👤 Kunal Sharma

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

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

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

BackgroundAlthough the molecular basis of Alzheimer's disease (AD) is often studied in Caucasians, its genetic basis in Bangladesh remains elusive.ObjectiveWe explored the association between single-nucleotide variants (SNVs) of Apolipoprotein E ( Show less

Mental illness conditions and neurodegenerative diseases are an emerging worldwide burden, with depression affecting over 300 million people and dementia cases projected to triple by 2050. Oxidative stress and inflammation are central mechanisms for neuronal injury and cognitive impairment. This review discusses the neurotherapeutic promise of egg-derived antioxidants. Importantly, yolk in polypeptide complex (isolated from egg yolk with immunoglobulin Y) enhances cognitive function by upregulating brain-derived neurotrophic factor via cAMP/PKA and PI3K/Akt signaling. We discuss their molecular modes of action such as reactive oxygen species scavenging, regulation of inflammatory cytokines, maintenance of mitochondrial function, and promotion of neurogenesis and synaptic plasticity. Further, bioavailability, allergenicity, and targeted delivery issues across the blood-brain barrier are addressed in light of progress in nanocarrier systems and encapsulation methods. Comparative observations with other diet-based antioxidants like curcumin, polyphenols, and omega-3 fatty acids are presented to put egg-derived compounds into perspective within the overall nutraceutical regime. Lastly, future directions highlight the importance of targeted clinical trials, regulatory factors, and inclusion in public health initiatives designed to prevent cognitive degeneration and mental illness through accessible nutritional interventions. This review highlights the promising potential of antioxidants derived from eggs as adjunctive neuroprotective therapy and indicates the need for interdisciplinary investigations to extend these findings into the clinic. © 2026 Society of Chemical Industry. Show less

Hypertension is a global target for noncommunicable diseases, and meditation-based interventions (MBIs) benefit patients with hypertension (HTN). The primary objective of this scoping review is to map the globally published MBI studies on patients with HTN. The secondary goal is to identify the role of brain-derived neurotrophic factor (BDNF) in HTN. Based on the Arksey and O'Malley protocol of the Joanna Briggs Institute framework for scoping review, 5 electronic databases were searched with search terms related to HTN and meditation. The open-access articles in the English language published between 1985 and 2024 were selected. The selected articles involved MBIs. All the studies were uploaded to the Rayyan software. Two reviewers worked independently and in duplicate to screen the studies first for title and abstract, and then for full text. Data were extracted based on the template for the intervention description and replication checklist. The data were summarized and reported as a narrative summary. In total, 966 studies were identified. After removing 429 duplicates, 537 studies were screened for their titles and abstracts. 467 studies were excluded based on the inclusion and exclusion criteria, 18 were not retrieved, and 20 were excluded with reasons. Finally, the full texts of 70 studies were read. 32 eligible studies were included in this review. The studies were divided into 3 categories based on meditation and into 7 categories based on outcome. Moreover, no study involving human subjects has analyzed the level of BDNF in HTN patients receiving MBIs. MBIs have shown promising results among HTN patients. There is a research gap in studies related to BDNF and meditation among hypertensive patients. The limitation of the review is the inclusion of open-access articles published only in the English language. Hypertension, Meditation, Mindfulness, Brain-Derived Neurotrophic Factor. Show less

