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This study sought to identify neurotransmitter receptor-related genes (NR-RGs) that are critically involved in non-small cell lung cancer (NSCLC) through bioinformatics approaches. The TCGA-NSCLC dataset was utilized as the training cohort, while the GSE50081 dataset served as the validation cohort. NR-RGs were curated, and single-sample gene set enrichment analysis (ssGSEA) scores were computed. Subsequently, weighted gene co-expression network analysis (WGCNA) and functional enrichment analyses were conducted. A risk prediction model and a prognostic model were constructed based on identified gene signatures. Finally, a competing endogenous RNA (ceRNA) network was established, and gene expression levels were experimentally validated. 192 differentially expressed genes were identified as candidate NR-RGs. The risk model ultimately highlighted six genes: CPS1, CDH17, NIPAL4, SOX2, CALB2, and KREMEN2 as potential biomarkers. The prognostic model demonstrated robust predictive performance for patient outcomes. Immune infiltration analysis revealed a significant positive correlation between neutrophil abundance and the risk score. Expression analysis indicated that CPS1 and CALB2 were downregulated in NSCLC samples, whereas CDH17, NIPAL4, SOX2, and KREMEN2 were upregulated. The genes CPS1, CDH17, NIPAL4, SOX2, CALB2, and KREMEN2 were identified as prognostic biomarkers in NSCLC, providing insights into their potential roles in disease progression and therapeutic targeting. Show less

Pine nut oil (PNO) is a candidate alternative to corn oil (CO) owing to comparable unsaturated fatty-acid profiles and enrichment in pinolenic acid (Δ5-18:3) and lipid-soluble micronutrients. We systematically compared extraction routes (solvent, supercritical CO₂, pressing), established solvent extraction as the optimal balance of yield and bioactive retention, and then characterized solvent-extracted oils from eight provenances using a weighted composite score to nominate Pinus tabuliformis for in vivo testing. In diet-induced obese mice (12-week Western diet, then 12-week intervention, n = 10 per group), replacing CO with PNO lowered body-mass gain and liver weight and improved serum lipids (triglycerides ↓ ∼ 28 %, total cholesterol ↓ ∼ 15 %, LDL-C ↓ ∼ 20 %) without affecting HDL-C or glucose; ALT and AST fell by ∼30 %, indicating hepatoprotection. Hepatic multi-omics revealed coherent remodeling toward PUFA-rich phospholipid species, activation of PPAR-centered peroxisomal/mitochondrial fatty-acid degradation and circadian pathways, and integrative correlations implicating Cyp4a10/14, Ehhadh, Slc27a2, Fgf21, Angptl4, and Plin5. Collectively, PNO reoriented hepatic lipid flux toward oxidation and membrane remodeling, supporting its development as a nutritionally advantaged culinary oil. Show less

This study aims to construct a prognostic model for hepatocellular carcinoma (HCC) based on palmitoylation-related genes and explore its molecular mechanisms through multi-dimensional analyses. The research integrated single-cell transcriptome data (GSE189903) with bulk transcriptome data (TCGA-LIHC, GEO datasets), focusing on palmitoylation-related genes in HCC epithelial cells. The scAB deconvolution algorithm was used to analyze the association between epithelial cell subsets and patient survival, and hdWGCNA was combined to construct a gene co-expression network. Through differential expression analysis, univariate Cox regression, and LASSO penalized regression, 7 key genes (SERPINE1, FMO3, ALDH2, CPS1, SLCO1B1, ACAT1, ACADS) were identified to build a prognostic risk model. Validation results showed that the model could effectively distinguish the survival prognosis of high-risk and low-risk patients (AUC values for 1/3/5 years in the TCGA cohort were 0.676, 0.656, and 0.642, respectively; those in the GSE14520 validation set were 0.702, 0.658, and 0.654, respectively), and the risk score was an independent prognostic factor. Further analyses revealed that the risk score was associated with tumor staging, immune cell infiltration (e.g., T cells, monocytes), response to immunotherapy, and drug sensitivity. Functional enrichment analysis indicated that the high-risk group was enriched in cell cycle regulation and oncogenic signaling pathways, while the low-risk group was related to metabolic pathways. This study is the first to analyze the regulatory network of palmitoylation in HCC epithelial cells by combining single-cell and bulk transcriptomes, providing new molecular targets and methodological references for HCC prognosis evaluation and precision therapy. Show less

