👤 Hong-bing Shen

Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance. PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes. GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement. Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine. The online version contains supplementary material available at 10.1186/s11658-026-00867-2. Show less

Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential. Show less

Dietary diversity plays a crucial role in maintaining physical function. This study explored the association and potential mechanisms between dietary diversity and gait characteristics measured by wearable devices in older adults. This cross-sectional study included 861 older adults aged 60 years or above. Dietary diversity score (DDS) was assessed using a standard food frequency questionnaire. A multi-sensor gait system was used to measure periodic, kinetic, and spatiotemporal gait parameters during a 12-meter walking test. The coefficient of variation (CV) was calculated for each parameter to assess gait stability. Multivariable linear regression models were conducted to examine the relationship between DDS and gait parameters, adjusting for demographics, lifestyle factors, cognitive function, and comorbidities. Participants had a mean age of 70.25 ± 6.19 years, with 58.30% being female. After adjusting for all covariates, each 1-SD increase in DDS was positively associated with Z-scores of landing control force (β = 0.072, SE = 0.033, P = 0.033), foot-off angle (β = 0.076, SE = 0.033, P = 0.021), gait speed (β = 0.086, SE = 0.033, P = 0.008), step length (β = 0.068, SE = 0.031, P = 0.032), and stride length (β = 0.078, SE = 0.033, P = 0.013). Furthermore, higher DDS was negatively associated with the CVs of initial limb support time, step time, stride time, ground reaction force, landing control force, foot-off angle, gait speed, and step length (all P < 0.05). We also identified biomarkers simultaneously related to both DDS and gait characteristics, including albumin, leptin, myostatin, brain-derived neurotrophic factor, insulin-like growth factor-1, high-sensitivity C-reactive protein, interleukin-6, and glutathione reductase. Higher DDS is associated with superior kinetic and spatiotemporal gait vigor performance and enhanced gait stability. Pathways involving nutritional status, energy metabolism, inflammatory regulation, antioxidant defense, and neural function may underpin this association. 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

Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with aging. The function of mitochondrial respiratory chain is dependent on M2-like polarization in microglia. A murine model of middle cerebral artery occlusion (MCAO) was used to perform animal behavioral assessments, immunoblotting, tube formation and chick embryo chorioallantoic membrane assays. A D-galactose-induced cellular senescence model was established in BV2 cells. Aging significantly exacerbates acute brain injury 24 hours post-cerebral ischemia-reperfusion, with increased expression of M1-like microglial markers and a concomitant decrease in M2-like microglial markers. Additionally, aging can inhibit DARS2 protein expression, adversely affect angiogenesis and reduce brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGFA) expression. In vitro, oxygen-glucose deprivation/reoxygenation and re-glucose (OGD/R) demonstrated that This study suggests that aging impedes M2-like microglial polarization by downregulating DARS2 expression in microglia, thereby impairing emergency angiogenesis during acute ischemic stroke and exacerbating neuronal damage. Show less

The primary treatment for schizophrenia currently relies on medication. Nevertheless, the efficacy of medication for Cognitive Impairment Associated with Schizophrenia (CIAS) is constrained, and it is also accompanied by side effects. Consequently, the investigation of novel non-pharmacological strategies is essential. High-definition transcranial direct current stimulation (HD-tDCS) and aerobic exercise (AE) have emerged as promising approaches for cognitive enhancement in individuals with schizophrenia. This study aims to evaluate the efficacy of integrating HD-tDCS with AE for CIAS and to elucidate the underlying mechanisms of this synergistic intervention. A randomized, double-blind, controlled trial will be conducted. The CIAS will be randomly allocated to one of four groups: MRI-guided HD-tDCS + AE, MRI-guided HD-tDCS alone, AE alone, and a control group. Structural magnetic resonance imaging (MRI) data will be obtained to determine the optimal electrode placement. The central electrode will be positioned over the medial prefrontal cortex (mPFC). Both HD-tDCS and AE will be administered five times per week over a four-week period, resulting in a total of 20 sessions. The primary outcome measure will be the change in cognitive function, evaluated using the MATRICS Consensus Cognitive Battery. Secondary outcomes will include changes assessed by the Repeatable Battery for the Assessment of Neuropsychological Status and the Wisconsin Card Sorting Test which are designed to evaluate global and executive functions. The Facial Emotion Perception Test and the Voice Emotion Perception Test will be utilized to assess social cognition. The severity of clinical symptoms will be quantified through the Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale. This study will incorporate functional near-infrared spectroscopy, MRI, electroencephalography, P300 event-related potential, eye movement examination and plasma brain-derived neurotrophic factor (BDNF) levels to investigate the underlying mechanisms. Assessments will be evaluated at baseline (T0), after 2 weeks (T1), after 4 weeks (T2), and after 6 months (T3). The integration of MRI-guided HD-tDCS targeting the mPFC and AE presents an efficacious and individualized treatment strategy for CIAS. This proof-of-concept study may provide a multi-dimensional view of biological mechanisms underlying HD-tDCS combined with AE in precision psychiatry. The study is registered with https://www.chictr.org.cn/ protocol registration number ChiCTR2500106980 (date of registration: 1. August. 2025). It was approved by the Research Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical University (Approval Code: XYEFYLL-2025-16, Approval Date: 17 February 2025). Recruitment began in December 2025. Show less

