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
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms rema Show more
FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a Show more
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF Show more
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ's effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis. Show less
Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein (ANGPTL) family, is a physiological inhibitor of lipoprotein lipase (LPL), and plays a critical role in lipoprotein and Show more
Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein (ANGPTL) family, is a physiological inhibitor of lipoprotein lipase (LPL), and plays a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 is implicated in a wide range of systemic and cellular processes and is closely associated with metabolic and cardiovascular diseases (CVD). Circulating ANGPTL8 is primarily secreted by the liver, with adipose tissue as a secondary source. Its expression is regulated by multiple transcription factors and microRNAs, and is responsive to fasting/refeeding states, hormonal signals, and stress conditions. In lipid metabolism, ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4 to modulate LPL activity under fasting and feeding conditions. In glucose metabolism, ANGPTL8 plays a complex role. While some studies suggest it may improve glucose tolerance and insulin resistance, others indicate it could exacerbate glucose metabolism disorders and diabetes, or have no effect. Cardiovascular diseases are intricately linked to metabolic disorders and diseases. Increasing evidence also links ANGPTL8 to various cardiovascular pathologies, including atherosclerosis, hypertension, cardiomyopathy, cardiac hypertrophy, aortic aneurysm, and dissection. Given the strong interplay between metabolic dysregulation and CVDs, elucidating the role of ANGPTL8 in these processes is of significant interest. This review provides a balanced assessment of ANGPTL8's roles in key pathophysiological processes, highlighting its established functions in metabolism alongside its emerging involvement in CVDs. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states will lead to new opportunities for therapeutic intervention in cardiometabolic disorders. Show less
Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge t Show more
Rodents are widely used in immunology but do not always recapitulate human immune functions. The tree shrew (Tupaia belangeri) is phylogenetically closer to primates than rodents and may help bridge this gap, yet its immune system has not been comprehensively characterised at single-cell resolution. Here, we present a single-cell transcriptomic atlas of the tree shrew immune system, profiling 39 cell types across 12 tissues. We uncover human-like tonsillar structures and two transcriptionally distinct splenic macrophage subsets: an NR1H3 Show less
Unhealthy diets characterized by high salt, fat, and fructose content are established risk factors for metabolic and cardiovascular disorders and may have indirect effects on cognitive function. Howev Show more
Unhealthy diets characterized by high salt, fat, and fructose content are established risk factors for metabolic and cardiovascular disorders and may have indirect effects on cognitive function. However, the combined impact of a high-salt, high-fat, and high-fructose diet (HSHFHFD) on systemic physiology and brain health remains to be fully elucidated. Sprague-Dawley (SD) rats received a customized high-salt, high-fat diet supplemented with 30% fructose water for 18 weeks. Physiological and brain parameters were assessed, in combination with multi-omics analyses including brain proteomics and metabolomics, serum metabolomics, and gut microbiota profiling. HSHFHFD significantly elevated blood glucose, blood pressure, and serum levels of TG, TC, and LDL in rats. Serum metabolomic profiling identified over 100 differentially abundant metabolites in the Model group. Proteomics, metabolomics, and gut microbiome integration revealed pronounced alterations in both brain proteomic and metabolomic profiles, with 155 differentially expressed proteins associated with glial cell proliferation and 65 differential metabolites linked to fatty acid and amino acid metabolism, among others. Experimental validation confirmed marked upregulation of GFAP and Bax protein, concomitant with downregulation of ZO-1 and occludin. Furthermore, HSHFHFD perturbed the CREB signaling pathway, leading to diminished BDNF expression. The levels of inflammatory factors, including IL-6, IL-10, IL-1β and TNFα, were significantly elevated in the brain. Oxidative stress was evident, as indicated by elevated malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) activity, and altered NAD HSHFHFD-induced depletion of gut Show less
