👤 Shamsha Ali

Indigenous chickens in tropical regions routinely survive high environmental temperatures (40-45 °C) that cause significant mortality and production loss in commercial breeds, yet the genetic mechanisms of thermotolerance remain poorly understood. This study integrated genome-wide selective scans across 14 geographically and climatically diverse chicken breeds with multi-tissue expression data, gene expression quantitative trait locus (eQTL) analysis, transcriptome-wide association study (TWAS), and cross-species phenome-wide association study (PheWAS) to validate candidate genes. We identified 25 high-confidence genes under selection, with ATP1A1, PLCB4, RYR2 and AKT3 forming a regulatory hub coordinating cardiovascular, calcium and survival signaling. These genes converge on interconnected adrenergic, calcium, and GnRH signaling pathways, with coordinated expression across heart, hypothalamus, and liver forming an integrated thermoregulatory axis. The eQTL integration analysis using ChickenGTEx data identified 359 tissue-specific cis-eQTLs in selected regions. Additionally, TWAS analysis linked ATP1A1 to 145 gene-trait associations across 13 tissues and 14 trait categories (hepatic regulation, β = -2.13, p = 4.21 × 10⁻¹²), and cross-species PheWAS validated conserved roles in cardiovascular function (RYR2, resting heart rate p = 4.9 × 10⁻¹²), and ionic homeostasis (ATP1A1, chloride p = 1.18 × 10⁻³). In parallel, we also identified robust genomic signatures of domestication in classic candidate genes (TSHR, TBC1D1, BDNF), highlighting how initial separation from Red Jungle Fowl and subsequent adaptation to diverse climates have shaped the genetic and physiological diversity of the domesticated chicken. Collectively, our results reveal an integrated cardio-neuroendocrine calcium network driving heat adaptation, providing potential targets for breeding heat-tolerant chickens. Show less

Neuroinflammation appears in a variety of neurological disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis. The adenosine A₂A receptor (A₂AR), a Gs protein-coupled receptor that affects cAMP signaling and downstream kinases like PKA, CREB, and NF-κB, is one of the primary regulators of this process. Context-dependent effects of A₂AR activation include lowering acute inflammation and promoting neuronal survival when stimulated moderately, but increasing glial activation and cytokine production when overexpressed over an extended period of time. In microglia and astrocytes, A₂AR signaling regulates inflammatory pathways mediated by NF-κB and MAPK, affecting oxidative stress, blood-brain barrier (BBB) stability, and excitotoxicity. Acute or transient (short-term) A₂AR activation, on the other hand, increases the production of anti-inflammatory cytokines like IL-10 and enhances neurotrophic support through BDNF. A₂AR antagonists, including istradefylline and SCH58261, may reduce microglial triggering and have neuroprotective benefits, according to clinical and experimental data. The context-dependent activity of the receptor is shown by the fact that total receptor blockage interferes with adaptive immune control. Therefore, the therapeutic challenge is to carefully modify A₂AR signaling in particular cell populations, specifically targeting astrocytic or microglial receptors while maintaining the peripheral immunoregulatory activities. The dual regulatory role of A₂AR in neuroinflammation is summarized in this review along with its molecular mechanisms, disease-specific actions, and therapeutic significance. Developing next-generation neuroprotective strategies that reduce A₂AR signaling's pro-inflammatory and neurotoxic effects while preserving its beneficial homeostatic effects will require an understanding of the temporal and cell-specific dynamics of this signaling. Show less

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-dependent and independent effects is instrumental for understanding the biology of AD. We conducted an APOE-stratified multi-omic analysis in multiple large datasets to identify AD-associated plasma proteins and metabolites. More than 64% of the identified proteins were not found in non-APOE stratified studies, and 17% of the proteins showed APOE-specific trends. Mitochondrial dysfunction was associated in AD independently of APOE and was accompanied by disruptions in glucose and lipid metabolism and cell death and increased in inflammatory signaling activation. Lipid upregulation was found in AD cases when compared with controls with the same APOE genotype, indicating that additional factors beyond APOE affect lipid regulation and AD risk. These findings may be informative in guiding the development of effective medications for AD. Show less

