👤 Xiao Zhao

Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanisms underlying lifespan and sarcopenia remain unclear. This study aimed to identify genes associated with longevity and muscle weakness and to characterize their shared genetic architecture. We integrated the largest genome-wide association studies (GWAS) on longevity (age > 90th: n = 11 262 cases; age > 99th: n = 3484 cases) and muscle weakness (European Working Group on Sarcopenia in Older People (EWGSOP): n = 48 596 cases; Foundation for the National Institutes of Health (FNIH): n = 20 335 cases) with Genotype-Tissue Expression (GTEx) v8 multi-tissue expression quantitative trait locus (eQTL) data. Gene-trait associations were evaluated using multi-tissue and single-tissue TWAS, and validated using Multi-marker Analysis of GenoMic Annotation (MAGMA). Mendelian randomization (MR) and colocalization were applied to test causality and shared variants. Cross-trait genetic correlation was estimated with LDSC, and pleiotropic loci were identified by pleiotropy analysis under the composite null hypothesis (PLACO) followed by Functional Mapping and Annotation (FUMA)/MAGMA annotation. Across TWAS approaches, APOC1 and TOMM40 were identified as longevity-associated genes, while DYM and TGFA were susceptibility genes for muscle weakness. In MR analysis, higher expression of APOC1 and TOMM40 increased the odds of longevity (OR > 1, p < 0.05), whereas higher expression of DYM and TGFA reduced the risk of muscle weakness (OR < 1, p < 0.05). Colocalization supported shared causal variants for APOC1 (rs429358, PP.H4 = 0.81) and TOMM40 (rs429358, PP.H4 = 0.85) with longevity (age > 90th survival percentile), and for DYM and TGFA with muscle weakness defined by both EWGSOP and FNIH (PP.H4 > 0.80). A significant negative genetic correlation was observed between longevity and muscle weakness (Rg < 0, p < 0.05). Cross-trait pleiotropy analysis identified several pleiotropic genes (PVRL2, PPP1R9A, SLC39A8 and the TOMM40/APOE/APOC1 gene cluster) that influence both longevity and muscle weakness. We identified susceptibility genes for longevity (APOC1, TOMM40) and muscle weakness (DYM, TGFA) and uncovered shared pleiotropic loci linking aging and muscle decline. These findings improve the understanding of the genetic architecture underlying aging-related phenotypes and provide potential molecular targets for promoting healthy aging and reducing late-life disability. Show less

Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson's disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the SNCA gene. Genetic risk factors strongly influence LBD susceptibility, including SNCA multiplication, particularly triplication, and the apolipoprotein E ε4 allele (APOE4), the strongest common genetic risk factor for LBD. While SNCA is predominantly expressed in neurons and APOE primarily in glial cells, how these genetic factors converge to impact neuronal vulnerability and regional pathology in the human brain remains poorly understood. Here, we applied spatial transcriptomics to postmortem temporal cortex tissue from LBD cases with SNCA triplication or different APOE genotypes, alongside age- and sex-matched controls, to map gene expression within intact cortical architecture. We identified layer 5 of the gray matter as a particularly vulnerable region, characterized by elevated SNCA expression, pronounced synaptic and metabolic dysregulation, and exacerbation of these alterations in APOE4 carriers. Reelin signaling emerged as a core Lewy body-associated pathway disrupted across cortical layers, validated in independent postmortem cohorts and human-induced pluripotent stem cell (iPSC)-derived cortical organoids. In contrast, white matter exhibited distinct molecular alterations, including disrupted myelination pathways, with APOE4 carriers showing increased myelin debris and glial responses compared with non-carriers. Cell-type deconvolution informed by single-nucleus RNA sequencing further revealed APOE4-associated impairments in neuronal vulnerability and intercellular communication. Together, these findings define spatially and cell-type-specific mechanisms through which SNCA dosage and APOE4 genotype impact LBD pathology, providing insight into regionally distinct disease processes and potential targets for genetically stratified therapeutic interventions. Show less