With global climate warming increasingly threatening aquatic ecosystems, prolonged exposure to high temperatures has become a major environmental stressor for both wild and cultured fish. However, the long-term effects of chronic heat stress on blood physiology and hematopoietic processes remain poorly understood. To assess the long-term impacts of chronic heat stress on hematopoiesis in largemouth bass (Micropterus salmoides), we conducted a 180-day acclimation experiment at 34 °C. Hematological analyses showed significant reductions in red blood cell counts and hemoglobin concentrations, indicating impaired oxygen transport capacity. Blood cell morphology was altered, with erythrocytes exhibiting a lower major-to-minor axis ratio and leukocytes (lymphocytes and granulocytes) showing increased volumes. Histological and ultrastructural observations of the head kidney revealed tissue loosening, hemosiderin deposition, mitochondrial damage, and elevated apoptosis. Furthermore, transcriptomic analysis combined with GO and KEGG enrichment revealed that pathways involved in vascular development, stress response, and fatty acid metabolism were significantly activated under heat stress. Notably, key genes associated with angiogenesis, lipid metabolism, stimuli response, apoptosis and immunity, including mmp9, angptl4, abca1 and stab2, were markedly upregulated, suggesting their crucial roles in vascular remodeling and thermotolerance. Together, these results provide the first integrative cellular and molecular characterization of hematopoietic responses to prolonged high temperature in M. salmoides. The findings enhance understanding of fish physiological plasticity under environmental stress and have implications for aquaculture management and the development of heat-resilient strains. Show less

Based on Traditional Chinese Medicine (TCM) theory, the efficacy and mechanism of Ginger juice processed Ziziphi Spinosae Semen (GJPZSS) for treating insomnia, particularly stress-related types, were investigated to provide empirical evidence. An insomnia model was induced in mice by DL-4-chlorophenylalanine (PCPA) and chronic tail clamping. The sedative effect was evaluated by behavioral tests. Serum components from GJPZSS were analyzed by UHPLC-Q-TOF-MS/MS, and 64 potential targets were identified. The cAMP signaling pathway was enriched as the core pathway by Kyoto Encyclopedia of genes and genomes (KEGG) analysis and was validated by molecular docking. GJPZSS was demonstrated to prolong sleep time, reduce immobility time, increase 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) levels, decrease hypothalamic-pituitary-adrenal (HPA) axis levels, and suppress neuronal death. The reduction of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain was also significantly inhibited. It was concluded that the sleep-improving effect of GJPZSS was mediated through the regulation of the HPA axis and the cAMP/PKA/CREB/BDNF signaling pathway. Show less

N. Aladdin and S. A. Ghareib, "Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway," Journal of Biochemical and Molecular Toxicology 38, no. 12 (2024): e70082, https://doi.org/10.1002/jbt.70082. The above article, published online on 09 December 2024 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Hari K. Bhat; and Wiley Periodicals, LLC. The retraction has been agreed upon following concerns raised by a third party regarding data reuse between this article and two other articles previously published elsewhere by the same authors. An investigation confirmed that there are substantial overlaps among the three papers. The authors provided some supporting data and explained that the three studies were related, and that data from a limited number of animals were shared to confirm the disease model. However, analysis of the data showed that the overlaps were not restricted to disease model validation. The editors have therefore lost confidence in the results presented in this article and consider the conclusions to be invalid. The authors disagree with the retraction. Show less

Post-traumatic stress disorder (PTSD) causes debilitating nightmares, flashbacks and anxiety stemming from a catastrophic, often life-threatening traumatic event. Originally described in soldiers exposed to the horrors of battle, PTSD is now recognized in civilian victims of assault, natural disasters and mass casualty events. Most people experiencing trauma do not develop PTSD, so understanding neurobiological mechanisms is crucial to predicting risk and developing targeted treatments. There have been many studies seeking to find biomarkers for PTSD, and their results have converged on several brain regions, molecular pathways and neuropsychological functions. In this review, we focus on selected findings about the glucocorticoid receptor (GR), the chaperone protein FKBP51 (FK506 binding protein 51), BDNF (brain-derived neurotrophic factor), fear memory reconsolidation and epigenetic regulation of gene expression in the hypothalamic-pituitary-adrenal (HPA) axis, amygdala and hippocampus. Together, these disparate aspects of brain function provide an emerging model for understanding the etiology and pathophysiology of PTSD. Avoidance of lethal threats is fundamental for survival, and this stringent evolutionary requirement has conserved many components of fear memory storage and behavioural response to danger. PTSD research can therefore rely on non-human animal model systems with better face and construct validity than most other psychiatric disorders. With this advantage, advances in PTSD biomarker identification are likely closer to clinical translation than in other mental illnesses. We attempt to highlight the most promising biomarkers that could be targeted by novel treatments and propose a map for future research work. Show less