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood-brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4's effects on AD pathology and BBB function. We then discuss ApoE's role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments-whether they involve anti-amyloid therapy or other pharmacological agents used for AD-emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4's effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD. Show less

American Indians have a high population risk for cerebrovascular disease, vascular brain injury (VBI), and dementia. The apolipoprotein ( We analyzed data from a population-based, longitudinal cohort of American Indians aged 64-95 years from the Strong Heart Study recruited from Northern Plains, Southern Plains, and Southwest regions. Magnetic resonance imaging markers included infarcts, lacunes, hemorrhages, and WMH. The sample size was 395 participants with a mean age of 71.3 (4.7) years and was comprised of 313 non-ε4-carriers and 82 ε4-carriers, predominantly female (70.1%). Cross-sectional analyses indicated no significant associations between Our findings echo previous work that Show less

Despite the emerging role of the gut microbiome in colorectal cancer (CRC), its significance in early-onset CRC (EOCRC, < 50 y) versus late-onset CRC (LOCRC) and the molecular differences between proximal and distal CRC remain poorly understood. To circumvent the logistical and patient compliance challenges of stool collection, we explored the utility of anal swabs as a convenient alternative for characterizing gut microbiome signatures in CRC. We profiled the CRC microbiome using anal swabs ( 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 characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD. Show less

Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ Show less

Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less

Inborn errors of metabolism (IEM) are frequently underdiagnosed in low-resource settings due to limited diagnostic infrastructure. We hypothesized that an integrated clinical-genomic approach could improve diagnosis and management of these conditions. Nineteen Pakistani families with clinically suspected IEM underwent systematic clinical assessment, available biochemical testing, and whole-exome sequencing (WES). Variants were classified according to ACMG/AMP guidelines using evidence from population databases, in silico prediction tools, segregation analysis, and genotype-phenotype correlation. Clinical diagnoses and management strategies were reassessed based on molecular findings. WES provided a molecular diagnosis in 90% (17/19) of families and enabled targeted therapeutic interventions in 70% (13/19). However, clinical outcomes were variable due to advanced disease in some cases and limited follow-up. Seven novel variants were identified in CYP27B1, DYM, MTTP, ALDH3A2, USP53, BRAF, and JAG1, while twelve recurrent mutations were detected in PIGN, GCDH, CLCN7, RNASEH2C, ABCB11, MPV17, IDUA, SMPD1, FBP1, SLC37A4, ACADM, and UGT1A1. Integrating genomic findings with clinical reassessment improved diagnostic precision. An integrated clinical-genomic approach enabled accurate diagnosis of pediatric IEM in resource-limited settings, with particular utility in children with metabolic disorders in a consanguineous population. Identification of both novel and recurrent variants expanded the genotypic and phenotypic spectrum of these disorders and highlighted the clinical utility of genomic diagnostics in optimizing patient care. Show less

Genetic variation and lived experiences shape how our hearts respond to chronic stress and development of heart failure, manifested as compromised pumping function and abnormal hemodynamics. The hallmark of heart failure etiology is excessive stress signals followed by maladaptive structural, electrical, and functional changes to the heart muscle, also known as cardiac remodeling. The specific genetic mechanisms which underly such phenomenon, however, are still unclear, due in part to difficulties in accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic β-adrenergic receptor stimulation with the β-agonist isoproterenol, which targets the common signaling gateway to heart failure, regardless of the particular upstream stressor. Across 8 founder and 63 CC lines, we measured non-failing and failing heart characteristics represented by cardiac structure and function, organ weights, and cell morphology. Genome-wide QTL mapping detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size. To identify high-confidence candidate genes from these loci, we augmented our trait mapping with coding variants drawn from sequencing data, tractability in our in vitro rat cardiomyocyte model, and previously reported protein functions and mouse or human phenotypes. This approach recovered both known regulators, such as Hey2, and new candidates. Functional tests in in vitro models highlight three candidate genes that modulate hypertrophic growth: Abcb10, Mrps5 and Lmod3. Abcb10 knockdown increased cell size at baseline and further with isoproterenol, consistent with loss of a mitochondrial stress-buffering role. Mrps5 knockdown blunted stress-induced hypertrophy, possibly related to its previously known involvement in oxidative stress regulation. Lmod3 knockdown also attenuated hypertrophy, potentially via actin-assembly control under adrenergic stress. Together, these results reveal heritable pathways of β-adrenergic remodeling in mice and provide an interpretable, translational, and stepwise framework to prioritize candidate genes within broad loci for mechanistic studies of heart failure. Show less