A single session of vagus nerve stimulation (VNS) has been shown to improve cognition in male rodents, but the influence of sex on the effects of VNS on behavior and synaptic plasticity are poorly understood. The present study investigated cognitive performance and hippocampal (HC) electrophysiology/brain derived neurotrophic factor (BDNF) expression in female healthy adult rats to examine changes in cognition and synaptic plasticity after VNS paired training. A total of 44 female rats were utilized for the cognitive neurobehavior experiments and a total of 68 female rats were utilized for the electrophysiology experiments. Animals were divided into four groups: SHAM in diestrus (SHAM-D), SHAM in estrus (SHAM-E), VNS in diestrus (VNS-D), and VNS in estrus (VNS-E). Electrode wires were surgically implanted around the left cervical vagus nerve (VN) prior to stimulation and experimentation in female Sprague–Dawley rats. A single 30 min session of VNS (100 µs biphasic pulses, 30 Hz, 0.8 mA) was administered after neurobehavior training in a Novel Object Recognition (NOR) and a Passive Avoidance Task (PAT) and testing was performed 24 h after VNS. Electrophysiology recordings for input/output, long-term potentiation, spontaneous spiking, and paired-pulse facilitation (PPF) were collected 90 min after VNS to assess the functional effects of VNS on HC slices. Immunohistochemistry (IHC) was conducted on HC slices collected 48 h after VNS to quantify HC subregion specific changes in BDNF. Stimulated rats exhibited improved performance in the PAT when tested in the diestrus phase. Among all subjects, VNS increased response amplitude and decreased PPF. However, among those in diestrus VNS increased long-term potentiation (LTP) amplitude and frequency of spontaneous spiking, and decreased PPF in the CA1. Among those in estrus, VNS did not change LTP amplitude or PPF, but frequency of spontaneous spiking was increased. VNS and estrous cycle stage additionally influenced the HC expression of BDNF in the CA1 and CA2. These findings suggest that a single session of VNS can increase synaptic plasticity, but that an interaction between estrous cycle phase and VNS influences the effects of VNS in females. This study is among the first to investigate the influence of estrous cycle phase on cognitive neurobehavior and synaptic plasticity outcomes after VNS and contributes to the understanding of VNS-induced cognitive enhancement. The online version contains supplementary material available at 10.1186/s42234-025-00196-3. 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

Familial hypercholesterolemia (FH) is a heritable condition that disrupts the body's ability to clear low-density lipoprotein cholesterol (LDL-C), commonly known as "bad cholesterol" from the bloodstream. This leads to persistently elevated LDL levels from birth, significantly increasing the risk of premature atherosclerosis and cardiovascular events, such as heart attack and stroke. This occurs due to variations in genes such as low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). The treatments that are available for FH include pharmacological interventions, microbiome-based treatments, molecular approaches, nanotechnology methods, surgical procedures, nutraceuticals, herbal therapy, yoga and physical fitness methods, along with lifestyle management. This review discusses the adverse effects associated with various conventional treatment methods for hypercholesterolemia and the need for a safe and effective approach for the treatment of this genetic condition. An integrated approach combining pharmacological, molecular, and lifestyle interventions has emerged as a pragmatic solution. Yoga and fitness-based therapies positively impact lipid profiles, offering non-pharmacological and holistic adjunctive options. This comprehensive approach addresses the multifaceted aspects of FH management, considering genetic factors, socioeconomic considerations, and individualized patient needs. Show less

Lp(a) is a genetically determined lipoprotein targeted by emerging therapies. In a UK Biobank analysis (1,026 abdominal aortic aneurysm [AAA] cases, 469,989 controls), elevated Lp(a) was associated with increased risk of AAA, including at clinically relevant thresholds while controlling for traditional risk factors, including ApoB. Multivariable Mendelian randomization confirmed a causal relationship between lipoprotein(a) [Lp(a)] and AAA independent of apolipoprotein B. These findings support Lp(a) as a modifiable risk factor and potential therapeutic target for AAA, a condition with limited medical treatment options. AAA should be considered as an outcome in future clinical trials of Lp(a)-lowering therapies. Show less

Machine learning enables scalable quantification of neuropathology, offering deeper phenotyping of Alzheimer's disease (AD). In this validation study, we quantified amyloid-beta (Aβ) deposits, evaluating multiple brain regions across institutions, and evaluated associations with clinical, demographic, and genetic factors in persons pathologically diagnosed with AD. All linear models were adjusted for sex, age of death, ethnicity, and center. We analyzed densities (#/mm2) of cored plaques, diffuse plaques, and cerebral amyloid angiopathy (CAA) in 273 individuals from 3 Alzheimer's Disease Research Centers. Formalin-fixed paraffin-embedded sections of frontal, temporal, and parietal cortices were immunostained and digitized, generating 799 whole-slide images (WSIs). Following log transformation, mixed-effects modeling revealed the parietal cortex had the highest cored plaque densities (P < .001); the temporal cortex had the highest diffuse plaque (P < .001); CAA showed no regional differences. Wilcoxon rank-sum test, and covariates adjusted linear models showed ApoE ε4- status was associated with higher cored plaque densities in the temporal lobe (P = .04). ApoE ε4+ status was associated with diffuse plaques in the temporal lobe (P = .001), and CAA in the frontal lobe (P = .004). These findings provide further validation and provide exploratory associations advancing deeper phenotyping of AD. 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

