknown significance (VUS) some of which were in non-classical genes: ABCG5, ABCG8, APOE, PPP1R17, SREBF2. Pathogenic variants were detected in 66.7% of those with definite FH,19.7% in probable FH and 2.7% in possible FH. Overall,66% were variant negative. Among variant negative (FH/V-) participants, 64% demonstrated high LDL-PRS, whereas 70% of variant positive participants also exhibited elevated scores; suggesting a contributory role of polygenic factors across both groups. Additionally, the observation that variant positive individuals with high LDL-PRS have an increased risk of coronary artery disease (CAD) adds important nuance to risk stratification within genetically confirmed FH patients. Confirmation of diagnosis by genetic testing is essential for the diagnosis of FH. Although LDL-PRS may offer little benefit in variant negative cases and improve CAD risk prediction in variant positive individuals, large scale studies are essential to validate its clinical utility and assess whether inclusion of additional LDL- raising SNPs could enhance the detection of polygenic FH in the Indian population. Show less

Anti-inflammatory colchicine therapy has emerged as a new era for atherosclerotic cardiovascular diseases. However, the therapeutic benefit of colchicine has not been clearly defined. Herein, we present a double coordination-driven approach to fabricate a stable metal-organic nano-assembly of colchicine (COL-TA-Zn) by uniting the tropolone ring of colchicine (COL), phenolic groups of tannic acid (TA), and Zn Show less

Lipoprotein glomerulopathy is a rare familial disease due to mutations in the apolipoprotein E gene. The characteristic histological finding is deposition of lipoprotein thrombi in the glomerular capillaries. We present two cases, aged 35 years, male and female, respectively, both of whom presented with nephrotic syndrome. Renal biopsy revealed glomeruli which appeared enlarged in size, with many of the glomerular capillaries filled with amorphous thrombi-like material that were lamellated, and vacuolated at a few places. These thrombi appeared PAS weak positive, MT pale blue, silver negative, and Congo-Red negative. These capillary luminal contents stained reddish with Oil-red O confirming lipid contents. Glomerular tufts were negative for all antisera on direct immunoflorescence. A final opinion of lipoprotein glomerulopathy was given, following which patients were worked up for dyslipidemia and were managed with fibrates. Our first case underwent renal transplant in 2019 and has shown recurrence of lipoprotein glomerulopathy in his recent post-transplant biopsy done in December 2024. Show less

Dementia, marked by a decline in mental abilities like memory that interferes with daily life, is primarily caused by Alzheimer's Disease (AD). Symplocos racemosa, rich in acetyl oleanolic acid, serves as a neuroprotective agent by lowering amyloid β levels in the brain. This study aims to develop a nanoemulsion for the targeted delivery of S. racemosa phytoconstituents to enhance therapeutic efficacy against dementia. The study also aims to find out the mechanism of the responsible molecules via molecular docking studies. S. racemosa bark was ultrasonically extracted with methanol and ethyl acetate, yielding six phytoconstituents: ellagic acid, betulinic acid, acetyl oleanolic acid, salireposide (from methanol), oleanolic acid, symlocoside (from ethyl acetate), isolated by column chromatography. Molecular docking against AChE and BACE-1 was conducted using CB Dock-2. A chitosan- based nanoemulsion containing all six compounds was prepared to enhance brain delivery and was physically characterized. All isolated phytoconstituents and nanoemulsions were evaluated for their in vitro enzyme inhibition (AChE and BACE-1) potential. Its anti-dementia efficacy was evaluated in scopolamine-induced rodent models using Hebb-Williams and Elevated Plus Maze tests, complemented by histopathological analysis of the brain cortex to assess therapeutic effects. Docking studies showed acetyl oleanolic acid had stronger binding to BACE-1 and AChE than donepezil. This was further supported by an in vitro enzyme inhibition assay. Nanoemulsion at 200 and 400 mg/kg significantly reduced the time taken by memory-impaired mice to complete the Hebb-Williams Maze and transfer latency in the Elevated Plus Maze. Histopathological analysis showed a significant recovery of cortical damage. This indicates that the nanoemulsion has strong potential for the treatment of Alzheimer 's-related neurodegeneration. The neuroprotective action of S. racemosa nanoemulsion (SRMN) is attributed to the large-scale presence of its phytoconstituents, which reportedly exhibit a better binding affinity and inhibitory action against AChE and BACE-1 than donepezil. Additionally, the nanoemulsion enhanced bioavailability, stability, and blood-brain barrier penetration, which in turn improved therapeutic outcomes. From behavioral and histological studies, we observed that SRMN performed well in terms of memory improvement and cortical protection, suggesting that it is a very good multi-target approach for dementia. The prepared nanoemulsion from S. racemosa's isolated phytoconstituents is reported to exhibit synergistic action, thereby effectively managing dementia through BACE-1 and AChE inhibition. Show less