Benign prostatic hyperplasia is a common public health problem in aging men across the globe. Diarylpropionitrile, a selective estrogen receptor-beta agonist, favorably regulates cell proliferation and inflammation, two major hallmarks of benign prostatic hyperplasia pathology.This study aimed to explore the mitigative impact of diarylpropionitrile on testosterone-induced benign prostatic hyperplasia in rats.Forty male rats were randomly divided into four groups ( Show less

Benign prostatic hyperplasia (BPH) is a common public health problem in ageing men worldwide. Diarylpropionitrile, a selective ERβ agonist, favorably regulates cell proliferation and inflammation, two major hallmarks of BPH pathology. This study aimed to explore the mitigative impact of diarylpropionitrile on testosterone-driven BPH in rats. 40 Sprague Dawley male rats aged 2.5-3 months were randomly divided into 4 groups (n = 10): a normal control group, a testosterone-induced BPH group, a finasteride-treated group, and a diarylpropionitrile-treated group. BPH was induced by daily subcutaneous testosterone injections for 4 weeks, with finasteride and diarylpropionitrile administered orally once daily for the same duration, one hour before each testosterone injection. After 4 weeks of treatment, macroscopic and microscopic features of prostatic hyperplasia and androgenic, proliferative, angiogenic, apoptotic, and inflammatory biomarkers in prostatic tissue homogenates were assessed. Testosterone administration significantly increased prostate weight, prostatic index, and hyperplasia scores, while treatment with either diarylpropionitrile or finasteride effectively ameliorated these testosterone-induced changes. Both treatments significantly lowered elevated prostatic DHT, 5αR2, β-catenin, and PCNA levels, demonstrating a strong anti-proliferative effect. They also attenuated the increased pro-inflammatory cytokines IL-6, IL-27, and PGE2 and growth factors TGF-β and VEGF. Furthermore, both agents inhibited testosterone-induced ERβ upregulation and increased expression of the anti-apoptotic protein BCL2. There were no substantial differences comparing finasteride and diarylpropionitrile in the majority of the tested parameters. Diarylpropionitrile alleviates testosterone-driven BPH in rats by modulating key pathways associated with cellular proliferation and inflammation. Diarylpropionitrile, as an ERβ agonist, represents a promising alternative for the BPH treatment through multi-targeted mechanisms. Show less

In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less

To evaluate the diagnostic performance of APOA4, CEACAM1, CD147, DJ-1/PARK7, Gamma-synuclein, S100A1, and Stathmin-1 in urothelial carcinoma and establish optimal immunohistochemical cutoffs for their use as diagnostic markers. This cross-sectional study included 141 histologically confirmed urothelial carcinoma cases and controls. Immunohistochemical staining was optimized for each biomarker, and semiquantitative scoring was applied. Diagnostic validity was assessed using receiver operating characteristic (ROC) analysis, comparing sensitivity and specificity across several cutoffs and biomarker panels. Among seven biomarkers, APOA4, DJ-1/PARK7, Gamma-synuclein, and Stathmin-1 demonstrated high diagnostic accuracy (≥80% sensitivity and specificity). Using an Allred score ≤2 as a cutoff, the sensitivity/specificity were as follows: APOA4, 96%/100%; DJ-1/PARK7, 97%/94%; Gamma-synuclein, 98%/84%; and Stathmin-1, 98%/90%. A combined panel of these four biomarkers achieved near-perfect diagnostic performance, reaching almost 100% sensitivity and specificity. A biomarker panel comprising Stathmin-1, DJ-1/PARK7, Gamma-synuclein, and APOA4 reliably distinguished urothelial carcinoma from benign urothelium. These markers, when integrated with cytology, could enhance the diagnostic precision and reduce dependence on invasive cystoscopy. The proposed cutoffs (10%-20% positive cells or Allred score ≤2) offer clinically actionable threshold for histopathological practice. Show less

