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 Show more
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
Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation pla Show more
Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation plays a crucial role in multiple cardiovascular diseases. The objective of this study is to examine whether diabetic atherosclerotic calcification is regulated by S-nitrosylation of AMP-activated protein kinase (AMPK), a regulator of VSMC phenotype switching. The atherosclerotic plaque was induced by feeding Apoe In cultured VSMCs, high glucose (HG), but not high osmotic pressure, triggered nitrosative stress, reduced AMPKβ1 protein levels, increased AMPKβ1 S-nitrosylation and ubiquitination, and led to calcification. These effects were abolished by mutating AMPKβ1 at cysteine 173 or 223. Furthermore, mutations of AMPKβ1 at Cys173/223 to alanine restored AMPKβ1 protein levels and suppressed the AKT/Runx2 pathway in HG-treated VSMCs. In vivo, enforced expression of mutated AMPKβ1 (Cys173Ala plus Cys223Ala), but not overexpression of wild-type AMPKβ1, significantly prevented atherosclerotic calcification in diabetic Apoe Nitrosative stress contributes to atherosclerotic calcification in diabetes through AMPKβ S-nitrosylation. In perspective, it is advisable to consider inhibiting AMPKβ S-nitrosylation in diabetic patients with atherosclerosis. Show less
Apolipoprotein B (apoB) is a well-known risk factor for atherosclerosis. However, studies examining its relation to atrial fibrillation (AF) have produced conflicting results and suggested possible se Show more
Apolipoprotein B (apoB) is a well-known risk factor for atherosclerosis. However, studies examining its relation to atrial fibrillation (AF) have produced conflicting results and suggested possible sex-specific differences. This study investigated the sex-specific associations between serum apoB concentrations and incident AF and offer insight into the inconsistencies in previous research. A prospective analysis of 26,803 participants without pre-existing AF was performed using data from the Malmö Diet and Cancer Study. Sex-specific associations between apoB and AF were assessed using multivariable Cox proportional hazards models. To ensure the robustness of the results, several sensitivity analyses, such as restricted cubic spline modeling, competing risks regression, alternative adjustment strategies, subgroup analyses, follow-up time restrictions, and multiple imputation for missing data, were conducted. For median follow-up periods of 21.2 and 24.8 years in men and women, respectively, 2,768 and 2,968 incident cases of AF were recorded, respectively. Among women, unadjusted models showed a strong positive association between apoB and AF, with the highest versus lowest quartile showing a hazard ratio (HR) of 1.65 (95% confidence interval [CI] 1.49–1.84; Results show sex-specific observational links between apoB concentrations and risk of AF. In women, higher apoB levels were linearly inversely associated with AF, whereas in men, the association was borderline non-linear, with inverse effects seen mainly at lower apoB concentrations. These sex differences in AF susceptibility may partly reflect underlying atrial electrophysiological variations and hormonal influences, though whether these factors directly mediate the apoB-AF association remains speculative. The online version contains supplementary material available at 10.1186/s12944-026-02905-6. Show less
Sleep traits, including sleep apnoea (SA), insomnia, daytime sleepiness, and snoring, frequently co-occur with cardiometabolic diseases (CMDs), with shared genetic factors suspected to underlie these Show more
Sleep traits, including sleep apnoea (SA), insomnia, daytime sleepiness, and snoring, frequently co-occur with cardiometabolic diseases (CMDs), with shared genetic factors suspected to underlie these associations. However, the contribution of shared genetic determinants to these associations is not fully understood. We conducted a genome-wide pleiotropic association study applying sequential genetic methods to identify shared genetic variants, genes, pathways and causal associations between the four sleep traits and seven CMDs, including LDSC, high-definition likelihood analysis, colocalisation, gene-based tests, enrichment analysis and Mendelian randomisation. Next, validation of those pleiotropic variants was performed in individuals from the All of Us and MVP studies. Among 28 pairs of sleep traits and CMDs, 25 showed significant genetic correlations. Pleiotropic analysis identified 754 independent SNPs (691 unique) and 102 colocalized loci (85 unique). Among these, 47 SNPs (44 unique) were validated as significantly associated with both traits in the pairs, and notably, rs429358 (19q13.32, APOE) demonstrated pleiotropic effects across SA, insomnia and type 2 diabetes (T2D). Forty-eight annotated genes were validated by gene-based tests. Shared genes were enriched in phenotypes related to mortality and growth. Pathway analysis highlighted Cushing syndrome, hormone secretion, and cGMP-PKG, Ras and calcium signalling pathways. After adjusting for glycaemic traits and blood pressure, genetically predicted T2D increased risk of SA, sleepiness, and snoring. Conversely, SA was positively associated with heart failure and T2D independently. This study of sleep traits and CMDs reveals shared genetic determinants that may partially explain their epidemiologic association and suggests potential treatment targets. Described in Acknowledgements. Show less
Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's diseas Show more
Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all-cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; Our study suggests that high blood PCSK9 levels are protective against AD risk in Show less
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-ce Show more
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-centered approaches fail to capture how distinct affective temperaments co-occur within individuals. This study aimed to identify latent profiles of affective temperaments and examine their association with NSSI, exploring the statistical mediating role of cognitive emotion regulation (CER). A cross-sectional study was conducted from February 2025 to September 2025 at the First Hospital of Hebei Medical University. A total of 290 adolescents (aged 10–19) diagnosed with Major Depressive Disorder were recruited, with 282 valid responses included in the final analysis. Participants completed the TEMPS-A, CERQ, and ASHS. Latent Profile Analysis (LPA) was utilized to identify temperament subgroups. Mediation analysis with bootstrapping was performed to test the indirect effects of CER strategies. LPA identified three distinct profiles: Resilient/Low-risk (Class 1, 32.6%), Anxious-Depressive (Class 2, 46.1%), and Mixed-Dysregulated (Class 3, 21.3%). The Mixed-Dysregulated group, characterized by simultaneous elevations in depressive, anxious, irritable, and cyclothymic temperaments, exhibited the highest frequency (45.2 ± 21.3 times/year) and prevalence (98.8%) of NSSI compared to other groups ( The findings delineate a specific “Mixed-Dysregulated” risk phenotype within adolescent depression that is associated with severe NSSI. Interventions should move beyond standard depression care to target cognitive flexibility and emotional regulation skills. Statistical mediation analysis suggests that this risk is mediated by maladaptive cognitive emotion regulation strategies. Not applicable. Show less
This study aimed to assess the childbirth readiness of women in their third trimester of pregnancy and to identify distinct readiness profiles using latent profile analysis (LPA). Additionally, it exp Show more
This study aimed to assess the childbirth readiness of women in their third trimester of pregnancy and to identify distinct readiness profiles using latent profile analysis (LPA). Additionally, it explored the factors influencing childbirth readiness in order to guide targeted interventions for improved maternal and neonatal outcomes. A cross-sectional study was conducted among women in their third trimester of pregnancy between May and November 2024. Eligible participants completed a general information questionnaire, the Childbirth Readiness Scale (CRS), the Childbirth Attitude Questionnaire (CAQ), and the Perceived Social Support Scale (PSSS). LPA identified three groups with distinct childbirth readiness levels: "Low Readiness - Childbirth Knowledge Deficit" (37.9%), "Moderate Readiness - Good Lifestyle Habits" (47.9%), and "High Readiness - Rich Health Knowledge" (14.2%). In addition, gestational age, previous childbirth history, adverse pregnancy outcomes, childbirth attitudes, and social support had different influences on women in different latent profiles of childbirth readiness. There was significant heterogeneity in childbirth readiness among women in their third trimester. Women with lower readiness-especially in childbirth knowledge-would greatly benefit from targeted educational programs, whereas those with moderate readiness levels would find enhanced emotional and psychological support most advantageous. These findings support the implementation of profile-based, personalized prenatal care strategies to improve childbirth preparedness and optimize maternal and neonatal outcomes. Show less
The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing Show more
The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing to its lipid-regulating and anti-inflammatory effects, paeoniflorin (Pae) inhibits VSMC phenotypic transformation, making it a promising candidate for AS treatment. Mouse aortic VSMCs were treated with oxidized low-density lipoprotein (ox-LDL) and Pae, and the effects on cell phenotype were examined. An AS model was established by feeding ApoE Pae reversed weight gain and elevated TG levels in the AS model. Oil Red O staining showed that Pae inhibited VSMC-derived foam cell formation in vitro and reduced aortic sinus plaque area, aortic wall lipid deposition, and hepatic steatosis in the AS model. Immunofluorescence staining of the aortic sinus revealed that Pae mitigated α-SMA overexpression and reversed ATP-binding cassette transporter A1 (ABCA1) downregulation. Western blotting analysis revealed that Pae inhibited ERK1/2 and p65 phosphorylation, curbed MMP2 overexpression, and restored downregulated ABCA1 expression. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, and wound healing assays demonstrated that Pae inhibited ox-LDL-induced VSMC proliferation and migration. Additionally, Pae significantly inhibited the expression of the inflammatory factors IL-6 and MCP-1 both in vivo and in vitro. Pae may treat AS by inhibiting VSMC phenotypic transformation. Show less
