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
Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to Show more
Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less
The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined Show more
The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. We comprehensively characterized efferocytosis in CRS and determined its association with inflammatory endotypes and clinical outcomes in CRSwNP. Efferocytosis-related marker expression between nasal polyps and healthy nasal mucosa was detected by quantitative real-time PCR and immunohistochemistry. Public single-cell RNA sequencing profiles of CRS were reanalyzed to dissect efferocytosis at single-cell resolution. Associations between efferocytosis and tissue inflammation were evaluated by Spearman correlation. Regression models and receiver operating characteristic analyses assessed the predictive capability of efferocytosis for CRSwNP recurrence. Compared with controls, CRSwNP exhibited widespread efferocytosis deficiency, including "find me" signals (CX3CR1, S1PRs, P2RY2, GPR132), "eat me" signals (ITGAV, MerTK, Tim1, ADGRB1), "don't eat me" signal CD300a, postengulfment signals (ABCA1, NR1H3/2, PPARδ/γ), and bridging molecule MFGE8. Macrophages, the principal efferocytic cells, shifted from homeostatic C3 Insufficient phagocytosis and increased antiphagocytosis activity are hallmarks of efferocytosis deficiency in CRS and are associated with the severity of inflammation and the clinical outcome of CRSwNP. Show less
American Indians have a high population risk for cerebrovascular disease, vascular brain injury (VBI), and dementia. The apolipoprotein ( We analyzed data from a population-based, longitudinal cohort Show more
American Indians have a high population risk for cerebrovascular disease, vascular brain injury (VBI), and dementia. The apolipoprotein ( We analyzed data from a population-based, longitudinal cohort of American Indians aged 64-95 years from the Strong Heart Study recruited from Northern Plains, Southern Plains, and Southwest regions. Magnetic resonance imaging markers included infarcts, lacunes, hemorrhages, and WMH. The sample size was 395 participants with a mean age of 71.3 (4.7) years and was comprised of 313 non-ε4-carriers and 82 ε4-carriers, predominantly female (70.1%). Cross-sectional analyses indicated no significant associations between Our findings echo previous work that Show less
The ratio of uric acid to high-density lipoprotein cholesterol (UHR) is a novel comprehensive indicator related to dyslipidemia. However, the association between UHR and coronary artery disease (CAD) Show more
The ratio of uric acid to high-density lipoprotein cholesterol (UHR) is a novel comprehensive indicator related to dyslipidemia. However, the association between UHR and coronary artery disease (CAD) risk in patients with chronic kidney disease (CKD) remains unclear. After matching based on age and gender propensity scores, 2124 subjects were included and divided into the CKD group (708 cases) and the non-CKD group (1416 cases). The predictive performance of UHR for CAD was evaluated by the area under the curve (AUC), and the independent association between UHR and the risk of CAD onset was analyzed using a multivariate logistic regression model. The correlation and dose-response relationship between the ratio of uric acid to high-density lipoprotein cholesterol (UHR) and the risk of CAD were analyzed using LOESS fitting and restricted cubic spline (RCS) analysis. After matching, the multiple lipid-related indices (Triglycerides (TG), Remnant Cholesterol (RC), Atherogenic Index (AI), Atherogenic Index of Plasma (AIP), Triglyceride Glucose Index (TyG), Lipoprotein Composite Index (LCI), Triglyceride to High-Density Lipoprotein Cholesterol Ratio (TG/HDL-C), Total Cholesterol to High-Density Lipoprotein Cholesterol Ratio (TC/HDL-C), Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol Ratio (LDL-C/HDL-C), UHR) in the CKD group were significantly higher than those in the non-CKD group. The AUC analysis showed that HDL-C, AIP, TG/HDL-C, and UHR had strong predictive performance in the overall cohort and the non-CKD group, while in the CKD group, HDL-C, AI, and TC/HDL-C are better predictive indicators. After adjusting for all confounding factors, multivariate regression analysis revealed that HDL-C, apolipoprotein A-1 (APOA-1), and the APOA-1/APOB ratio were independent protective factors for CAD in the entire cohort. Among them, the protective effect of HDL-C was the most stable (overall population aOR = 0.26, 95% CI: 0.17-0.39, p < 0.001), and it was significantly in both the CKD (aOR = 0.18, 95% CI: 0.09-0.40, p < 0.001) and non-CKD subgroups (aOR = 0.31, 95% CI: 0.18-0.52, p < 0.001). In CKD, UHR is significantly correlated with CAD (aOR = 6.23, 95% CI: 1.89-20.60, p = 0.003), and the association was more significant in the non-CKD group (aOR = 15.15, 95% CI: 4.20-54.72, p < 0.001). CKD status significantly modified the association between UHR and CAD (P for interaction = 0.015). LOESS fitting suggested that UHR was positively correlated with the probability of CAD occurrence (the correlation was more significant at low UHR, and it slowed down when UHR > 0.5, r = 0.2, p < 0.001), and negatively correlated with eGFR (r = -0.38, p < 0.001). RCS analysis confirmed a significant nonlinear association between UHR and CAD (overall P < 0.001, nonlinear P = 0.002), and the risk of CAD increased when UHR was > 0.41 in CKD patients. UHR is an independent risk factor for coronary heart disease, with higher adjusted OR values and more significant independent risk effects in non-CKD populations. 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
