👤 Shengping Hou

Chronic psychological stress drives neuroimmune crosstalk and accelerates atherosclerosis progression. Physical exercise confers broad health benefits and is associated with reduced inflammation. However, the exercise-mediated factors and mechanisms that mitigate stress-induced vascular inflammation remain unclear. Chronic restraint stress (CRS) and voluntary exercise models were established to investigate the role of exercise in neuroimmune crosstalk. RNA sequencing identified kinesin family member 4 (Kif4) as a key gene associated with the attenuation of stress-induced inflammatory responses in peripheral blood monocytes following exercise. Combined co-immunoprecipitation-mass spectrometry and membrane proteomics identified T cell-interacting activating receptors on myeloid cell 1 (TARM1) as the Kif4 cargo. The function of TARM1 was validated using an immobilized TARM1-Fc fusion protein. Brain-derived neurotrophic factor (BDNF), a key effector during exercise and stress, regulated the Kif4-TARM1 axis using recombinant BDNF (rBDNF) and the TrkB inhibitor ANA-12. Finally, exercise-mediated effects and mechanisms were examined in atherosclerotic CRS-exposed mouse models and in patients with coronary artery disease (CAD) experiencing high psychological stress. Physical exercise alleviated stress-induced neuroimmune crosstalk, reduced the proinflammatory CD11b Physical exercise alleviates stress-induced neuroimmune crosstalk through the BDNF-Kif4-TARM1 axis, revealing a novel neuroimmune-mediated brain-heart axis that supports exercise-based therapeutic strategies for psychogenic CAD. Chronic psychological stress drives systemic inflammation through neuroimmune mechanisms, thereby accelerating the progression of coronary artery disease (CAD). Physical exercise alleviates stress-induced neuroimmune crosstalk, partly by suppressing proinflammatory responses in monocytes/macrophages. This study provides novel insights into exercise-regulated neuroimmune mechanisms involving the monocyte BDNF-Kif4-TARM1 axis. In both an atherosclerotic mouse model and patients with CAD, exercise mitigated stress-induced inflammation via the BDNF-Kif4-TARM1 axis. Show less

Chronic toxoplasmosis has been increasingly associated with behavior disorders, including depression-like behaviors, while the underlying mechanisms remain poorly understood. In this study, we demonstrated that chronic toxoplasmosis induced depression-like behaviors in mice, which were observed together with neuroinflammation, neuronal injury, and suppression of the BDNF-TrkB pathway. Treatment with the TrkB agonist 7,8-DHF alleviated these behavioral deficits by restoring BDNF-TrkB signaling, preserving neuronal function, and reducing neuroinflammation through inhibition of NF-κB and MAPK pathways. Additionally, 7,8-DHF also reduced astrocyte overactivation and protected blood-brain barrier structure integrity. These findings highlight that disruption of BDNF-TrkB signaling contributes to T. gondii-induced behavioral abnormalities and that targeting this pathway may represent a promising therapeutic strategy against neuroinflammation and neuronal damage associated with chronic infection. Show less

MicroRNAs, as key regulators in gene expression, may hold the key to understanding Alzheimer disease (AD) pathogenesis and diagnosis. To explore the expression level of miR-106b-3p in the serum of AD patients, and evaluate its diagnostic value for AD. A total of 250 AD patients and 200 healthy controls were enrolled. Real-time quantitative PCR with fluorescence detection was used to determine the relative expression level of miR-106b-3p. Correlation was analyzed by the Pearson linear correlation analysis. The receiver operating characteristic was used to evaluate the diagnostic efficacy of serum miR-106b-3p for AD. In vitro AD cellular models were established to explore the potential mechanism of miR-106b-3p in AD. The expression of miR-106b-3p in the serum of AD patients is significantly elevated, and its level is negatively correlated with the MMSE score. ROC curve analysis shows that it has certain diagnostic value. miR-106b-3p is a risk factor associated with AD. In addition, miR-106b-3p targets BDNF, affects the functions of SH-SY5Y cells, and promotes the occurrence and development of AD. Serum miR-106b-3p is significantly elevated in AD and may serve as a diagnostic biomarker. Preliminary evidence suggests it promotes AD progression by targeting BDNF, highlighting its potential as a therapeutic target for early intervention. Show less

