Sudden sensorineural hearing loss (SSNHL) has serious harm to human hearing health, where blood lipid and inflammatory levels may play a key role in it. Thus, the purpose of this investigation was to Show more
Sudden sensorineural hearing loss (SSNHL) has serious harm to human hearing health, where blood lipid and inflammatory levels may play a key role in it. Thus, the purpose of this investigation was to assess the connection between inflammatory and lipid variables and SSNHL. Patients diagnosed with SSNHL had an analysis of serum lipid parameters, such as total cholesterol (TC), triglycerides, HDL-C, LDL-C, apolipoprotein A (apo A), apolipoprotein B (apo B), and lipoprotein A (Lp(a)), as well as inflammatory factors like TNF-α and IL-10. After that, risk factor analysis was carried out utilizing univariate, multivariate regression, and LASSO retrospective modeling. In all, 72 SSNHL patients and 67 healthy control individuals were involved. The LDL/HDL, total cholesterol, ApoB, LP(a), IL-10, TNF-α, and IFN-γ considerably higher in the SSNHL group than in the healthy control group, however, nervonic acid and coenzyme Q were decreased significantly in SSNHL than Control group. The multivariate logistic regression model's analysis using multifactorial retrospective modeling revealed significant changes in LDL, LDL/HDL, IL-10, and TNF-α. In addition, in the LASSO regression model, the model demonstrated high discrimination, as evidenced by the C-index for the cohort's prediction nomogram, which was 0.998 (95% CI, 0.154-1.115) and confirmed to be 0.925 following bootstrapping validation. Finally, IL-10 and LDL/HDL were the main risk factors in SSNHL. LDL/HDL and IL-10 may be closely related to SSNHL's progress and should be evaluated promptly before treating patients with SSNHL. Show less
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as Show more
While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance. We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors. A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size ≤2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size ≤10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with ≥4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window. Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size ≤2 cm, solid component ≤10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity. Show less
Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Show more
Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Fritillariae Thunbergii Bulbus, Leonuri Herba, and Forsythiae Fructus, has shown efficacy in treating cardiovascular diseases, although its mechanisms are unclear. This study aimed to explore the protective effects of QRSJF against atherosclerosis and the mechanisms involved. The composition of QRSJF was analyzed using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. An 8-week high-fat diet (HFD)-induced atherosclerosis model was established in ApoE Both low- and high-dose QRSJF effectively attenuated dyslipidemia and decreased serum inflammatory cytokine levels in HFD-fed ApoE QRSJF improves dyslipidemia and reduces atherosclerotic plaque in ApoE Show less
Left-behind adolescents in China may face heightened risks of involvement in cyberbullying due to their psychological vulnerability and complex social circumstances. Considering the potential heteroge Show more
Left-behind adolescents in China may face heightened risks of involvement in cyberbullying due to their psychological vulnerability and complex social circumstances. Considering the potential heterogeneity within this population, this study aimed to identify distinct patterns of cyberbullying and cybervictimization among left-behind adolescents and to explore how reactive anger, left-behind patterns, gender, and grade level predict membership in these subgroups. A total of 1,351 junior high school students (752 left-behind, 599 non-left-behind) were recruited from five schools. Latent profile analysis (LPA) was used to identify distinct patterns, and multinomial logistic regression was used to examine the relationships between predictors and various profiles. (1) Three distinct profiles of cyberbullying and cybervictimization were identified among left-behind adolescents. (2) Left-behind adolescents were more likely to experience cybervictimization compared to their non-left-behind peers. (3) Reactive anger, left-behind patterns, gender, and grade level significantly predicted subgroup membership. These findings underscore the importance of developing targeted interventions and considering the specific psychosocial vulnerabilities of left-behind youth. Show less
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an impo Show more