Ferroptosis is an iron-dependent form of necrosis that promotes AS by accelerating endothelial dysfunction in lipid peroxidation. This study aims to investigate the role of deubiquitinase USP7 in ferr Show more
Ferroptosis is an iron-dependent form of necrosis that promotes AS by accelerating endothelial dysfunction in lipid peroxidation. This study aims to investigate the role of deubiquitinase USP7 in ferroptosis of VECs during AS. AS models were established using HFD-fed ApoE USP7, KIAA1429, and NEAT1 were upregulated in mouse AS models and ox-LDL-treated HUVECs. USP7 inhibition attenuated AS pathology and VECs ferroptosis. USP7 deubiquitinated and stabilized KIAA1429, which facilitated YTHDF1-mediated m6A modification to stabilize NEAT1. NEAT1 recruited CTCF to maintain H3K27me3 modification at the SLC7A11 promoter, repressing SLC7A11 transcription and triggering HUVECs ferroptosis. Overexpression of KIAA1429 or NEAT1 reversed protective effects of USP7 inhibition on ferroptosis. USP7 promotes VECs ferroptosis in AS via the KIAA1429/NEAT1/CTCF axis. Show less
Enhancing students' subjective well-being (SWB) is an inevitable requirement for achieving comprehensive human development. This study utilized data from 11,990 students in Beijing, Shanghai, Jiangsu, Show more
Enhancing students' subjective well-being (SWB) is an inevitable requirement for achieving comprehensive human development. This study utilized data from 11,990 students in Beijing, Shanghai, Jiangsu, and Zhejiang from the PISA 2018 survey to identify distinct SWB profiles and examine the mechanisms linking parental emotional support to these profiles. Using latent profile analysis (LPA), we identified three distinct SWB profiles: 'Low Affect-Low Cognition' (30.6 %), 'Moderate Affect-High Cognition' (45.9 %), and 'High Affect-High Cognition' (23.5 %). Path analyses, controlling for gender, age, and socioeconomic status, revealed that: (1) Parental emotional support exerted significant direct effects on membership in all three profiles. (2) Parental support influenced the 'Low Affect-Low Cognition' through the mediating role of psychological resilience alone and the serial mediation of growth mindset and psychological resilience. Parental support influenced the 'Moderate Affect-High Cognition' through the mediating role of growth mindset alone and the serial mediation of growth mindset and psychological resilience. (3) For the 'High Affect-High Cognition' profile, parental support operated through three pathways: the specific indirect effects of growth mindset and psychological resilience independently, plus their serial mediation. The findings suggest that interventions for students with low SWB should prioritize building psychological resilience, while for other groups, fostering both a growth mindset and resilience is beneficial. The research results are primarily applicable to adolescents in China's high-development level regions and caution should be exercised in generalizing them to other contexts. Show less
Parents of children with congenital heart disease (CHD) face chronic stress impairing family functioning and well-being. As a key protective factor, family resilience aids their adaptation. However, e Show more
Parents of children with congenital heart disease (CHD) face chronic stress impairing family functioning and well-being. As a key protective factor, family resilience aids their adaptation. However, existing research predominantly measures general family resilience, neglecting heterogeneous resilience patterns and subgroup profiles. Our study uses person-centered Latent Profile Analysis (LPA) to identify latent family resilience classes in Chinese culture to provide tailored support. This study adopted a cross-sectional survey design. From October 2024 to July 2025, convenience sampling was used to recruit 426 eligible parents of children with CHD from two tertiary hospitals in Yunnan Province, China. Data were collected using the General Information Questionnaire, Family Hardiness Index (FHI), Simplified Coping Style Questionnaire (SCSQ), and Social Support Rating Scale (SSRS). LPA was applied to classify the family resilience levels of these parents. Subsequently, univariate and multivariate ordinal logistic regression analyses were conducted to explore the factors associated with different latent classes of family resilience. A total of 400 valid questionnaires were collected, with an effective response rate of 93.9%. The mean total score for family resilience in parents of children with CHD was 58.13 ± 5.79, suggesting a moderate overall level of family resilience in this group. The family resilience of parents of children with CHD was classified into three latent profiles: “High family resilience responsibility-anchored type” ( Parents of children with CHD demonstrate heterogeneity in family resilience. Healthcare professionals should pay attention to the family resilience differences among parents of children with CHD and implement targeted intervention measures based on the characteristics of different subgroups, thereby enhancing parents’ family resilience and further promoting family well-being. The online version contains supplementary material available at 10.1186/s12889-025-26143-0. Show less