Schizophrenia primarily depends on pharmacotherapy, which has demonstrated limited efficacy in enhancing cognitive impairments. High-definition transcranial direct current stimulation (HD-tDCS) and computerized cognitive remediation therapy (CCRT) hold potential for improving cognitive impairments. This study aims to investigate the effects of combining HD-tDCS with CCRT on cognition and to explore the mechanisms of this approach in schizophrenia. This is the protocol of a randomized controlled trial. Schizophrenia patients will be randomly assigned to one of 4 groups: HD-tDCS + CCRT group (Group 1), HD-tDCS group (Group 2), CCRT group (Group 3), and a control group (Group 4). The central electrode will be personalized using magnetic resonance imaging (MRI)-guided localization in the medial prefrontal cortex (mPFC). CCRT includes 6 therapeutic modules and 10 distinct tasks. Both HD-tDCS and CCRT will be administered once daily, 5 days per week, for 4 consecutive weeks, culminating in a total of 20 sessions. Assessments will occur at baseline (T0), after 10 sessions (T1), after 20 sessions (T2), and after 6 months of follow-up (T3). The primary outcome measure is the change in cognition. We will employ multimodal MRI, serum concentrations of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to explore the underlying mechanisms. An involvement of mPFC and synaptic plasticity in response to HD-tDCS and CCRT is hypothesized. The study will provide empirical evidence for the effectiveness of combined therapy at an individual level, explore its mechanisms, and may ultimately result in personalized medicine. ChiCTR2500102731, https://www.chictr.org.cn/hvshowprojectEN.html?id=276964&v=1.0. Show less

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics. Show less

Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its active components and underlying mechanisms of action remain largely unexplored. Bauhinia brachycarpa Benth (BBB), an ethnic medicine in China, has antinociceptive effect on neuropathic pain (NP). In this study, an effective portion from BBB was screened and its antinociceptive mechanism was investigated. After the preparation of ethanolic extract from BBB (EEBb) and different soluble portion from EEBb (peEEBb, eaEEBb, nbEEBb), the total content of flavonoids and phenolic acids were measured. A partial sciatic nerve ligation (PSNL) model in vivo was applied to evaluate the antinociceptive effect and the influence on microglia function of these samples. The possible acting target of BBB was predicted by network pharmacology. And the mechanism of nbEEBb, the most effective antinociceptive portion, were studied by PSNL model in vivo and ATP-induced activation of BV2 model in vitro. nbEEBb had the strongest ability of alleviating NP as well as the obvious effect on microglia polarization. The action of nbEEBb was positively correlated to the total content of flavonoids or phenolic acids. nbEEBb inhibited the protein and gene expressions of most key components in P2X4-BDNF-TrkB signaling pathway. nbEEBb is the most effective portion from BBB on NP, and its mechanism refers to the inhibition of P2X4-BDNF-TrkB signaling pathway, which involved in neuron-microglia interaction. Show less