Alzheimer's disease (AD) is increasingly recognized as a multisystem disorder shaped not only by central neurodegeneration but also by peripheral metabolic and immune dysregulation. Growing evidence highlights the gut microbiota and its metabolites as key modulators of amyloid accumulation, tau phosphorylation, neuroinflammation, and microglial dysfunction. This review aims to synthesize current advances on how plant-derived bioactive compounds modulate AD pathophysiology through microbiota-dependent metabolic and neuroimmune mechanisms, and to establish a systems-level framework linking botanical interventions to gut microbiota remodeling and metabolite signaling. A comprehensive literature survey was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar, covering publications from 2010 to 2026. Studies investigating gut microbiota, microbial metabolites, and plant-derived bioactive compounds in AD-related metabolic, immune, and neurodegenerative pathways were systematically reviewed and integrated. Plant-derived bioactive compounds, including phytochemicals, polysaccharides, and multi-herb formulations, interact extensively with the gut microbiota, undergoing microbial biotransformation to yield more active metabolites while simultaneously reshaping microbial community structure and metabolite profiles. These bidirectional interactions position the microbiota as a central mediator of plant-derived therapeutic activity. We summarize current evidence on how plant-derived compounds influence AD pathophysiology through microbiota-dependent metabolic and neuroimmune pathways. Major microbial metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and indole derivatives, are discussed, together with their regulatory roles in signaling networks such as nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/Akt (PI3K/Akt), cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF), and triggering receptor expressed on myeloid cells 2 (TREM2)-associated microglial states. We further summarize evidence for synergistic strategies combining plant bioactives with probiotics and highlight advances in microbial biotransformation, precision metabolite modulation, and engineered microbial systems. Finally, future directions integrating multi-omics, personalized microbiota-guided interventions, and synthetic biology are outlined to support the development of targeted, mechanism-based therapies. By framing AD through a gut microbiota-centered perspective, this review provides a unified mechanistic foundation for the development of next-generation interventions based on plant-derived compounds and microbiota regulation. Show less

Buchanania lanzan Spreng. (Anacardiaceae) seeds (BLHA) are the cheaper alternative to almonds used in the confectionery industry. The flour powder of seeds is used as a thickening agent to prepare sauces and flavourings for a batter. The socioeconomic importance of this species lies in its medicinal properties for curing diabetes. The study explored the multifaceted neuroprotective role of BLHA (500 mg/kg) in hyperlipidic high-fat diet streptozotocin (HFD/STZ)-induced type2 diabetic neuropathy (T2DN) rats via glucose metabolism, insulin resistance, and inflammation to mitigate nerve damage. Molecular docking analysis was performed to identify specific molecular targets of bioactive compounds in T2DN pathogenesis. Serum diabetic parameters, such as serum glucose (SG), insulin (SI), total protein (TP), triglycerides (TG), blood urea nitrogen (BUN), creatinine (Cr), HDL-C, and LDL-C, were studied. A strong correlation between HbA1C and insulin resistance assessed by HOMA-IR. Oxidative stress triggers the production of free radicals, so the antioxidant indicators in serum, tissues, and proinflammatory cytokines in the liver, brain, and pancreas were measured in T2DN rats. Effects on neurochemicals, BACE1, Aβ BLHA at 500 mg/kg significantly improved hyperglycemic (SG, SI, HOMA-IR, HbA1C), hepatic (AST, ALT, ALP, TP, TB), dyslipidemic (TC, TG, HDL-C, LDL-C), and kidney function markers (creatinine, BUN) in T2DN rats. BLHA restored oxidative (CAT, GSH, SOD, MDA) and cytokine markers (TNF-α, IL6) in the liver, pancreas, and brain cortex. Oxidative stress-impaired neurotransmitters were alleviated by enhancing cholinesterase (AChE, BChE) and BACE1 activities, and by ameliorating Aβ The multifaceted actions of dietary polyphenols, antioxidants, and antidiabetic compounds (Catechol, 2-Hydroxy-5-methylbenzaldehyde, 8-Octadecenoic acid methyl ester, n-Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl)ethyl ester, β-Sitosterol, Hexadecenoic acid methyl ester) in BLHA modulated glucose metabolism, restored HOMA-IR, and reduced inflammation by protecting against oxidative stress, as a result, it improved neurotransmission and reduced neuropeptide aggregation in T2DN rats. The dock score of β-sitosterol (AChE: -12.7; BChE: -14.8; IL6: -9.8; and Atp1a3: -13.3 kcal/mol) correlated with the experimental evidence. Show less