Yukang Mao, Tingting Wu, Yuer Jiang+3 more · 2026 · Obesity reviews : an official journal of the International Association for the Study of Obesity · Blackwell Publishing · added 2026-04-24
Obesity is a well-documented cardiovascular risk factor. Here, we sought to investigate whether obesity causes subclinical cardiac remodeling and heart failure (HF), and if so, to perform a systematic Show more
Obesity is a well-documented cardiovascular risk factor. Here, we sought to investigate whether obesity causes subclinical cardiac remodeling and heart failure (HF), and if so, to perform a systematic scan of the plasma protein for novel drug targets. We leveraged visceral adipose tissue (VAT), waist circumference (WC), and waist-to-hip ratio (WHR)-all adjusted for body mass index (BMI)-as indicators of obesity. Two-sample Mendelian randomization (MR) analyses were used to estimate the independent, causal effects of obesity on cardiovascular magnetic resonance (CMR)-derived cardiac traits and HF risk. Mediation analyses followed by druggability assessment were conducted to identify promising protein targets for therapeutic translation. Genetically determined VATadjBMI, WCadjBMI, and WHRadjBMI presented broad causal associations with alterations of distinct cardiac phenotypes, most of which remained significant after controlling for obesity-induced cardiometabolic risk factors, including hypertension, type 2 diabetes, and adverse lipid profiles. By contrast, WHRadjBMI is the only independent causal predictor for HF risk. Of 142 proteins with mediating effects, scavenger receptor class A member 5 (SCARA5), membrane cofactor protein (CD46), and alpha-1-antichymotrypsin (SERPINA3) may contribute to the early-stage adverse cardiovascular effect of obesity, whereas apolipoprotein C-III (APOC3), mitochondrial aldehyde dehydrogenase 2 (ALDH2), and chordin-like protein 2 (CHRDL2) may further promote the development of obesity-driven HF. Medications targeted at these candidate proteins are either approved or under evaluation in clinical trials. Our MR findings provided genetic evidence for the direct, causal associations of obesity with cardiac remodeling and HF, while also outlining druggable proteins as promising therapeutic targets. Show less
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildu Show more
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized as a slowly progressing neurodegenerative disease marked by senile plaques and neurofibrillary tangles due to the buildup of amyloid-beta peptide (Aβ) and phosphorylated tau in the brain. It is reported that arctigenin (ATG) reduces the level of the enzyme 1 that cleaves β-site amyloid precursor protein and increases Aβ clearance by enhancing autophagy. Compound ARC-18 is a derivative of ATG. The main objective of this study is to investigate whether ARC-18 could improve cognitive function and disease progression by promoting autophagy in Alzheimer-like animal models. Three-month-old 5 × FAD mice were orally treated with the drug for three consecutive months. Water maze and novel object recognition were used to assess cognitive abilities of 5 × FAD mice. In the hippocampus of the mice' brain, APP processing-related proteins (sAPP Show less
Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is n Show more
Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is no effective treatment available. Various modalities of magnetic stimulation have emerged for recovery from spinal cord injuries; however, the underlying mechanisms remain unclear, significantly hindering the application of magnetic stimulation technologies in treating such injuries. This study aims to elucidate these relevant mechanisms by establishing a simulated closed-loop magnetic stimulation system. In this study, we established a right hemisection model at T8 in mice and administered continuous simulated closed-loop magnetic stimulation targeting the left motor cortex and right L5 nerve root over six weeks. We subsequently utilized a spinal cord dorsal hemisection model to examine regeneration of the corticospinal tract (CST). Motor-evoked potential assessments and calcium imaging techniques were employed to explore neural circuit