Despite therapeutic advances, atherosclerosis remains a major global health challenge. Most current treatments target systemic risk factors rather than the diseased vascular wall. Our previous work identified genistein, a soy isoflavone, as a cannabinoid receptor 1 (CB1) antagonist capable of suppressing CB1-mediated vascular inflammation and atherosclerosis. However, its poor water solubility and low oral bioavailability limit clinical application. We aimed to develop water-soluble, orally bioavailable CB1 antagonists for atherosclerosis and to investigate the role of endothelial CB1 in hemodynamic regulation. RNA-sequencing datasets from the NCBI GEO repository were analyzed to assess CB1 expression in atherosclerotic patients. Apolipoprotein E-deficient (Apoe We found CB1 was upregulated in atherosclerotic lesions from patients and mice, and in endothelial cells exposed to disturbed flow. Mechanistically, this was driven by ZNF610 and Spi1 binding and KLF4 dissociation at the CB1 promoter. Daidzein, a soy isoflavone structurally similar to genistein, was identified as a novel CB1 antagonist. To enhance solubility and bioavailability, we developed genistein 7-O-phosphate (G7P) and daidzein 7-O-phosphate (D7P). Pharmacological treatment with these isoflavone monophosphates or genetic CB1 ablation reversed disturbed flow-induced endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT). Oral administration of G7P and D7P significantly reduced atherosclerotic plaque formation in mice. This is the first study to identify transcriptional regulators that drive endothelial CB1 upregulation in response to disturbed flow. We further demonstrated that isoflavone monophosphates ameliorate disturbed flow-induced endothelial dysfunction and EndMT via CB1 inhibition, offering promising oral therapeutics for atherosclerosis. Show less

To explore the therapeutic mechanism of The active components and disease targets of JZQBR were screened using TCMSP and GeneCards databases, followed by protein-protein interaction analysis and GO and KEGG enrichment analyses. In the animal experiments, Network pharmacology identified 65 potential targets, with quercetin, kaempferol, and luteolin as the core components and IL-6, IL-1β, and TNF‑α as the key targets. The targets were enriched mainly in the pathways involving inflammatory responses and diabetic complications. In the JZQBR improves T2DM complicated with hyperlipidemia possibly by multi-target regulation of the inflammation-metabolism network. 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

Atherosclerosis (AS) is a major underlying cause of cardiovascular diseases, with hypercholesterolemia, inflammatory responses, and macrophage polarization being established key contributors. The roles of NLRP3 inflammasome activation and macrophage polarization in AS pathogenesis have garnered significant research interest. This study investigated the therapeutic potential of Schisandrol B (Sol B) against AS using an in vivo model of ApoE Show less

Fusobacterium nucleatum (F. nucleatum), a key periodontal pathogen, is increasingly detected in atherosclerotic plaques, yet its epigenetic regulatory mechanisms in atherosclerosis remain enigmatic. This study investigates how F. nucleatum reshapes the non-coding RNA landscape to drive atherosclerosis progression. Periodontal infection with F. nucleatum significantly increased atherosclerotic lesion area (p < 0.001) and necrotic core ratio, while reducing collagen content (p < 0.05) in ApoE Show less

Perirenal fat deposition significantly impacts sheep carcass quality and economic efficiency. To elucidate the underlying genetic regulation, we performed a genome-wide association study (GWAS) on 556 Hu sheep and a comparative transcriptome analysis on 24 Hu sheep (12 with high- and 12 with low-perirenal fat deposition), all with accurate phenotypic records. Furthermore, hub genes and tissue-specific genes (TSGs) were discerned through weighted gene co-expression network analysis (WGCNA) and by leveraging RNA-Seq data from 12 tissues, respectively. qRT-PCR is used to validate the accuracy of RNA-Seq data. GWAS identified significant SNPs near genes including SETD4, TIMP2, SOCS3, and DNAH17. Comparative transcriptome analysis of HPF and LPF groups identified 2072 differentially expressed genes (DEGs), which were significantly associated with lipid storage (LPL), fatty acid homeostasis (APOE, GOT1), and biosynthesis (ACACA). A total of 2333 differential alternative splicing events were identified in 1169 genes, with skipped exons (SE, 30.65 %) being the most common. GO analysis of these SEs showed links to RNA splicing and lipid metabolism, with genes like BSCL2, DGAT1, PLIN5, and PNPLA2 involved in lipid droplet organization and triglyceride storage. WGCNA revealed key modules that were positively and negatively correlated with perirenal fat deposition, emphasizing hub genes (SAR1B, THRSP, ACSS2, KIF5B) associated with lipid droplet organization and metabolism. The integrated analysis of GWAS and RNA-seq identified TIMP2, SOCS3, and DNAH17 as potential key genes involved in regulating perirenal fat deposition in sheep. An association analysis of 372 Hu sheep populations identified significant links (P < 0.05) between perirenal fat deposition traits and mutations in the TIMP2 (g.9759169 G > A) and DNAH17 (g.9494469C > T) genes. Crucially, tissue-specific gene analysis across 12 tissues identified 448 perirenal fat TSGs, of which 75 were also differentially expressed genes (e.g., LPL, THRSP, LEP, ADRB3). In conclusion, our multi-omics study identified key genes influencing perirenal fat deposition in sheep. Notably, mutations in TIMP2 and DNAH17 could serve as candidate markers for enhancing carcass quality through marker-assisted selection. Show less

