👤 Rohit Singh

Chronic Unpredictable Mild Stress (CUMS) is a well-established model for inducing behavioral, cognitive, neurochemical, and metabolic impairments associated with neurobehavioral alterations. This study assessed the neuroprotective, antidepressant, and metabolic regulatory effects of Lonafarnib, a selective farnesyltransferase inhibitor, in mice subjected to chronic unpredictable mild stress (CUMS) for 28 days. The in silico docking analysis revealed encouraging binding energies of Lonafarnib with AChE (- 11.58 kcal/mol), CRF1 (- 10.94 kcal/mol), BDNF (- 5.99 kcal/mol), 5HT1A (- 10.48 kcal/mol), and 5HT2A (- 10.77 kcal/mol). This suggests a potential structural compatibility with cholinergic, serotonergic, neurotrophic, and stress-related proteins as preliminary results which requires experimental validation. The in -vivo study of Lonafarnib (20 or 40 mg/kg, i.p.) were effective in preventing the neurobehavioral alterations in CUMS mice. As, the behavioral evaluations demonstrated that CUMS resulted in anxiety-like behaviors, depressive-like behaviors, and cognitive impairments (p < 0.0001), all of which were significantly alleviated by Lonafarnib, particularly at a dosage of 40 mg/kg. The administration of Lonafarnib resulted in significant improvements in behavioral performance, a reduction in oxidative and inflammatory markers (IL-6, TNF-α), stabilization of HPA-axis related parameters, normalization of corticosterone, glucose, and lipid profiles, along with an increase in BDNF levels. Histological findings also indicated the preservation of neuronal structure within the hippocampus. In conclusion, these findings suggest that Lonafarnib may offer protective advantages against neurobehavioral and metabolic dysfunction caused by CUMS. However, a comprehensive mechanistic validation of prenylation-dependent signaling pathways is essential for further investigation. 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

The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a synaptic modulation and cognitive maintenance agent, is declined and, thus, aggravates pathology and cognition in AD. BDNF expressed from the liposome nanoparticles supplements the reduced BDNF and aids in ameliorating AD pathology. We found four weekly doses of our formulation reduced the amyloid burden by 3.04-fold ( Show less

Cadmium (Cd) is a potent neurotoxic heavy metal associated with cerebral oxidative disturbances. The beta-lactam antibiotic ceftriaxone has been known to modulate the expression of GLT-1, the primary glutamate transporter. This research has been framed to evaluate the potential neurodefensive activity of ceftriaxone against cadmium chloride (CdCl Show less

Psychedelic compounds such as psilocybin, Lysergic Acid Diethylamide (LSD), N,Ndimethyltryptamine (DMT), and 3,4-methylenedioxymethamphetamine (MDMA) are emerging as novel therapeutics for neuropsychiatric disorders, including depression, Post-Traumatic Stress Disorder (PTSD), and addiction. Acting primarily through serotonin 5-HT2A receptor agonism, they activate intracellular cascades involving Brain-Derived Neurotrophic Factor (BDNF), Tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR) pathway, leading to enhanced neuroplasticity and synaptogenesis. Recent evidence demonstrates direct TrkB binding and sustained cortical remodeling, underlying their rapid and durable antidepressant effects. Advanced Drug Delivery Systems (DDS)-including liposomes, Solid Lipid Nanoparticles (SLNs), and Poly(lactic-co-glycolic acid) (PLGA) carriers-are being engineered to achieve controlled, braintargeted, and stimuli-responsive release while minimizing systemic toxicity. Integration with microfluidic fabrication, Artificial Intelligence (AI)-based dosing, and non-invasive routes such as intranasal and transdermal delivery improves precision and patient adherence. By merging neuropharmacology with materials science, these innovations are redefining psychedelic-assisted therapy through enhanced safety, personalized dosing, and translational potential for central nervous system disorders. Show less