Depression has emerged as a concerning factor in colon cancer progression and treatment, yet its underlying mechanisms and therapeutic targets remain poorly defined. This study aimed to elucidate how depression affects colon cancer progression and chemotherapeutic response, and to explore potential molecular targets and therapeutic interventions involving the traditional Chinese medicine formula Sinisan (SNS) and its bioactive component Quercetin. A mouse model combining depression and colon cancer was established to evaluate behavioral alterations, tumor progression, and pathological features. RNA sequencing was performed to screen the differentially expressed genes. The effects of corticosterone (CORT) on proliferation, colony formation, migration, and GSTM2 expression were examined in HCT116 cells, followed by functional validation through GSTM2 overexpression and inhibition assays. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) were used to validate the binding of Quercetin to GSTM2. The therapeutic efficacy of SNS and Quercetin was assessed with respect to depressive symptoms, serum BDNF levels, NLRP3 inflammasome activity, and the potency of 5-fluorouracil (5-FU) chemotherapy. Mice with depression and colon cancer exhibited aggravated depressive behaviors and accelerated tumor progression. RNA-sequencing and network pharmacology analyses identified GSTM2 as a promising candidate target in colon cancer treatment, which was markedly down-regulated in the DP-CC group. CORT enhanced proliferation, colony formation, and migration of HCT116 cells while simultaneously suppressing GSTM2 expression. Conversely, GSTM2 levels negatively correlated with cell proliferation, colony formation, and chemoresistance in HCT116 cells. Treatment with SNS alleviated depressive symptoms, elevated serum BDNF, reduced NLRP3 inflammasome activity, and potentiated the efficacy of 5-FU chemotherapy. Quercetin, a bioactive component of SNS, bound to GSTM2 through hydrogen-bond and van-der-Waals interactions, up-regulated GSTM2 expression, and mitigated CORT-induced proliferation, colony formation, and chemoresistance. Our findings suggest that depression promotes colon-cancer progression by down-regulating GSTM2, whereas SNS restores GSTM2 expression and enhances chemotherapeutic response. Show less

“Surrogate” definitions of intrinsic subtypes, which imply the Ki67 proliferation marker, help to clinically distinguish luminal breast carcinomas (Lum BC). Here, mass spectrometry–based proteomics can help analyse the protein content of malignant and normal cells and eventually distinguish patient samples from healthy controls at the molecular level. In this work, peripheral blood CD14 + monocyte proteomes of the LumA, LumB-HER2 − and LumB-HER2 + subtypes and those with benign disease were compared to healthy controls (HCs). Among differentially expressed proteins (DEPs), The online version contains supplementary material available at 10.1038/s41598-026-39686-y. Show less

Physical activity can improve health-related quality of life (HRQoL); however, it is not clear whether this association is direct or indirect. The aims of this study were to examine the associations of daily movement behaviours with physical and mental HRQoL in older adults, and the mediating role of muscle strength and body composition on it. Three hundred thirty-four community-dwelling older adults wore the Intelligent Device for Energy Expenditure and Activity for two consecutive days to quantify time spent in sedentary behaviour (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). HRQoL was assessed using the 12-Item Short-Form Health Survey, yielding physical (PCS) and mental (MCS) component scores. For muscle strength, a handgrip dynamometer and the Sit-to-Stand test were used. Body mass index (BMI), waist circumference, and estimates of skeletal muscle mass and fat mass by bioelectrical impedance were included as body composition variables. Association analyses were examined using linear regression models, and for mediation analysis, structural equation modelling was used. MVPA was positively associated with PCS [β (95%CI): 0.39 (0.19, 0.59)], whereas no significant associations were observed between MVPA, LPA, or SB and MCS. The association between MVPA and PCS was partially mediated by lower-limb muscle strength and fat mass percentage [8.5% (z = 1.753, p = 0.080) and 28.9% (z = 1.912, p = 0.056), respectively], and fully mediated by skeletal muscle mass normalized by BMI [28.2% (z = 2.016, p = 0.044)].Regular engagement in MVPA is positively associated with the physical component of HRQoL in older adults, both directly and indirectly through muscle strength and skeletal muscle mass. Show less

Copyright: © 2026 Adeyika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aberrant DNA methylation changes lead to abnormal gene expression that contributes to the development and progression of prostate cancer (PCa). Inquiry of genome-wide DNA methylation dataset, we identified the homeodomain pancreatic and duodenal homeobox 1 (PDX1) gene as differentially hypermethylated in PCa compared to normal prostate tissues. Immunohistochemical analysis of matched PCa and normal prostate tissues using tissue microarray showed a significant 2.33-fold (p = 0.0001) higher PDX1 protein expression in the PCa compared to the normal prostate tissues. In PCa cell lines (PC-3 and LNCaP) engineered to stably overexpress or knockdown PDX1, the ectopic PDX1 expression significantly enhanced cell proliferation and migration, whereas PDX1 knockdown suppressed these phenotypic processes. Quantitative RT-PCR and Western blot analysis demonstrated that PDX1 overexpression was associated with increased expression of key metabolic regulators; INSR, IGF1R, CXCR4, CDH2, TWIST1, and SNAI1, whereas there is decreased expression of ESR2, and TNFα. Conversely, PDX1 knockdown led to the opposite effect in expression profiles of these metabolites. Notably, these effects were more pronounced under high-glucose conditions compared to low-glucose environments. Overall, our findings suggest that PDX1 plays a tumor-promoting role in human PCa cells by influencing expression of metabolites in insulin, inflammatory, and epithelial-mesenchymal transition (EMT) signaling pathways. Given its potential role in metabolic regulation, full insights into the function of PDX1 in PCa could contribute to improved treatment and prevention strategies, particularly for men with PCa and comorbidities such as obesity and diabetes. Show less