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the Show less

Although immune-mediated diseases (IMDs) and major depressive disorder (MDD) commonly co-occur, the bidirectional relationship between them remains to be fully elucidated. Using data from the prospective UK Biobank cohort, we evaluated the bidirectional associations by time-varying Cox proportional hazards regression models and assessed shared genetic architecture using genome-wide association study summary statistics. Additionally, we employed collagen-induced arthritis (CIA) and chronic social defeat stress (CSDS) mouse models to investigate the relationship between rheumatoid arthritis (RA) and depression. Over 5,226,841 person-years of follow-up, 23,534 incident MDD cases were identified. The presence of any IMD was associated with higher MDD risk (hazard ratio [HR]: 1.95; 95% CI: 1.89-2.01). Conversely, 59,742 incident cases of IMD were documented. MDD was associated with increased IMD risk (HR: 1.47; 95% CI: 1.40-1.54). We observed significant global genetic correlations between IMDs and MDD (r Show less

Women face a heightened risk of Alzheimer's disease (AD), partly attributed to post-menopausal estrogen loss. Given that ERβ activation avoids the oncogenic risks of ERα and GPR40 plays a pivotal role in neuronal function, the ERβ/GPR40 axis show a promising therapeutic target for anti-AD drug discovery. To inspect the role of this axis, we employed Vincamine (Vin), a monoterpenoid indole alkaloid from Madagascar periwinkle that we previously identified as a GPR40 agonist. To elucidate the role of ERβ/GPR40 axis in AD pathogenesis and to investigate the therapeutic potential of Vin in ameliorating AD-related deficits. We combined analyses of clinical data from female AD patients (GSE33000) with the research in 3×Tg-AD mice to examine the differences in ERβ/GPR40 expression. The binding of ERβ and GPR40 was detected by CUT&Tag assay, protein-DNA docking simulation and molecular dynamics simulation assays. Vin was used to evaluate the therapeutic potential of ERβ/GPR40 axis activation for AD. The underlying mechanisms were investigated by assay against the adeno-associated virus (AAV)-CMV-PHP.eB-KD-GPR40 injected 3×Tg-AD female mice. ERβ and GPR40 are both downregulated in brains of female AD patients and 3×Tg-AD mice, and ERβ directly binds to GPR40 promoter. Brain-specific GPR40 knockdown caused cognitive impairment in female wild type (WT) mice. Vin as a GPR40 agonist but not an ERβ ligand ameliorated AD-like pathology in 3×Tg-AD female mice. Specifically, Vin suppressed neuroinflammation via GPR40/NF-κB/NLRP3 pathway, inhibited neuronal tau hyperphosphorylation via GPR40/GSK3β/CaMKII pathway, while promoted synaptic plasticity via GPR40/PKA/CREB/BDNF pathway. To our knowledge, our study provides the first identification of the specific ERβ-binding regions and key residues within the GPR40 promoter, offering novel mechanistic insight into their transcriptional regulation. Furthermore, our work establishes ERβ/GPR40 axis as a potentially therapeutic strategy for female AD and highlight the medication interest of Vin in treating this disease. Show less

Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of 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 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

Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood. We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization. MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10 Ambient air pollution likely promotes CKM-sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations. Show less

Staphylococcus aureus is a significant pathogen that poses a threat to both human and animal health. Its pathogenicity in humans has been extensively studied, however, the signaling pathways and key genes in Koi Carp responding to S. aureus from human rhinitis remain unclear. In this study, we established an intraperitoneal infection model in koi carp (Cyprinus carpio) using an S. aureus isolate from patients with rhinitis and integrated RNA-seq, qPCR, and ELISA to dissect the host response. Our findings reveal a dual-module immune evasion strategy employed by S. aureus in koi carp. Module I: The pathogen down-regulated the entire complement coagulation cascade (C3, C9, CFH, F7/9/10) and apolipoprotein-mediated opsonins (APOA1, APOB, APOC1/2), thereby crippling innate clearance. Module II: The host mounted a restricted but potent counter-response, characterized by type I IFN signalling (gvin1, MHC-I), NK/T-cell co-stimulation (CD244, SLAMF5), and the selective induction of IL-8 and IL-1β, while IL-6, IL-10, and TNF-α remained unchanged. Functionally, serum superoxide dismutase (SOD), catalase (CAT), and lysozyme (LZM) activities surged, confirming an oxidative burst, whereas splenic CD22R protein decreased, indicating B-cell disinhibition. These results establish a molecular basis for understanding the interaction between human-derived S. aureus and the immune system of aquatic organisms. Show less