Macrophages differentiated with macrophage colony-stimulating factor (M-CSF) (M-Mac) are widely used as an experimental model. Interleukin 27 (IL-27)-polarized M-Mac (27M-Mac) suppresses HIV replication; however, the effects of IL-27 polarization on granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced macrophages (GM-Mac) remain less investigation. Here, we compare multiple functional properties and gene expression profiles of 27M-Mac and IL-27-polarized GM-Mac (27GM-Mac). M-Mac and GM-Mac were generated from monocytes of healthy donors and subsequently treated with IL-27 for three days. HIV replication in 27M-Mac, GM-Mac, and 27GM-Mac was suppressed to nearly 10% of that in M-Mac; however, single-cell RNA sequencing showed that M-Mac clustered with GM-Mac, and 27M-Mac clustered with 27GM-Mac. Expression of CD38 and secretion of CXCL9 and C1q were significantly increased in 27M-Mac and 27GM-Mac compared with M-Mac and GM-Mac. Although CD16 and CD64 expression increased in 27M-Mac and 27GM-Mac relative to their respective controls, phagocytic activity in 27M-Mac and 27GM-Mac was 30% of that in M-Mac. Autophagy was promoted 3.7-fold more strongly in 27M-Mac than in M-Mac, reaching levels comparable to those in GM-Mac and 27GM-Mac. Collectively, these findings indicate that IL-27 polarizes M-Mac and GM-Mac toward transcriptionally and functionally similar subtypes, providing insight into the role of IL-27 in macrophage polarization and plasticity. Show less

Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from patients with T-ALL and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNF-α, IL-27, and IFN-γ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization. Show less

Lipoprotein(a) [Lp(a)] is a well-established, genetically determined risk factor for atherosclerotic cardiovascular disease, but its short-term response to aggressive lipid-lowering therapy after acute coronary syndrome (ACS) remains unclear. To evaluate 1-month changes in Lp(a) and assess whether baseline Lp(a) levels are associated with low-density lipoprotein cholesterol (LDL-C) goal achievement in statin-naive ACS patients undergoing triple oral lipid-lowering therapy. We retrospectively analyzed 345 patients with ACS treated with rosuvastatin (20-40 mg), ezetimibe (10 mg), and bempedoic acid (180 mg) for 1 month after percutaneous coronary intervention. Lp(a) and LDL-C were measured at baseline and 1 month. Multivariable logistic regression identified predictors of achieving the LDL-C goal (<50 mg/dL). Despite a 59.1 ± 17.3% reduction in the mean LDL-C, the average Lp(a) increased by 91% (from 42.2 ± 39.2 mg/dL to 80.5 ± 66.3 mg/dL, P < .001). LDL-C targets of <50 mg/dL and <55 mg/dL were achieved in 68.9% and 78.6% patients, respectively. Baseline Lp(a) independently predicted failure to reach LDL-C goals (adjusted odds ratio [OR] 0.97; 95% CI 0.96-0.98; P < 0.001), while diabetes mellitus increased the likelihood of achieving targets (adjusted OR 2.69; 95% CI 1.36-5.61; P = .006). A strong inverse relationship was observed between Lp(a) change and LDL-C goal achievement (ρ = -0.38, P < 10⁻¹²). In Indian patients with ACS, aggressive triple oral lipid-lowering therapy quickly reduces LDL-C, while being accompanied by a substantial rise in Lp(a) levels, likely reflecting an acute-phase response. Baseline Lp(a) may independently limit LDL-C target attainment. Early Lp(a) testing may improve residual risk assessment and help guide the use of emerging Lp(a)-focused treatments. Show less

Risk estimation tools have been developed to predict coronary heart disease (CHD) in type 2 diabetes (T2D). To evaluate augmentation following the addition of lipoprotein(a) [Lp(a)] to risk calculation, we performed a pilot study. A total of 90 successive T2D patients were included. Details of clinical and biochemical features were obtained. Lp(a) was determined using ELISA. CHD risk estimation was performed using Framingham, QRISK-3, SCORE-2D, INTERHEART, and European Atherosclerosis Society (EAS) algorithms with and without Lp(a). Descriptive statistics are reported. Mean age of patients was 55.0 ± 8 years, BP systolic/diastolic 133.7 ± 12/95.0 ± 9 mm Hg, body mass index (BMI) 26.0 ± 1.9 kg/m Substantial variation in coronary artery disease (CAD) risk prediction using various clinical algorithms is observed in T2D. The EAS algorithm provides the most robust estimate. The addition of Lp(a) to the risk algorithms augments risk stratification significantly. The results of this pilot study need confirmation with larger prospective studies. Show less