Both brain-derived neurotrophic factor (BDNF) and ovarian hormones are powerful neuromodulators, yet evidence of their impact on human cognition remains mixed. As prior work has studied them in isolation, examining their interacting effects presents a key empirical opportunity for explicating their effects on cognition. We genotyped participants for the BDNF Val66Met single nucleotide polymorphism, which is associated with less efficient activity-dependent BDNF secretion and altered hippocampal function, and examined their performance on a complex learning task at two points in the menstrual cycle: early follicular (characterized by low levels of ovarian hormones) and late follicular (characterized by high estradiol). While met carriers showed advantages during the early follicular timepoint, val homozygotes outperformed them at the late follicular timepoint. Furthermore, effects in met carriers were largely driven by increased sensitivity to both absolute levels and changes in levels of estradiol. The current findings provide the first evidence of BDNF Val66Met interacting with the menstrual cycle to predict cognition, demonstrate nuanced genotype- and hormone-specific outcomes, and underscore the importance of studying effects of interacting biological systems on human cognition. Show less

Microcystin-LR (MC-LR) is the most prevalent and toxic microcystin congeners, posing a significant threat to aquatic organisms as well as humans; however, its underlying toxic mechanisms remain incompletely elucidated. In this study, the negative impacts of MC-LR and the underlying mechanisms in zebrafish larvae were investigated. The results demonstrated that MC-LR could penetrate zebrafish larvae and induce developmental toxicity, characterized by reduced heart rate, decreased body length, and smaller eye area. H&E staining revealed that MC-LR exposure significantly reduced the thickness of retinal layers. qPCR analysis showed altered expression levels of phototransduction and retinoic acid metabolism related genes (rho, gnat1, gnat2, opn1sw1, opn1lw1, opn1mw1, rdh1, rbp4, cyp26a1, and aldh1a2). These findings suggest that MC-LR may disrupt retinal structure and impair normal visual function in larvae. Behavioral analyses indicated that MC-LR exposure weakened spontaneous movements in embryos and impaired swimming ability in larvae, potentially due to significant alterations in the levels of glutamate, γ-aminobutyric acid, and brain-derived neurotrophic factor. Additionally, MC-LR exposure reduced visuomotor responses, delayed reactions to external stimuli, and disrupted circadian rhythms, which may be attributed to altered expression levels of circadian rhythm-related genes (clock1a, bmal1a, per1b, cry1a, and per2), as well as changes in melatonin and arylalkylamine N-acetyltransferase 2 levels. Overall, these findings indicate that MC-LR exposure induces developmental neurotoxicity in zebrafish, and that impaired visual function and disrupted circadian rhythm may serve as key contributing factors to MC-LR-induced behavioral abnormalities, which warrant further emphasis in future ecological and health risk assessments. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa Show less

Alzheimer's disease (AD) and osteoporosis are common age-related degenerative diseases. Emerging evidence suggests that amyloid-β (Aβ) deposition may contribute to the pathogenesis of both conditions. This study investigated whether probucol could alleviate AD-associated bone loss and Aβ42-induced osteoblast dysfunction, and further explored the underlying mechanisms. Female mice were divided into four groups (n = 5 per group): C57BL/6 wild-type (WT), WT treated with probucol (WT + PBC), APP/PS1 transgenic (AD) mice, and AD treated with probucol (AD+PBC). Bone mineral density (BMD) was assessed by micro-CT. Levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) along with bone metabolism markers including fibroblast growth factor 23 (FGF23), sclerostin, and brain-derived neurotrophic factor (BDNF) in bone and brain tissues were measured by ELISA. FOXO3a was knocked down in the bone marrow of APP/PS1 mice via stereotactic injection of lentiviral vectors. Expression of APP and FOXO3a in bone tissue was evaluated using RT-qPCR and Western blotting (WB). Mitochondrial damage in osteoblasts and neuronal cells was assessed by transmission electron microscopy (TEM). In vitro study, osteoblast differentiation and mineralization deficits were evaluated using Alizarin Red staining. WB was used to measure the expression of AKT, FOXO3a, autophagy and apoptosis related proteins. Probucol attenuated bone loss and mitochondrial damage in both APP/PS1 and FOXO3a-knockdown APP/PS1 mice, and improved cognitive impairment and neuronal ultrastructure in APP/PS1 mice. Furthermore, probucol attenuated Aβ42-induced osteoblast differentiation and mineralization via the AKT/FOXO3a signaling pathway in vitro. These findings demonstrate that probucol ameliorates AD-associated bone loss and Aβ42-induced osteoblast impairments by regulating AKT/FOXO3a signaling pathway. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E Show less