Acacetin, a natural flavonoid compound, exhibits anti-inflammatory, antioxidant, and lipid-lowering properties, indicating promising therapeutic potential for the prevention and treatment of cardiovascular diseases (CVD). However, the mechanisms underlying its therapeutic effects on atherosclerosis (AS) remain incompletely understood. This study aims to systematically elucidate the role and molecular mechanisms of Acacetin in the pathological progression of AS. First, network pharmacology was employed to predict the potential therapeutic targets of Acacetin in combating AS. Subsequently, both in vivo and in vitro experiments were established to investigate the underlying mechanisms. The in vivo AS model was generated by feeding apolipoprotein E knockout (ApoE Show less

Hemodynamic abnormalities within atherosclerotic plaque regions, particularly localized high shear stress and endothelial dysfunction, present novel targets for intervention by drug delivery systems. In this study, we designed a polysaccharide-based carrier (HF-AF) from fucoidan, featuring a dynamic supramolecular structure. A dynamic supramolecular network was established within this carrier via dynamic supramolecular interactions between hydroxypropyl-β-cyclodextrin and adamantane-methylamine. The anti-inflammatory compound tilianin, formulated into nanocrystals (Til NCs), was then encapsulated to create a shear-responsive nanosystem (HF-AF@Til NCs). The system's primary therapeutic strategy is its response to pathological hemodynamic forces: upon encountering high shear stress at a stenosis, the supramolecular network undergoes dissociation, triggering a mechanically-gated release of the encapsulated Til NCs. This shear-triggered function is complemented by the natural P-selectin affinity of the fucoidan backbone, which facilitates the anchoring of the nanocarrier at the inflamed lesion site. This sophisticated "anchor-and-release" mechanism enables superior drug accumulation precisely at plaque sites. In ApoE Show less

Cognitive impairment is a significant health concern in aging populations, but the interplay between biological aging, lifestyle factors, and genetic susceptibility remains unclear. This study examined whether accelerated biological aging is associated with cognitive impairment, whether lifestyle modifies this association, and how genetic background influences these relationships in Chinese older adults. In this cross-sectional study (2022-2023), 7033 participants from southwestern China were included. Accelerated biological aging was calculated as the residual difference between biological age (based on 10 biomarkers) and chronological age. Lifestyle was assessed via a composite index (smoking, alcohol, physical activity, diet, sleep). Cognitive function was measured using the Chinese Mini-Mental State Examination (C-MMSE), and genetic risk was evaluated through polygenic scores and APOE ε4 status. Linear and logistic regression models assessed associations between accelerated aging and cognition. Accelerated biological aging was associated with lower MMSE scores ( β = -0.243, 95% CI: -0.354, -0.133) and higher cognitive impairment prevalence (OR = 1.098, 95% CI: 1.040, 1.158). An unhealthy lifestyle exacerbated cognitive impairment in biologically older individuals (RERI = 0.25). Those with both accelerated aging and unhealthy lifestyle had the lowest MMSE scores ( β = -1.424, 95% CI: -1.846, -1.003) and highest odds of cognitive impairment (OR = 1.467, 95% CI: 1.194, 1.803). These effects were consistent across all genetic background subgroups. Accelerated aging was associated with lower cognitive function, especially in individuals with unhealthy lifestyles, regardless of genetic susceptibility. This highlights lifestyle modification as a potential intervention target for aging-related cognitive impairment. Show less