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder with progression leading to a decline in cognition. Despite the extensive research, conventional therapies have limited activity and often cause side effects. This demands the need for novel, safer, and effective treatment of AD.ObjectiveThe objective of this study was to determine the phytochemical constituents and determine the anti-Alzheimer's activity of Show less

In this study, we evaluated the therapeutic potential of DMB, a berberine derivative known for its enhanced bioavailability and reduced toxicity. DMB was synthesized and administered orally at doses of 5 and 10 mg/kg in an in vivo rat model of insulin resistance-induced Alzheimer's disease (AD). This model was established using a combination of a high-fat diet (HFD), streptozotocin (35 mg/kg; intraperitoneally), and amyloid-β Show less

Cinnamomum zeylanicum Blume, known for its medicinal and culinary value, was analyzed for comparative phytochemical profiling and antioxidant potential between Indian (Shillong, Kolkata) and African (Tanzania) stem bark varieties. Using HPTLC and GC-MS, the essential oils revealed key variations in chemical constituents, notably the exclusive presence of eugenol in the Tanzanian variety and higher cinnamaldehyde dimethyl acetal content. Physicochemical and organoleptic differences reflected geographic influence. Antioxidant studies using DPPH and FRAP assays confirmed superior activity in the Tanzanian sample, with the lowest IC50 (22.05 µg/ml) and highest FRAP value (579 µM). Phytochemical screening confirmed the presence of multiple bioactive compounds in the samples. These results underscore the significance of geographical origin in the quality and efficacy of medicinal plants, supporting the need for standardization protocols. This study provides a robust framework for evaluating regional variations in C. zeylanicum, enhancing its pharmacological validation and ensuring authenticity in herbal formulations. Molecular docking study with eugenol revealed strong binding affinity of eugenol with protein targets PTP1B, PPARγ, PPARδ, and PPARα in diabetes, and with BACE1 in Alzheimer's disease. Show less

Obstructive sleep apnea (OSA) is characterized by recurrent intermittent hypoxia (IH) and has been increasingly associated with lung cancer incidence and mortality. However, how IH-related biological programs relate to immune remodeling, stemness-associated phenotypes, and therapeutic resistance in lung cancer remains incompletely understood. We integrated single-cell RNA sequencing data from IH-exposed murine lung tissues (GSE301350) with bulk transcriptomic datasets from TCGA-LUAD and GSE31210 to examine hypoxia-associated cellular and transcriptional patterns. Stemness was quantified using CytoTRACE and transcriptome-based stemness scoring, and its associations with immune infiltration, immune checkpoint expression, TIDE scores, predicted drug sensitivity, and immunotherapy response were evaluated. A stemness-based prognostic model was constructed using LASSO Cox regression and validated in independent cohorts. Single-cell analysis revealed marked immune remodeling under intermittent hypoxia (IH), including expansion of effector T cells, and monocytes/macrophages, populations alongside reduced B cells and dendritic cells. In human LUAD cohorts, stemness-high tumors were associated with mitochondrial and metabolic stress-related transcriptional programs, and increased expression of immune checkpoint genes (PD-1, PD-L1, CTLA4, LAG3). Elevated stemness scores correlated with higher TIDE scores, poorer overall survival, and reduced predicted responsiveness to immunotherapy. LASSO modeling identified a six-gene stemness signature (EIF5A, MELTF, SEMA3C, CPS1, TCN1, SELENOK), that consistently stratified patients into high- and low-risk groups across TCGA and GSE31210 cohorts. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Drug sensitivity analyses further suggested that stemness-high tumors may exhibit increased susceptibility to selected kinase inhibitors (Dasatinib, A-770041) and metabolic modulators (Phenformin, Salubrinal). OSA-associated IH is linked to stemness-associated transcriptional plasticity, immune suppression, and adverse clinical outcomes in lung cancer. The identified stemness-based gene signature provides a robust prognostic biomarker and highlights potential therapeutic vulnerabilities, supporting integrative strategies that combine stemness and immune -targeted approaches with immunotherapy in OSA-associated lung cancer. Show less

SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies. Show less

NSCLC-Squamous cell carcinoma (SCC) is characterized by poor survival largely due no definitive markers for targeted therapy. KRAS (Kirsten rat sarcoma viral oncogene homolog) is a proto-oncogene associated with resistance standard chemotherapy regimens. Discoidin domain receptor 2 (DDR2), fibroblast growth factor receptor-1(FGFR-1) and mesenchymal epithelial transition (MET) are receptor tyrosine kinases that regulate proliferation, apoptosis and invasion. The objectives were to assess frequency of FGFR1, DDR2,c-MET protein over-expression and KRAS mutations in NSCLC-SCC and to co-relate expression of molecular markers with clinico-pathological parameters. The study was a retrospective and prospective case series of 150 cases of NSCLC-SCC. Testing for KRAS, DDR-2, cMET and FGFR1 was done using immunohistochemistry (IHC). KRAS IHC was validated using real time polymerase chain reaction testing. Molecular marker expression was identified in 37.33% (n=56/150) cases, among which 80.35% (n=45/56) cases had a single mutation and 19.64% cases(n=11/56) had multiple mutations. FGFR-1 protein over-expression was identified in 8% cases and cMET protein over-expression in 4.67% cases. DDR-2 over-expression was present in 19.33% cases and KRAS protein over-expression in 14.67% cases. Co-expression of DDR-2 and KRAS was identified in 72.72% cases. DDR2 protein over-expression is identified in smokers and cases with distant metastasis. KRAS protein over-expression was more frequent in cases >40 years of age with advanced disease stage. The targets evaluated have potential drugs currently under trial phase. This may help to define the subgroup for use of targeted therapy in NSCLC-SCC and in designing new treatment protocols. Show less

Long overshadowed by VEGF-A, vascular endothelial growth factor B (VEGF-B) has emerged as a critical regulator of vascular, metabolic, and immune cross-talk. Unlike the potent angiogenic factor VEGF-A, VEGF-B does not induce vascular leakage but modulates tissue-specific functions, including fatty acid transport, neuronal survival, and immunometabolism, through its receptors VEGFR1 and NRP1. Its roles are often paradoxical, suppressing angiogenesis in some cancers while promoting metastasis and immune evasion in others, highlighting its profoundly context-dependent nature of action. Recent discoveries, such as the identification of FGFR1 as a key receptor and the essential role of VEGF-B in T cell survival, have revitalized interest in its therapeutic potential. However, clinical translation remains challenging, as exemplified by the recent failure of the anti-VEGF-B antibody CSL346 in diabetic kidney disease, underscoring our incomplete understanding of VEGF-B biology. This review integrates cutting-edge insights into the diverse functions of VEGF-B, proposes a mechanistic framework for its complex signaling networks, and outlines a roadmap for developing precision therapies for metabolic, cardiovascular, neurodegenerative, and oncological diseases. We address the critical translational challenges to maximize the therapeutic benefits while preserving the crucial homeostatic functions of VEGF-B. Show less