Obesity is closely associated with cognitive dysfunction, and markedly increases the risk of developing neurodegenerative diseases. Currently, obesity-related cognitive impairment lacks effective ther Show more
Obesity is closely associated with cognitive dysfunction, and markedly increases the risk of developing neurodegenerative diseases. Currently, obesity-related cognitive impairment lacks effective therapeutic interventions. Shenling Baizhu Powder (SLBZ) is a classical formula used to strengthen the spleen and promote the ascent of clear qi in traditional Chinese medicine (TCM). According to the TCM, this formula has great potential for the treatment of obesity-related cognitive impairment. However, research on SLBZ has focused primarily on its gastrointestinal effects, leaving its neurocognitive mechanisms largely unexplored. This study aimed to elucidate the therapeutic mechanisms of SLBZ in obesity-related cognitive impairment. Obese mice were obtained by subjecting male mice to a 16-week high-fat diet (HFD, 60 kcal % fat). During the final four weeks of the study, a SLBZ decoction (10 and 20 g/kg/day) was administered orally. The mice were then subjected to two behavioral tests and a glucose tolerance test. To evaluate the therapeutic effects of HFD on metabolic dysregulation, neuroinflammation, and intestinal barrier impairment, a range of analytical techniques, including biochemical analysis, immunofluorescence, RT-qPCR, and Western blotting, were used. Subsequently, 16S rRNA gene sequencing and metabolomic profiling were used to detect changes in the gut microbes and metabolite levels. Finally, fecal microbiota transplantation was performed to assess the functional link between SLBZ remodeling of the gut microbiota, metabolic alterations, and hippocampal cognitive function. Our study demonstrated that HFD-fed mice developed significant cognitive impairment, supporting the notion that obesity adversely affects cognitive function. In the Morris water maze and open-field tests, SLBZ administration effectively ameliorated HFD-induced cognitive dysfunction. This improvement was accompanied by the restoration of the hippocampal synaptic ultrastructure and the recovery of the key synaptic proteins BDNF and PSD95. In agreement with this, SLBZ suppressed microglial activation and associated neuroinflammatory responses in HFD-fed mice. In the colon, SLBZ administration markedly alleviated HFD-induced gut barrier impairment, as evidenced by increased colonic mucus thickness and elevated expression of tight junction proteins, ZO-1, Occludin, and Claudin-1. Furthermore, SLBZ reduced endotoxin translocation and downregulated the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. Notably, HFD-induced gut microbiota dysbiosis was remodeled by the SLBZ treatment, which was characterized by an increased capacity for microbial vitamin B6 synthesis. SLBZ increased the serum levels of vitamin B6 in HFD-fed mice. Intriguingly, fecal microbiota transplantation from SLBZ-treated HFD-fed mice facilitated the amelioration of cognitive deficits, including superior performance in behavioral tests and synaptic repair in the hippocampus compared to recipients of HFD-microbiota. Our findings highlight that SLBZ is a promising therapeutic agent mitigating obesity-related cognitive impairment via the "gut microbiota-vitamin B6-neuroprotection" axis. 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 syste Show more
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
To evaluate the effectiveness of personalized moderate-intensity aerobic brisk walking intervention based on real-time feedback from wrist-worn photoplethysmography (PPG) in improving mild-to-moderate Show more
To evaluate the effectiveness of personalized moderate-intensity aerobic brisk walking intervention based on real-time feedback from wrist-worn photoplethysmography (PPG) in improving mild-to-moderate depressive symptoms. Using an N-of-1 randomized crossover trial design, 33 patients with mild-to-moderate depression (PHQ-9 scores 10-19) completed a 6-week trial consisting of three personalized PPG feedback periods (Period A) and three standardized exercise prescription periods (Period B), each lasting 7 days with 2-day washout periods between phases. The personalized group dynamically adjusted exercise intensity based on real-time heart rate variability (HRV) monitoring (40-59% heart rate reserve), while the standardized group adopted fixed intensity parameters (walking speed 5-6 km/h). The primary outcome was change in PHQ-9 depression scale score, with secondary outcomes including heart rate variability, 6-minute walking distance, serum BDNF, and inflammatory cytokine levels. Compared to standardized prescription, personalized intervention additionally reduced PHQ-9 scores by 2.8 points (95% CI: 1.9-3.7, P < 0.001) with an effect size of 0.73; HRV RMSSD increased by 8.7 ms versus 4.3 ms (P < 0.001), and HRV improvement predicted subsequent symptom relief (β = -0.42); exercise adherence rate in the