This study aims to investigate the underlying pathophysiological relationship between obesity and osteoporosis (OP) in obese individuals, involving lipid metabolism, inflammation, and bone mineral density (BMD). Data from 318 patients diagnosed OP at our hospital between January 2023 to December 2025 were collected and analyzed. The basic information of the patient included gender, age, BMI, drinking and smoking history, diabetes, hypertension and bone mineral density (T-scores) were recorded. Baseline peripheral blood was employed to calculate lipid markers and inflammatory cytokines. Linear regression and mediation analyses were employed to assess the relevance and differences. Increased level of blood lipids and inflammatory cytokines were associated with increased risks of OP in obesity. Compared to normal-weight individuals, obese subjects exhibited significantly lower BMD. Dysregulated lipids (TC, TG, HDL-C, ApoB) negatively correlated with BMD in obesity. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) inversely associated with BMD, while anti-inflammatory IL-10 showed positive association. Hyperlipidemic obese individuals had elevated inflammatory cytokines (TNF-α, IL-1β) and exacerbated BMD loss. Mediation analysis revealed TNF-α mediated 41.91% and IL-6 mediated 33.20% of the TC-BMD association; TNF-α and IL-6 mediated 28.76% and 37.38% of HDL-C-BMD effects, respectively. Obesity-associated dyslipidemia drives BMD loss partly through inflammation-mediated pathways. Key inflammatory cytokines significantly mediate lipid metabolism’s impact on bone health. Targeting lipid-inflammatory crosstalk may optimize OP management in obese populations. Show less

The triglyceride-glucose (TyG) index, an insulin resistance marker linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), underscores the redox imbalance-mediated crosstalk between MASLD and cardiovascular-liver-metabolic health (CLMH), although its causal mechanisms and molecular drivers remain unresolved. We employed a multi-omics framework to integrate Mendelian randomization (MR) and transcriptome-wide association studies (TWAS). MR leveraged 192 genome-wide significant single-nucleotide polymorphisms for TyG from the UK Biobank, employing inverse-variance weighted (IVW) and generalized summary-data MR (GSMR). Transcriptomic integration utilized four approaches: Multi-marker Analysis of GenoMic Annotation for gene-set enrichment; Joint-Tissue Imputation PrediXcan (JTI-PrediXcan) for tissue-specific expression; Sparse Multi-Tissue Imputation Xcan (SMulTiXcan) for cross-tissue meta-analysis; and Fine-mapping of Causal Gene Sets (FOCUS) for Bayesian fine-mapping. Comorbid genes were validated using Functional Summary-based Imputation (FUSION) and prioritized based on the Polygenic Priority Score (PoPS). Single-cell spatial transcriptomics (sc-ST) in embryonic mice (E16.5) mapped tissue-specific expression via genetically informed spatial mapping (gsMap). The MR analysis demonstrated a causal effect of TyG on MASLD risk [IVW: odds ratio (OR) = 1.58, 95% CI = 1.04-2.38, P = 0.030; GSMR: OR = 1.43, 95% CI = 1.27-1.61, P = 5.20 × 10 -9 ]. TWAS identified 12 comorbid genes (C2orf16/SPATA31H1, FNDC4, GCKR, GMIP, HAPLN4, LPAR2, MAU2, MEF2B, NDUFA13, NRBP1, TM6SF2, and ZNF513). Independent validation using the FUSION framework confirmed nine TyG-MASLD comorbid genes with genome-wide significant false discovery rate-adjusted associations. Notably, TM6SF2 (TyG-PoPS = 7.2491) and GCKR (TyG-PoPS = 6.7102) showed strong positive associations in TyG, whereas NDUFA13 exhibited negative scores in MASLD (PoPS = -0.5028). Spatial mapping revealed conserved enrichment of APOA1, APOB, and APOC4 (sc-ST, P < 0.001) in murine liver and vascular tissues. Organ-specific analysis showed significant MASLD signals including the liver (sc-ST, P = 6.43 × 10 -5 ), adrenal gland (Cauchy P = 0.0064), and connective tissue (sc-ST, P = 3.29 × 10 -5 ). This study establishes TyG as a causal MASLD driver mediated by redox-sensitive hubs and evolutionarily conserved apolipoproteins, linking hepatic lipid peroxidation to systemic metabolic dysregulation. Targeting these pathways may mitigate dual hepatic-cardiovascular risks, advancing precision therapies for CLMH. Show less