Cardiac microvascular injury from hyperlipidaemia and hyperglycaemia is associated with increased major adverse cardiovascular events (MACE). Semaglutide, a long-acting GLP-1 receptor agonist, reduces diabetic cardiovascular complications beyond its glycaemic and weight-lowering effects. However, the impact of semaglutide on diabetes-induced coronary microvascular injury and the integrated mechanisms involved remain unclear. A combined streptozotocin (STZ) and high-fat diet (HFD) induced diabetes model was established in ApoE Diabetic mice showed disrupted cardiac microvascular structure and reduced microvascular density. Semaglutide attenuated or reversed these changes. It reduced advanced glycation end products (AGEs) and their receptors, activated the Nrf2/HO-1/NQO1 pathway, inhibited the MCP-1/CCR2a/NF-κB pathway, lowered inflammatory cytokines, and reduced apoptosis, exerting a protective effect on the cardiac microvascular system. Early and sustained semaglutide treatment mitigates diabetes-related cardiac microvascular injury via multiple mechanisms, including preserving microvascular structure and density, inhibiting perivascular fibrosis, and attenuating inflammation, oxidative stress, and apoptosis. Show less

Macrophages can develop into pro-inflammatory M1-like macrophages and anti-inflammatory M2-like macrophages when stimulated by distinct internal environment. Dynamic changes of the two kinds of macrophages play key roles in atherosclerosis progression. The study aims to explore the role of ring finger protein 10 (RNF10) in regulating macrophage polarization during atherosclerosis. Mice with macrophage-specific depletion of RNF10 (RNF10 Show less

Previous studies indicate associations between inflammatory cytokines and glioma, meningioma, and astrocytoma. We conducted two-sample Mendelian randomization with genetic data for tumors from FinnGen R10 and cytokine data from GWAS. Primary analysis used inverse variance weighting, supplemented by sensitivity analyses including weighted median, simple mode, weighted mode, and MR-Egger. For glioma, TNF-related apoptosis-inducing ligand (TRAIL) was a risk factor, while Fibroblast growth factor 21 (FGF21) was protective. For meningioma, Axin-1 and Matrix metalloproteinase-1 were risk factors, whereas Fms-related tyrosine kinase 3 ligand was protective. For astrocytoma, risk factors included Eotaxin, Macrophage colony-stimulating factor 1, and Interleukin-8; protective factors were T-cell surface glycoprotein CD5 and Tumor necrosis factor ligand superfamily member 12. This Mendelian randomization study identified specific inflammatory cytokines associated with these tumors, providing direction for future mechanistic research. Show less

Mild depression in women is a distinct disorder with unclear immune mechanisms. This study aims to identify peripheral inflammatory biomarkers and to explore acupuncture's immunomodulatory effects via Olink proteomics. Thirty female participants (18-45 years) were assigned to healthy controls (HC), mild depression (MD), and acupuncture treatment (ACU). Plasma samples were analyzed using the Olink https://www.chictr.org.cn/showprojEN.html?proj=189355, identifier ChiCTR2300068054. 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 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

Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD. In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated. Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice. Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD. Show less

Alzheimer's disease (AD) is characterized by a complex pathophysiology, involving abnormal aggregation of amyloid b (Ab) and tau proteins, neuroinflammatory responses, and significant synaptic dysfunction, which collectively contribute to cognitive decline. This review offers a novel perspective by focusing on the pivotal role of synaptic plasticity in the pathogenesis of AD, underscoring its potential as a therapeutic target. The study uniquely synthesizes current molecular and clinical research to illustrate how Ab and tau pathologies disrupt synaptic signaling and structure, further exacerbated by neuroinflammation. We explore both pharmacological interventions, such as BACE1 inhibitors and tau stabilizers, and non-pharmacological strategies, including cognitive therapy and neuromodulation techniques, which have shown promise in modulating synaptic plasticity and slowing cognitive deterioration. Despite these advancements, the field faces significant challenges, including the complexity of AD's underlying mechanisms and limitations in early diagnosis. This review not only highlights the significance of synaptic plasticity in AD but also proposes future research directions that could lead to innovative therapeutic approaches, offering new hope for effective treatment strategies. Show less

