👤 Liang Gong

Histone deacetylation has been shown to be related to memory decline in aging and neurodegenerative diseases. Chronic stress, which has been shown to induce histone deacetylation, is associated with cognitive impairment. In this study, we hypothesized that histone deacetylation induced by chronic stress contributes to cognitive dysfunction after long-term isoflurane anesthesia. A mouse model of 6-h isoflurane anesthesia was established. The repeated social defeat stress (RSDS) mouse model was established by repeated socialization of aggressive CD-1 mice and C57 mice. Plasma corticosterone levels were measured by ELISA assay. Cognitive function was assessed by the fear condition test. RbAp48-overexpression adenovirus was injected into the ventricles of mice and transfected into primary hippocampal neurons to enhance of RbAp48 expression. Immunofluorescence was employed to detect viral fluorescent protein expression. The expression levels of retinoblastoma-associated protein 48 (RbAp48), histone deacetylase 2(HDAC2), acetylation of H3K9 and H4K12 and brain-derived neurotrophic factor (BDNF) were detected by Western blot. Co-Immunoprecipitation (Co-IP) and Western blot were used to detect the interaction between RbAp48 and HDAC2. Mice inhaling isoflurane for 6 h exhibited more severe impairment of contextual fear memory and sustained elevation of plasma corticosterone levels compared to control group mice. Notably, RSDS mice demonstrated similar behavioral and plasma corticosterone patterns post-isoflurane anesthesia compared to anesthesia group and control group mice, accompanied by decreased acetylation of H3K9 and H4K12, reduced RbAp48 expression, elevated HDAC2 levels, and enhanced RbAp48-HDAC2 interaction. Overexpression of RbAp48 effectively ameliorated these alterations both in vivo and in vitro Perioperative chronic stress exacerbates cognitive dysfunction after 6-h long-term isoflurane anesthesia. The activity of RbAp48/HDAC2-induced histone deacetylation modification plays a critical role in these negative effects on cognition. Show less

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents have become a standard strategy for advanced hepatocellular carcinoma (HCC). There remains an urgent need for effective biomarkers to guide treatment, with C-reactive protein and alpha-fetoprotein in immunotherapy (CRAFITY) scores and cytokine levels representing promising candidates. We aimed to assess the efficacy, safety, and potential biomarkers of anlotinib plus TQB2450 in patients with advanced HCC. This study was a single-arm, phase Ib trial. Twenty-five patients with advanced HCC were enrolled. Patients received an intravenous infusion of TQB2450 (1200 mg, on Day 1) and oral administration of anlotinib (initiated at 10 mg, once a day, from Day 1 to Day 14), which was repeated every 3 weeks. Blood was collected at baseline for serum cytokine analysis. After a median follow-up of 41.80 months, the median progression-free survival (mPFS) was 5.49 months, and the median overall survival (mOS) was 8.94 months. Treatment-related adverse events (TRAEs) occurred in 22 patients, with grade ⩾3 TRAEs observed in 12 patients. Patients who achieved clinical benefit (CB) had higher baseline serum brain-derived neurotrophic factor (BDNF) levels than non-CB patients (median, 227.97 vs 129.26 pg/ml, Anlotinib plus TQB2450 demonstrated promising efficacy with manageable safety in advanced HCC. Elevated serum BDNF levels might serve as a potential positive prognostic marker and, together with ECOG score, may help complement the CRAFITY score in identifying subgroups that could benefit from ICIs and antiangiogenic therapy. Show less

Leptin, a key adipokine regulating energy homeostasis, has been extensively studied for its potential in the management of obesity. However, its therapeutic efficacy is often limited due to leptin resistance. This review synthesizes animal and clinical evidence on leptin's role in obesity, focusing on models such as genetically deficient mice (e.g., ob/ob, db/db), diet-induced obesity mice, and clinical conditions such as congenital leptin deficiency (CLD), leptin receptor deficiency (LRD), lipodystrophy, and common obesity. The mechanisms underlying leptin resistance are summarized, including hyperleptinemia, impaired JAK2-STAT3 signaling, reduced blood-brain barrier permeability, defective autophagy, endoplasmic reticulum stress, inflammation, decreased leptin receptor expression, leptin signaling pathway dysfunction, increased mTOR activity, and peripheral leptin resistance. Due to these leptin receptor and/or post-receptor signaling pathway defects, leptin or its analogs usually fail to produce the expected weight-loss effect in individuals with overweight or obesity, although they remain highly effective in individuals with CLD and lipodystrophy, as well as in ob/ob mice. Alternative strategies, such as melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide) for LRD treatment, are very promising. Future directions include enhancing leptin sensitization, combining leptin with other drugs, and exploring partial leptin reduction to mitigate compensatory responses during weight loss. The review emphasizes the complexity of leptin resistance and the necessity of targeted approaches in obesity therapy. Show less

Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4 Show less

Gallbladder cancer (GBC) is a biliary tract cancer with a poor prognosis. Consistent evidence suggests that fasting has extensive antitumor effects in various cancers and influences levels of poly (rC)-binding protein 2 (PCBP2). However, whether fasting and PCBP2 are involved in GBC remains unknown. We assessed the expression of PCBP2 in GBC tumor tissues and cells. Knockdown and overexpression of PCBP2, combined with in vitro and in vivo assays using fasting mimic medium or diets, were conducted to provide functional significance. The effect of PCBP2 on glycolysis was assessed by glucose uptake, lactate production, oxygen consumption rate, and limiting glycolytic-associated enzymes (PDK1, PKM2, and HK-2). We found that fasting could inhibit glycolysis and cell migration/invasion in GBC cells and that fasting mimic diets could significantly inhibit GBC cell proliferation in a mouse xenograft model. PBCP2 was upregulated in GBC tumor tissues and cells. Moreover, PCBP2 is a key downstream target of fasting, and fasting decreases PCBP2 expression in GBC cells. PCBP2 knockdown inhibits GBC cell proliferation, migration/invasion, and glycolysis, whereas PCBP2 overexpression has the opposite effect. Through co-immunoprecipitation, we identified a physical connection between PCBP2 and the angiopoietin-like protein ANGPTL4. PCBP2 can negatively regulate the expression of ANGPTL4. Hence, fasting inhibits cell proliferation, migration/invasion, and glycolysis through PCBP2/ANGPTL4 signaling. We conclude that PCBP2 is a target of fasting and is involved in cell migration/invasion and glycolysis through the negative regulation of ANGPTL4 in GBC. PCBP2 represents a potential therapeutic target for GBC. Show less

NDRG1, a cell differentiation-associated factor, has recently emerged as a regulator ferroptosis. Nevertheless, its role in modulating ferroptosis within hepatocellular carcinoma (HCC) remains uncharacterized. The differential expression of NDRG1 and its prognostic value were analyzed in HCC using data from TCGA and GEO. Ferroptosis in HepG2 and Huh7 cells was assessed using flow cytometry, transmission electron microscopy, and propidium iodide staining following NDRG1 knockdown using shRNA. RNA-seq was performed to characterize the mRNA expression profiles in HepG2 cells, identifying differentially expressed mRNAs (DE-mRNAs) and NDRG1-related hub genes. NDRG1 was overexpressed in multiple malignant tumors, including HCC, and was associated with a significantly poor prognosis in HCC patients. A nomogram model integrating NDRG1 expression and clinical parameters demonstrated robust prognostic accuracy. NDRG1 knockdown potentiated erastin-induced alterations in Fe NDRG1 exhibits strong predictive value for HCC, and accelerates tumor progression by suppressing ferroptosis. Show less

Lipoprotein lipase (LPL) participates in the development of obesity by regulating triglyceride hydrolysis and fat storage or oxidation. In this study, the anti-obesity effects of lotus seed skin catechins and its mechanisms associated with LPL modulation were demonstrated. In vivo, catechins reduced body weight in high-fat diet-induced obese mice, improved lipid metabolism and antioxidant indices, and modulated LPL activity in adipose and skeletal muscle tissues. The expression of peroxisome proliferator-activated receptor γ (PPARγ) and (angiopoietin-like 4 proteins) ANGPTL4 mRNA and protein was significantly upregulated in epididymal fat depot but downregulated in skeletal muscle tissue. In vitro cell experiments and chromatin immunoprecipitation (ChIP) assays further revealed that the binding sites of PPARγ protein in the ANGPTL4 promoter region were enriched in adipocytes or reduced in skeletal muscle cells in response to catechin treatment. Therefore, lotus seed skin catechins exhibit anti-obesity activity in vivo and in vitro by specifically regulating the activity and expression of LPL in target tissues. Show less