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
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
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
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
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
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
Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been iden Show more
Sodium perfluorononenoxybenzene sulfonate (OBS), a substitute for perfluorooctane sulfonate (PFOS), has been frequently detected in the environment and human blood. Although OBS exposure has been identified as a novel risk factor for atherosclerosis associated with endothelial dysfunction, the underlying molecular mechanisms remain unclear. In this study, in vitro experiments using human umbilical vein endothelial cells (HUVECs) demonstrated that OBS exposure induced oxidative stress, activated the PERK-eIF2α-ATF4 axis of endoplasmic reticulum stress (ERS) and triggered NF-κB signaling. Pharmacological inhibition with N-acetylcysteine (NAC, an antioxidant), 4-phenylbutyric acid (4-PBA, an ERS inhibitor), and BAY 11-7082 (an inhibitor for NF-κB signaling pathway) revealed a sequential pathogenic cascade, in which oxidative stress acts upstream to initiate ERS and compromise endothelial barrier function, leading to NF-κB activation, which drives inflammatory responses, monocyte adhesion, and impaired endothelial migration. Consistent with these findings, in vivo experiments in ApoE Show less
Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF Show more
Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF-κB, but its role in POCD is unknown. Dendrobine, a sesquiterpenoid alkaloid from Dendrobium species, exhibits anti-inflammatory and neuroprotective activity. POCD was induced in aged C57BL/6 mice via sevoflurane anesthesia combined with exploratory laparotomy. Dendrobine (10 or 20 mg/kg) was administered, and cognitive outcomes were evaluated by Morris Water Maze and Novel Object Recognition. RNA sequencing, Western blotting, immunofluorescence, and in vitro microglia-neuron co-culture systems were employed to investigate inflammatory responses, apoptosis, synaptic plasticity, and signaling pathway activation. Functional roles of Runx1 were validated via siRNA knockdown, pharmacological inhibition (Ro5-3335), and overexpression in BV2 cells. Dendrobine improved spatial and recognition memory in POCD mice, reduced hippocampal microglial activation, proinflammatory cytokine expression (TNF-α, IL-1β, IL-6), and neuronal apoptosis while enhancing synaptic protein levels (BDNF, PSD95, SYN1). Transcriptomic and KEGG analyses revealed suppression of NF-κB signaling by dendrobine, with Runx1 identified as an upstream modulator. Dendrobine downregulated Runx1 expression in vivo and in vitro. Runx1 inhibition enhanced dendrobine's anti-inflammatory effects, whereas RUNX1 overexpression abolished them. Dendrobine ameliorates POCD by inhibiting the Runx1/NF-κB signaling pathway, suppressing neuroinflammation, promoting synaptic resilience, and preventing neuronal apoptosis. Runx1 appears to act as a key upstream mediator of NF-κB signaling in POCD. Targeting the Runx1/NF-κB axis represents a promising strategy for perioperative neuroprotection. 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
The formation and retrieval of reward memories within the hippocampus are critical mechanisms underlying the development of substance use disorder. Nitrous oxide (N
Although glass-based long-persistent luminescence (LPL) materials offer superior transparency and integration capability compared with conventional phosphors, their emission has been predominantly res Show more
Although glass-based long-persistent luminescence (LPL) materials offer superior transparency and integration capability compared with conventional phosphors, their emission has been predominantly restricted to the blue-green region, leaving warm-color LPL largely unexplored. In this work, Mn Show less
Early-life stress (ELS) is a key risk factor for adolescent depression. Si-Ni-San (SNS), a classic traditional Chinese medicine formula, has shown antidepressant potential, yet its effects on the dors Show more
Early-life stress (ELS) is a key risk factor for adolescent depression. Si-Ni-San (SNS), a classic traditional Chinese medicine formula, has shown antidepressant potential, yet its effects on the dorsal raphe nucleus (DRN)-nucleus accumbens (NAc) serotonergic circuit remain unclear. This study aimed to investigate whether SNS alleviates adolescent depression by restoring DRN-NAc serotonergic circuit function and to identify the serotonin receptor mediating its synaptic effects in the NAc. Firstly, the antidepressant efficacy of SNS was evaluated in a mouse model of ELS. Subsequently, its underlying mechanism was explored through integrated neurophysiological, molecular, and pharmacological analyses. Depressive- and anxiety-like behaviors were assessed using behavioral tests (sucrose preference, tail suspension, forced swim, open field, and elevated plus maze). In vivo electrophysiolog was employed to monitor DRN neuronal activity. Chemogenetic manipulation was employed to regulate the DRN-NAc serotonergic circuit, while 5-HT4R function was assessed