Diabetic peripheral neuropathy (DPN), a severe complication of diabetes, is a key risk factor for diabetic foot (DF) that contributes highly to amputation and mortality. The pathogenesis of DPN remains unclear and complex, with no effective treatments currently available. Monoamine oxidase (MAO), a flavin adenine dinucleotide (FAD)-dependent enzyme, catalyzes the oxidative deamination of critical biogenic amines. The MAO family comprises two subtypes, MAOA and MAOB, which play distinct roles in pathophysiology. In this study, we identified that MAOB but not MAOA is pathologically upregulated in the sciatic nerve (SN) tissues of DPN patients and in the SN/dorsal root ganglion (DRG) tissues of DPN model mice. Notably, the selective MAOB inhibitor Khellin (Khe) effectively alleviated DPN-like pathology in mice. To explore the mechanistic role of MAOB in DPN, we performed proteomic profiling of DRG tissues from DPN mice and validated the findings using a MAOB-specific knockdown DPN mice model treated with adeno-associated virus (AAV) 8-MAOB-RNAi. Our results demonstrate that Khe targets MAOB to mitigate DPN pathology through HIF-1α/BACE1/Aβ/NLRP3/tau pathway, mediated by Schwann cell/DRG neuron crosstalk. All findings suggest that selective MAOB inhibition represents a promising therapeutic strategy for DPN, with Khe as a potential candidate for clinical translation against this disease. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder associated with the loss of memory, accumulation of amyloid-beta (Aβ) plaques, and inflammation of the nervous system. Scopolamine, an antagonist of muscarinic receptors, is commonly used to mimic the cognitive and behavioral deficits of AD in laboratory animals. In this study, we aimed to test the neuroprotective properties of hyperforin (HPF), a compound extracted from the St. John's wort plant (Hypericum perforatum), in a scopolamine rat model of AD. Sprague-Dawley rats were divided into four groups: control (saline), scopolamine (10 mg/kg, i.p.), scopolamine + hyperforin (10 mg/kg, p.o. for 7 days), and scopolamine + donepezil. Biochemical, and histopathological assessments were performed. Protein analysis related to inflammation, apoptosis, and the HMGB1/RAGE signaling pathway was performed using Western blotting. IL-1α, levels were measured by ELISA. Nissl staining evaluated neuronal damage in the hippocampus. Hyperforin significantly suppressed the activation of the HMGB1/RAGE signaling axis. Furthermore, hyperforin in this model also suppressed pyroptotic cell death and lowered IL-1α, IL-1β, and IL-18 levels. In addition, HPF reduced Aβ formation by downregulating BACE1 and blocking the activity of inflammasomes composed of canonical and non-canonical caspase-1/11. HPF appears to be a potential therapeutic candidate for neurodegeneration associated with AD, given that hyperforin actively demonstrated neuroprotective effects in a scopolamine-induced AD model, most likely through blocking the HMGB1/RAGE signaling pathway, mitigating neuroinflammation and pyroptosis, and inhibiting Aβ synthesis. Show less

β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we developed a bioinspired neuroenhancer that concurrently targets both Aβ aggregation and neuroinflammation. Rutin and small interfering RNA targeting beta-site amyloid precursor protein cleaving enzyme 1 (siBACE1) were co-loaded into the calcium phosphate core, which was further coated with lipid bilayers and Angiopep-2/rabies virus glycoprotein 29 peptides to form the multifunctional neuroenhancer (RB@LCP-AR). RB@LCP-AR not only releases siBACE1 to silence BACE1 expression and block Aβ production from the cleavage of amyloid precursor protein, but also releases Rutin to suppress the Aβ aggregation. Moreover, the released Rutin of RB@LCP-AR directly alleviates Aβ-induced mitochondria dysfunction and intracellular ROS production in neuronal cells. Notably, the targeting of RB@LCP-AR to neurons and the inhibition of Aβ reduce the microgliosis and astrogliosis, further alleviating neuroinflammation and synapse loss. Consequently, AD mice receiving RB@LCP-AR treatment efficiently recovered their memory and cognition. Our study thus provides a coordinated targeting of Aβ and neuroinflammation inhibition, holding considerable potential to promote the recovery of memory and cognition in AD. Show less

