Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study dem Show more
Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exert profound therapeutic effects in a rat model of moderate-to-severe CP established via bilateral carotid artery occlusion with hypoxia. Intravenously administered hUCMSC-Exos displayed sustained brain retention and significantly restored motor coordination and cognitive function. The recovery was primarily mediated through enhanced remyelination driven by promoted oligodendrocyte maturation and differentiation (elevated oligodendrocyte lineage transcription factor 2 and myelin basic protein). Concurrently, the treatment attenuated key pathological processes involving sustained neuroinflammatory responses (reduced ionized calcium-binding adapter molecule 1, tumor necrosis factor-α, and interleukin-6) while elevating brain-derived neurotrophic factor. Our findings establish hUCMSC-Exos as a promising dual-modality therapy for moderate-to-severe CP, mechanistically linked to robust remyelination and coordinated modulation of core disease mechanisms. Show less
Angiopoietin-like 4 (ANGPTL4) is a hepatokine involved in metabolism and inflammation and has been implicated in oncogenesis, yet its relationship with cancer risk in humans remains unclear. We analyz Show more
Angiopoietin-like 4 (ANGPTL4) is a hepatokine involved in metabolism and inflammation and has been implicated in oncogenesis, yet its relationship with cancer risk in humans remains unclear. We analyzed 35,716 cancer-free UK Biobank participants with baseline plasma ANGPTL4. Multivariable Cox models and restricted cubic splines assessed associations with 24 site-specific incident cancers; bidirectional two-sample Mendelian randomization (MR) evaluated causality. During a median follow-up of 12.5 years, 9304 incident cancer cases occurred. Compared with the lowest quartile (Q1), the higher quartiles (Q2, Q3, and Q4) of ANGPTL4 levels were significantly associated with the risks of ten cancers, including cancers of the bladder, breast, cervix uteri, colorectum/anus, esophagus, kidney, liver, mesothelial/soft tissues, multiple myeloma, and ovary (hazard ratios ranging from 1.02 to 3.98). Risks generally increased across ANGPTL4 quartiles, and spline analyses supported approximately linear dose-response patterns. Adding ANGPTL4 to an age-sex model improved discrimination across several sites (ΔC-index 0-0.071), with statistical significance observed only for breast cancer. Associations were directionally consistent but heterogeneous by age, sex, and BMI. Forward MR provided no evidence that genetically proxied ANGPTL4 causally increases cancer risk. In reverse MR, genetic liability to liver cancer showed a nominal positive association with circulating ANGPTL4, suggesting ANGPTL4 may be elevated as part of tumor-related biology. Higher circulating ANGPTL4 is associated with increased risk of multiple cancers, with sex-and tissue-specific heterogeneity. Although MR does not support a universal causal role, ANGPTL4 remains a promising pan-cancer biomarker for risk stratification and early prevention. Show less
Given the complexity of dementia, the inconsistent evidence on statins and dementia highlights the need for robust methods to assess heterogeneous treatment effects (HTEs). We emulated a target trial Show more
Given the complexity of dementia, the inconsistent evidence on statins and dementia highlights the need for robust methods to assess heterogeneous treatment effects (HTEs). We emulated a target trial using UK Biobank comparing statin initiators and non-initiators aged ≥55 years. Marginal structural models were fitted to estimate 5-year adjusted risk difference (aRD). We used iterative causal forest, a causal machine learning subgrouping algorithm, to identify subgroups with HTEs. Among 18,366 participants, the overall aRD for all-cause dementia was -1.0‰ (95% CI: -4.2‰ to 2.3‰). We identified subgroups by polygenic risk score for Alzheimer's disease (AD) excluding apolipoprotein E (APOE) genotype ("non-APOE PRS"). Participants with high non-APOE PRS showed cognitive benefit (all-cause dementia: aRD -5.9‰, 95% CI: -8.1‰ to 1.2‰; AD: aRD -5.0‰, 95% CI: -8.2‰ to -0.2‰). Participants with high non-APOE PRS may benefit from statins, suggesting genetic susceptibility beyond APOE could modify statins' cognitive effects. Show less
According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of th Show more