Dyslipidemia remains a central contributor to residual cardiovascular risk despite the widespread use of statins. Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, has shown potential as an adjunctive lipid-lowering therapy by favorably modifying key lipid parameters. This study aimed to systematically evaluate the lipid-lowering efficacy of obicetrapib based on current evidence from randomized controlled trials (RCTs). A comprehensive literature search was conducted on PubMed, Embase, Scopus, and ClinicalTrials.gov to identify RCTs assessing the lipid-lowering effects of obicetrapib. Mean differences (MDs) with 95% CIs were calculated using a random-effects model. Nine RCTs (n = 3706) were included. Patients treated with obicetrapib exhibited significant reductions in low-density lipoprotein cholesterol (LDL-C) (MD: -36.5% [95% CI: -41.1 to -31.9]), apolipoprotein B (Apo-B) (MD: -23.8% [95% CI: -28.2 to -19.3]), non-high-density lipoprotein cholesterol (non-HDL-C) (MD: -30.9% [95% CI: -34.6 to -27.1]), and lipoprotein (a) [Lp(a)] (MD: -36.1% [95% CI: -44.4 to -27.8]) compared to placebo. High-density lipoprotein cholesterol (HDL-C) levels significantly increased (MD: 142.6% [95% CI: 128.6-156.6]). Triglyceride levels did not differ significantly (MD: 0.13% [95% CI: -7.01 to 7.26]). Moreover, combination therapy with ezetimibe led to greater reductions in LDL-C by 17.8% (95% CI: 12.05-23.6), Apo-B by 9.7% (95% CI: 5.8-13.7), and non-HDL-C by 17.5% (95% CI: 12.3-22.8), compared to monotherapy. Obicetrapib significantly improves key lipid parameters, including LDL-C, Apo-B, non-HDL-C, HDL-C, and Lp(a), with enhanced efficacy in lowering LDL-C, Apo-B, and non-HDL-C when combined with ezetimibe. These findings support its potential role in comprehensive lipid management strategies. Show less

This umbrella review aims to synthesize evidence from previously conducted meta-analyses and review articles to assess the effects of bempedoic acid on lipid profile and cardiovascular events. While adhering to the Preferred Reporting Items for Overviews of Reviews guidelines, PubMed, Google Scholar, Web of Science, and Scopus were searched from the database inception to June 2024 to identify relevant articles. The outcomes were total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL cholesterol, triglyceride (TAG), apolipoprotein B (APOB), high-sensitivity CRP (hs-CRP), major cardiovascular events (MACE), cardiovascular mortality, and myocardial infarction (MI). A corrected covered area (CCA) assessment was performed to determine overlap among reviews. Each included review was assessed for its quality and rigor via the AMSTAR-2 tool. From 18,297 articles identified during the literature search, 18 meta-analyses were included. A significant overlap was noted across studies with a corrected cover area of 44.4%. Bempedoic acid's effects on cardiovascular outcomes and lipid levels have been extensively studied. For cardiovascular mortality, the evidence is mixed: Goyal et al. Our findings show that bempedoic acid significantly reduces the risk of MACE, nonfatal MI, coronary and noncoronary revascularization, and hospitalizations for unstable angina. While results on cardiovascular mortality are mixed, suggesting a need for further study, bempedoic acid proves to be an effective treatment for improving lipid profiles and reducing cardiovascular events, especially in patients who cannot tolerate statins. It presents a valuable option for cardiovascular risk management, potentially enhancing patient outcomes and quality of life. Further research is needed to assess its long-term benefits and broader applicability. Show less