Vascular calcification (VC) is prevalent in patients with chronic renal failure (CRF), and it is closely related to the morbidity and mortality of cardiovascular diseases; however, no medical treatments are available for this condition. Recent clinical studies have shown that plasma apolipoprotein C3 (ApoC3) levels are positively correlated with VC. However, whether ApoC3 is involved in VC remains unclear. Sections of calcified renal arteries from CRF patients were immunostained to measure calcium deposition and ApoC3 expression. VC was induced in ApoC3 transgenic (Tg) and knockout (KO) mice by both 5/6 nephrectomy and vitamin D ApoC3 expression levels were increased in calcified arteries from mice and patients with CRF. ApoC3 overexpression exacerbated calcium deposition in the calcified aortas from Tg mice in vivo, and in calcified aortic rings of Tg mice ex vivo and VSMCs infected by adenovirus of ApoC3 in vitro. Consistently with these findings, ApoC3 deficiency alleviated these effects. Furthermore, ApoC3 overexpression increased ferroptosis in calcified aortas and VSMCs, whereas ApoC3 deficiency suppressed ferroptosis. Further investigation revealed that ApoC3 inhibited the AMPK/NRF2 signaling pathway through toll-like receptor 2 (TLR2) in calcified VSMCs, downregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), subsequently increased lipid peroxidation and promoted ferroptosis, ultimately exacerbating calcification in the VSMCs. Furthermore, we found that knockdown of ApoC3 by siRNA remarkably attenuated calcification of renal arterial rings in humans. We demonstrated that ApoC3 exacerbated VC and increased the osteogenic transdifferentiation in VSMCs by increasing ferroptosis. ApoC3 might be a potential target for VC treatment. Show less

Vascular smooth muscle cell (VSMC) phenotype switching plays a significant role in the pathogenesis of atherosclerosis (AS). However, the subtypes of VSMC transdifferentiation and their impact on AS progression and atherosclerotic plaque instability remains unclear. We reanalysed scRNA-seq datasets of GSE155513 and GSE253903 and performed single-sample gene set enrichment analysis (ssGSEA) in three transcriptome datasets from unstable plaques to determine the major subtypes contributing the most to plaque instability. Using high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified hub genes in macrophage (MP)-like smooth muscle cells (SMCs) of unstable plaques. We conducted cell communication analysis according to tensin1 (TNS1) gene levels in VSMCs. TNS1 expression was analysed in human AS plaques. Finally, an AS model was established in VSMC-specific Tns1 knockout ApoE MP-like SMC was identified as the key subtype for plaque instability. hdWGCNA analysis for MP-like SMC identified blue module as the key gene module involved in unstable plaques. Decreased TNS1 expression in VSMCs was positively correlated with the down-regulation of contractile VSMC marker genes, SRF and MYCOD genes, negatively correlated with the up-regulation of CD68 and KLF4 genes, and activated VCAM, PDGF, THBS and CXCL signalling pathways. TNS1 mRNA expression levels were lower in human atherosclerotic arteries than in healthy arteries, and even lower in unstable plaques than in early and stable plaques. TNS1 protein levels in VSMCs were lower in human atherosclerotic plaques than in healthy arteries, and even lower in advanced plaques than in early plaques. VSMC-specific Tns1 gene deficiency aggravated AS progression and enhanced plaque instability with increased MP-like SMC transdifferentiation. The reduction of TNS1 gene in VSMCs might drive contractile VSMC transdifferentiation into MP-like SMC, the major subtype contributing to plaque instability. In vivo experimental results confirmed the role of Tns1 gene in contractile VSMC transdifferentiation into MP-like SMC and plaque instability. Show less