repair. Additionally, we integrated transcriptomics, proteomics, and metabolomics approaches to investigate related mechanisms. The findings indicate that simulated closed-loop magnetic stimulation effectively restores motor function in the hind limbs, promotes the regeneration of corticospinal tracts in mice with spinal cord injuries, and facilitates the reconstruction of sensorimotor circuits and functions within the spinal cord. Simulated closed-loop magnetic stimulation significantly enhances axonal regeneration of the CST following SCI. This effect may be mediated through the activation of the AMPK-CREB-BDNF signaling pathway, which promotes neurotrophic factor secretion and subsequently induces nerve axon regeneration. This study suggests that simulated closed-loop magnetic stimulation represents a promising therapeutic approach for the treatment for impaired gait following SCI. Show less
MicroRNAs (miRNAs) are key regulators of myelination and cognitive functions, with miR-219 being particularly important for the differentiation and maturation of oligodendrocyte precursor cells (OPCs) Show more
MicroRNAs (miRNAs) are key regulators of myelination and cognitive functions, with miR-219 being particularly important for the differentiation and maturation of oligodendrocyte precursor cells (OPCs). However, its role in myelin damage and cognitive dysfunction during acute cerebral ischemia is not well understood. In this study, we used the MCAO/R rat model to investigate the mechanistic involvement of miR-219. Our results show that miR-219 alleviates cognitive dysfunction induced by MCAO/R. The agonist group showed a reduced time to locate the platform in the water maze, while the antagonist group showed an increased time compared to the solvent control. Additionally, miR-219 reduced myelin damage, as demonstrated by Luxol Fast Blue (LFB) staining, which indicated substantial hippocampal demyelination repair in the agonist group, whereas the antagonist group exhibited aggravated demyelination. Electron microscopy revealed enhanced myelin sheath regeneration and increased thickness in the agonist group, while the antagonist group displayed fewer and thinner myelin sheaths. Furthermore, miR-219 regulated OPC maturation, with more CNPase-positive cells in the agonist group and fewer in the antagonist group than the solvent control. In NG2 staining, the agonist group had fewer positive cells, while the antagonist group had more. miR-219 also decreased Lingo-1 expression, leading to reduced levels of AKT, RhoA, and mTOR in the downstream signaling pathway. These findings suggest that activating the miR-219-Lingo-1 signaling pathway during ischemia-reperfusion could offer a potential therapeutic approach for improving myelin damage and alleviating cognitive dysfunction in cerebral ischemia. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for 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
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating Show more
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less
Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant t Show more
Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC. Show less
The choroid plexus (CP), known for producing cerebrospinal fluid, is increasingly implicated in the pathogenesis of Alzheimer's disease (AD). Neuroimaging studies document structural CP alterations in Show more
The choroid plexus (CP), known for producing cerebrospinal fluid, is increasingly implicated in the pathogenesis of Alzheimer's disease (AD). Neuroimaging studies document structural CP alterations in aging and AD. One such alteration, calcium deposition, increases with age and is typically considered benign, though the mechanism and clinical significance of CP calcification remain uncertain. Given established association between peripheral vascular calcification and cardiovascular risk, we hypothesized that the volume of calcium within CP would correlate with systemic cardiovascular health. Based on prior findings of APOEε4-specific associations between CP calcium and neurodegeneration, participants were stratified by APOEε4 status, a strong genetic risk factor for AD also implicated in cardiovascular disease. In this retrospective analysis of 105 adults (mean age 58.9 years; 39 APOEε4+), we examined whether CP calcium correlates with cardiovascular risk in cognitively normal adults. CP calcium was quantified using a previously validated MRI-CT method. Spearman correlations assessed the association of CP calcium and Framingham Cardiovascular Risk Score (FCRS), as well as individual cardiovascular risk factors. Overall, CP calcium was not associated with FCRS. Among APOEε4- subjects, CP calcium correlated positively with FCRS ( Show less