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

Pancreatic cancer (PC) is among the deadliest malignancies, characterized by poor treatment response. Natural bioactive compounds, such as Morin, a flavonoid, have gained interest as potential therapeutic agents due to their anticancer properties but remain unexplored in PC. This study investigates the anticancer effects of Morin on PC cells, particularly its ability to induce mitophagy via the PINK1/Parkin pathway and modulate mitochondrial function and cancer stemness. PANC-1 cells were treated with Morin, and its impact on tumorigenic potential was evaluated using in vitro assays, including cell viability, colony formation, migration, invasion, and spheroid formation, as well as in vivo studies in a nude mice model. Mitochondrial function and apoptosis were assessed through flow cytometry, gene expression analysis, PCR microarrays, transmission electron microscopy (TEM), immunofluorescence, ELISA, western blotting, and molecular docking. Morin exhibited dose-dependent cytotoxicity, significantly reducing viability, colony formation, migration, and invasion in PC. It downregulated mesenchymal and stemness markers (N-cadherin, SNAI1, ZEB1, SOX2, NANOG, OCT4) while upregulating E-cadherin. Morin disrupted spheroid morphology and decreased ALDH activity, indicating reduced cancer stemness. Additionally, Morin-induced mitochondrial dysfunction, as evidenced by decreased membrane potential, ATP synthase activity, and mitochondrial mass, along with increased mitochondrial superoxide production. Upregulation of mitophagy markers (PINK1, Parkin, pAMPK, LC3A/B) and downregulation of fusion (MFN2) confirmed PINK1-mediated mitophagy. Apoptosis induction was supported by Annexin V/PI staining, TEM, elevated caspase-3/-9 levels, and cytochrome c release. Molecular docking confirmed strong Morin-PINK1 interaction. Morin induces mitophagy, promotes apoptosis, and suppresses cancer invasiveness in PC cells, highlighting its potential as an adjuvant therapeutic agent. Future clinical studies are warranted to evaluate its relevance. Show less

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the Show less

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Show less

Traditional risk reduction strategies like diet, exercise, and existing lipid- lowering medications have minimal impact on Lp(a) levels. Recent therapies targeting Lp(a) at the level of mRNA transcription of apo(a) or binding of apo(a) to apoB-100 have demonstrated substantial reductions of Lp(a). Lepodisiran is a GalNAc-conjugated small interfering RNA (siRNA) developed to inhibit LPA transcription, reducing apo(a) synthesis and circulating Lp(a) levels. This is an updated review of the mechanism of action, pharmacokinetics, clinical efficacy, and safety of Lepodisiran, as well as its effects on lipoprotein(a), with potential applications in treating patients with elevated cardiovascular risk. We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Lepodisiran," "small interfering RNA therapies," and "lipoprotein(a)". Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels, achieving a maximum reduction of up to 97% at the highest dose in a Phase 1 trial. A Phase 2 placebo-controlled trial similarly showed robust and durable decline in Lp(a) with a favorable safety profile. Lepodisiran is a promising therapy, with sustained Lp(a) reduction and good safety. Ongoing phase 3 trials are poised to provide robust data on its long-term safety, clinical efficacy, and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Lepodisiran demonstrates potent and sustained reductions in Lp(a) levels with a favorable safety profile, making it a promising therapeutic candidate for Lp(a)-mediated cardiovascular risk. Ongoing long-term outcome studies are essential to confirm its clinical benefit. Show less