Rapid platelet inhibition is essential for effective management during emergency percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). However, the oral dosage form of clopidogrel (CLP) commonly used in clinical practice shows a delayed onset due to gastrointestinal absorption, first-pass metabolism, and the requirement for hepatic cytochrome P450 (CYP450)-mediated bioactivation, which limits its applications in urgent scenarios and complicating post-PCI bleeding management. To address these challenges, we developed an intravenous micellar formulation (CLP/PM) using FDA-approved mPEG-PLA copolymers to promote rapid hepatic exposure and metabolic activation. By tuning the PLA chain length, micellar core density and PEG conformation were modulated, thereby influencing protein corona (PC) formation and liver-affinity interactions. Proteomic profiling revealed that micelles with intermediate PLA length selectively recruited liver-affinity apolipoproteins (ApoM, ApoH, ApoA1, and ApoB), which are known ligands of LDLR and SR-BI, while minimizing adsorption of inflammatory and opsonization proteins. The optimized CLP/PM (3.9 k) exhibited a hepatotropic-like PC that was associated with hepatocyte-enriched uptake in primary liver cell analyses. In vivo biodistribution showed rapid liver-level signal, and pharmacokinetic studies supported enhanced CYP450-mediated activation, achieving a higher C Show less

Doxorubicin (Dox) is a classic anthracycline chemotherapy drug with cause cumulative and dose-dependent cardiotoxicity. This study aimed to investigate the potential role and molecular mechanism of phenylacetylglutamine (PAGln), a novel gut microbiota metabolite, in Dox-induced cardiotoxicity (DIC). DIC models were established in vivo and in vitro, and a series of experiments were performed to verify the cardioprotective effect of PAGln. RNA sequencing (RNA-seq) was employed to explore the mechanism of PAGln in DIC. Subsequently, the differentially expressed genes (DEGs) were subjected to comprehensive analysis using diverse public databases, and RT-PCR was used to confirm the expression levels of the candidate genes. Finally, molecular docking techniques were used for validation. PAGln effectively prevented both in vivo and in vitro Dox-induced myocardial injury and cell apoptosis. RNA-seq results showed that 40 genes were up-regulated and 54 down-regulated in the Dox group compared to the Con group, displaying opposite changes in the Dox + PAGln group. Enrichment analysis highlighted several mechanisms by which PAGln alleviated Dox-induced cardiotoxicity, including the lipid metabolic process, calcium-mediated signaling, positive regulation of store-operated calcium channel activity, and hypertrophic cardiomyopathy. In vitro and in vivo experiments confirmed that PAGln treatment could reverse the changes in the expression levels of Klb, Ece2, Nmnat2, Casq1, Pak1, and Apob in Dox. Molecular docking results showed that these genes had good binding activity with PAGln. PAGln shows potential in alleviating Dox-induced cardiotoxicity, with Ece2 identified as key regulatory molecules related to endothelial dysfunction. Show less

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder driven by metabolic dysregulation and chronic inflammation, for which targeted pharmacotherapies remain limited. Rutin, a bioactive flavonoid from Sophora japonica and Fagopyrum esculentum, possesses notable anti-inflammatory and antioxidant properties. This study explored its pharmacological effects and underlying mechanism in NAFLD using a combination of in vivo and in vitro approaches. We found that rutin administration markedly attenuated hepatic steatosis, reduced oxidative stress, restored mitochondrial function, and improved liver injury markers, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), in both high-fat diet (HFD)-fed ApoE Show less