The aim of the study was to characterize the prevalence of comorbidities and molecular genetic status in patients with familial hypercholesterolemia (FH) and non-familial hypercholesterolemia (non-FH). This cross-sectional observational study included 323 patients. Assessments comprised personal and family histories, physical examination, fasting lipid profiling, and molecular genetic testing. Patients with FH were not characterized by an increased prevalence of type 2 diabetes mellitus. In contrast, the non-FH group demonstrated a pronounced cardiometabolic comorbidity profile with a high prevalence of recurrent chronic pancreatitis. Patients with probable or definite FH had a higher prevalence of coronary heart disease and peripheral atherosclerosis, whereas myocardial infarction (MI) was common across all studied groups. Among patients with definite and probable FH, pathogenetic variants were identified in 78.2% and 71.4%, respectively, predominantly in the Show less

Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to July 2025 involved 1773 older adults from various areas in Jiangsu province. Data were collected via Wenjuanxing and included demographics, the Influenza Vaccine Hesitancy Scale, and the vaccine literacy scale. Group differences were examined using chi-square tests and one-way ANOVA; latent profile analysis (LPA) identified vaccine hesitancy subgroups, and multinomial logistic regression estimated correlates of profile membership. Three profiles emerged: Low Hesitancy (23.0%), Moderate Hesitancy (35.0%), and High Hesitancy (42.0%). Rural residence predicted Moderate (OR = 2.030) and High (OR = 2.993) hesitancy. Lower household income and chronic disease were associated with the Moderate Hesitancy profile, whereas male sex was associated with the High Hesitancy profile. Higher interactive (OR = 0.686) and critical (OR = 0.599) vaccine literacy were inversely associated with High hesitancy.Concerns about vaccine quality predicted both Moderate (OR = 1.433) and High (OR = 1.376) groups; knowledge gaps and fear of adverse reactions concentrated in the High group. Older adults show heterogeneous vaccine hesitancy phenotypes. Uptake efforts should move beyond one-size-fits-all messaging toward segmented strategies. These strategies should integrate cost-related measures with literacy-sensitive, trust-oriented communication, prioritizing rural residents, older men, and those with chronic conditions. The reported proportions of hesitancy profiles reflect our sample only and should not be viewed as nationally representative. Show less

Regular physical activity can improve the blood lipid profile, yet athletes may still experience dyslipidemia. This study examined lipid profiles in Turkish endurance and strength athletes in relation to the dietary intake. Eighty-four participants, including strength athletes ( Endurance athletes had a lower body mass index (BMI), body fat (%), fat mass, waist-to-hip ratio, and waist-to-height ratio than strength athletes and non-athletes ( Endurance athletes displayed a more favorable lipid profile than strength athletes and non-athletes. Group differences in lipids likely reflect a combination of adiposity, dietary patterns, and sport-specific behaviors. Show less

This cross-sectional study aimed to examine the associations between the 24-h movement behaviors and mental health among university students in China, and to determine the optimal behavioral balance based on the top 5% of model-predicted mental health outcomes using compositional data analysis. A total of 6,084 university students aged 17–24 years in Southwest China self-reported their daily durations of moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), sedentary behavior (SED), and sleep (SLP). They were stratified by gender and then randomly and equally assigned to the “recommendation” group and the “validation” group. Using compositional data analysis, time-use compositions (MVPA, LPA, SED, SLP) were transformed into isometric log-ratios (with quadratic terms as needed) and subsequently used in regression models to predict the three mental health outcomes. All possible combinations of motion components were examined to determine the combination with the highest correlation (top 5%) for each outcome. Through research and analysis of the recommendation groups, the optimal combination of average (range) time usage is determined as follows: for males, MVPA 92 (60–110) min/day, LPA 361 (310–400) min/day, SED 372 (350–480) min/day, SLP 614 (530–680) min/day; for females, MVPA 58 (40–90) min/day, LPA 290 (180–390) min/day, SED 445 min (400–560), SLP 665 (580–740) min/day. The recommended durations served as benchmarks for the validation group. Participants who met the optimal 24-h movement behavior time showed significantly lower depression (males: β = –1.290, The optimal 24-h movement behavior time differs between men and women. Males tend to require a longer optimal MVPA duration than females, while females require a longer optimal SLP duration than males. The findings provide valuable reference for developing 24-h movement guidelines and promoting healthy and balanced lifestyles among university students. [Image: see text] The online version contains supplementary material available at 10.1186/s12889-026-26534-x. Show less