The aging process is associated with gradual cognitive decline resulting from deficits in synaptic plasticity, the brain's natural ability to adapt and reshape its neural circuitry. This review highlights the importance of synaptic plasticity in cognitive function. It provides a full overview of the molecular, cellular, and systemic mechanisms involved in enhanced or diminished synaptic plasticity in the aging brain. We also go over issues in neurotransmitter systems, calcium signaling, neurotrophic support (ex., BDNF-TrkB), cellular signaling pathways (e.g. mTOR, CaMK, CREB, and MAPK/ERK), and neuroinflammation, oxidative stress, and vascular integrity, all of which redirect the trajectory of synaptic failure associated with cognitive decline in aging. Therapeutic approaches toward increasing or restoring synaptic plasticity are evaluated, including pharmacological (e.g., nootropics, cholinesterase inhibitors, NMDA receptor modulators), natural (e.g., curcumin, resveratrol, bacoside A), and new interventions (e.g., psychoplastogens, gene therapy, nanocarriers, and digital therapeutics). Lifestyle approaches, especially physical exercise, cognitive training, intermittent fasting, and mindfulness approaches to stimulation, have highly potent effects on plasticity enhancements and employ multiple neurobiological mechanisms. Despite much promise, there remain substantial translational challenges, including limited clinical efficacy, lack of personalized biomarkers, and ethical considerations concerning cognitive enhancement. As we look ahead, a multidisciplinary integrative approach that includes molecular therapeutics, lifestyle interventions, and next-generation neurotechnologies will be most useful for protecting cognitive health and enhancing brain resilience in aging individuals. This review highlights the immediate necessity for personalized, ethical, and evidence-based approaches to take advantage of synaptic plasticity for healthy cognitive aging. 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

Advanced prostate cancer remains challenging, driven in part by Epidermal Growth Factor (EGF) signaling that promotes migration, invasion, and angiogenesis. We evaluated LA3IK ( The online version contains supplementary material available at 10.1038/s41598-026-41933-1. 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

Familial hypercholesterolemia (FH) is characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels and an increased risk of premature cardiovascular disease. The present study aimed to investigate the genetic background, associated biochemical profiles, clinical manifestations, and therapeutic response in patients with clinically suspected FH in Serbia. A total of 101 patients with clinically suspected FH were recruited from the Clinic for Endocrinology, Diabetes and Metabolic Diseases in Serbia between 2015 and 2023. Clinical diagnosis was established using the Dutch Lipid Clinic Network (DLCN) criteria. Genetic profiles of all patients were previously determined using next-generation sequencing. Fasting serum lipids, apolipoprotein A-I [ApoA-I], apolipoprotein B [ApoB], and lipoprotein(a) (Lp(a)) were measured enzymatically. Levels of serum lipids were compared between genetically FH-positive (carriers of variants in LDLR, APOB, PCSK9 and LDLRAP1 genes) and FH-negative patients. Therapeutic response was assessed by achieving the LDL-C target level. Statistical analyses were conducted in SPSS (version 30.0). Genetically confirmed FH patients exhibited significantly higher levels of ApoB (p=0.001) compared with variant-negative individuals, while ApoA-I (p=0.413) and Lp(a) (p=0.421) levels did not differ significantly between groups. Patients with pathogenic FH-associated variants were less likely to reach target LDL-C levels after therapy than those without identified variants. This study demonstrates biochemical diversity in familial hypercholesterolemia associated with genetic background in the Serbian population. Pathogenic FH mutations were associated with higher ApoB levels, underscoring the importance of combining genetic testing with lipid profiling for precise diagnosis and management. Show less

PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI). Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs. Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB (apolipoprotein B), APOE (apolipoprotein E), APOC2 (apolipoprotein C2), and APOC3 (apolipoprotein C3), as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI. Most apolipoprotein changes after PCSK9 mAb therapy following MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a). URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844. Show less

Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau 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

Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events. Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing. A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro. This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies. Show less