Hypertriglyceridemia is an independent risk factor for cardiovascular diseases. In previous trials, apolipoprotein C-III (APOC3) inhibition through the antisense oligonucleotides volanesorsen, olezarsen, and plozasiran reduced triglyceride levels. However, the three medications' safety and efficacy have yet to be compared. A network meta-analysis was performed to compare multiple doses of the three medications to each other through the placebo. Randomized controlled trials (RCTs) were retrieved by searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane until November 22nd, 2024. The mean difference (MD) and 95% confidence interval (CI) were used for continuous outcomes. The risk ratio (RR) and 95% CI were used for dichotomous outcomes. Ten RCTs with a total of 1,129 patients were included. volanesorsen 300 mg once weekly showed the most significant percent reduction in triglyceride levels (MD = -91.0%, 95% CI: (-109.2%; -72.8%); P < 0.01). Only plozasiran once monthly, regardless of the dose, showed a non-significant percent reduction in triglycerides. This finding should be taken cautiously as the data were derived from a phase 1 trial with a small sample size. All the regimens significantly reduced APOC3 levels compared to placebo, with plozasiran 100 mg monthly and volanesorsen 300 mg once weekly showing the most significant reduction (MD range: -92.8% to -88.5%; P < 0.01). None of the treatments showed a statistically significant difference in overall adverse events rate compared to the placebo. APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen. Show less

Early life air pollution exposure may play a role in development of respiratory infections, but underlying mechanisms are still not understood. We utilized data from two independent prospective birth cohorts to investigate the influence of prenatal and postnatal ambient air pollution exposure of PM Show less

Alzheimer's disease (AD), the most common form of dementia, is a major global health issue. Its complex pathology, including amyloid-beta (Aβ) aggregation, leads to neuronal damage and cognitive decline. Since Aβ plays a major role in AD, therapies targeting its production, aggregation, and clearance are being actively explored. This review discusses recent advances in gene therapy, enzyme inhibitors, molecular modeling, and nano-delivery systems aimed at modifying AD progression, highlighting their potential and challenges. This review compiles findings on BACE1 and γ-secretase inhibitors, gene therapies that modify amyloid metabolism, and combination therapies. Studies have been selected based on their focus on Aβ regulation and their impact on disease progression, cognitive function, and breakthroughs in diagnostics, molecular modeling, and drug delivery for neurodegenerative conditions. BACE1 inhibitors, such as verubecestat, and γ-secretase inhibitors, shows potential, however, they face significant challenges related to BBB penetration and adverse effects. Gene therapies using AAV vectors and CRISPR/Cas9 technologies are promising, particularly for individuals genetically predisposed to these diseases. Combination therapies targeting amyloid, tau, and neuro-inflammation have emerged as effective approaches. Advancements in PET, SPECT, MRI, small molecule probes, molecular modeling, and nano-particle-based drug delivery are improving diagnostic and treatment options. The findings emphasize the multifactorial complexity of amyloid disorders and the limitations of mono-therapies. While certain agents demonstrated efficacy in early disease stages, most treatments have failed in advanced phases due to poor central nervous system (CNS) bioavailability, adverse effects, or insufficient target engagement. Novel delivery systems, combination therapies, and computational design approaches offer enhanced translational potential. However, challenges such as immune responses, delivery efficiency, and off-target effects continue to pose significant barriers. Aβ-targeted therapies, including enzyme inhibitors and gene therapies, hold promise, though challenges such as BBB penetration and toxicity still remain. Combination therapies, along with advancements in diagnostics and drug delivery technology, are essential for finding effective treatments for Alzheimer's, Parkinson's, and other neurodegenerative diseases. Future research should prioritize overcoming the persistent barriers to BBB penetration, enhancing therapeutic selectivity, and refining drug delivery systems to enable more precise, targeted interventions, to ultimately reduce the progression of disease at the molecular level. Show less

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer with poor prognosis and limited response to conventional therapies. The fibroblast growth factor receptor 1 (FGFR1) has emerged as a pivotal molecular target among the oncogenic drivers of OSCC because of its critical role in tumor cell proliferation, migration, and chemoresistance. This research employed a comprehensive multi-tiered computational drug-discovery approach, integrating multi-class QSAR modeling, virtual screening, and molecular dynamics simulations, to identify novel small-molecule FGFR1 inhibitors with therapeutic potential for OSCC. The ChEMBL database was utilized to create a dataset of 3,222 distinct inhibitors, subsequently categorized into four bioactivity classes. Exploratory data analysis revealed that more potent compounds had a higher average molecular weight, an increased number of hydrogen bond acceptors, a higher count of rotatable bonds, and a higher. The ROS technique was employed on the training set to address the issue of dataset imbalance. We employed 10 distinct machine learning techniques to develop and assess multi-class QSAR models. These models explain how the chemical structures of substances connect to their biological functions mathematically. The Extra Trees (ET) classifier had the best performance, achieving a test set accuracy of 0.926 and MCC of 0.902. This made it the optimal model for our upcoming virtual screening. We employed the validated ET model to examine a repository of FDA-approved drugs and identified high-priority potential drugs. Molecular docking studies in the FGFR1 active site (PDB ID: 6MZW) followed by 200 ns molecular dynamics simulations demonstrated the stability of the top candidates. The study identified two significant lead compounds, CHEMBL155526361 and CHEMBL155529723, exhibiting robust binding affinities and strong interactions. This study provides a robust computational framework and remarkable molecular scaffolds for further preclinical investigation. This will expedite the search for innovative therapeutics for OSCC. The online version contains supplementary material available at 10.1186/s12885-025-15471-4. Show less