This study aims to investigate the effects of mulberry anthocyanin (MA) in high-fat and high-cholesterol (HFHC) diet-fed ApoE-/- mice. ApoE-/- mice were randomly divided into control (ACON), mulberry fruit anthocyanin extract (MFAE), cyanidin-3-glucoside (C3G) group 1 (C3GT), and C3G group 2 (C3GP). After 7 weeks of HFHC diet feeding and following 2-3 weeks of treatment, samples were collected and analyzed. The C3GT group significantly decreased low-density lipoprotein (7.3 ± 1.5 mmol/L) and interleukin-1β (355.4 ± 41.7 pg./mL) levels. Moreover, the MFAE (636.3 ± 90.7 pg./mL), C3GT (611.5 ± 65.4 pg./mL), and C3GP (757.5 ± 47.6 pg./mL) significantly increased glutathione peroxidase (GSH-PX) levels compared with those in the ACON group. The MA treatments significantly increased the number of MA treatment may attenuate AS-associated risk factors by decreasing inflammatory factor-related gut microbial genera. The mechanism may be related to regulating liver glutamine, ATP, and related metabolic pathways. Show less

Individuals with prediabetes or diabetes face elevated dementia risk, yet robust prediction tools and mechanistic insights remain limited. This study aimed to develop and validate a protein-based risk score for dementia prediction in this high-risk population while elucidating underlying biological pathways and therapeutic targets. Utilising data from 10 433 UK Biobank participants with prediabetes or diabetes and proteomic profiling (2911 plasma proteins measured), we developed a dementia protein risk score in a training set ( In the training set, 23 out of 2911 proteins were selected. In the testing set, compared with the basic model (age and sex, C-index: 0.78; 95% confidence interval [CI] 0.74-0.82), the dementia protein risk score (C-index: 0.84; 95% CI 0.81-0.88) significantly improved the performance in predicting incident dementia (C-index increase: 0.06; 95% CI 0.02-0.12), while cardiovascular risk factors, ageing and dementia incidence risk factors (C-index: 0.80; 95% CI 0.76-0.83) and apolipoprotein E (APOE; age and sex included, C-index: 0.81; 95% CI 0.77-0.85) had no significant improvement. Six key proteins (glial fibrillary acidic protein [GFAP], neurofilament light polypeptide [NEFL], Brevican core protein [BCAN], protein MENT [MENT], APOE and growth/differentiation factor 15 [GDF15]) captured the most predictive power. Pathway analyses implicated extracellular matrix remodelling and cholesterol metabolism, whereas Mendelian randomisation identified causal roles for APOE, haematopoietic prostaglandin D synthase (HPGDS), BAG family molecular chaperone regulator 3 (BAG3) and GDF15. Nine proteins were prioritised as druggable targets, including HPGDS, with existing Food and Drug Administration-approved drugs. This study establishes a highly accurate protein-based risk score for dementia prediction (including 6-23 proteins) in individuals with prediabetes or diabetes, uncovering actionable biological pathways and therapeutic targets. The findings enable precision risk stratification and accelerate translational opportunities for dementia prevention in this population. Show less

Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2's function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology. Show less