Gynecologic carcinosarcoma is an uncommon but aggressive malignancy that frequently requires systemic therapy but therapeutic options are limited. Development of preclinical models is therefore important for therapeutic advancement. Carcinosarcoma tumor (6 uterine and 1 tubo-ovarian) from 7 surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and/or cell line development. The histologic, immunophenotypic and genetic features were characterized. Based on the observed molecular profiles and targetable molecular alterations, in vivo studies were conducted to evaluate the efficacy of targeted therapy on tumor growth. We established 1 cell line and 6 PDX models which recapitulated the dominant phenotype of the respective parental tumors with preserved mesenchymal differentiation lineage in the sarcomatous component. Genomically, the PDX/cell line models preserved similar complex pattern of copy number alterations and similar mutation landscape when compared to the respective parental tumors. All 7 parental carcinosarcoma tumors and PDX/cell line models harbored pathogenic TP53 mutations. Moreover, we identified recurrent copy number gain/amplification involving several receptor tyrosine kinases (RTK), including amplification and protein over-expression of FGFR1. In vivo drug evaluation using a small molecule inhibitor (AZD4547) of FGFRs showed significant growth inhibition in the carcinosarcoma PDX tumor with the highest FGFR1 amplification and protein expression whereas AZD4547 showed no significant growth effects on carcinosarcoma lacking high level FGFR1 amplification, indicating oncogenic dependency on the amplified RTK pathway. These findings demonstrate the utility of patient-derived tumor models in the identification and the functional validation of potentially targetable molecular alterations in preclinical setting. Show less

The fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in cancer development and progression, primarily through mechanisms involving carcinogenesis and angiogenesis. Aberrant FGFR1 signalling has been implicated in various cancers, including lung, breast, neck and urothelial carcinoma. Despite the recognized oncogenic potential of FGFR1, therapeutic strategies targeting its kinase domain remain inadequately explored. This underscores an urgent need for the development of novel FGFR1 inhibitors, particularly through de novo drug design approaches, to effectively counteract FGFR1-driven malignancies. This research aims to develop novel FGFR1 inhibitors through a multi-step approach involving fragment-based drug design, virtual screening, molecular dynamics simulation (MD) and density functional theory studies (DFT), with the goal of targeting FGFR1's kinase binding domain to inhibit tumor angiogenesis. Initially, known FGFR inhibitor molecules were retrieved and subjected to fragment-based drug designing and virtual screening. Through thorough analysis, molecules containing the pyrido[2,3-d]pyrimidine scaffold were identified as promising candidates. A pyrido[2,3-d]pyrimidine-based database containing 90,952 molecules was subsequently retrieved from PubChem and filtered using molecular docking-based virtual screening resulting 94 molecules having better binding affinity than derazantinib, reference drug. After pharmacokinetic profiling (ADME), and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) studies, out of 94 molecules only 11 compounds with favorable pharmacokinetic properties and superior MM-GBSA binding free energies were selected. Docking-based screening revealed that selected 11 compounds demonstrated better binding scores than the reference drug, derazantinib. Among them, HIT1, was selected for 150ns molecular dynamics simulation to assess its conformational stability. DFT calculations further confirmed its bio-feasibility by analyzing the HOMO-LUMO energy gap. Overall, the selected lead compounds exhibited enhanced binding affinity, superior conformational stability, favorable pharmacokinetic and pharmacodynamic profiles compared to derazantinib. Present findings suggest that the identified hit molecules hold strong potential for inhibiting FGFR1's kinase domain and disrupting FGFR-associated tumor angiogenesis. Show less

Visceral leishmaniasis, caused by the protozoan parasite Leishmania donovani is one of the most life threatening neglected tropical disease with no licensed human vaccine and increasing risks of resistance to chemotherapeutic agents. Current vaccine approaches are hindered by suboptimal immunogenecity, underscoring the need for potent adjuvant that can steer a durable and protective immune response. Here, we reported for the first time immunotherapeutic potential of a synthetic TLR7/8 agonist, 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4 aminedihydrochloride (p-AM-BBIQ), in combination with heat-killed L. donovani antigen (HKA) in a murine model. Mice immunized with the adjuvanted formulation exhibited significant reduction in splenic parasite load, alongside enhanced production of nitric oxide and reactive oxygen species. Trancriptional profiling revealed increased upregulation of iNOS and Nf-κB, indicating activation of innate immune response. Flow cytometric analysis demonstrated increased frequencies of CD4 Show less