Plasma accumulation of the gut microbial metabolite 4-ethylphenylsulfate (4EPS), derived from dietary amino acid, tyrosine, has been associated with cardiovascular, renal, metabolic, and neurological disorders. AngII (angiotensin II) infusion increases circulating 4EPS in mice, suggesting a potential mechanistic role. We hypothesized that 4EPS modulates AngII-regulated pathophysiology and disease progression by directly inhibiting AT1R (angiotensin II type 1 receptor). This hypothesis was tested by combining AT1R pharmacology, cell signaling assays, ex vivo vascular studies, an AngII-induced aortic aneurysm growth model, and plasma proteomics analysis. in vitro, 4EPS reduced the binding of both AngII and the antagonist candesartan to AT1R and suppressed AngII-induced calcium signaling. Ex vivo, 4EPS attenuated AngII-mediated vasoconstriction. In vivo, high-fat diet-fed ApoE-null mice coinfused with AngII and 4EPS showed significant blunting of blood pressure elevation and a marked reduction in aortic aneurysm-related mortality compared with mice infused with AngII alone. Analysis of aortic remodeling revealed increased elastin preservation and decreased thickening of the intimal and medial layers in 4EPS-treated animals. Plasma proteomics indicated alterations in actin-cytoskeletal signaling pathways consistent with reduced activation of ERK (extracellular-regulated kinase) 1/2, filamin-A, and proteins involved in vascular smooth muscle cell motility. These findings identify 4EPS as a benign, endogenous AT1R antagonist that diminishes AngII-mediated hemodynamic and vascular pathology. By suppressing cytoskeletal signaling associated with vascular remodeling, 4EPS provides significant protection against hypertension and aortic aneurysm progression in mice, revealing a previously unrecognized protective role for a gut microbial metabolite in modulating renin-angiotensin system activity. Show less

Evidence linking modifiable risk factors to age-related brain diseases, such as dementia, stroke, and depression (DSD), is robust, yet limited regarding long-term change in modifiable risk factors in association with these conditions, particularly in real-world settings. This study aimed to assess whether longitudinal changes in modifiable brain health risk factors were associated with reduced risk of DSD. We analyzed UK Biobank data (2006-2019) from 155,469 participants with general practitioner-linked data. The Brain Care Score (BCS) assesses 12 modifiable risk factors across lifestyle, physical, and social-emotional domains. Longitudinal BCS measurements were derived from repeated general practitioner (GP)-recorded measurements. Changes in the BCS were modeled using linear mixed-effects models, and associations with DSD were evaluated using multivariable Cox models, adjusting for baseline BCS and genetic risk (polygenic risk scores for stroke and depression, and APOE genotype for dementia). Among 155,469 participants (median age = 51 years, 54.3% women), the median annual BCS change was 0.14 (Q1-Q3 = 0.008-0.30) points over a median follow-up of 12.3 years (Q1-Q3 = 11.5-13.1 years). Over time, 82.1% improved their BCS, 12.9% remained stable, and 5.0% worsened over time. Each 1-point annual increase in the BCS was associated with 4% lower risk of incident age-related brain diseases (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.95-0.97). In this large real-world cohort, improvements in modifiable risk factor profiles were associated with lower incidence of DSD, regardless of genetic risk or baseline BCS. Our results provide important information for communicating with patients about the brain health benefits of improving risk factor profiles. ANN NEUROL 2026;99:1113-1123. Show less

Alzheimer's disease (AD) is moving toward earlier, biology-driven diagnosis, which increases the need for blood-based markers that are reliable, scalable, and interpretable across populations. This review integrates the AT(N) framework with a maturity model for circulating biomarkers. We first describe core and largely validated plasma measures, including LC-MS or automated immunoassay Aβ42/Aβ40 ratios, p tau217 and p tau231, glial fibrillary acidic protein (GFAP), and neurofilament light, and we relate them to recent multi-stakeholder recommendations on analytical performance and regulatory status. We then summarize replicated but context-dependent markers, such as soluble TREM receptors, CHI3L1, and MCP 1, which improve risk stratification when interpreted together with amyloid and tau. A separate section examines emerging readouts that capture central nervous system (CNS) processes indirectly, focusing on neuron-enriched extracellular vesicles (EVs) and EV-carried microRNA panels. These signatures are biologically plausible and often precede symptoms, although current datasets are small, Alzheimer's disease neuroimaging initiative (ADNI)-based, and require standardized pre-analytical handling and external validation before clinical triage can be recommended. We also discuss platform selection, comparing automated electrochemiluminescence (ECL) and single-molecule assays with LC-MS, and outline how composite plasma panels that include APOE genotype can support screen-confirm-monitor workflows in memory clinics. Finally, we propose a tiered implementation path in which genomic risk profiling and blood tests identify candidates for cerebrospinal fluid (CSF) or positron emission tomography (PET) studies. This shows how circulating and multi-omics biomarkers can be layered onto established plasma Amyloid beta (Aβ) and p tau assays to widen the measurable blood space in Alzheimer's disease. Show less