Mitogen-activated protein kinase (MAPK) pathway alteration is a major oncogenic driver in paediatric low-grade gliomas (LGG) and some adult gliomas, encompassing BRAF (most common) and non-BRAF alterations. The aim was to determine the frequency, molecular spectrum and clinicopathological features of MAPK-altered gliomas in paediatric and adult patients at our neuropathology site in Kuwait. We retrospectively searched the data of molecularly sequenced gliomas between 2018 and 2023 for MAPK alterations, revised the pathology in view of the 2021 WHO classification and evaluated the clinicopathological data for possible correlations. Of 272 gliomas, 40 (15%) harboured a MAPK pathway alteration in 19 paediatric (median 9.6 years; 1.2-17.6) and 21 adult patients (median 37 years; 18.9-89.2), comprising 42% and 9% of paediatric and adult cases, respectively. Pilocytic astrocytoma and glioblastoma were the most frequent diagnoses in children (47%) and adults (43%), respectively. BRAF V600E (n=17, 43%) showed a wide distribution across age groups, locations and pathological diagnoses while KIAA1549::BRAF fusion (n=8, 20%) was spatially and histologically restricted to cerebellar paediatric LGGs. Non-V600E variants and BRAF amplifications accompanied other molecular aberrations in high-grade tumours. Non-BRAF MAPK alterations (n=8) included mutations and gene fusions involving FGFR1, NTRK2, NF1, ROS1 and MYB. Fusions included KANK1::NTRK2, GOPC::ROS1 (both infant hemispheric gliomas), FGFR1::TACC1 (diffuse LGG), MYB::QKI (angiocentric glioma) and BCR::NTRK2 (glioblastoma). Paradoxical H3 K27M/MAPK co-mutations were observed in two LGGs. The study provided insights into MAPK-altered gliomas in Kuwait highlighting the differences among paediatric and adult patients and providing a framework for planning therapeutic polices. Show less

17-beta hydroxysteroid dehydrogenase-3 enzyme is an enzyme expressed almost exclusively in the testes; it plays a crucial role in gonadal differentiation by catalysing the conversion of androstenedione (Δ4) to testosterone (T). The enzyme is encoded by the 17-B-hydroxysteroid dehydrogenase-3 ( Show less

Lung cancer is the second most common malignancy globally and the leading cause of cancer-related deaths. Interleukin-39 (IL-39), a member of the IL-12 family secreted by B cells, acts as a pro-inflammatory cytokine and induces IL-23p19 expression in endothelial cells. Recent findings suggest reduced IL-39 expression in autoimmune thyroid disorders and breast cancer, indicating its possible role in disease progression. To evaluate the role of IL-39 as an early prognostic biomarker in lung cancer. A case-control study was conducted between February and September 2024, involving 180 individuals aged 45-77. The cohort included 90 lung cancer patients (45 with small-cell carcinoma and 45 with non-small cell carcinoma) and 90 healthy controls. Blood samples were analyzed using ELISA to quantify IL-39 and additional tests, including CBC, liver enzymes (ALT, AST, ALP), and lipid profile (cholesterol, triglycerides). Statistical analysis was performed to assess correlations and diagnostic performance. IL-39 levels were significantly lower in stage IV compared to stage III in both cancer types, with a greater reduction observed in small-cell carcinoma. Significant negative correlations were found between IL-39 and total cholesterol, NLR, ALT, AST, and ALP, while positive correlations were noted with hemoglobin and triglycerides. IL-39 demonstrated excellent diagnostic accuracy in small-cell carcinoma with a cut-off value of 3.26950 pg/mL (sensitivity 100%, specificity 100%, AUC 1.000). In non-small cell carcinoma, the cut-off value was 4.88700 pg/mL (sensitivity 63.5%, specificity 92.6%, AUC 0.689). IL-39 shows promise as a predictive and diagnostic biomarker in lung cancer, particularly in small-cell carcinoma, and may play a protective role in disease modulation through immune-related pathways. Show less