personalized group was 87.3% compared to 82.1% in the standardized group (P = 0.029); BDNF increased by 28.4% versus 18.7% (P = 0.018); participants with baseline HRV < 25 ms derived greater benefit from personalized intervention (additional improvement of 3.8 points versus 2.1 points, P = 0.008). Both intervention conditions produced clinically meaningful within-group PHQ-9 improvements, though the between-group difference of 2.8 points did not reach the minimal clinically important difference (MCID) threshold of 5 points. Both personalized and standardized moderate-intensity walking interventions substantially improved mild-to-moderate depressive symptoms. Personalized exercise intervention based on real-time PPG monitoring provided statistically significant additional benefits over standardized prescriptions, with advantages in physiological adaptation, exercise adherence, and biomarker improvement. The incremental benefit of personalized monitoring was most pronounced among individuals with impaired autonomic function, providing evidence for precision exercise medicine approaches in depression management. Show less
Lipoprotein glomerulopathy (LPG) is a rare hereditary glomerular disease with lipoprotein thrombi deposition in glomerular capillaries, which is caused by pathogenic variants in
Recent evidence has shown that bone marrow mesenchymal stem cells (BMSCs) have multiple biological applications and play an important role in improving cognitive dysfunction. However, it is still uncl Show more
Recent evidence has shown that bone marrow mesenchymal stem cells (BMSCs) have multiple biological applications and play an important role in improving cognitive dysfunction. However, it is still unclear whether BMSCs play a role in cognitive impairment induced by chronic pain. This study aimed to evaluate the therapeutic effect of BMSCs on neuropathic pain-induced cognitive dysfunction and explore its potential mechanisms. A mouse chronic constriction injury (CCI) model was established, and the new object recognition task and fear conditioning were used to detect cognitive function; the expression of CXCL12/CXCR4 in blood and hippocampus was detected. After intravenous injection of BMSCs, changes in cognitive function and expression of the CXCL12/CXCR4 pathway, dentate gyrus neurogenesis, and excitability of hippocampal neurons were detected. In addition, induction of cognitive impairment in normal mice by CXCL12 recombinant protein was used to clarify whether the CXCL12/CXCR4 pathway mediates the cognitive function improvement effect of BMSCs. Our results found CCI mice showed significant cognitive impairment 21 days after surgery, with significantly increased expression of CXCL12/CXCR4 in blood and hippocampus. Intravenous injection of BMSCs significantly improved cognitive function, inhibited expression of CXCL12/CXCR4 in blood and hippocampus, promoted neurogenesis in dentate gyrus of CCI mice, and increased expression of BDNF and c-Fos in the hippocampus. In addition, BMSCs alleviate cognitive impairment induced by intravenous injection of CXCL12 recombinant protein in mice. In summary, BMSCs improve chronic neuropathic pain-induced cognitive dysfunction through peripheral blood CXCL12/CXCR4, and BMSCs may develop into therapeutic targets for chronic pain induced cognitive impairment. Show less
Speed capability is critical for early childhood development, but troubling patterns are emerging in the motor fitness of Chinese preschoolers (3-6 years). This study investigated how compositional 24 Show more
Speed capability is critical for early childhood development, but troubling patterns are emerging in the motor fitness of Chinese preschoolers (3-6 years). This study investigated how compositional 24-h movement behaviours (sleep, sedentary behaviour [SB], light physical activity [LPA] and moderate-to-vigorous physical activity [MVPA]) relate to speed capability. Via compositional data analysis and isotemporal substitution modelling, we assessed relationships between 24-h movement behaviours (sleep, SB, LPA and MVPA) and speed capability in 275 preschoolers (mean age 4.98 ± 0.76 years). Participants completed 20-m sprint tests and 7-day accelerometry. Time-reallocation effects were quantified through pairwise behavioural substitutions (5- to 30-min durations), with all models adjusted for age, sex and BMI z scores (z-BMI). Higher relative MVPA time significantly predicted faster sprint times (β = -1.302, p < 0.001), while higher LPA predicted slower times (β = 1.570, p = 0.003). Reallocating 15 min from sleep, SB or LPA to MVPA reduced sprint times by 0.176, 0.201 and 0.385 s, respectively (all p < 0.05). Conversely, reallocating MVPA to other behaviours worsened performance. The effects exhibited asymmetry: displacing time away from MVPA impaired speed capability to a greater extent than equivalent gains in MVPA time improved it. MVPA is the strongest positive predictor of speed capability in preschoolers. Optimizing 24-h movement patterns by reallocating time from LPA or SB to MVPA is associated with enhanced speed performance, supporting targeted interventions for early childhood development. Show less
Cognitive reserve (CR) refers to differences in the adaptability of cognitive processes that modify the impact of Alzheimer's disease (AD) pathology on cognitive performance. Currently there are no es Show more