According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of the femoral head. As the exact biological mechanism among the three is still unclear, Mendelian randomization, computer-aided drug design, and transcriptomics sequencing were used to explore the specific mechanism of action. The study validated the specific signaling pathways through which dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head using animal experiments and transcriptomics sequencing. Data were obtained from public databases for Mendelian randomization analysis, and a two-sample Mendelian randomization was used to determine the intermediary role of core pathway-related targets. Computer-aided drug design was employed to assess the binding affinity between dihydroartemisinin and core targets. Transcriptome sequencing determined that dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head by regulating ferroptosis. We obtained 564 ferroptosis-related targets that met the analysis criteria and 1812 plasma proteins from the UK Biobank, and analyzed finngen_R11_OSTEON_DRUGS in the Finnish database as outcome. The results showed that there were two quantitative trait loci that had a causal relationship with ferroptosis targets. There were 110 protein quantitative trait loci causally associated with plasma proteins from the UK Biobank, and none of these loci had an inverse causal relationship with SONFH. Through mediation analysis, 7 mediating pathways were identified, yielding eight targets including ZP3, CCL17, APOE, C7ORF50, SPINK4, SPINK2, FTMT, and PRDX6. Computer-aided drug design revealed that CCL17 and PRDX6 exhibited the best docking effects. The study determined that CCL17 and PRDX6 have a significant causal relationship with SONFH. It also clarified the specific mechanism by which DHA may regulate ferroptosis to treat SONFH, which will provide a reference for the discussion of the prevention and treatment mechanisms of SONFH. Show less
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Show more
Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less
Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth fact Show more
Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth factor 21 (FGF21) in the development and progression of chronic hepatitis B (CHB). A total of 336 participants were recruited, including 320 CHB patients and 16 healthy controls. The expression of FGF21, immune cytokines, and OS-related molecules in peripheral blood mononuclear cells (PBMCs) was detected using real-time quantitative polymerase chain reaction. The methylation level of the FGF21 gene promoter in PBMCs was detected using TaqMan probe-based quantitative methylation-specific PCR. The expression level of FGF21 in the peripheral blood of CHB patients was higher than that of HC, but the methylation level of the FGF21 promoter was lower than that of HC, especially in patients during the immune activation phase. The mRNA expression levels of CXCR3 and CCL5 in PBMCs of CHB patients during the immune activation and reactivation phases were higher than those in other clinical stages. Single-cell analysis revealed that CXCR3 and CCL5 expression in the immune tolerance and immune activation phases with high HBsAg expression was closely related to T lymphocytes (T cells) and natural killer cells (NK cells) and was highly expressed in CD4 and CD8 T cells and NK cells. In addition, the mRNA expression levels of Nrf2 and GPX4 in the reactivation phase were higher than those in other clinical stages. The mRNA expression level and methylation level of FGF21 in PBMCs of CHB patients were correlated with the viral load, immune inflammation, and OS levels during the antiviral treatment course of CHB. The methylation level of the FGF21 promoter has the potential to become a non-invasive biomarker for monitoring the progress of antiviral treatment in CHB.IMPORTANCEThis study conducted an in-depth exploration of the application of methylation detection technology, analyzing its value and driving mechanism in the oxidative stress and immune-inflammatory balance during the course of chronic hepatitis B. The study analyzed the methylation patterns of the FGF21 promoter and the expression levels of its receptor FGFR1, as well as the expression levels of chemokines CXCR3, CCL5, and oxidative stress factors GPX4 and Nrf2 in the immune tolerance period, immune clearance period, immune control period, and reactivation period of chronic hepatitis B. It clarified the association between these molecules and the FGF21/FGFR1 axis and revealed the synergistic or antagonistic mechanisms of these molecules in the oxidative stress and inflammatory vicious cycle. At the same time, this study also explored the value of FGF21 promoter methylation in disease diagnosis and prognosis, providing a theoretical basis for evaluating the antiviral treatment effect and disease progression of chronic hepatitis B. 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 g Show more
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