The established body of knowledge attests to the pivotal influence of ANGPTL4 on lipid metabolism and vascular biology. Nevertheless, its potential implication in neurodegenerative disease remains to be fully characterized. The present investigation delves into the involvement of ANGPTL4 in the pathological progression of PD, both in vitro and in vivo. PD models were induced by intraperitoneal administration of MPTP and LPS in WT and ANGPTL4 The observations unveiled that ANGPTL4 deficiency exacerbated behavioral aberrations, intensified dopaminergic neuron loss, and stimulated microglial activation along with p21-dependent senescence. There was an elevation in the expression of proinflammatory cytokines in the PD model. Furthermore, the administration of rANGPTL4 protein reversed the observed phenotypes in ANGPTL4 Our findings posit a salutary role for ANGPTL4 in counteracting PD, rendering it a prospective therapeutic target for the development of innovative drugs aimed at treating neuroinflammation-associated neurological diseases, including PD. Show less

The objective of this study was to assess the correlation between the ApoB/ApoA ratio and the recurrence of kidney stones in a Chinese adult population. We collected electronic records of patients with kidney stones who underwent surgical treatment at our hospital from March 2016 to March 2022. These patients were followed up and categorized into groups based on the recurrence of kidney stones. Parameters related to routine blood and biochemical tests, as well as the history of hypertension and diabetes mellitus, were gathered. Multiple imputation was applied for missing data. Subsequently, differences between the recurrence and non-recurrence groups were assessed using the chi-square test, independent samples t test, or Wilcoxon rank sum test. Logistic regression analysis, subgroup analysis, and propensity-matched analysis were conducted to evaluate the relationship between the ApoB/ApoA ratio and kidney stone recurrence. The study included a total of 923 participants aged > 18 years, among whom 296 experienced kidney stone recurrence during the follow-up period. An elevated ApoB/ApoA ratio was identified as a risk factor for kidney stone recurrence (adjusted OR = 2.48, 95% CI 1.04, 5.92). Propensity-matched analyses further supported the association, showing that elevated ApoB/ApoA ratios were linked to a higher risk of renal stone recurrence (OR = 3.37, 95% CI 1.24-9.17). The dose-response curve illustrated a positive linear correlation between the ApoB/ApoA ratio and the risk of kidney stone recurrence. Increased ApoB/ApoA ratios are positively correlated with the risk of kidney stone recurrence. This association remains significant, although a causal relationship cannot be definitively established. Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Lipids are a principal component of drusen and are involved in the pathobiology of age-related macular degeneration (AMD). Nonhuman primates (NHPs) develop macular drusen and may provide insight into circulating or local lipids in AMD. We evaluated aged rhesus macaques by fundus photography, optical coherence tomography (OCT), and fundus autofluorescence, as well as measured fasting plasma glucose, total cholesterol, high- and low-density lipoproteins, triglycerides, and apolipoprotein (Apo) A1, B, CIII, and E. Retinal tissues were collected for electron microscopy and immunostained for oil red O, ApoE, and ApoB. Among 203 adult macaques (mean age 19.1 ± 3.1 years), 25 animals (12.1%) exhibited soft drusen with sub-RPE deposits, while 59 (28.6%) had yellow punctate dots that were mostly hyperautofluorescent without RPE elevation on OCT. Drusen prevalence increased with older age (P = 0.001) but not with plasma lipids (P > 0.05 for all), while the punctate dot phenotype was associated with older age (P = 0.014), higher fasting glucose (P = 0.023), low-density lipoprotein cholesterol (P = 0.022), and ApoB (P = 0.017). Ultrastructure revealed NHP drusen consisting of extracellular sub-RPE lipid particles, whereas punctate dots appeared to correspond to individual RPE cells with intracellular lipid vacuoles. Both sub-RPE and intra-RPE lipids of the two phenotypes contained neutral lipids and ApoE, while ApoE and ApoB appeared to be expressed in RPE. In rhesus macaques, soft drusen are extracellular lipid deposits associated with older age, while punctate dots are intracellular lipids linked to age, hyperglycemia, and hyperlipidemia, suggesting differential dysregulation of lipid transport in these NHP models of AMD. Show less