Cognitive reserve (CR) refers to differences in the adaptability of cognitive processes that modify the impact of Alzheimer's disease (AD) pathology on cognitive performance. Currently there are no established blood-based biomarkers of CR in prodromal AD. In this study, we operationalize CR as memory reserve, defined as moderation (attenuation) of the CSF pTau181-memory association. DNA methylation (DNAm) integrates genetic and environmental influences and may capture biological processes that mitigate the impact of AD pathology on memory. We aimed to identify blood DNAm loci that moderate the association between cerebrospinal fluid (CSF) phosphorylated tau (pTau181) and memory in mild cognitive impairment (MCI). We also sought to determine if a DNAm-based signature of memory reserve predicts future memory decline. We analyzed 92 amyloid positive MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with blood DNAm, CSF pTau181, and memory scores (PHC_MEM) collected at the same visit. We first regressed memory scores on covariates (age, sex, number of After removing CpGs with low variability, we identified 6 CpGs with suggestive significance for DNAm×pTau181 interaction ( Blood DNAm patterns that moderate the pTau-memory relationship capture biology underlying memory reserve involving synaptic, vascular, immune, and metabolic pathways, and can be summarized into an MRS that predicts longitudinal memory trajectories in MCI. These findings support blood DNAm as a promising, non-invasive biomarker of cognitive resilience to AD pathology. Show less
To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the w Show more
To determine the prevalence of CHD7, FGFR1 and ANOS1 variants and the impacts of their splicing variants on mis-splicing in patients with congenital hypogonadotropic hypogonadism (CHH). Based on the whole-exome sequencing data from 280 CHH probands, we identified 15 potential splice-site variants in CHD7, ANOS1 and FGFR1 by using in silico software. The functional consequences of these variants were analyzed by the minigene assay or RT-PCR analyses of RNA taken from the peripheral lymphocytes. Detailed phenotyping was performed in the CHH patients harboring deleterious variants and their available family members. 11 out of 15 potential splice-site variants were demonstrated to cause mis-splicing, resulting in loss of function through deletion, insertion or frameshift of amino acids in the proteins. Most patients with deleterious splice-site variants in CHD7, ANOS1, FGFR1 presented with gene-specific non-reproductive phenotypes, confirming the pathogenic contribution of these variants to CHH. Our study indicated that splice-site variants in CHD7, ANOS1, FGFR1 underlie the genetic basis of ~3.9% of CHH patients, warranting the inclusion of potential splice-site variants for genetic diagnosis and counseling of CHH. Show less
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. T Show more
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. This study aimed to observe the mechanism of EA as an adjunct therapy to escitalopram oxalate (EO) on depressed patients. This study was designed as a single-blinded, double-dummy randomized controlled trial. 61 participants were diagnosed with mild-to-moderate depression according to the International Classification of Diseases 10th Edition (ICD-10, F32) were randomly allocated to receive EA + EO placebo, EO + sham EA, or EA + EO for six weeks treatment. The clinical assessment including depression severity, quality of life (QOL) and clinical safety. Biological indicators of immune-inflammation, the brain-derived neurotrophic factor and glucocorticoid inducible genes in peripheral blood of participants were measured by using enzyme linked immunosorbent assay and real-time polymerase chain reaction respectively before and after treatment. Three interventions improved the depression severity and QOL (P < 0.05), and no inter-group difference was found in the 6th week (P > 0.05). Anxiety psychic and somatic general symptoms in the EA + EO group were improved significantly than those of the other two groups (P < 0.05). After six-week treatment of EA + EO, blood SGK1 mRNA, GILZ mRNA, and BDNF levels were increased significantly ( Show less
Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinica Show more
Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinical benefits for CC, highlighting the need to find more effective therapeutic targets. LILRB4, a member of the leukocyte immunoglobulin-like receptor superfamily, is considered a key mediator of cancer immunosuppression. However, its role in the CC immune microenvironment remains unclear. Here, LILRB4 expression was upregulated in CC tissues, and high expression levels were positively associated with advanced disease and immunosuppressive genes in tumors. In an immunocompetent mouse model, LILRB4 expression in CC tumors increased with tumor growth, whereas blocking LILRB4 reduced tumor growth. Flow cytometry analysis revealed that blockade of LILRB4 reduced CD8 Show less
Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechan Show more
Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechanisms of fibroblast growth factor receptor 1 (FGFR1) in OC remain incompletely understood. In this study, we investigated the expression pattern and biological function of FGFR1 in OC and explored its underlying molecular mechanisms. FGFR1 expression was analyzed using TCGA, GTEx, and tissue microarray datasets, and its prognostic significance was evaluated by Kaplan-Meier survival analysis. Functional assays were performed in OVCAR-3 and SK-OV-3 cells following FGFR1 knockdown or overexpression to assess cell proliferation, migration, invasion, and metabolic activity, including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lactate production and histone lactylation were measured by biochemical assays and Western blotting. Protein interaction between FGFR1 and SIRT3 was examined by co-immunoprecipitation and immunofluorescence, and rescue experiments were conducted to determine SIRT3 dependency. In vivo subcutaneous xenograft models were used to evaluate the role of FGFR1 in tumor growth. We found that FGFR1 expression was significantly reduced in OC tissues and that low FGFR1 levels were associated with unfavorable clinical outcomes. Functionally, FGFR1 silencing promoted OC cell proliferation, migration, invasion, and metabolic activity, whereas FGFR1 overexpression exerted inhibitory effects. Mechanistically, FGFR1 interacted with SIRT3 and stabilized its protein expression. Importantly, SIRT3 knockdown abrogated the FGFR1-mediated reductions in lactate production, glycolytic enzyme expression, ATP levels, and histone lactylation, indicating that FGFR1 regulates metabolic reprogramming through a SIRT3-dependent mechanism. Consistently, FGFR1 knockdown promoted the formation of larger and more invasive tumors in vivo. Collectively, these findings demonstrate that FGFR1 functions as a context-dependent tumor suppressor in OC by modulating SIRT3-mediated metabolic reprogramming and histone lactylation, suggesting that targeting the FGFR1-SIRT3 axis may represent a potential therapeutic strategy for ovarian cancer. Show less
The formation and retrieval of reward memories within the hippocampus are critical mechanisms underlying the development of substance use disorder. Nitrous oxide (N
Low-intensity pulsed ultrasound (LIPUS) shows promising anti-inflammatory and neuroprotective effects for different types of neurological disorders. This study aims to investigate the therapeutic effe Show more
Low-intensity pulsed ultrasound (LIPUS) shows promising anti-inflammatory and neuroprotective effects for different types of neurological disorders. This study aims to investigate the therapeutic effects of LIPUS on LPS-induced depression-like behavior and neuroinflammation and to elucidate the underlying molecular mechanisms. A depressive mouse model is established by intraperitoneal injection of LPS (1.0 mg/kg/day for 7 days). LIPUS is applied to the hippocampal region (30 min/day). Behavioral assessments include the open field test (OFT), forced swim test (FST), and tail suspension test (TST). Molecular analyses, including Western blotting, immunofluorescence, and qPCR, are performed to evaluate the expression of P2X4R, IBA1, inflammatory cytokines (IL-1β, IL-6, TNF-α), BDNF/TrkB signaling pathway, and apoptosis-related proteins (Bax, Bcl-2). The involvement of P2X4R is further examined using ivermectin (IVM), a selective P2X4R agonist. LIPUS significantly alleviates the LPS-induced depression-like behavior, suppresses hippocampal pro-inflammatory cytokine expression, inhibits microglial activation, and reduces neuronal apoptosis. Mechanistically, LIPUS downregulates P2X4R and IBA1, upregulates BDNF protein levels and TrkB phosphorylation, and modulates the Bax and Bcl-2 expression. Co-localization studies confirm that P2X4R is predominantly expressed in microglia, and LIPUS markedly reduces the overlap. Notably, the anti-inflammatory, neuroprotective, and antidepressant effects of LIPUS are significantly attenuated by IVM, highlighting the critical role of P2X4R suppression in mediating therapeutic effects. LIPUS mitigates LPS-induced neuroinflammation, neuronal apoptosis, and depression-like behavior by targeting microglial P2X4R and activating the BDNF/TrkB pathway. The findings provide mechanistic insights and demonstrate that LIPUS is a promising non-pharmacological intervention for depression, underscoring the translational potential of P2X4R as a therapeutic target. Show less
To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD). This retrospective cohor Show more
To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD). This retrospective cohort study included 88 propensity-score-matched patients with GAD from Beidahuang Group Neuropsychiatric Hospital. Based on clinical records, patients were classified into an observation group (vitamin D3 + NAC + usual care) and a control group (usual care only). Anxiety symptoms and cognitive function were assessed using the Beck Anxiety Inventory (BAI), Automatic Thought Questionnaire (ATQ), and Dysfunctional Attitudes Scale (DAS). Serum levels of 25-hydroxyvitamin D [25(OH)D], inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)], oxidative stress parameters [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD)], and neurochemical markers [brain-derived neurotrophic factor (BDNF), dopamine (DA), Serotonin (5-HT), norepinephrine (NE)] were measured at baseline and week 8. After 8 weeks, both groups showed significant improvements in BAI, ATQ, and DAS scores, with greater reductions in the observation group (all In this retrospective cohort, combined vitamin D and NAC supplementation was associated with significantly greater improvements in anxiety symptoms, cognitive patterns, and relevant metabolic biomarkers in patients with GAD compared to usual care alone, supporting its potential as an adjunctive therapy. Show less
Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflam Show more
Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2X7 receptor (P2X7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2X7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2X7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2X7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2X7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression. Show less
The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that ha Show more
The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that has been increasingly investigated for its potential to support cognitive function in older adults. Clinical evidence suggests that RT may be associated with benefits in certain cognitive domains, including memory, executive function, processing speed, and visuospatial ability. However, findings across studies remain heterogeneous, with several trials reporting neutral outcomes. Most intervention studies involve structured RT programs conducted at moderate to high intensity and performed multiple times per week. However, optimal training parameters have not yet been clearly established due to variability in study design and the absence of formal dose-response analyses. Emerging evidence suggests that the cognitive effects of RT may be mediated, at least in part, through muscle-brain axis signaling involving exercise-induced myokines. Factors such as irisin, brain-derived neurotrophic factor, interleukin-6, interleukin-15, and insulin-like growth factor-1 have been implicated in processes related to neuroplasticity, neuroinflammatory regulation, and neurovascular function, primarily based on preclinical and translational research. This review synthesizes current evidence on RT-related molecular mechanisms and clinical findings to provide an integrative perspective on the potential role of resistance training in mitigating age-related cognitive decline. Show less
Radiotherapy (RT) for breast cancer may increase atrial fibrillation (AF) risk. This study explored the association between RT and expression of AF-related genes in breast tumor tissues. A total of 10 Show more
Radiotherapy (RT) for breast cancer may increase atrial fibrillation (AF) risk. This study explored the association between RT and expression of AF-related genes in breast tumor tissues. A total of 1094 breast cancer patients (RT group: 1020; non-RT group: 74) were included based on inclusion criteria. Clinical data and RNA-seq profiles (TPM) were retrieved. Six AF-related genes (MYBPC3, LMNA, PKP2, FAM189A2, KDM5B, MYL4) were analyzed. Gene expression was compared using Wilcoxon rank-sum test after Log2(TPM + 1) transformation. Subgroup analyses were conducted by AJCC stage (I–III), laterality (left/right), age (< 65/≥65 years), clinical subtype (Luminal, HER2-positive, Triple-negative), and PAM50 molecular subtype (Basal, Her2, LumA, LumB, Normal). Multivariate linear regression was applied to evaluate RT’s independent effect on gene expression. In tumor tissues, expression levels of MYBPC3, LMNA, and MYL4 were significantly higher in the RT group compared to the non-RT group.Subgroup analysis revealed higher MYBPC3 expression in the RT group specifically in Stage III tumors, but lower expression in left-sided tumors and in patients < 65 years old. LMNA expression was higher in the RT group in Stage III tumors. MYL4 expression was higher in the RT group in Stage II tumors, in both left and right-sided tumors, and in both age groups (< 65 and ≥ 65 years). No significant differences were found across clinical or molecular subtypes for any gene.Multivariate regression confirmed RT as an independent predictor of increased MYL4 expression (β = 0.204), but not for MYBPC3 or LMNA expression. Sensitivity analysis in the 45–65 age subgroup supports the above findings. Based on tumor tissue analysis, breast cancer radiotherapy is associated with altered expression of AF-related genes (particularly MYL4) in tumor tissues, suggesting a potential molecular link worthy of further exploration in relation to atrial fibrillation. These findings warrant future validation in cardiac or circulatory tissues. The online version contains supplementary material available at 10.1007/s12672-026-04468-5. Show less
Residual cardiovascular risk persists in type 2 diabetes mellitus (T2DM) despite intensive risk-factor management. Apolipoprotein B (apoB) and excess apoB are potentially promising biomarkers for iden Show more