Elevated lipoprotein(a) [Lp(a)] is a genetically determined and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is largely resistant to conventional lipid-lowering ther Show more
Elevated lipoprotein(a) [Lp(a)] is a genetically determined and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is largely resistant to conventional lipid-lowering therapies. Novel Lp(a)-targeted agents, including small interfering RNA (siRNA), antisense oligonucleotides (ASO), and the oral small-molecule inhibitor muvalaplin, have shown potent efficacy in early trials. We conducted a systematic review and network meta-analysis to comprehensively compare their efficacy and safety. A total of 25 randomized controlled trials (RCTs) involving 7715 participants were included, evaluating six siRNA agents, four ASO agents, and one small-molecule inhibitor. The primary outcome was percentage change from baseline in Lp(a). Secondary outcomes included absolute change in Lp(a), percentage changes in apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C), and adverse events. SiRNA therapies achieved the greatest Lp(a) reductions (olpasiran: mean difference [MD] -92.1%, 95% CI -100.1 to -84.0%; zerlasiran: -80.6%, 95% CI -87.7 to -73.5%), followed by muvalaplin (-76.8%, 95% CI -90.3 to -63.2%) and ASO therapy (pelacarsen: -54.2%, 95% CI -72.2 to -36.2%; all P < 0.001). Most agents achieved absolute Lp(a) reductions exceeding 105 nmol/L, suggesting clinically meaningful benefit. Baseline Lp(a) levels significantly modified treatment response (P < 0.001), and concomitant proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use further enhanced LDL-C reduction (P = 0.024). All therapies were well tolerated, with injection-site reactions most frequent for injectables, while muvalaplin was well tolerated. These findings indicate that targeted Lp(a)-lowering therapies substantially reduce circulating Lp(a), with siRNA showing the greatest potency and muvalaplin offering a convenient oral alternative for personalized ASCVD risk reduction. Show less
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective coho Show more
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective cohort study. Two large multi-center cohorts (UK Biobank [UKB] and Whitehall II [WHII] study) across the UK and an Eastern multi-center cohort ONE-IBD Study from China. UK Biobank discovery cohort (n=10,229) for signature derivation, internal validation cohort (n=91,306), external validation cohort Whitehall-II (n=7,893), and three additional cohorts (two Western and ONE-IBD) for validation of key metabolic drivers. Primary outcomes were UPF-related circulating metabolic signatures and their associations with CD risk; secondary outcomes included evidence supporting causal roles of candidate metabolites and genetic pathways assessed by Mendelian randomization, colocalization, and gene-environment analysis. A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HR The adverse effects of UPF on CD risk may be driven by a relative deficiency of protective metabolites such as DHA, apart from additive harm to metabolic depletion. This reframes UPF-related risk and highlighting potential targets for precision nutrition in CD prevention. Show less
Diabetic foot ulcers (DFU) are a major complication of diabetes, and its pathogenesis remains incompletely elucidated. Converging evidence indicates that oxidative stress and dysregulated mitochondria Show more
Diabetic foot ulcers (DFU) are a major complication of diabetes, and its pathogenesis remains incompletely elucidated. Converging evidence indicates that oxidative stress and dysregulated mitochondrial polarization participate in DFU progression, nominating these processes as therapeutically actionable targets. This study integrates bulk and single-cell transcriptomic data with machine learning to reconstruct cross-scale, cell type-resolved molecular atlases and regulatory networks. Macrophages and fibroblasts emerged as communication hubs, dominating pathway enrichment and ligand-receptor programs such as macrophage migration inhibitory factor signaling pathway (MIF), ANNEXIN signaling pathway, and COMPLEMENT signaling pathway. Peptidylprolyl isomerase F (PPIF), which encodes cyclophilin D (CypD) and apolipoprotein E (APOE) were further prioritized as putative drivers within macrophages and fibroblasts, and a five-gene classifier was derived with robust performance (internal/external AUC = 0.833/0.933). Within DFU lesions, under the control of non-coding RNA circuitry, SOX5 may shape the inflammatory microenvironment, APOE may participate in lipid-metabolic remodeling, and PPIF (CypD) likely links reactive oxygen species (ROS) accumulation to a p53-dependent mitochondrial death pathway (necroptosis/apoptosis). Orthogonal validation showed