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the deposition of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Seizures have also emerged as a prevalent clinical feature of AD and are associated with APOE4, the major genetic risk factor of AD. However, the mechanism by which APOE4 induces seizures and neuronal hyperexcitability is incompletely understood. We discovered that human APOE4 targeted replacement mice showed increased seizure severity and seizure-induced death at 5.5-7 but not 2-3 months of age compared to APOE3 mice using the kainic acid model of status epilepticus which preferentially arises from the hippocampus. While Tau burden alone did not alter seizure susceptibility in mice, APOE4 together with Tau burden enhanced seizure severity in female mice. Notably, APOE4 was associated with decreased hippocampal levels of sodium/potassium-ATPase, ATP-generating glycolytic enzymes, including phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M, and ATP. While inhibition of Na 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

Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment. Show less

Alzheimer's Disease (AD) is a disabling neurodegenerative illness characterized by Amyloid-beta (Aβ) plaque deposition, tau tangles, and neuroinflammation. These pathological characteristics lead to progressive cognitive decline, and drug therapeutic approaches are bedeviled by extreme difficulty with the Blood-Brain Barrier (BBB) that prevents most drugs from effectively crossing into the brain. Extracellular vesicle-based nanomedicine is a prospective approach to overcome this hurdle. Extracellular vesicles are endogenously derived extracellular vesicles that can cross the BBB and deliver a variety of therapeutic cargos, including small interfering RNAs (siRNAs), microRNAs (miRNAs), proteins, and other small molecules. Since they can cross the BBB and exhibit low immunogenicity and toxicity, extracellular vesicles represent a promising strategy for drug delivery against AD. Recent studies have highlighted the potential of extracellular vesiclebased treatments to deliver anti-amyloid and anti-tau therapies, neuroprotectants (e.g., antioxidants), and immune-modulatory factors. Engineered extracellular vesicles containing siRNA against βsecretase eta-site app cleaving enzyme 1 (BACE1), anti-tau oligonucleotides, and anti-inflammatory cytokines have shown promising preclinical efficacy by reducing Aβ deposition, tau aggregation, and neuroinflammation. These changes have been associated with enhanced cognitive function. Besides, extracellular vesicle-based systems were investigated for gene-editing therapeutics with Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9 (CRISPR/ Cas9) and Antisense Oligonucleotides (ASOs). Besides scalability concerns, cargo-loading efficiency, and long-term toxicity, extracellular vesicle-based nanomedicine is an innovative platform for targeted drug deli. 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

Of all the skin malignancies, melanoma is the most invasive and challenging to treat. Melanoma patients have a poor prognosis and a high recurrence rate despite advancements in treatment. There is substantial evidence that plant-derived bioactives prevent and treat melanoma effectively. The naturally occurring bioactive compound dalbergin, found in certain species of the The online version contains supplementary material available at 10.1007/s40203-026-00604-9. Show less