ObjectiveTo evaluate the effects of a combined psychological and functional exercise intervention on emotion, quality of life, and brain-derived neurotrophic factor (BDNF) levels in patients with Park Show more
ObjectiveTo evaluate the effects of a combined psychological and functional exercise intervention on emotion, quality of life, and brain-derived neurotrophic factor (BDNF) levels in patients with Parkinson's disease (PD).MethodsIn this randomized controlled trial, 172 patients with PD were randomly assigned into 2 groups with 86 patients in each group. The control group received routine care, while the intervention group received a 12-week intervention combining psychological support with functional exercise in addition to routine care. Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Parkinson's Disease Questionnaire-39 (PDQ-39), Barthel Index, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and serum BDNF levels were assessed before and after the intervention. Adherence rates were also determined for each group. Spearman correlation analysis was used to examine associations between changes in BDNF (ΔBDNF) and changes in HAMA (ΔHAMA) and HAMD (ΔHAMD) scores.ResultsAt the end of the 12-week clinical trial, the intervention group demonstrated significantly lower HAMA, HAMD, PDQ-39, and MDS-UPDRS scores ( Show less
Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform Show more
Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform (MDQIP) that uses a model to objectively calculate and rank compound activities, addressing the limitations of traditional "experience-driven" evaluations, accelerates the screening and evaluation of potential AChE inhibitors from Red Gastrodia elata, offering a more efficient approach to drug discovery. Ultrafiltration-LC screening identified parishin A as having the most stable binding, with binding degree and recovery rates of 98.85% and 99.39%, respectively. Molecular docking revealed that parishins A and C were the strongest AChE inhibitors, exhibiting stable binding through hydrogen bonds, π-alkyl, and π-π interactions. Molecular dynamics simulations confirmed the stability of these compounds, with binding energies of -82.65 ± 4.24 and - 80.69 ± 4.19 kcal/mol. Enzyme kinetics showed that parishins A and C are mixed-type inhibitors, with IC Show less
Caloric restriction (CR) improves metabolic health and reduces the risk of aging-related vascular diseases. However, the systematic metabolic reprogramming associated with CR remains unclear. To addre Show more
Caloric restriction (CR) improves metabolic health and reduces the risk of aging-related vascular diseases. However, the systematic metabolic reprogramming associated with CR remains unclear. To address this, we performed multi-tissue metabolomic profiling (liver, heart, and serum) in apolipoprotein E-deficient (ApoE-/-) mice subjected to CR. Metabolomic analyses of the multiple tissues revealed that glycerophospholipid metabolism pathway was consistently modulated by CR. To explore its relevance in vascular diseases, we performed serum metabolomic profiling in an abdominal aortic aneurysm (AAA) model induced by angiotensin Ⅱ (AngⅡ) infusion in ApoE-/- mice. The level of lysophosphatidylethanolamine (LPE) (16:0/0:0), a metabolite in the glycerophospholipid metabolism pathway, was elevated during AAA progression and significantly reduced by CR intervention, suggesting its potential as a vascular disease risk factor. Notably, glycerophospholipid metabolism and LPE (16:0) were significantly associated with vascular diseases and aging-related indicators in human multi-omics data, including public transcriptomic and lipidomic, and our serum multi-omics profiling of 76 healthy aged individuals. Collectively, our findings establish glycerophospholipid metabolism and LPE (16:0) as systemic signatures of CR with diagnostic potential. They highlight a crucial link between systemic metabolism and vascular remodeling and remodeling-associated vascular diseases, while also functioning as indicators of systemic aging. Show less
Ulcerative colitis (UC) is characterized by chronic colonic mucosal inflammation, with its pathogenesis involving multidimensional interactions and limitations in clinical treatment. Dietary restricti Show more