through pharmacological intervention and viral knockdown. Synaptic and molecular mechanisms were examined using Western blotting, qPCR, ELISA, and immunofluorescence. SNS alleviated depressive-like behaviors, enhanced neural activity and low-frequency oscillations in the DRN, and restored 5-hydroxytryptamine (5-HT) levels in the NAc. Mechanistically, SNS upregulated tryptophan hydroxylase 2 (TPH2) while downregulating indoleamine 2,3-dioxygenase 1 (IDO1), thus promoting 5-HT synthesis. Critically, the antidepressant effects of SNS were blocked by either chemogenetic inhibition of the DRN-NAc serotonergic circuit or pharmacological blockade of 5-HT4R in the NAc. Meanwhile, the knockdown of 5-HT4R abolished the ameliorative effects of SNS on depressive-like behaviors and associated synaptic remodeling, including the upregulation of brain-derived neurotrophic factor, postsynaptic density protein 95, and mushroom spine density. These results demonstrate that SNS alleviates depressive-like behaviors in adolescent male mice by restoring DRN-NAc serotonergic circuit function, enhancing 5-HT bioavailability, and promoting 5-HT4R-dependent synaptic plasticity in the NAc, revealing a circuit- and receptor-specific therapeutic mechanism. Show less
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
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
Intrahepatic cholangiocarcinoma (ICC) remains one of the most lethal malignancies with an increasing incidence worldwide. Gemcitabine has been considered the standard first-line chemotherapeutic agent Show more
Intrahepatic cholangiocarcinoma (ICC) remains one of the most lethal malignancies with an increasing incidence worldwide. Gemcitabine has been considered the standard first-line chemotherapeutic agent for ICC but the therapeutic response is unsatisfactory due to the development of chemoresistance. Caspase-3-mediated pyroptosis has been reported to play significant roles in chemotherapeutic response but the relevant therapeutic strategy remains unstated due to the unclear molecular mechanisms under pyroptosis in ICC. This study was designed to comprehensively explore the crucial role and underlying mechanisms of NRXN3 in pyroptosis and chemosensitivity of ICC. We performed genome-scale CRISPR-Cas9 screen integrated with transcriptomic analysis to identify key regulators of pyroptosis and gemcitabine sensitivity in ICC. In vitro and in vivo experiments were employed to investigate the effects of NRXN3 on gemcitabine-induced pyroptosis. RNA-seq and IP-MS were conducted to explore the mechanisms of NRXN3-regulated pyroptosis and chemosensitivity. NRXN3 was identified to be a critical contributor to pyroptosis and chemosensitivity in ICC. Low NRXN3 expression correlates with poor prognosis and worse therapeutic response. Mechanistically, NRXN3 competitively blocks caspase-3 binding to the RSK1 serine/threonine-protein kinase, thereby inhibiting RSK1-dependent phosphorylation of caspase-3 at T152. Inhibition of caspase-3 phosphorylation impairs its interaction with the ubiquitin ligase component FBXO1 and enhances its stability, thus facilitating caspase-3/GSDME-dependent pyroptotic cell death and chemosensitivity. Furthermore, administration of an RSK1 inhibitor or caspase-3 activator boosts the efficacy of gemcitabine in murine models of ICC. NRXN3 plays a crucial role in maintaining chemotherapy-induced pyroptosis in ICC. Targeting the NRXN3/RSK1/FBXO1/caspase-3 axis emerges as a promising strategy for ICC treatment, with the potential to improve chemosensitivity and survival. 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
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
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
Clutch length is a key determinant of reproductive efficiency in geese and strongly positively correlates with egg production. We recorded daily egg production in 280 individually housed Zi geese, cal Show more
Clutch length is a key determinant of reproductive efficiency in geese and strongly positively correlates with egg production. We recorded daily egg production in 280 individually housed Zi geese, calculated clutch-related indices, and selected 12 geese to form long-clutch (LC) and short-clutch (SC) groups for ovarian transcriptomic, proteomic, and metabolomic analyses. The results showed that egg number, large clutch length, large clutch number, average clutch length, and average clutch number were significantly higher in LC than in SC groups (P < 0.0001). Transcriptomic analysis identified 885 differentially expressed genes enriched in oocyte development and ovarian steroidogenesis, with APOB, PLA2G4C, MMP2, MMP9, and NOBOX as key genes; proteomic analysis identified 437 differentially abundant proteins enriched in arachidonic acid metabolism and mitophagy, with CXCL12, RARB, and MAD2L1 as key proteins; and metabolomic analysis identified 35 differentially abundant metabolites enriched in glycolysis/gluconeogenesis, with lactic acid, guanidinoacetic acid, and 3-hydroxybutyrylcarnitine as key metabolites. Integration of multi-omics datasets highlighted a lactate-associated cross-omics signature supported by YWHAZ at the protein level and by the lactate transporter SLC16A3. Collectively, these findings deepen our understanding of the molecular basis underlying clutch-length variation in goose ovaries and highlight candidate genes, proteins, and metabolites for future functional validation. 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