This study characterizes the expression of fibroblast growth factors (FGFs) and their receptors in the porcine corpus luteum (CL) across distinct stages of the oestrous cycle, and evaluates the regulatory role of FGF2 on angiogenesis, steroidogenesis, and cell survival in vitro. The CL was classified morphologically into four phases: Phase I (days 1-8; corpus haemorrhagicum; ELP), Phase II (days 9-14; highly vascularized CL; MLP), Phase III (day 15 onward; ischemic regression; LLP), and Phase IV (corpus albicans; avascular and regressed; RR). Each phase included 10 biological replicates (n = 10). Quantitative RT-PCR revealed significant upregulation (p < 0.001) of FGF1, FGF2, FGF7, FGFR1, FGFR2, and FGFR4 during early and mid-luteal stages. FGFR3 and FGFR2IIIC showed no significant variation, while FGFR2IIIB was downregulated (p < 0.001) during early/mid-luteal stages and upregulated during luteal regression. FGF10 expression declined significantly (p < 0.001) during regression. Western blotting Densitometry confirmed trends mRNA expression. In-vitro supplementation of FGF2 (1, 10, and 100 ng/ml) during the mid-luteal stage enhanced mRNA expression of angiogenic (vWF), steroidogenic (StAR, CYP11A1, 3β-HSD), and cell survival (PCNA, BAX) markers. StAR, CYP11A1, and 3β-HSD were significantly upregulated (p < 0.001) from 24 to 72 h in a dose-dependent manner. vWF and PCNA showed significant increases at 48 and 72 h, while BAX expression progressively declined (p > 0.001). The 100 ng/ml dose elicited the most pronounced effects. These findings suggest that FGF family members exert autocrine/paracrine effects that support luteal cell proliferation, differentiation, angiogenesis, steroidogenesis, and survival, underscoring their critical role in porcine ovarian physiology. Show less

Fluoroquinolones (FQs) are key components of World Health Organization (WHO)-recommended regimens for multidrug-resistant tuberculosis (MDR-TB). Accurate detection of FQ resistance is essential for optimizing treatment. This study evaluated the concordance between the Second-Line Line Probe Assay (SL-LPA) and Liquid Culture Drug Susceptibility Testing (LC-DST) for detecting FQ resistance in Mycobacterium tuberculosis isolates. In this retrospective study, 1402 non-duplicate clinical isolates of MDR TB were tested using SL-LPA and LC-DST at a reference laboratory. Genotypic resistance was identified through mutations in the gyrA and gyrB genes identified by SL-LPA, while phenotypic resistance was determined using MGIT-based LC-DST at critical concentrations for fluoroquinolones. Targeted nanopore sequencing was performed on a subset of isolates with discordant molecular and phenotypic results to investigate resistance-associated mutations. SL-LPA detected FQ resistance in 907 (64.7%) isolates, whereas LC-DST identified resistance in 852 (60.8%) isolates. Using LC-DST as the reference standard, SL-LPA showed a sensitivity of 93.2%, specificity of 98.6%, positive predictive value of 99.2%, and negative predictive value of 88.7%. Overall concordance between the two methods was observed in 1292 (92.2%) isolates. Discordant results occurred in 110 (7.8%) isolates, mainly involving low-level resistance mutations or inferred resistance due to missing wild-type bands on SL-LPA. Nanopore sequencing of 15 discordant isolates identified high-confidence mutations (Asp94Tyr, Asp94Gly, Asp94Asn) and interim or low-confidence mutations (Ala90Val, Ser91Pro, Asp94Ala, gyrB Asn499Asp, Asp461Asn). SL-LPA demonstrates excellent specificity and positive predictive value for detecting FQ resistance; however, discordance associated with low-confidence mutations and heteroresistance highlights the importance of integrating molecular assays with phenotypic DST and sequencing to improve MDR-TB resistance detection and guide treatment decisions. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein linked to atherosclerotic cardiovascular disease (CVD). Although well studied in adults, its familial determinants in children remain unclear. This systematic review and meta-analysis quantified Lp(a) across pediatric subgroups defined by familial cardiovascular risk, familial hypercholesterolemia (FH), sex, and ethnicity. Following PRISMA 2020 guidelines, fifty-one observational studies were analyzed using random-effects models (Review Manager 5.4.1). Mean differences (MD) with 95% confidence intervals (CI) were calculated. Subgroup, sensitivity, and meta-regression analyses explored heterogeneity. Among children and adolescents with FH, those with a parental history of premature cardiovascular disease (pCVD) had significantly higher Lp(a) concentrations than FH children without parental pCVD (MD = 10.24 mg/dL; 95% CI 3.06-17.43; Elevated Lp(a) in children with parental CVD or pCVD reflects a strong heritable pattern from early life. FH was associated with modest but consistent Lp(a) elevation, indicating an independent risk-modifying role rather than a defining feature. Sex-related differences were minimal, whereas ethnic variation was prominent. These findings support targeted Lp(a) assessment in children with familial cardiovascular risk using ancestry-aware reference standards, with consideration of repeat evaluation in early adulthood in higher-risk individuals. Show less