Ulcerative colitis (UC) is characterized by chronic colonic mucosal inflammation, with its pathogenesis involving multidimensional interactions and limitations in clinical treatment. Dietary restriction (DR) is a commonly used approach for UC patients to alleviate symptoms, and exploring the role of DR-related genes in UC could provide new directions for the development of precision therapies. Bioinformatics analysis was performed on UC-related datasets (GSE75214, GSE73661) obtained from the GEO database. Candidate genes were acquired by intersecting differentially expressed genes (DEGs) with dietary restriction-related genes (DRRGs). Subsequently, key genes were identified via machine learning algorithms and ROC curve analysis. A deep neural network (DNN) model and a diagnostic nomogram were constructed. In addition, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), immune infiltration analysis, and single-cell RNA sequencing (scRNA-seq) analysis were conducted. Finally, the expression of key genes was validated through experiments. CPT1A, ANGPTL4, and CLDN1 were identified as the key genes. The deep neural network (DNN) model achieved area under the curve (AUC) values of 0.914 and 0.933 in the two datasets, respectively; the diagnostic nomogram exhibited high predictive performance (AUC > 0.7), and decision curve analysis (DCA) revealed its potential clinical net benefit. Enrichment analyses demonstrated that the key genes were significantly enriched in dietary restriction (DR)-related pathways, including cytokine-receptor interaction, the IL2-STAT5 signaling pathway, and fatty acid metabolism. Thirty-two activated pathways and five inhibited pathways were detected in UC patients (e.g., the oxidative phosphorylation pathway was suppressed). Immune infiltration analysis identified 27 differentially infiltrating immune cell types. CLDN1 was localized to epithelial cells, ANGPTL4 to fibroblasts, and CPT1A to endothelial cells. Macrophages were identified as a signaling hub in UC, showing intensified crosstalk with stromal and vascular cells via pathways such as ACKR1. Experimental validation confirmed that ANGPTL4 and CLDN1 were highly expressed in UC, whereas CPT1A was lowly expressed, a pattern consistent with the expression trends observed in public database analyses. These results indicated that CPT1A, ANGPTL4, and CLDN1 are involved in the pathological regulation of UC by DR through modulating the metabolism-immune-barrier axis, providing novel biomarkers and potential intervention targets for the clinical diagnosis and targeted therapy of UC. Show less
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by whi Show more
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Because MASLD progression poses serious health risks, elucidating the underlying mechanisms is essential to guide early intervention and therapeutic strategies. Proteomic analysis was used to identity high-fat diet (HFD)-induced proteins in mouse liver. Galectin-1 (GAL1) expression was assessed via immunohistochemistry in human liver tissues. Liver-specific GAL1-deficient mice were generated using adeno-associated virus. Mice were fed either a chow diet or an HFD. Functional studies were performed in cell lines using western blotting, RT-qPCR, immunofluorescence, co-immunoprecipitation, mass spectrometry, and molecular docking analysis. GAL1 expression was elevated in liver tissues from patients with MASLD and in mouse models. Liver-specific GAL1 knockdown alleviated hepatic steatosis and enhanced fatty acid oxidation (FAO). Mechanistically, GAL1 competitively bound to the BRCT domain of poly (ADP-ribose) polymerase 1 (PARP1), thereby interfering with its interaction with the WW domain -containing E3 ubiquitin protein ligase 2 (WWP2). Hepatic GAL1 knockdown promoted the PARP1 -WWP2 interaction and subsequently facilitated ubiquitin-dependent degradation of PARP1. This degradation led to increased NAD Hepatic deficiency of GAL1 alleviates hepatic steatosis by enhancing FAO through promotion of ubiquitin-dependent PARP1 degradation, thereby restoring NAD Show less
The formation and retrieval of reward memories within the hippocampus are critical mechanisms underlying the development of substance use disorder. Nitrous oxide (N
The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growt Show more
The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growth factor 21 (FGF21) emerging as a critical regulator linking environmental stimuli to adipose plasticity and mitochondrial function. However, the precise mechanisms of FGF21 secretion and its specific role in adipose tissue browning and subsequent NST potentiation remain incompletely elucidated. FGF21 regulates NST via distinct spatiotemporal mechanisms. Acute cold exposure triggers hepatic FGF21 secretion through a β FGF21 exhibits dual regulation: hepatic (acute lipid mobilization) and adipose-based (chronic browning); adipose-targeted FGF21 delivery is essential for therapeutic efficacy, and future studies should integrate FGF21 with UCP1-independent pathways (e.g., creatine/succinate cycles) to advance obesity treatment. 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 ph Show more
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