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is the most common cause of dementia. An important pathological basis for AD lesions is the excessive generation and deposition of β-amyloid (Aβ) caused by increased expression of the β-secretase, known as the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Effective suppression of the BACE1 overexpression has become a key AD treatment. Nuclear factor of activated T cells (NFAT) is a key transcription factor that regulates the expression of BACE1 in AD lesions, while Calcineurin (CaN) is a key regulatory protein that affects the transcription function of NFAT. Several lines of evidence have indicated that FK506 may promote the Aβ degradation via upregulation of the matrix metalloproteinase-9 (MMP-9) expression, which is associated with reduction of Aβ plaque deposition in the cerebral cortex and hippocampus. In this study, behavioral, histological, and biochemical methods were used to investigate the key role and molecular mechanisms of CaN inhibitor FK506 in cognitive dysfunction, regulation of BACE1 expression, and Aβ production in APPswe/PS1dE9 transgenic mice. Results The results indicate that FK506 inhibits NFAT1 levels in the cerebral cortex and hippocampus, thereby reducing the expression of BACE1 and mediating APP processing towards non-amyloidosis pathways, significantly reducing Aβ overproduction, which in turn saved cognitive deficits in APPswe/PS1dE9 transgenic mice. In addition, FK506 treatment had no significant effect on the expression of a disintegrin and metalloprotease (ADAM10) in α - secretase. FK506 rescues cognitive deficits in APPswe/PS1dE9 mice by reducing Aβ production and deposition in the brain. Show less

Pancreatic cancer (PC) is a common gastrointestinal malignancy whose initiation and progression may be closely linked to the gut microbiota. Previous research indicates that Scutellaria barbata D. Don and Scleromitrion diffusum (Willd.) R.J. Wang (SB-SD) exhibit diverse biological activities, such as anti-inflammatory, antioxidant, and antitumor effects, though their precise regulatory mechanisms are not fully elucidated. Here, we treated PC cells with SB-SD to assess its impact on cell viability, apoptosis, migration, and cell cycle progression, while Western blotting analyzed the expression of HSP90AA1, MAPK3, p53, CDK1, and p21. We also established a pancreatic cancer xenograft model in nude mice to evaluate the in vivo inhibitory effect of SB-SD on tumor growth. Furthermore, we employed metagenomic sequencing, untargeted metabolomics, and quantitative proteomics to comprehensively profile changes in the gut microbiota, serum metabolites, and differentially expressed proteins, with Western blotting subsequently validating BCKDK, GATM and p53 expression. The results show that SB-SD significantly inhibited PC cell proliferation, promoted apoptosis, and induced S/G2 phase cell cycle arrest, potentially via modulation of the HSP90AA1/MAPK3 signaling pathway. Measurements of tumor volume and weight, complemented by histopathological analysis, confirmed that SB-SD effectively suppressed the growth of PANC-1 xenograft tumors. Integrated multi-omics analyses suggest that the antitumor effects of SB-SD may involve the modulation of key gut microbes like Bacteroides caccae and Lactobacillus, the promotion of choline metabolism, and the regulation of BCKDK and GATM. Together, these findings not only corroborate the direct antitumor activity of SB-SD against pancreatic cancer but also offer novel mechanistic insights by constructing a microbiota-metabolite-protein interaction network. Show less

Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain incompletely understood. Here, we demonstrate that GBM cells outcompete NK cells for branched-chain amino acid (BCAA), leading to BCAA depletion, suppression of NK and CD8 Show less