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXRα in AR after liver transplantation (LT) has not been elucidated. We aimed to investigate LXRα anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models. LXRα anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXRα in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT. In this study, we found that LPS can inhibit the expression of LXRα and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXRα agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone. Our results suggest that the activation of LXRα can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages. Show less
Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing Show more
Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this Show more
Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear-localized branched-chain α-ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage-inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin-mediated degradation of RAD51, thereby facilitating HRR-mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p-RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage-inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer. Show less
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported Show more
Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less
To investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship. Mediation Mendelian randomization was p Show more
To investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship. Mediation Mendelian randomization was performed to investigate the causal effect of lipid-modifying drug targets on type 2 diabetes (T2D) outcomes and the proportion of this association that is mediated through ectopic fat accumulation traits. Specific sets of variants in or near genes that encode 11 lipid-modifying drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, LPL, PPARA, ANGPTL3, APOC3, and CETP; for expansion of gene symbols, use search tool at www.genenames.org) were extracted. Random effects inverse variance weighted were performed to evaluate the causal effects among outcomes. Mediation analyses were performed to identify the mediators of the association between lipid-modifying drugs and T2D. The study was conducted from November 10, 2023, to April 2, 2024 RESULTS: The genetic mimicry of HMGCR and APOB inhibition was associated with an increased T2D risk, whereas the genetic mimicry of LPL enhancement was linked to a lower T2D risk. Gluteofemoral adipose tissue volume was a mediator for explaining 9.52% (P=.002), 16.90% (P=.03), and 10.50% (P=.003) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Liver fat was a mediator for explaining 21.12% (P=.005), 12.28% (P=.03), and 9.84% (P=.005) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Our findings support the hypothesis that liver fat and gluteofemoral adipose tissue play a mediating role in the prodiabetic effects of HMGCR and APOB inhibition, as well as in the antidiabetic effects of LPL enhancement. Show less
Yu Zhang, Gang Jiang, Wenrong Feng+4 more · 2025 · Comparative biochemistry and physiology. Part A, Molecular & integrative physiology · Elsevier · added 2026-04-24
The effects of starvation and re-feeding on Jian carp (Cyprinus carpio var. Jian) remain incompletely understood. This study investigated changes in growth performance, liver antioxidant capacity, int Show more
The effects of starvation and re-feeding on Jian carp (Cyprinus carpio var. Jian) remain incompletely understood. This study investigated changes in growth performance, liver antioxidant capacity, intestinal morphology, fatty acid profile, and expression of genes related to lipid metabolism. Juvenile C. carpio var. Jian, with initial body weight of 29.50 ± 2.00 g, were reared in 15 cylindrical culture barrels (200L) at a stocking density of 10 fish per barrel. These fish were subjected to five feeding regimes: a continuous feeding group (control group, treatment A), complete fasting (treatment B), 1, 2, and 3 days starvation within one week, followed by re-feeding 6 days (treatment C), 5 days (treatment D), and 4 days (treatment E). The results indicated significantly lower growth performance in C. carpio var. Jian in treatments B and E compared to the control and treatment C (P < 0.05). Intestinal length (only 627 ± 13.14 μm in treatment B) was significantly reduced, and an increase in vacuoles was observed in C. carpio var. Jian with the prolonged starvation. Antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were significantly (P < 0.05) improved in treatment C when compared with treatments B, D and E.. In contrast, malondialdehyde (MDA) value was lowest (12.62 ± 0.60 nmol/mL) in treatment B. Furthermore, continuous