Hemodynamic abnormalities within atherosclerotic plaque regions, particularly localized high shear stress and endothelial dysfunction, present novel targets for intervention by drug delivery systems. Show more
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
Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abno Show more
Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abnormally elevated levels of amyloid-β (Aβ) deposition and tau phosphorylation. Given the rapid rate of population aging, many scientists are investigating AD, focusing on its pathogenic mechanisms and potential treatments. Unfortunately, to date, no highly effective therapeutic strategies have emerged. Intriguingly, multiple studies have revealed alterations in the gut microbiome of individuals with AD, suggesting it may serve as a novel avenue for investigating AD pathogenesis. Show less
This study aimed to investigate the effects of glycerol monolaurate (GML) on lipid metabolism in young broilers, with focus on the AMPKα1 protein and the cecal microbiota. A total of 144 one-day-old m Show more
This study aimed to investigate the effects of glycerol monolaurate (GML) on lipid metabolism in young broilers, with focus on the AMPKα1 protein and the cecal microbiota. A total of 144 one-day-old male Arbor Acres broilers were randomly assigned to two groups, with each group consisting of six replicates of twelve birds. The groups were fed diets supplemented with either 0 or 1,200 mg/kg of GML for a period of 14 d. The results showed that GML increased high-density lipoprotein cholesterol levels in the serum (P < 0.05) while reducing total cholesterol, triglyceride, low-density lipoprotein cholesterol, and aspartate aminotransferase levels (P < 0.05). GML also decreased liver lipid droplets and increased the mRNA levels of AMPKα1, CPT1, ApoB, and LXR (P < 0.05). Molecular docking results indicated that GML exhibited good binding affinity with AMPKα1. Root-mean-square deviation values for AMPKα1 and the AMPKα1/GML complex remained stable at 1 to 2 Å within the first 50 ns. The residues in the AMPKα1/GML complex exhibited root-mean-square fluctuation values of less than 2 Å, and the binding energy of the complex was -133.515 kJ/mol. Moreover, GML significantly increased the expression levels of GPR119 and AMPKα1 in the jejunum (P < 0.05). Notably, the genera CHKC1001, Coprobacter, and Ruminococcaceae_UCG₀₀₅ were significantly enriched in the GML group (P < 0.05). PICRUSt2 function prediction revealed that GML-induced alterations in the cecal microbiota primarily involved fatty acid degradation (P < 0.05). In conclusion, dietary supplementation with 1200 mg/kg GML enhanced lipid metabolism in young broilers. Show less
Shuhui Chai, Yihang Zhang, Yi Guo+17 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current th Show more
Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear. To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism. We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL. Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway. Show less
Residual cardiovascular risk persists in statin-treated patients with coronary artery disease (CAD), even when low-density lipoprotein cholesterol (LDL-C) targets are met. Excess apolipoprotein B (apo Show more
Residual cardiovascular risk persists in statin-treated patients with coronary artery disease (CAD), even when low-density lipoprotein cholesterol (LDL-C) targets are met. Excess apolipoprotein B (apoB), defined as measured apoB minus LDL-C-predicted apoB, may capture atherogenic particle burden beyond LDL-C, but its prognostic value for long-term mortality in secondary prevention remains uncertain. We conducted a pooled analysis of two nationwide Chinese cohorts (CIN-II and RED-CARPET) comprising 68,616 statin-treated CAD patients. Excess apoB was calculated using an internal reference population (triglycerides ≤ 1.0 mmol/L). Associations with all-cause and cardiovascular mortality were assessed using multivariable Cox models, with adjustment for clinical covariates including nutritional status. External validation was performed in 13,702 participants from the UK Biobank. Over a median follow-up of 5.2 years, 10,835 deaths occurred (5,090 cardiovascular). Each 1-standard deviation (15.4 mg/dL) increase in excess apoB was associated with a 12% higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.12, 95% CI 1.06-1.18) and a 24% higher risk of cardiovascular mortality (aHR 1.24, 95% CI 1.15-1.34). Patients in the highest excess apoB quartile (≥ 11.5 mg/dL) had significantly worse survival. Notably, these associations persisted consistently across all achieved LDL-C strata (< 2.0 to > 4.0 mmol/L). These findings were robustly confirmed in the external validation cohort. Excess apoB is an independent predictor of long-term mortality in statin-treated CAD patients, even among those with well-controlled LDL-C. Its incorporation into risk assessment could improve prognostic stratification and guide personalized management in secondary prevention. CIN-II: ClinicalTrials.gov, NCT05050877 (Retrospectively registered, 21 September 2021); RED-CARPET: Chinese Clinical Trial Registry, ChiCTR2000039901 (Prospectively registered, 14 November 2020). The UK Biobank study is covered by generic ethical approval from the NHS National Research Ethics Service (Ref: 99231). Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, ac Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by irreversible cognitive decline and synaptic dysfunction and represents the most prevalent etiology of dementia, accounting for an estimated 60-70% of all clinically diagnosed cases worldwide. The growing focus on microglia-neuron interactions in AD research highlights their diverse, region-specific responses, which are driven by the functional and pathological heterogeneity across different brain regions. Therefore, investigating the interactions between microglia and neurons is of crucial importance. To explore the regional heterogeneity of microglia-neuron crosstalk in AD, we integrated human single-nucleus RNA sequencing data from the prefrontal cortex (PFC), hippocampus (HPC), and occipital lobe (OL) provided by the ssREAD database. Our study delineated four microglial subtypes and uncovered a pseudotime trajectory activation trajectory leading to the disease-associated microglia (DAM) phenotype. The transition along this trajectory is driven and stabilized by a key molecular switch: the coordinated downregulation of inhibitory factors (e.g., LINGO1) and upregulation of immune-effector and antigen-presentation programs, which collectively establish the pro-inflammatory DAM state. Furthermore, we observed that each brain region displayed unique microglia-neuron communication patterns in response to AD pathology. The PFC and OL engage a THY1-ITGAX/ITGB2 signaling axis; the HPC predominantly utilizes the PTPRM pathway. Notably, THY1 dysregulation strongly correlates with pathology in the PFC, HPC, and OL, suggesting that microglia-neuron crosstalk in AD possesses both heterogeneity and commonality. The main contribution of this study is the systematic characterization of region-specific microglia-neuron interactions and the identification of THY1 as a potential mediator that may be targeted therapeutically to modulate microglial function in affected brain regions. Show less
Daiyue Li, Yu Zhang, Ruonan Wang+6 more · 2026 · Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · Elsevier · added 2026-04-24
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key dr Show more
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less
Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous- Show more
Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic Show less
We developed a viscosity-activated near-infrared (NIR) fluorescent probe, QV-S. This probe features a long emission wavelength (815 nm), a large Stokes shift (135 nm), high viscosity sensitivity (431- Show more
We developed a viscosity-activated near-infrared (NIR) fluorescent probe, QV-S. This probe features a long emission wavelength (815 nm), a large Stokes shift (135 nm), high viscosity sensitivity (431-fold signal enhancement), and specific lysosome-targeting capability. QV-S allows for not only real-time monitoring of lysosomal viscosity changes in inflammatory and foam cells but also the precise imaging of atherosclerotic plaques in the aortas of ApoE Show less
Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, ne Show more
Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, neonatal mice were administered SCFAs for 28 days to evaluate their impacts on growth, intestinal barrier integrity, immune modulation, bone development, and gut microbiota composition. Valerate supplementation significantly increased body weight and intestinal length. It enhanced the villus structure, crypt depth, and goblet cell number, alongside upregulation of tight junction and mucin genes, indicating improved barrier function. Valerate and propionate also promoted the expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) and reduced pro-inflammatory cytokines, suggesting an immunomodulatory shift. In the skeletal system, valerate improved the microarchitecture, increased bone mineral density (BMD), and upregulated osteogenic genes runt-related transcription factor 2 (Runx2), fibroblast growth factor receptor 1 (FGFR1), and growth hormone receptor (GHR). Microbiota profiling showed enrichment of several genera ( Show less