Colon cancer is reported as third most prevalent malignancy worldwide, while sericin being an antioxidant, is now used in biomedical applications due to its biochemical characteristics and has shown potential efficacy to treat colon cancer. Sericin was isolated by the degumming process followed by the characterization by using FTIR, UV, XRD, and SEM techniques to confirm the successful synthesis of SAgNPs and SChiAgNPs. The male Balb C mice were then divided into 13 groups. Group 1: Control, Group 2: DMH (20 mg/kg) (injected (IP) thrice a week for 14 weeks). Groups 3,4,5: Sericin (S) (100 mg/kg), Sericin silver nanoparticles (SAgNPs) (100 mg/kg), and Sericin Chitosan silver nanoparticles (SChiAgNPs) (100 mg/kg) were given orally for 14 weeks respectively. Groups 6,7,8,9 were considered as preventive groups and were given DMH (IP) + 5-FU (IP), DMH(IP) + S (orally), DMH (IP) + SAgNPs (orally), DMH (IP) + SChiAgNPs (orally) respectively for the period of 14 weeks Groups 10,11,12,13 were considered as treatment groups and were given 5-FU (5 mg/kg) (IP), (S) (100 mg/kg) (orally), (SAgNPs) (100 mg/kg) (orally), (SChiAgNPs) (100 mg/kg) (orally) for a period of first 7 weeks after 7 weeks of DMH administration (IP). After 14 weeks period study, blood samples and colon tissue were used for the analysis of biochemical markers i.e., CEA, CA19-9, TIMP-1, and IL-6, IL-8, IL-27, SOD, CAT, GR, GSH, GST, MDA and MMP-7 via ELISA and histopathological analysis. The UV absorption peaks obtained at 435 and 463 nm indicated the formation of SAgNPs and SChiAgNPs formation respectively. FTIR spectra peaks obtained, indicate NH stretching of primary and secondary amine group), (NH stretching of amine salt) (N=C=S stretching of thiocyanate compound), (CC stretching of alkene), (NO stretching of nitro compound), (SO stretching of sulfonyl chloride), (CN stretching of amine) and (C-O-O stretching) for sericin, SAgNPs, and SChiAgNPs, confirming, the presence of theses functional groups. The XRD pattern revealed that SAgNPs and SChiAgNPs had structure crystalline structures. EDX characterization peaks for SAgNPs indicated the presence of silver along with other elements including; calcium, oxygen carbon, while EDX characterization peaks for SChiAgNPs indicated the presence of silver along with other elements including; oxygen, carbon, sodium, phosphorus, Sulphur and chlorine. SEM analysis showed that SAgNPs are of spherical shape, while the SChiAgNPs displayed the rectangular shape. The results for biomarker analysis indicated significantly elevated levels of CEA, CA19-9, TIMP-1, IL-6, IL-8, IL-27, MDA, and MMP-7 in DMH treated group (p ≤ 0.001) which were decreased significantly in SChiAg(T) (p ≤ 0.001). In contrast, levels of SOD, GR, GSH, CAT and GST were reduced significantly in DMH treated group, which were increased significantly in SChiAg(T) (p ≤ 0.001). The histopathological analysis of proximal and distal parts of colon tissue of the DMH-treated group showed low-grade dysplasia (LGD), and high-grade dysplasia (HGD) while SChiAgNPs improved the histopathological changes induced by DMH. The findings suggest that Sericin Chitosan conjugated silver nanoparticles showed their efficacy against DMH-induced colon cancer, making a potential future in the anticancer research field. Show less