Existing evidence suggests that elevated 1-hour post-load plasma glucose (1-h PG ≥ 8.6 mmol/L) during an oral glucose tolerance test (OGTT) is associated with atherogenic lipid parameters which are linked to an increased risk of cardiovascular disease (CVD). However, it remains unclear whether normal glucose tolerance (NGT) individuals with elevated 1-h PG (NGT-1hPG-high) should still be considered low-risk. Therefore, this study aims to demonstrate comprehensive lipid characteristics in individuals with different glycemic status stratified by 1-h PG, with a particular focus on those with NGT-1hPG-high. This cross-sectional study included individuals aged 25-55 years with high-risk of diabetes from the Daqing Diabetes Prevention Study II (Daqing DPS-II). Individuals were categorized into different glycemic status based on the World Health Organization's 1999 criteria and the International Diabetes Federation's 2024 position statement on 1-h PG. Traditional (TC, TG, HDL-C, LDL-C) and non-traditional lipid parameters [ApoA-1, ApoB, sdLDL-C, Lp(a), non-HDL-C, remnant cholesterol (RC), ApoB/ApoA-1, LDL-C/ApoB] were measured. Dyslipidemia was defined according to the 2023 Chinese Guidelines for Lipid Management. The China-PAR equation was used to estimate 10-year CVD risk. Spearman's correlation coefficients were calculated to evaluate the correlation between lipid parameters and 10-year CVD risk. Logistic and multiple linear regression models were performed to assess the association between 1-h PG and dyslipidemia as well as lipid parameters adjusting for covariates. Among 2 469 individuals, 22.7% had NGT with normal 1-h PG (NGT-1hPG-normal), 19.9% had NGT-1hPG-high, 2.6% had prediabetes with normal 1-h PG (PDM-1hPG-normal), 34.2% had prediabetes with elevated 1-h PG (PDM-1hPG-high), and 20.6% had newly diagnosed diabetes. The prevalence of dyslipidemia did not significantly differ between NGT-1hPG-high and PDM-1hPG-high (OR = 1.13, 95%CI: 0.88-1.44, P > 0.05). Higher 1-h PG levels were consistently associated with an atherogenic lipid profile, characterized by increased TC, TG, LDL-C, ApoB, sdLDL-C, non-HDL-C, RC and ApoB/ApoA-1, along with decreased ApoA-1, HDL-C and LDL-C/ApoB (all P < 0.05). Among lipid parameters, TG, sdLDL-C, RC, ApoB/ApoA-1, LDL-C/ApoB and HDL-C showed the strongest correlation with 10-year CVD risk, with Spearman's correlation coefficients of 0.41, 0.38, 0.35, 0.31, - 0.37 and - 0.36, respectively. In the NGT-1hPG-high, TG, sdLDL-C, and ApoB/ApoA-1 levels were significantly higher, while HDL-C and LDL-C/ApoB levels were significantly lower compared to counterparts with NGT-1hPG-normal (all P < 0.05). Moreover, except for TG and RC (both P < 0.01), the majority of lipid parameter levels in NGT-1hPG-high did not significantly differ from those in PDM (all P > 0.05). NGT-1hPG-high exhibited a similar atherogenic lipid profile to that observed in PDM. 1-h PG could serve as a potential indicator for the early identification of at-risk individuals who may otherwise go undetected among NGT population. Show less

Aromatase, encoded by Cyp19a1, is the rate limiting enzyme in biosynthesis of estrogens, and excessive aromatase can reduce the semen quality in roosters. Seminal plasma extracellular vesicles (SPEV) are nanoscale vesicles that carry and transmit signaling molecules, thereby affecting semen quality. Currently it is still unclear whether SPEV are involved in the process of that aromatase affects the quality semen in chicken. To clarify this issue, lentivirus carrying Cyp19a1 (LV-CYP19A1) for over-expression of aromatase was constructed and injected to testis of 35-week-old roosters. Semen quality and seminal plasma hormone were measured, and SPEV were also extracted and proteome sequencing was performed after treatment of LV-CYP19A1. The results indicated that semen volume, fertility, sperm motility, testosterone (T) levels were significantly decreased, and estradiol (E Our results reveal that aromatase can down-regulate the protein expression related to regulation of ATP synthesis and metabolism, and sperm motility in SPEV, thereby reducing semen quality in roosters. Show less

Observational studies have identified a possible connection between lipid-lowering medications and respiratory illnesses. However, it remains unclear whether lipid-lowering drugs is causative for respiratory diseases, and we aimed to answer this question. We performed Mendelian randomization (MR) analyses by integrating data from genome-wide association studies (GWAS). Three statistical approaches were employed for MR analysis: inverse variance weighting (IVW), MR-Egger, and weighted median. The purpose was to evaluate the causal relationships between 10 drug targets that lower lipid levels and the likelihood of developing 7 respiratory diseases. Additional sensitivity analyses were conducted to ensure the robustness and validity of the results. After adjusting for multiple testing, our MR analysis identified APOB (odd ratios [OR]: 0.86; 95% confidence interval [CI]: 0.77 to 0.97; P Our findings suggest a likely causal relationship between respiratory diseases and lipid-lowering drug targets. Further mechanistic and clinical research is needed to confirm and validate these findings. Show less