Atherosclerosis is fundamentally a pathology of unresolved inflammation perpetuated by the collapse of Regulatory T cell (Treg)-mediated tolerance. Emerging evidence indicates that Treg functional integrity is intrinsically dictated by mitochondrial fatty acid oxidation (FAO), a metabolic checkpoint often compromised under systemic metabolic stress. Current lipid-lowering therapies, such as statins, often fall short in correcting this maladaptive immunometabolic defect and may introduce collateral metabolic perturbations. This study aimed to elucidate the immunometabolic therapeutic mechanism of Dingxin Recipe III (DXR III) in ameliorating atherosclerosis. We employed an integrated systems pharmacology strategy-combining serum pharmacochemistry, multi-omics profiling, and extensive high-dimensional flow cytometry-to elucidate the therapeutic mechanism of DXR III, a traditional Chinese herbal formula in an in vivo study. ApoE DXR III treatment effectively attenuating atherosclerotic progression. Serum pharmacochemistry identified 254 prototypical absorbed constituents, including Tanshinone I (a potential Peroxisome Proliferator-Activated Receptor Gamma agonist), as bioactive candidates. Multi-omics analysis revealed that DXR III modulated the metabolic environment, coinciding with restored FAO flux. This shift was associated with a favorable metabolic niche characterized by increased FAO substrates, which correlated with the rescue of Treg differentiation and phenotypic stability. Specifically, DXR III facilitated the redistribution of Tregs from the spleen to plaque sites and significantly inhibited their trans-differentiation into Th1-like or Th17-like phenotypes. Conversely, Simvastatin treatment, despite lowering lipids, resulted in peripheral Th17 accumulation and failed to alleviate hyperglycemia. In contrast, DXR III maintained Th17 homeostasis-abolishing the pathogenic non-classical Th17 subset-and exerted dual-regulatory effects on both lipid and glucose metabolism. DXR III ameliorates atherosclerosis, a process closely associated with the modulation of the FAO metabolic checkpoint to correct the immune imbalance driving plaque progression. By rescuing the Treg differentiation, functional integrity, and phenotypic fidelity while avoiding the immunological trade-offs associated with Th1/Th17, DXR III represents a promising candidate for comprehensive cardiovascular protection. Show less

Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration. Show less

Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE High-cholesterol diet-fed apoE Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia. Show less

Sex differences in the association between vascular factors and cognitive outcomes remain unclear. We aimed to investigate the associations of blood pressure metrics (hypertension, systolic blood pressure [SBP), pulse pressure, ankle and brachial pressures, and ankle to brachial pressure index [ABI]) with the risk of cognitive decline and dementia. We conducted a population-based longitudinal analysis using data from the Atherosclerosis Risk in Communities (ARIC) study (begun in 1987-1989) in the United States. We analyzed a total of 12,268 participants aged 45-64 years who had validated exposure measurements, cognitive function tests (first administrated 1990-1992), and followed up for incidence of dementia through December 2019. Cognitive function was assessed using the Digit Symbol Substitution Test, the Delayed Word Recall Test, and the Word Fluency Test. Dementia cases were identified through a standardized clinical evaluation process, mostly adjudicated by expert reviewers. We performed sex-stratified analyses to examine the associations of blood pressure metrics and APOE ε4 allele with the risk of cognitive decline and dementia. Over a median follow-up of 26.4 years, 2698 participants developed dementia. Women aged 55-64 had a significantly higher incidence of dementia than men aged 55-64 (14.8 vs. 11.8 per 1000 person-years; p < These findings highlight notable sex differences in the association between vascular factors and cognitive decline and dementia risk. Women appear more vulnerable to both genetic and vascular risk factors, emphasizing the need for sex-specific approaches in research, prevention, and intervention strategies for cognitive impairment. NIH. Show less

Autoimmune uveitis (AU) is a category of sight-threatening diseases with different pathological causes. Transcriptomic analysis of patients with AU revealed a highly oxidative stress profile as well as an up-regulated Show less

We sought to examine the cross-sectional associations of social support and depressive symptoms with cognitive function in dementia-free rural older adults. This population-based cross-sectional study included 4719 participants (age ≥ 60 years) living in rural China. Social support and depressive symptoms were measured using the Social Support Rating Scale and the 15-item Geriatric Depression Scale, respectively. Global cognition, memory, verbal fluency, attention, and executive function were assessed using a neuropsychological test battery. Mild cognitive impairment (MCI) was defined following Petersen's criteria. Data were analyzed using general linear and logistic regression models. Greater social support was associated with lower likelihood of MCI and greater z-scores of global cognition, memory, verbal fluency, and executive function (all P < 0.05). Having depressive symptoms was associated with increased likelihood of MCI and lower z-scores of global cognition, memory, verbal fluency, attention, and executive function (all P < 0.05). Greater social support was associated with higher global cognitive z-score in men, higher memory z-score in APOE ε4 non-carriers, and higher executive function z-score in participants with school education (all P < 0.01). The association of depressive symptoms with lower z-scores of global cognition and attention was stronger among people with formal schooling than those without (P < 0.01). Furthermore, depressive symptoms could significantly mediate 46.97 % of the cross-sectional association between social support and global cognition. Late-life social support and having no depressive symptoms are associated with a reduced likelihood of MCI and better cognitive function in a rural Chinese older population, with the associations varying by sex, education, and APOE genotype. Show less

Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms. ApoE METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs-but not in macrophages-by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome. METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease. Show less

AXIN1 (axis inhibition protein 1), as a rate-limiting component of canonical Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin signaling pathway, may influence midbrain dopaminergic neurons. A recent genome-wide association study identified AXIN1 as a candidate gene for Parkinson's disease (PD). Our study aimed to investigate the potential relevance of AXIN1 single nucleotide polymorphisms (rs13337493 and rs9921222) in the risk, clinical characteristics, and pathology of PD. Data were collected from the Northern Han Chinese and Parkinson's Progression Markers Initiative (PPMI) cohorts. Associations between AXIN1 variants, PD-related biomarkers, and clinical manifestations were analyzed. Both loci were identified as risk factors in the Northern Han Chinese population, and the A allele of rs13337493 [odds ratio (OR) 1.320, 95% confidence interval (CI) 1.052, 1.653, P Our findings support a gatekeeper role for AXIN1; its polymorphisms contribute to increased PD susceptibility and accelerated motor progression, yet may also trigger a compensatory presynaptic response, as evidenced by elevated CSF DOPA levels, to counteract neurodegeneration. Future studies should include larger sample sizes, more diverse ethnic populations, and protein-level investigations. Show less

Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer's disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. Show less

Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A-overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A overexpression significantly reduced Aβ plaque deposition in brain tissue of APP/PS1 mice. Mechanistically, SV2A was identified as a novel APP-binding protein that attenuated the amyloidogenic processing of APP by inhibiting its interaction with β-site APP cleaving enzyme 1 (BACE1). Furthermore, SV2A overexpression altered the subcellular distribution of APP, shifting its localization away from the endosomal-lysosomal compartments. Collectively, our findings unveil SV2A as a critical regulator of APP metabolism and propose it as a promising therapeutic target for intervening in the early pathological progression of AD. Show less

N-carbamylglutamate (NCG) is an activator of arginine biosynthesis, but its specific role in crustaceans remains poorly understood. This study aimed to investigate the effects of NCG on arginine biosynthesis capacity, metabolism, digestion, and the gene expression of the mTOR signaling pathway in Eriocheir sinensis. In Experiment 1, hepatopancreas was cultured in vitro with NCG medium (0, 65, 75, and 85 mg/L NCG). In Experiment 2, crabs were fed either regular feed or NCG feed (content: 302.96 ± 4.07 mg/kg) for 14 days. In Experiment 1, NCG significantly upregulated pyrroline-5-carboxylate synthase (p5cs) gene expression (P < 0.05), an enzyme that is related to arginine biosynthesis. Similarly, dietary NCG upregulated p5cs expression and significantly increased the activities of carbamoyl-phosphate synthase-1 (CPS-1) and P5CS in the hepatopancreas and intestine (P < 0.05). Metabolomics analysis indicated that NCG altered the metabolic profile of the hepatopancreas, promoting cholesterol metabolism, and arginine and proline metabolism. In the intestine, trypsin and α-amylase activities were significantly elevated (P < 0.05). NCG also altered the composition of intestinal microflora, with an increase in Proteobacteria and in the ratio of Firmicutes to Bacteroidota. Additionally, NCG increased the content of signaling molecule nitric oxide (NO) and upregulated the expression of genes in the mTOR signaling pathway (P < 0.05). In conclusion, NCG supplementation enhanced arginine biosynthesis capacity, stimulated intestinal enzymatic activities, and upregulated mTOR signaling pathway gene expression in Eriocheir sinensis, indicating the potential for improved metabolism and digestion. Show less