The cardiac lymphatic system plays a crucial role in maintaining myocardial homeostasis by regulating fluid equilibrium, immune surveillance, and metabolite clearance. This review highlights recent advances in understanding its development, molecular regulation, dual roles in pathophysiology, and translational potential. Cardiac lymphatic endothelial cells (LECs) develop from diverse progenitors, including venous endothelium and Isl1⁺ precursors from the second heart field (SHF) under sex-specific molecular guidance. Functionally, the Vascular endothelial growth factor C (VEGFC)/Vascular endothelial growth factor receptor 3 (VEGFR3) signaling is paramount, modulated contextually by factors like adrenomedullin and branched-chain ketoacid dehydrogenase kinase (BCKDK). Lymphatic dysfunction impacts cardiovascular disease paradoxically. While protective in the acute phase of myocardial infarction by limiting inflammatory edema, it becomes detrimental in chronic hypertension and calcific aortic valve disease (CAVD). Single-cell transcriptomics (scRNA-seq) resolve this contradiction by revealing distinct functional LEC subpopulations: Transforming growth factor-beta 1 (TGF-β1)⁺/Interleukin 10 (IL-10)⁺ LECs promote post-infarction repair, while Reelin⁺/C-C motif chemokine ligand 21 (CCL21)⁺ LECs promote osteogenesis and valve calcification in CAVD. Emerging strategies focus on cardiac-targeted nanotherapeutics, epigenetic and metabolic LEC modulation, and sex-specific dosing. Critical unresolved questions involve autonomic nerve-lymphatic integration and lineage-specific epigenetic memory. Advancing precision lymphatic imaging, genotype-informed clinical trials, and spatiotemporal control of LEC phenotypes is critical for therapeutic translation. Deeper understanding promises novel treatments for heart failure, inflammatory cardiomyopathies, and fibrosis. Show less

Diabetic foot ulcer (DFU), a severe complication of diabetes, impose substantial global health burdens. Dampness-heat syndrome (DHS), a common syndrome in traditional Chinese medicine (TCM), is highly prevalent among DFU patients and closely correlated with treatment response and prognosis. However, the molecular biomarkers associated with DFU in patients with DHS remain poorly understood. Serum 4D-data-independent acquisition (DIA) proteomics was performed on 16 DFU-DHS patients and six healthy controls (HCs). Differentially expressed proteins (DEPs) were screened by |fold change (FC)| > 1.2 and p < 0.05. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were conducted. Key biomarkers were validated via enzyme-linked immunosorbent assay (ELISA) in 28 independent DFU-DHS cases. A total of 201 DEPs were identified between DFU-DHS patients and HCs. Bioinformatics revealed DEPs enriched in lipid metabolism (high-density lipoprotein [HDL] remodeling and cholesterol metabolism) and complement-coagulation cascades. PPI network analysis revealed a core functional module centered on four proteins, APOA1, LCAT, PLTP, and CETP. ELISA validation confirmed the significant dysregulation of these four apolipoproteins in the independent DFU-DHS cohort (all p < 0.05 vs. HCs). The combination of the biomarkers APOA1, LCAT, PLTP, and CETP exhibited a high diagnostic efficacy for DFU-DHS, with an area under the curve (AUC) of 0.9672 based on receiver operating characteristic (ROC) analysis. To our knowledge, this is the first study to employ 4D-DIA proteomics on DFU-DHS. We identified four serum biomarkers (APOA1, LCAT, PLTP, and CETP) linked to dysregulated cholesterol metabolism in DFU-DHS patients, which show diagnostic potential and provide insights for integrating TCM syndrome differentiation with precision medicine. Show less

Congenital heart disease (CHD) is the most common birth defect worldwide, with over half of cases lacking a defined etiology. Maternal metabolic dysregulation has been implicated in CHD risk, but the specific metabolites and mechanisms involved in embryonic heart development remain poorly understood. Carbamoyl phosphate (CP), a key urea cycle intermediate, has not previously been linked to cardiac morphogenesis. This study aimed to identify maternal metabolites associated with offspring CHD risk and to elucidate the role of CP in regulating cardiac development. Untargeted metabolomic profiling was performed on early-pregnancy serum from 98 mothers of CHD offspring and 50 age-matched controls. Functional validation was performed using two pregnant mouse models: pharmacological inhibition of glutamine metabolism via BPTES and Cps1 heterozygous knockout (Cps1 Maternal serum CP levels were significantly reduced in CHD cases and negatively correlated with upstream nutrient levels. In mice, both BPTES treatment and maternal Cps1 knockdown increased CHD incidence in offspring. Conversely, NCG supplementation reduced CHD risk in Cps1 Maternal CP deficiency increases offspring CHD risk by disrupting TET2-mediated DNA demethylation through impaired lysine carbamylation. These findings highlight maternal CP and TET2 carbamylation as potential metabolic-epigenetic targets for CHD prevention. Show less

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

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

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC. Show less