starvation significantly decreased the total lipid and fatty acids contents in the muscle (P < 0.05). Compared with the control group, the reduction of total lipid and fatty acids contents was 31.53 % and 4.57 %, respectively, particularly affecting n3PUFA and n6PUFA. However, after one-day re-feeding, these contents resumed. Lipid metabolism is closely related to fish health, while in the current study, the genes related to lipid metabolism including lipoprotein lipase (LPL), 6-phosphogluconate dehydrogenase (G6PD), and peroxisome proliferator-activated receptor alpha (PPARα) did not differ significantly in treatment C compared to the control group (P > 0.05). In contrast, expressions in treatments B, D, and E were significantly reduced (P < 0.05). Taken together, prolonged starvation (>one day per week) not only affected the growth, which may further disrupt the intestinal structure, weaken antioxidant capacity, but also attenuate lipid deposition. Show less
High-intensity exercise promotes visceral adipose tissue (VAT) breakdown in females via the hypothalamic ERα pathway, and exogenous lactate infusion combined with aerobic training (AT) mimics this eff Show more
High-intensity exercise promotes visceral adipose tissue (VAT) breakdown in females via the hypothalamic ERα pathway, and exogenous lactate infusion combined with aerobic training (AT) mimics this effect. However, whether lactate administration can independently mediate hypothalamic plasticity and VAT catabolism as a standalone nutritional strategy remains unexplored. Firstly, using a two-factor design (Lactate × AT) in female SD rats, we showed that long-term exogenous lactate infusion independently induced co-expression of Estrogen receptor α (ERα) and Brain-derived neurotrophic factor (BDNF) in the ventromedial hypothalamus (VMH) and elevated local field potential spectral power in specific bands. These neural adaptations were accompanied by increased resting metabolic rate, enhanced fat oxidation, and enhanced lipolysis, thereby preventing excessive VAT accumulation induced by a high-fat diet. Furthermore, pharmacological inhibition confirmed that Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-α (PGC-1α) acts as a co-upstream signal of ERα and BDNF mediating this process. Our findings reveal that standalone lactate administration induces functional plasticity and metabolic reprogramming through the VMH PGC-1α-ERα pathway, independent of exercise, and effectively suppresses pathological VAT accumulation in female rats. This study identifies potential nutritional interventions and mechanistic targets for preventing female-centered obesity. Show less
This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to Show more
This study aims to comprehensively analyze the intricate relationship between unsaturated fatty acids (UFAs, particularly omega-3 and omega-6 UFAs) and acne, from their clinical therapeutic effects to their underlying genetic regulatory mechanisms, to elucidate the role of UFAs in acne pathogenesis. Clinical evidence synthesis: we systematically reviewed randomized controlled trials (RCTs) to evaluate the impact of UFA supplementation on acne treatment outcomes. Genetic analysis: two-sample Mendelian randomization (MR) analysis we used to investigate causal relationships between serum UFA metabolites and acne, identifying potential key regulatory enzymes. The synthesis of these RCT studies confirmed that UFA supplementation improved acne conditions. MR analysis revealed causal links between three serum UFA metabolites and acne, with dihomo-gamma-linolenic acid (DGLA) (OR = 8.457; 95% CI: 2.367-30.214; P-value = 0.001) as a risk factor and arachidonic acid (AA) (OR = 0.209; 95% CI: 0.071-0.618; P-value = 0.005) and eicosapentaenoic acid (EPA) (OR = 0.318; 95% CI: 0.102-0.991; P-value = 0.048) as protective factors. Functional annotation suggested enzymes such as Δ5 desaturase (FADS1) and Δ6 desaturase (FADS2) may play a role in acne regulation. This study offers evidence that supports a connection between UFAs and acne, examining this relationship from both clinical and genetic angles. These findings highlight the role of specific UFAs and their associated metabolic enzymes in the development of acne. Omega-3 UFAs seem to have a protective effect against acne, whereas certain types and ratios of omega-6 UFAs might contribute to acne formation. The varied impacts of UFAs on acne could be attributed to disease processes mediated by specific enzymes. However, the study's limitations include its genetic analysis being primarily based on European populations, which limits the applicability of the findings to other groups. Future research should aim to include a more diverse range of participants to improve the generalizability of the results. Show less