Lipoprotein(a) [Lp(a)] is a causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Although elevated Lp(a) affects approximately 20% of the global population, specific pharmacological options have long been unavailable, leaving a major gap in residual risk management. This review synthesizes current understanding of Lp(a) molecular architecture, genetics, and metabolism, and integrates mechanistic evidence linking Lp(a) to pro-atherogenic, pro-inflammatory, and pro-thrombotic pathways. We summarize epidemiological and genetic data associating Lp(a) with a broad spectrum of cardiovascular outcomes and discuss current clinical guidelines on screening and risk stratification. Furthermore, we provide an up-to-date overview of the emerging therapeutic landscape, including RNA-targeted therapies and novel oral small molecules. With pivotal phase 3 outcome trials nearing completion, the field is transitioning from viewing Lp(a) as an untreatable biomarker to an actionable therapeutic target, with important implications for precision cardiovascular prevention. Show less

We recently demonstrated the utility of the 'TB Concentration & Transport' kit for bio-safe, ambient-temperature transport of dried sputum samples on Trans-Filter, along with the 'TB DNA Extraction' kit for efficient DNA extraction from Trans-Filter for use in the Line Probe Assay (LPA) for diagnosing drug-resistant tuberculosis (TB). The present study aimed to develop and evaluate a new 'Quick TB DNA Extraction' kit ('Quick DNA' kit) for rapid DNA isolation from Trans-Filter samples and assess its compatibility with LPA for the detection of multidrug-resistant TB (MDR-TB). Consecutive presumptive TB/MDR-TB/XDR-TB patients (n = 1823) were screened using LED-FM and/or TBDetect microscopy at 2 Designated Microscopy Centres associated with the National Institute of Tuberculosis and Respiratory Diseases (NITRD), New Delhi. Smear-positive samples (n = 235) were processed in duplicate using the 'TB Concentration and Transport' kit. Dried sputum on bio-safe Trans-Filters was transported at ambient temperature, along with sputum samples, in a 3-layer packing in cooling conditions to NITRD Hospital (a National Reference Laboratory). DNA was extracted from Trans-Filters using 'Quick DNA' kit and the 'TB DNA Extraction' kit, and from sputum using Hain's GenoLyse® DNA Extraction kit for first-line LPA for MDR-TB detection. Quick Kit-LPA and Kit-LPA (LPA with DNA extracted from Trans-Filter using 'Quick DNA' kit and 'TB DNA Extraction' kit, respectively) showed similar sensitivity of 88.9% (95% CI: 65.3-98.6) and 88.5% (95% CI: 69.9-97.5) and specificity of 100% (95% CI: 98.2-100) and 99.5% (95% CI: 97.3-99.9) for rifampicin and isoniazid resistance detection, respectively against Direct-LPA (LPA with DNA extracted from sputum samples using GenoLyse kit). User feedback obtained from laboratory technicians corroborated that the one-step 'Quick DNA' kit procedure was rapid (5 minutes), easy to perform, seamlessly integrated with LPA testing, and was suitable as a replacement for Kit-LPA or Direct-LPA. The gap between drug-resistant TB detection and treatment initiation can be narrowed through Universal-Drug Susceptibility Testing by implementing (i) bio-safe and ambient temperature transport of sputum from primary healthcare centres to central laboratories, and (ii) by using Quick Kit-LPA over Direct-LPA in patients residing in remote areas. Show less