Peripheral artery disease (PAD) is a major manifestation of systemic atherosclerosis and affects vascular health in older adults. Dyslipidaemia contributes significantly to PAD, but the predictive value of composite lipid indices remains unclear. The non-high-density lipoprotein cholesterol (non-HDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) reflects the balance between atherogenic and protective lipoproteins. This study aimed to explore the association between the NHHR and PAD among vascular surgery inpatients aged ≥50 years in Kunshan, China. This retrospective cross-sectional study included 3,532 patients (aged ≥ 50 years) hospitalized at the Affiliated Kunshan Hospital of Jiangsu University, Suzhou, from December 2017 to August 2024. NHHR, calculated as (total cholesterol - HDL-C)/HDL-C, was the exposure variable; PAD, defined as PAD-like symptoms with an ankle brachial index < 0.9, was the outcome. Covariates included age, sex, lipoprotein(a) level [Lp(a)], apolipoprotein A1 level (Apo A1), alanine aminotransferase (ALT) level, neutrophil count (NEUT), hypertension status, diabetes status, smoking status, and alcohol consumption status. Multivariate logistic regression, smooth curve fitting, and threshold analyses were performed. After adjustment for confounders, the NHHR was nonlinearly associated with PAD (OR = 0.77; 95% CI: 0.65-0.93; The NHHR was associated with the presence of PAD, with the evidence suggesting a nonlinear relationship and potential sex-specific differences. Given the retrospective cross-sectional design, this association does not support causal inference or strong predictive claims. The NHHR may help identify individuals who could benefit from further clinical evaluation for PAD, but prospective studies are needed to confirm its clinical relevance before its routine application. Show less

Lipoprotein(a) (Lp(a)) is increasingly recognized as a significant contributor to the risk of atherosclerotic cardiovascular disease (ASCVD). We report the case of a 53-year-old woman who presented with chest pain and has notable family history of premature cardiovascular events. Investigation revealed a markedly elevated Lp(a) level of 492 nmol/L, alongside the presence of coronary artery disease necessitating stenting. Despite adherence to high-intensity statin therapy, her low-density lipoprotein (LDL) cholesterol levels remained suboptimal. Consequently, we initiated treatment with a PCSK9 inhibitor to achieve further reductions in LDL cholesterol. This case underscores the importance of routinely measuring Lp(a), as recommended by European guidelines, which advocate for its assessment at least once during adulthood for effective risk stratification. While lifestyle interventions play a critical role in cardiovascular health, targeted therapies such as PCSK9 inhibitors and emerging nucleic acid-based treatments, including Zerlasiran, offer promising options for significantly lowering Lp(a) levels. Recognizing and addressing elevated Lp(a) is vital for identifying patients at high cardiovascular risk and for informing tailored management strategies aimed at improving patient outcomes. Show less

Calcific aortic valve disease (CAVD) is a cardiovascular disease closely associated with aging. The role of lipoprotein(a) [Lp(a)] has attracted considerable attention in recent years. However, limited research has simultaneously explored the relationships between Lp(a), age, and CAVD. This study sought to assess the relationship linking Lp(a), time-weighted Lp(a), and CAVD. A total of 5,156 inpatients with comprehensive clinical data were recruited for this study. The associations of Lp(a) and time-weighted Lp(a) with CAVD were examined via multivariate logistic regression analysis, alongside the application of restricted cubic spline analysis. The diagnostic utility of Lp(a) and time-weighted Lp(a) for CAVD was assessed by constructing receiver operating characteristic (ROC) curves. CAVD prevalence rose with age, whereas the rate of increase diminished with advancing age. The average Lp(a) level in the young populations with CAVD was more than twice that in the No-CAVD group, particularly among those aged 55 years or younger. The prevalence of CAVD in non-elderly populations was markedly 2–4 fold greater in the higher Lp(a) group (> 30 mg/dL) than in the lower Lp(a) group (≤ 30 mg/dL). Multivariate adjusted odds ratios ‌(ORs) for CAVD increased with advancing Lp(a) or age. Time-weighted Lp(a), which takes into account both age and Lp(a), was more strongly linked to elevated CAVD risk than Lp(a) alone. Time-weighted Lp(a) enhanced the diagnostic value of CAVD, improving both sensitivity and specificity. The risk of CAVD is strongly associated with both age and elevated Lp(a) levels. Time-weighted Lp(a), which integrates these factors, serves as a superior indicator that better captures cumulative long-term Lp(a) variation and yields stronger CAVD risk stratification. The online version contains supplementary material available at 10.1186/s12944-026-02884-8. Show less