Pancreatic ductal adenocarcinoma (PAAD) metastasis is driven by complex tumor-microenvironment interactions. Here, we integrated single-cell and bulk transcriptomic analyses of 104,855 cells from 10 p Show more
Pancreatic ductal adenocarcinoma (PAAD) metastasis is driven by complex tumor-microenvironment interactions. Here, we integrated single-cell and bulk transcriptomic analyses of 104,855 cells from 10 patients to delineate the cellular and molecular landscape of primary versus metastatic PAAD. We identified metastasis-associated epithelial (LMO7⁺, TOP2A⁺, PIGR⁺), fibroblast (IGKC⁺, RGS5⁺), and M2-like macrophage (APOE⁺, CD14⁺, FOLR2⁺, SPP1⁺) subpopulations, validated via bulk deconvolution. Functional analyses revealed upregulated Wnt signaling, epithelial-mesenchymal transition, and angiogenesis in metastatic epithelial and fibroblast compartments. Intercellular communication analysis highlighted SPP1-mediated macrophage-epithelial/fibroblast crosstalk involving key receptor-ligand pairs, contributing to immune suppression and metastatic niche formation. Integrating gene expression and cell proportions, we developed a prognostic model with high predictive accuracy (C-index > 0.85), stratifying patients into risk groups with distinct immune landscapes. Furthermore, PTK6 was identified as a driver of PAAD proliferation, migration, and invasion. Collectively, our study elucidates TME-driven mechanisms of PAAD metastasis, identifies prognostic and therapeutic targets, and provides a framework for precision intervention. Show less
This study aimed to investigate the association between objectively and subjectively measured 24-hour movement behaviors and physical fitness, and explore how the reallocation of time between 24-hour Show more
This study aimed to investigate the association between objectively and subjectively measured 24-hour movement behaviors and physical fitness, and explore how the reallocation of time between 24-hour movement behaviors is associated with changes in physical fitness in adolescents. A total of 690 adolescents aged 14-17 years (55% girls) were included in this cross-sectional study conducted in Foshan, China. Moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior, and sleep were assessed using accelerometers in combination with a questionnaire. Physical fitness was tested through body mass index, forced vital capacity, 50-m sprint, standing long jump, sit-and-reach, gender-specific 800/1000-m run, and pull-ups/sit-ups. MVPA was significantly associated with better performance in the 50-m sprint ( Show less
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, infla Show more
Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect Show more
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect of 24-hour physical activities components on changing Life expectancy among patients with type 2 diabetes diagnosed. To address the abovementioned research gap, the study has a two-fold aims: first, to examine the mediation effect of 24-hour physical activities in type 2 diabetes and mortality; and second, to address how reallocating time on different daily activities would affect life expectancy. Analysis was conducted on the accelerometer data of 103,359 participants in the UK Biobank, with a median age of 57 years (range 39 to 70). Compositional mediation cox model was conducted to analyze the mediating effects of 24-hour physical activities. Additionally, the cohort Life table method was utilized to estimate the changes of Life-years over the next 10 years resulting from the substitution effect of different physical activities. During a mean follow-up of 13.95 (range 2.95-16.28) years, 2,649 deaths were recorded. Diabetes was significantly associated with increased time spent engaging in sedentary behavior (SB), and reduced time spent on moderate-to-vigorous physical activity (MVPA) and light-intensive physical activity (LPA), thereby demonstrating an association with higher mortality risk. The indirect effect of physical activity (HR = 1.27, 95% CI 1.23-1.30) accounted for 41.9% of the total effect of diabetes on mortality. Furthermore, the Life expectancy gains with a maximum of 1.32 years over the next 10 years was found when reallocating SB time to MVPA. The results revealed that 24-hour physical activities might mediate the association between diabetes and mortality. Therefore, promoting participation in MVPA and reducing sedentary activities among diabetes patients was expected to have a positive effect on Life expectancy over the next 10 years. Show less
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a li Show more