Residual cardiovascular risk persists in type 2 diabetes mellitus (T2DM) despite intensive risk-factor management. Apolipoprotein B (apoB) and excess apoB are potentially promising biomarkers for identifying residual cardiovascular risk. We assessed apoB and excess apoB in T2DM for incremental prediction of atherosclerotic cardiovascular disease (ASCVD) risk. This prospective cohort included 11,918 UK Biobank participants (mean age 59.7 ± 6.6 years; 61% male) with T2DM and no ASCVD at baseline. Excess apoB was defined as the observed minus predicted apoB, where the predicted value was derived using a linear regression model of apoB on low-density lipoprotein cholesterol (LDL-C) fitted in a statin-naïve reference subset with triglycerides ≤ 1.0 mmol/L. The primary endpoint was incident ASCVD. Secondary endpoints included major adverse cardiovascular events (MACE) and all-cause mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox models. Nonlinearity was assessed using restricted cubic splines. Incremental improvements were quantified using the C-index, net reclassification improvement (NRI). During a median 185.3-month follow-up, 2,548 ASCVD and 1,205 MACE events occurred. ApoB was linearly related to ASCVD and MACE, while excess apoB showed J-shaped associations with a nadir near - 7.5 mg/dL for ASCVD. Both apoB and excess apoB showed positive associations with ASCVD across ascending percentile categories. Versus < 50th percentile, HRs (95% CIs) for ASCVD in higher apoB categories (50-<75th, 75-<90th, ≥ 90th) were 1.31 (1.16-1.49), 1.51 (1.25-1.81), and 1.47 (1.10-1.95); corresponding HRs (95% CIs) for excess apoB were 1.50 (1.36-1.66), 1.45 (1.29-1.63), and 1.53 (1.33-1.76), respectively. Similar but weaker risk gradients were observed for MACE. Neither apoB nor excess apoB was associated with all-cause mortality. Excess apoB yielded greater prediction improvement than apoB (ΔC-index: 0.009 vs. 0.002; NRI: 0.270 vs. 0.101) and better stratified risk in statin users and those with LDL-C ≤ 100 mg/dL (P for interaction < 0.05). In T2DM, apoB is independently associated with ASCVD but adds limited discrimination over conventional lipids. Excess apoB yielded improved discrimination and reclassification, and may serve as a complementary ASCVD risk marker, particularly in statin-treated settings. However, its clinical application requires external validation and standardization. Show less
The identification of plasma biomarkers for the diagnosis of Alzheimer's disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine cli Show more
The identification of plasma biomarkers for the diagnosis of Alzheimer's disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine clinical practice. This study enrolled 141 participants, including 71 patients with AD, 44 individuals with mild cognitive impairment, and 28 cognitively healthy controls (HC). A total of 16 plasma inflammatory proteins were quantified using multiplex liquid-chip assays, and APOE genotyping was performed. The diagnostic utility of plasma proteins was assessed using the least absolute shrinkage and selection operator (LASSO) with nested cross-validation. Patients with AD exhibited marked alterations in plasma inflammatory profiles, with elevated levels of IFN-γ, IL-33, and IL-18, and reduced levels of IL-7 and CCL11. Integrating inflammatory markers with clinical variables and APOE genotype substantially improved discrimination between AD and HC, increasing the area under the ROC curve from 0.863 to 0.953. Among all biomarkers, IFN-γ emerged as the most informative predictor and was significantly elevated in AD patients carrying the APOE ϵ4 allele. Analyses of single-nucleus RNA sequencing data further revealed pronounced enrichment of IFN-γ signaling in APOE4/4 AD-associated lipid droplet-accumulating microglia (LDAM), defined by high ACSL1 expression. Notably, IFN-γ stimulation enhanced ACSL1 expression in ApoE4-overexpressing HMC3 microglial cells. These findings provide a new perspective on the involvement of plasma inflammatory markers for AD diagnosis, and suggest a novel link between IFN-γ and APOE ϵ4-associated AD risk through modulating the ACSL1-driven pathogenic LDAM phenotype. Show less
Male infertility affects approximately one in seven couples worldwide. Prenatal cadmium (Cd) exposure has been shown to affect offspring phenotypes and increase susceptibility to diseases later in lif Show more
Male infertility affects approximately one in seven couples worldwide. Prenatal cadmium (Cd) exposure has been shown to affect offspring phenotypes and increase susceptibility to diseases later in life. However, the effects of prenatal Cd exposure on multi-generational offspring fertility and the mechanisms remain unknown. A novel murine multi-generational (F1-F3 offspring) male subfertility model induced by prenatal Cd exposure was developed. The levels of testosterone and steroidogenic enzymes were also lower in these offspring's testes. The ubiquitin-dependent degradation of NR4A1, the upstream transcription factor regulating steroidogenic enzymes, was enhanced across generations upon prenatal Cd exposure. After treatment with MG132, an inhibitor of the ubiquitin-proteasome system, the levels of NR4A1 and steroidogenic enzymes were higher in offspring testes with prenatal Cd exposure. Based on the analysis of the UbiBrowser database and testicular global transcriptome, RAPSN was identified as a novel ubiquitin E3 ligase containing the RING-H2_Rapsyn domain that mediates multi-generational testicular NR4A1 ubiquitination. m Show less