FGFRs genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in cancers, leading to the initiation and progression of tumors by enhancing FGFR signaling. The substantial problems arising from the lack of decisive clinical evidence have resulted in the cessation of some inhibitor applications, and identifying effective small molecule inhibitors that selectively target FGFRs can advance the therapy of cancers driven by FGFRs abnormalities. The three-dimensional structure of the FGFR1/2/3/4 protein and the amino acid positions within the tyrosine kinase domain were downloaded from the PDB database, and small molecule data were extracted from the ZINC15 database. Then, we used molecular docking and dynamics simulations to assess compounds interacting with FGFR proteins, and screening potential small molecules targeting FGFR. Finally, we evaluated its effects by two CRC cell line HCT116 and NCI-H716. In the study, by docking with 2.8 million small molecules, we identified three promising FGFR small molecule inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of the three compounds, we found that ZINC000101867325 could form the stable binding interactions with FGFR1/2/3. And, ZINC000101867325 inhibited the activity of FGFR signaling, and resulted in cell apoptosis and decrease in cell proliferation and migration in colorectal cancer cell lines. In addition, ZINC000101867325 is also predicted to target FGFR2 mutations in colorectal cancer patients. We predicted three small molecules targeting FGFRs, and ZINC000101867325 shows superior chemical bond types and stability with FGFR1/2/3, and inhibits FGFR signaling in CRC cell lines. This study provides novel FGFRs inhibitors, which enrich treatment strategies for cancers. Show less

Abnormalities in protein tyrosine kinases (PTKs) are one of the primary drivers of cancer. As a receptor subfamily, fibroblast growth factor receptors (FGFRs) comprise four subtypes-FGFR1 to FGFR4. Their abnormal intracellular expression is a significant cause of tumorigenesis, making FGFRs key therapeutic targets in cancer treatment. This paper primarily summarizes the latest research advances in FGFR inhibitors, aiming to provide insights for future design and synthesis studies of FGFR inhibitors. Show less

Aortic aneurysm (AA) is a life-threatening vascular disease with high fatality upon rupture. While physical activity (PA) reduces cardiovascular risk, its role in AA prevention remains uncertain, particularly when assessed objectively. We analyzed 93,165 UK Biobank participants (56% women; median age 57 years) with valid 7-day wrist-worn accelerometer data. PA was categorized as light (LPA), moderate (MPA), vigorous (VPA), and moderate-to-vigorous (MVPA). Diagnosed AA was ascertained through linked hospital, death, and primary care records. Cox models estimated hazard ratios (HRs) for AA across quartiles and per-standard deviation (SD) increments, with adjustment for demographic, lifestyle, and cardiometabolic factors. Over a median 7.9-year follow-up, 499 clinically recorded AA cases occurred. Higher accelerometer-measured PA was inversely associated with AA risk. Per-SD increments in total PA, MPA, VPA, and MVPA corresponded to 17%, 22%, 19%, and 23% lower risks, respectively. Compared with the lowest quartile, the highest MVPA quartile had a 44% lower AA risk (HR = 0.56, 95% CI 0.42-0.76). Subtype analyses revealed stronger protective effects for abdominal aortic aneurysm (AAA) than thoracic aortic aneurysm (TAA), while LPA was not significantly associated. These findings demonstrate that higher levels of accelerometer-measured MVPA are robustly associated with a decreased risk of clinically detected AA in a dose-dependent manner. The associations were particularly pronounced for AAA. This study provides objective evidence supporting the potential benefits of MVPA for aortic health. Show less

To evaluate the predictive value of novel lipid parameters for coronary lesion severity in pCAD and to develop a nomogram-based prediction model. Patients newly diagnosed with pCAD at Qingdao Municipal Hospital (2021-2024) were enrolled and randomly assigned to training and validation cohorts in a 7:3 ratio. Coronary lesion severity was assessed using the Gensini score (GS), with patients stratified into mild or significant stenosis groups. Spearman correlation analysis was performed between GS and lipid parameters. Key predictors were selected using LASSO regression, and independent risk factors were identified by multivariable logistic regression to construct the nomogram model. The model's discrimination, calibration, and clinical utility were evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Lp(a), non-HDL-C, RC, FFA, and BAR were positively correlated with GS (r = 0.34, 0.34, 0.18, 0.19, 0.18; all The proposed nomogram provides an effective tool for identifying pCAD patients with severe coronary artery stenosis, demonstrating robust predictive accuracy and potential clinical utility. Show less