Metabolic dysfunction-associated fatty liver disease (MAFLD), driven by dyslipidemia and hepatic lipid deposition, has become a major public health concern. Angiopoietin-like protein 3 (ANGPTL3), a lipoprotein lipase (LPL) activity inhibitor, can inhibit triglycerides (TGs) decomposition, and fibroblast growth factor 21 (FGF21) enhances fatty acids' β-oxidation in liver. We constructed a novel fusion protein combining the anti-ANGPTL3 nanobody FD03 and FGF21 (FD03-FGF21), which exerted appropriate binding affinities to ANGPTL3 and β-Klotho respectively. Our results showed FD03-FGF21 restored bioactivity of LPL which inhibited by ANGPTL3 and activated downstream pathway of FGF21 in iLite FGF21 assay-ready cells. Next, FD03-FGF21 showed a significant therapeutic effect in MAFLD mice, including attenuation of metabolic dyslipidemia, hepatic lipid accumulation, and impaired glucose tolerance. Compared to other treatments, FD03-FGF21 achieved the most significant therapeutic effect with a 79.78 % attenuation of low-density lipoprotein cholesterol (LDL-C) and a 95.8 % reduction of hepatic lipid accumulation. Mechanistically, transcriptomic analysis revealed that differential expression genes (DEGs) were principally clustered into lipid metabolism and oxidative stress pathways after the fusion protein treatment, especially the key lipid metabolism genes of LDLR and CD36 were significantly upregulated and downregulated respectively, as confirmed by WB. Furthermore, lipidomic and metabolomic analysis indicated the fusion protein ameliorated disorders in lipid and protein metabolism mainly through the downregulation of DG and upregulation of PC. Hepatic oxidative stress and inflammation were significantly reduced after administration of the fusion protein in MAFLD mice. Collectively, FD03-FGF21 represents an effective therapeutic strategy for MAFLD therapy through ameliorating lipid metabolism and oxidative stress. Show less
Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the p Show more
Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Show less
Despite the critical role of e-Health literacy (eHL) in modern healthcare, current research predominantly concentrates on conditions such as cancer and diabetes, as well as outpatient care settings. H Show more
Despite the critical role of e-Health literacy (eHL) in modern healthcare, current research predominantly concentrates on conditions such as cancer and diabetes, as well as outpatient care settings. However, there remains a significant gap in studies specifically addressing the eHL needs of patients with maintenance hemodialysis (MHD). This study aims to explore the latent categories of eHL among MHD patients and its impact on health-promoting lifestyle (HPL). A survey was conducted using a convenience sampling method involving 500 MHD patients from three tertiary hospitals in Baoding. Data were analyzed using latent profile analysis (LPA) and a mixed regression model. This study showed that MHD patients could be classified into low (23.17%), middle (49.78%), and high (27.05%) eHL groups, with the three-class model showing optimal fit (AIC = 2321.213, BIC = 2271.168, entropy = 0.967). MHD Patients in the high literacy group scored significantly higher in all dimensions of e-HL and overall HPL (119.58 ± 13.86) compared to those in the low literacy group (91.82 ± 11.73) (all The findings suggest a heterogeneous stratification of eHL among MHD patients, closely linked to HPL. Stratified intervention strategies should be developed for different patient groups to potentially improve their health behaviors. The study provides evidence-based support for personalized health management. Show less
Elevated circulating lactate serves as a critical biomarker in sepsis, yet the epigenetic mechanisms by which lactate influences disease progression remain unclear. This study aims to identify lactate Show more
Elevated circulating lactate serves as a critical biomarker in sepsis, yet the epigenetic mechanisms by which lactate influences disease progression remain unclear. This study aims to identify lactate-associated genes in sepsis, decode their regulatory roles, and assess their potential as therapeutic targets. We performed transcriptome-wide bioinformatic analyses to identify lactylation-related differentially expressed genes (DEGs) between sepsis patients and healthy controls. Pathway enrichment highlighted immune signaling circuits. Five DEGs (ZC3H4, RBM10, PCBP2, RBM25, HNRNPM) were prioritized via ROC analysis, and their combined expression formed a prognostic signature with strong predictive power (AUC > 0.85). Validation in murine sepsis-induced acute lung injury (ALI) models (cecal ligation-puncture and LPS challenge) confirmed significant upregulation of these five genes by qRT-PCR. RBM25 was selected for deeper functional study. Mechanistic assays implicate an RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Notably, we propose the RBM25-Acly axis that couples altered metabolism to histone lactylation and transcriptional reprogramming. Our work uncovers a novel metabolic-epigenetic circuit in sepsis driven by lactylation, with RBM25 and its regulation of ACLY as a key node. The lactylation-based gene signature offers a high-fidelity prognostic tool, and targeting the RBM25-Acly pathway may open new therapeutic avenues. These findings lay a foundation for precision interventions that integrate metabolic and epigenetic strategies in sepsis care. Show less