To investigate whether vaccinia-related kinase 1 (VRK1) mediates transforming growth factor-beta2 (TGF-β2)-caused epithelial-mesenchymal transition (EMT) and inflammatory responses in retinal pigment epithelial (RPE) cells through regulating snail family transcriptional repressor 1 (SNAI1), and to validate its role in a proliferative vitreoretinopathy (PVR) mouse model. Human RPE cell line ARPE-19 cells were treated with TGF-β2 to construct an EMT model. Western blot detected VRK1 level. The effects of VRK1 on SNAI1 expression and biological behavior of ARPE-19 cells were detected by immunofluorescence, ELISA, Transwell, and scratch assay, and the interaction between VRK1 and SNAI1 was confirmed through immunoprecipitation. A PVR mouse model was constructed, and the effects of VRK1 or/and SNAI1 on retinal damage were assessed by pathologic staining. Inflammatory factors and EMT-related proteins were assessed with ELISA and Western blot. VRK1 was upregulated in ARPE-19 cells after TGF-β2 treatment. Overexpression of VRK1 increased cell viability, promoted cell migration and EMT, and the levels of inflammatory factors. Silencing of VRK1 reversed the above indexes. There was a direct interaction between VRK1 and SNAI1, and overexpresssion SNAI1 weakened the impacts of silencing of VRK1. In PVR mice, silencing of VRK1 ameliorated retinal structural damage, decreased proinflammatory factor levels, and suppressed SNAI1 and mesenchymal marker expression. SNAI1 overexpression antagonized the protective effects of silencing VRK1 and exacerbated EMT and inflammatory responses. VRK1 plays a key role in retinal structural and inflammatory damage in PVR mice by regulating SNAI1 and mediating TGF-β2-caused EMT and inflammatory responses in RPE cells. Show less

Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain-derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1-silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal-induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti-inflammatory effects by directly binding to and antagonizing Toll-like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233-244 of BDNF as the key functional domain responsible for this effect. A synthetic 12-mer peptide derived from this region, termed BDP12, retains TLR4-antagonizing ability, demonstrating strong anti-inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte-derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis-mediated ALI/ALF. Show less

Early-life stress (ELS) is a key risk factor for adolescent depression. Si-Ni-San (SNS), a classic traditional Chinese medicine formula, has shown antidepressant potential, yet its effects on the dorsal raphe nucleus (DRN)-nucleus accumbens (NAc) serotonergic circuit remain unclear. This study aimed to investigate whether SNS alleviates adolescent depression by restoring DRN-NAc serotonergic circuit function and to identify the serotonin receptor mediating its synaptic effects in the NAc. Firstly, the antidepressant efficacy of SNS was evaluated in a mouse model of ELS. Subsequently, its underlying mechanism was explored through integrated neurophysiological, molecular, and pharmacological analyses. Depressive- and anxiety-like behaviors were assessed using behavioral tests (sucrose preference, tail suspension, forced swim, open field, and elevated plus maze). In vivo electrophysiolog was employed to monitor DRN neuronal activity. Chemogenetic manipulation was employed to regulate the DRN-NAc serotonergic circuit, while 5-HT4R function was assessed through pharmacological intervention and viral knockdown. Synaptic and molecular mechanisms were examined using Western blotting, qPCR, ELISA, and immunofluorescence. SNS alleviated depressive-like behaviors, enhanced neural activity and low-frequency oscillations in the DRN, and restored 5-hydroxytryptamine (5-HT) levels in the NAc. Mechanistically, SNS upregulated tryptophan hydroxylase 2 (TPH2) while downregulating indoleamine 2,3-dioxygenase 1 (IDO1), thus promoting 5-HT synthesis. Critically, the antidepressant effects of SNS were blocked by either chemogenetic inhibition of the DRN-NAc serotonergic circuit or pharmacological blockade of 5-HT4R in the NAc. Meanwhile, the knockdown of 5-HT4R abolished the ameliorative effects of SNS on depressive-like behaviors and associated synaptic remodeling, including the upregulation of brain-derived neurotrophic factor, postsynaptic density protein 95, and mushroom spine density. These results demonstrate that SNS alleviates depressive-like behaviors in adolescent male mice by restoring DRN-NAc serotonergic circuit function, enhancing 5-HT bioavailability, and promoting 5-HT4R-dependent synaptic plasticity in the NAc, revealing a circuit- and receptor-specific therapeutic mechanism. Show less

The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the "M1-like microglia-A1-like astrocyte axis (M1-A1 axis)" in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the "M1-A1 axis". This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(BBB)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translation. Show less