Genome-wide association studies (GWAS) are rapidly advancing due to the improved resolution and completeness provided by Telomere-to-Telomere (T2T) and pangenome assemblies. While recent advancements in GWAS methods have primarily focused on identifying genetic variants associated with discrete phenotypes, approaches for quantitative traits (QTs) remain underdeveloped. This has often led to significant variants being overlooked due to biases from genotype multicollinearity and strict p-value thresholds. We propose an enhanced ensemble learning approach for QT analysis that integrates regularized variant selection with machine learning-based association methods, validated through comprehensive biological enrichment analysis. We benchmarked four widely recognized single nucleotide polymorphism (SNP) feature selection methods-least absolute shrinkage and selection operator, ridge regression, elastic-net, and mutual information-alongside four association methods: linear regression, random forest, support vector regression (SVR), and XGBoost. Our approach is evaluated on simulated datasets and validated using a subset of the PennCATH real dataset, including imputed versions, focusing on low-density lipoprotein (LDL)-cholesterol levels as a QT. The combination of elastic-net with SVR outperformed other methods across all datasets. Functional annotation of top 100 SNPs identified through this superior ensemble method revealed their expression in tissues involved in LDL cholesterol regulation. We also confirmed the involvement of six known genes (APOB, TRAPPC9, RAB2A, CCL24, FCHO2, and EEPD1) in cholesterol-related pathways and identified potential drug targets, including APOB, PTK2B, and PTPN12. In conclusion, our ensemble learning approach effectively identifies variants associated with QTs, and we expect its performance to improve further with the integration of T2T and pangenome references in future GWAS. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) primarily results from dysregulated lipid metabolism in hepatocytes. However, the mechanisms governing hepatic lipid metabolism remain incompletely understood. Our preliminary experiments demonstrated elevated expression of R-spondin 2 (RSPO2), a matricellular protein, in steatotic livers. Therefore, we investigated the role of RSPO2 in MASLD and potential underlying mechanisms. Comprehensive RSPO2 expression was significantly increased in steatotic livers of high-fat diet-fed wild-type ( These findings identify RSPO2 as a key suppressor of hepatic steatosis and fibrosis, and highlight its potential as a therapeutic target for MASLD. Given the hepatic/extrahepatic complications associated with MASLD (metabolic dysfunction-associated steatotic liver disease) and its high prevalence, it is crucial to decipher the precise molecular mechanisms regulating its pathogenesis to identify novel druggable targets. In this study, we demonstrate for the first time that hepatocyte RSPO2 plays a protective role against hepatic steatosis, fibrosis, and inflammation. Show less

Innate immunity, the primary defence mechanism, encompasses a range of protective processes like anatomical barriers, cytokine secretion, and the action of various immune cells. Cattle breeds might differ in these processes because of their genetic differences such as copy number variations (CNVs). Therefore, the present investigation employed an array comparative genomic hybridisation (aCGH) approach on breed representative pooled DNA samples to evaluate CNVs across six cattle breeds: four indigenous Indian breeds, Kangayam (KNG), Tharparkar (TP), Sahiwal (SW), Gir (GIR), one crossbred Karan Fries (KF), and one exotic breed, Holstein Friesian (HF). In aCGH, HF DNA was used as control, while test DNA was from the other breeds. Each pooled test DNA sample was a representative of 18 animals belonging to three distinct geographical locations of India. The study using Aberration Detection Method 2 (ADM-2) of Agilent Genomic Workbench revealed the highest number of duplications in KNG (1189 genes), followed by TP (534 genes), and the greatest number of deletions in SW (774 genes). Among these genes, 183 and 76 innate immune genes with hub genes TGF-β1, CD79A, and IL4 showed duplications in KNG and TP, respectively. In SW, 113 innate immune genes with hub genes PSMC5, MAPK1, and AXIN1 showed deletions. In contrast, KF and HF showed no genes with deletions and fewer duplicated innate immunity genes, reflecting either lower genetic variability in their immune gene repertoire or a potential bias due to HF DNA as a control in aCGH. Functional enrichment of innate immune genes revealed duplications in KNG enriched in interleukin-1 receptor (IL1R) activity (p = 9.9 × 10 Show less

Present paper elicits the synthesis of a series of 2,2-dimethyl-2H-[1,3]dioxino[4,5-b]pyrrol-4(7H)-one derivatives as novel selective BACE1 inhibitors for the treatment of Alzheimer's disease (AD). A four-component, solvent-free condensation process, catalyzed by 10 mol% NiCl₂·6H₂O strategy was explored to achieve their synthesis. The structures of the synthesized compounds were ascertained using different spectroscopic techniques, including FT-IR, Show less

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