significantly increased CypD in diabetic foot ulcer skin (DFUS) and diabetic foot ulcer tendon (DFUT) relative to diabetic foot skin (DFS) and DFT (Diabetic foot tendon), with up-regulated p53 and Cytc and down-regulated ApoE in DFUS; in primary foot-skin fibroblasts, a high-glucose plus tert-butyl hydroperoxide (HG+TBHP) model reproduced elevated ROS, loss of mitochondrial Δψm (mitochondrial membrane potential), growth restriction, and apoptosis, supporting a ROS-CypD/mPTP (mitochondrial permeability transition pore)-Δψm depolarization-p53/Cytc apoptosis axis. The delineated PPIF-centered regulatory network includes upstream transcription factors CEBPB/REL/SPI1 and a downstream ceRNA axis comprising miR-128-3p/miR-23a-3p-long non-coding RNA OIP5-AS1. Additionally, the significant role of polarization-specific reprogramming in regulating macrophage function highlights therapeutic strategies focused on metabolic reprogramming and inhibition of the PPIF/mPTP pathway. Collectively, a cell type-resolved molecular map of DFU is provided, healing-relevant cell populations and regulatory circuits are prioritized, and a translational, testable intervention framework is proposed. Show less
Atherosclerosis is a chronic inflammatory disease marked by lipid accumulation and immune cell infiltration in arterial walls. Macrophages contribute by internalizing oxidized low-density lipoprotein, Show more
Atherosclerosis is a chronic inflammatory disease marked by lipid accumulation and immune cell infiltration in arterial walls. Macrophages contribute by internalizing oxidized low-density lipoprotein, forming foam cells, and driving inflammation. The ubiquitin-proteasome system regulates immune and inflammatory responses in atherosclerosis. This study investigated the protective role of TRIM31 (tripartite motif-containing 31), an E3 ubiquitin ligase, in macrophage lipid metabolism and inflammation through selective regulation of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1). Transcriptomic profiling, macrophage-specific TRIM31 was selectively upregulated in macrophages under oxidized low-density lipoprotein stimulation and in atherosclerosis plaques. Trim31 deficiency exacerbated plaque burden, foam cell formation, and inflammatory signaling (n=8 per group). Single-cell analysis revealed enrichment of lipid transport and inflammatory pathways in Trim31-deficient plaques. LOX-1 was identified as a key TRIM31 substrate. TRIM31 promoted K48-linked ubiquitination of LOX-1 at lysine 12, facilitating its degradation. The atheroprotective effects of Trim31 were abolished in TRIM31, an inducible, macrophage-enriched protective factor in atherosclerosis, restricts foam cell formation and inflammation by targeting LOX-1 for proteasomal degradation. These findings position TRIM31 as a promising therapeutic target for macrophage-driven atherogenesis. Show less
To develop and validate a prediction model for in-hospital cardiogenic shock (CS) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) based on machine lea Show more
To develop and validate a prediction model for in-hospital cardiogenic shock (CS) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) based on machine learning (ML) algorithms. A total of 1608 AMI patients admitted to the First Hospital of Lanzhou University during 2023 and 2024 were retrospectively enrolled in this study. The 851 patients from 2023 were randomly divided into a training set ( LASSO regression initially identified 13 candidate features, while the random forest (RF) model demonstrated the best predictive performance in the training set. Following Boruta refinement, seven key features were retained, leading to the construction of an updated RF model. This model achieved an AUROC of 0.906, an accuracy of 0.977, a precision of 0.900, a sensitivity of 0.643, a specificity of 0.996, and a F1 score of 0.750 on the internal validation set. Temporal external validation at the same center showed an AUROC of 0.988, an accuracy of 0.967, a precision of 0.701, a sensitivity of 0.904, a specificity of 0.972, and a F1 score of 0.790. Furthermore, the model demonstrated excellent calibration, with a Brier score of 0.023 and 0.027. The SHAP analysis ranked feature importance as Killip class, D-dimer (DD), creatinine (Crea), alanine aminotransferase (ALT), apolipoprotein B/A (APOB/A), diastolic blood pressure (DBP) and lactate (Lac). We developed and validated a RF model based on seven key variables—Killip class, DD, Crea, ALT, APOB/A, DBP and Lac—that serves as a predictive tool for identifying the risk of in-hospital CS in AMI patients post-PCI. Additionally, we created an online prediction application using Streamlit, which facilitates the implementation of this model into clinical practice. Show less