The feeding rhythm is a major temporal regulator of metabolic physiology, yet its impact on microbiome-derived functional traits relevant to cardiometabolic disease remains insufficiently understood. Show more
The feeding rhythm is a major temporal regulator of metabolic physiology, yet its impact on microbiome-derived functional traits relevant to cardiometabolic disease remains insufficiently understood. Our previous work demonstrated that ad libitum, daytime-restricted, and nighttime-restricted feeding produce markedly different atherosclerotic outcomes in Apoe Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying ef Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)-a bioactive glycoside from Show less
Clinical guidelines recommend the use of statins to reduce portal pressure and alleviate portal hypertension (PH). However, there is a lack of population-level studies on the use of non-statin Low-Den Show more
Clinical guidelines recommend the use of statins to reduce portal pressure and alleviate portal hypertension (PH). However, there is a lack of population-level studies on the use of non-statin Low-Density Lipoprotein Cholesterol (LDL-c) reduction agents for the treatment of PH. This study utilized a novel method, Mendelian Randomization (MR) analysis, to investigate the impact of commonly used LDL-c-lowering medications on PH. Instrumental variables (IVs) for eight lipid-lowering drug-related genes were extracted from three large-scale LDL-c databases of Genome-Wide Association Studies (GWAS), followed by MR analysis. The MR results indicated that, compared to normal individuals, lower expression of CETP and NPC1L1 in whole blood (result of meta-analysis: CETP [OR: 0.322, 95%CI:0.130-0.795, P = 1.396e-02], NPC1L1 [OR: 0.057, 95%CI: 0.022-0.146, P = 2.670e-09]) is associated with reduced portal pressure. The IVs of target genes were subjected to MR analysis with coronary atherosclerosis (CAD) as a positive control, confirming that the IVs can effectively substitute for the biological function of the target gene, thereby further enhancing the reliability of the results. Subsequently, Summary-based Mendelian Randomization (SMR) analysis was conducted by using expression quantitative trait loci (eQTL) data to validate the results of the MR analysis. The SMR results suggested that only NPC1L1 is associated with PH (OR: 0.648, 95%CI: 0.472-0.891, P Show less
The proportion of n-6 and n-3 polyunsaturated fatty acid (PUFA) in commercial pig feed is severely unbalanced. This study was conducted to investigate the effects of different n-6/n-3 PUFA ratios on g Show more
The proportion of n-6 and n-3 polyunsaturated fatty acid (PUFA) in commercial pig feed is severely unbalanced. This study was conducted to investigate the effects of different n-6/n-3 PUFA ratios on growth performance and lipid metabolism of nursery pigs. A total of 240 nursery pigs (Duroc × Large White × Landrace) were fed diets with different n-6/n-3 PUFA ratios, including 10:1, 5:1, 3:1, and 1.5:1. Pigs fed diet with n-6/n-3 PUFA ratio of 1.5:1 or 3:1 had optimum average daily gain and feed to gain ratio ( Show less
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical Show more
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The Show less
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From Show more
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies. Plasma biomarkers, including BCAAs and branched-chain ketoacids (BCKAs), were lowered in vivo with enhanced pharmacodynamic effect upon chronic dosing due to BDK degradation. This molecule improves metabolic and heart failure end points in rodent models. PF-07328948 is the first known selective BDK inhibitor candidate to be examined in clinical studies, with Phase 1 single ascending dose data showing good tolerability and a pharmacokinetic profile commensurate with once-daily dosing. Show less
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be exp Show more
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions. Show less