Pulmonary fibrosis is a common and life-threatening complication of Parkinson's disease (PD), yet the molecular mechanisms linking the two diseases remain unclear, creating a critical gap in targeted therapeutic strategies for comorbid patients. Angiotensin-converting enzyme 2 (ACE2) plays a key role in neuroprotection and lung homeostasis; its deficiency exacerbates PD-related neuroinflammation and α-synuclein aggregation, while also promoting pulmonary inflammation and fibrotic remodeling. Clarifying how ACE2 deficiency drives PD-exacerbated pulmonary fibrosis is therefore an urgent unmet need. This study explored the underlying mechanisms using MPTP-induced PD mouse models and bioinformatics analyses of PD/idiopathic pulmonary fibrosis (IPF) datasets from the GEO database. In MPTP-induced PD mice, ACE2 deficiency significantly worsened motor/non-motor dysfunction, dopaminergic neuron loss, microglial/astrocytic activation, and lung fibrosis (evidenced by elevated α-SMA/TGF-β and increased collagen deposition). Bioinformatics identified 41 overlapping differentially expressed genes (DEGs) between PD and IPF, enriched in critical pathways: downregulated FoxO1 (impairing antioxidant defense) and upregulated TNF, JAK1-STAT3, and AGE-RAGE (amplifying inflammation/fibrosis). ROC analysis validated hub genes (e.g., BDNF, FOSL2) with good diagnostic value (AUC > 0.7), and molecular docking identified Smilagenin, Fostamatinib, Olopatadine, and Amlexanox as potential therapeutics. This study confirms ACE2 deficiency is a central driver of PD-exacerbated pulmonary fibrosis via the FoxO1/TNF/JAK1-STAT3/AGE-RAGE pathways, providing novel biomarkers and drug candidates to address the clinical need for managing this comorbidity. Show less

The cornerstone of treating lower extremity deep venous thrombosis (LEDVT) lies in anticoagulation therapy to prevent thrombus progression and recurrence. However, patient adherence to medication is a critical factor influencing treatment efficacy. Traditional research often simplifies adherence into binary categories of "adherent" and "non-adherent," which fails to comprehensively reflect the complex behavioral patterns. Based on latent profile analysis (LPA), medication adherence in LEDVT patients can be categorized into distinct classes, enabling more precise identification of their characteristics. Therefore, exploring these latent classes and their influencing factors holds significant importance for optimizing intervention strategies and improving prognosis. A cross-sectional survey was used to study LEDVT. From March 14, 2024 to September 20, 2024, a random sampling method was used to recruit 469 patients with LEDVT from four grade-A tertiary hospitals in Urumqi, China. Participants completed questionnaires on general demographic information, the Medication Adherence Scale, the Perceived Health Competence Scale, the Herth Hope Index, the Patient Activation Measure, the Beliefs about Medicines Questionnaire-Specific. LPA was conducted to analyze the medication adherence characteristics of patients with LEDVT. Univariate analysis and multivariate logistic regression were used to identify the influencing factors of their latent profiles. Data analysis was performed using Mplus 8.3 and SPSS 25.0 software. LPA was employed to investigate medication adherence in LEDVT patients, revealing three distinct latent classes: the poorest adherence group (44.99%), the moderate adherence group (19.83%), and the good adherence group (35.18%). The logistic regression results demonstrated that, perceived health competence, hope, activation, beliefs about medication necessity, and concerns about medication were influential factors affecting the potential profile of medication adherence (all p < 0.05). LEDVT patients exhibit significant individual differences in medication adherence. Personalized intervention strategies can be designed based on different adherence classes to enhance medication adherence. Additionally, targeted interventions addressing perceived health competence, hope, positive affect, and medication beliefs can effectively improve adherence. Show less

Aging triggers gut microbiota dysbiosis that disrupts the gut-brain axis (GBA), promoting neuroinflammation and neurodegeneration. Elderly exhibit reduced microbial diversity, depleted beneficial bacteria, and expanded pathobionts, elevating neurotoxic metabolites-lipopolysaccharides (LPS), trimethylamine-N-oxide, kynurenine derivatives, and secondary bile acids. These drive "inflammaging," blood-brain barrier breakdown, microglial activation, mitochondrial impairment, and proteinopathies in Alzheimer's and Parkinson's disease. Conversely, neuroprotective metabolites from commensals-short-chain fatty acids, indole-3-propionic acid, and urolithins-preserve gut integrity, suppress inflammation, upregulate BDNF for synaptic plasticity, and enhance mitophagy. Postbiotics, stable probiotic-derived bioactives (butyrate, polyphenol metabolites, and lactate derivatives), surpass live probiotics in safety and precision. They modulate GBA via histone deacetylase inhibition, GPR41/43 signaling, NF-κB blockade, and microglial M2 shift, blocking LPS translocation and bolstering neuronal resilience. Preclinical rodent studies demonstrate robust neuroprotection, but human translation reveals challenges: inter-individual microbiota variability (diet/genetics/comorbidities), inconsistent metabolite absorption/brain penetration between species, methodological limitations (16S rRNA vs. functional metagenomics), postbiotic standardization barriers, and sparse Phase I/II trials showing biomarker benefits without cognitive endpoints. This review synthesizes gut dysbiosis-metabolite-brain aging mechanisms, positioning postbiotics as precision therapeutics. Multi-omics stratified controlled trials are essential to validate long-term efficacy for delaying neurodegeneration and extending cognitive health. Show less