Calcific aortic valve disease (CAVD), the most common human valve disease on a global scale, ranks and persists as an unaddressed clinical challenge. This is primarily attributed to the absence of efficacious pharmacological approaches. The Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1), intricately associated with the pathogenesis of multiple cardiovascular diseases, has emerged as a pivotal target for the diagnosis and treatment of numerous ailments. However, the specific molecular mechanisms and the functional significance of NR4A1 in the pathogenesis of CAVD are yet to be comprehensively elucidated. By performing in-depth analyses on human aortic valve tissues and carrying out functional investigations using primary valvular interstitial cells (VICs), we were able to demonstrate that NR4A1 significantly facilitated cellular proliferation and intensifies the osteogenic differentiation process of VICs. Evidently, this is reflected in the elevated expression of key osteogenic markers, namely runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP). Mechanistically, the pro-calcific effects were achieved via NR4A1-dependent modulation of the cell cycle regulatory protein Cyclin D2 (CCND2). Significantly, Show less

Increasing evidence indicates that modulating pyroptosis in endothelial cells (ECs) can alleviate atherosclerosis (AS) progression; however, despite reports that nucleolin (NCL) regulates vascular smooth muscle cell proliferation in AS, the potential mechanism by which cell surface NCL mediates pyroptosis in ECs during AS remains poorly understood. AS was induced in ApoE AS model mice developed severe aortic lesions accompanied by pronounced EC pyroptosis and inflammation, together with elevated NCL expression in ECs of the aortic root. Both inhibition of NLRP3 and NCL knockdown alleviated atherosclerotic lesion severity in ApoE This study demonstrates that, in AS, NCL exacerbates EC pyroptosis and promotes disease progression by facilitating nuclear transport of RASSF2. This study defines the mechanistic roles of NCL in AS, thereby identifying a new molecular pathway and suggesting potential therapeutic targets. Show less

Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. Show less

Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study introduces a furin-responsive photoacoustic/fluorescence dual-modal probe (FRP) to investigate intraplaque furin activity in ApoE Show less

Coronary restenosis remains a major challenge following percutaneous coronary intervention (PCI), necessitating the development of effective stent-eluting drugs. Previous studies indicate that scutellarin protects vascular endothelial cells and exhibits anti-thrombotic and anti-platelet effects. Notably, our prior research demonstrated that scutellarin specifically counteracts oxidative stress-driven endothelial dysfunction, a key initiating event in restenosis. This combined evidence strongly suggests its potential against in-stent restenosis (ISR). Therefore, this study explores the efficacy of scutellarin in preventing ISR after PCI. We investigated scutellarin, derived from Erigeron breviscapus, for its potential to prevent ISR following PCI. The efficacy and mechanism of scutellarin were evaluated using both in vivo and in vitro models. An experimental atherosclerosis model was established in APOE In APOE This study establishes the efficacy of scutellarin in mitigating ISR using two complementary in vivo models. Scutellarin-eluting stents in atherosclerotic minipigs overcome translational barriers through full interventional simulation. Furthermore, scutellarin inhibits VSMCs proliferation, migration and promotes autophagy-coordinated apoptosis by the coordinated downregulation of both the Pl3K/AKT and lKKs/NF-κB cascades.These findings highlight scutellarin as a promising candidate for next-generation bioactive stent coatings, bridging phytopharmacology and precision interventional cardiology. Show less

Atherosclerosis (AS) is closely associated with gut microbiota that plays an important role in regulating intestinal mucosal barrier function, chronic inflammation, and immune homeostasis. Thus, targeting the modulation of gut microbitoa repesents a promising strategy for the control of AS. Clostridium butyricum (C. butyricum) serving as a kind of probiotics has shown a variety of biological benefits, but it's impact on atherosclerosis remains poorly understood. Sixty male ApoE C. butyricum ameliorated dyslipidemia and attenuated atherosclerotic plaque formation in ApoE C. butyricum intervention may exert anti-AS effects by reshaping gut homeostasis via the regulation of immune cells, providing a potential strategy for clinical treatment. Show less