Patients with dyslipidemia are at higher risk for inflammatory bowel disease (IBD), yet the impact of lipid-lowering medications on IBD remains unclear. This study investigates the causal relationship between lipid-lowering drug target and IBD, with a focus on the roles of gut microbiota and inflammatory cytokines. Genetic variants associated with lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium, whereas summary statistics for IBD, Crohn's disease (CD), and ulcerative colitis were sourced from the International Inflammatory Bowel Disease Genetics Consortium. Drug-target Mendelian randomization analysis revealed that inhibiting angiopoietin-like protein 3 increased the risk of IBD and CD, whereas inhibition of apolipoprotein C-III (APOC3) heightened the risk of CD. Conversely, enhancement of LPL and LDL receptor reduced the risk of IBD and CD. Mediation analysis demonstrated that gut microbiota and inflammatory cytokines partially mediated these effects, with specific pathways such as Lachnospiraceae FCS020 (17.26%) for APOC3 and Clostridium sensu stricto 1 (20.12%) for LPL accounting for significant portions of the effects. These findings suggest that lipid-lowering drugs targeting angiopoietin-like protein 3 and APOC3 may increase the risk of IBD, whereas those targeting LPL and LDL receptor may reduce the risk. The results highlight potential for repurposing lipid-lowering drugs for IBD prevention and warrant future clinical trials to explore these targets further. Show less

Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventual progression to mild cognitive impairment or dementia in individuals with SCD, highlighting the necessity for early detection and intervention. Previous studies have identified the retina and choriocapillaris as potential biomarkers for AD; however, these investigations have not thoroughly examined large and medium-sized choroidal vessels. Ultra-wide swept-source optical coherence tomography angiography (SS-OCTA), an innovative noninvasive imaging modality, facilitates rapid and precise quantitative assessment of retinal and choroidal boundaries and vasculature through dynamic scanning, encompassing large and medium-sized choroidal vessels. This study aims to characterize the outer retinal and choroidal vasculature and structure in individuals with SCD, examine the correlation between altered choroidal vasculature parameters and amyloid burden, and the presence of the apolipoprotein E (APOE) ε4 allele in SCD participants, to identify potential ocular biomarkers for high-risk SCD screening. In this study, 57 individuals with SCD and 45 matched normal controls were enrolled. Ultra-wide SS-OCTA was employed to assess the thickness of the outer retina and choroid and the blood flow within the choriocapillaris and large, medium-sized choroidal vessels. Show less

This study aimed to elucidate the bidirectional causal relationships between Alzheimer's disease (AD), cerebral small vessel disease (CSVD), and the effect of inflammatory cytokines on AD and CSVD using Mendelian randomization (MR). We employed publicly available summary-level data from genome-wide association studies for AD, CSVD, and 91 inflammatory cytokines. Genetic variants strongly associated with each risk factor were selected as instrumental variables. The inverse variance weighted (IVW) method was primarily used for causal inference, with sensitivity analyses including MR-Egger and weighted median estimators. MR analysis revealed that genetically predicted CSVD significantly increased the risk of AD (odds ratio [OR] = 1.035, 95% CI, 1.015-1.056, P = 0.001). Conversely, AD did not significantly influence CSVD risk (OR = 0.878, 95% CI, 0.701-1.100, P = 0.257). Among inflammatory cytokines, Axin1 (OR = 1.082, 95% CI, 1.009-1.159, P = 0.026) and bNGF (OR = 1.061, 95% CI, 1.001-1.125, P = 0.048) increased AD risk, while CD5 (OR = 0.937, 95% CI, 0.887-0.991, P = 0.022) and CXCL11 (OR = 0.951, 95% CI, 0.912-0.992, P = 0.019) decreased AD risk. FGF19 (OR = 0.560, 95% CI, 0.405-0.773, P < 0.001) and TNFSF14 (OR = 0.744, 95% CI, 0.580-0.954, P = 0.020) were protective against CSVD. Our findings suggest that CSVD may increase AD risk, while specific inflammatory cytokines exhibit differential associations with these conditions. Targeting vascular health and inflammation may offer promising therapeutic avenues for managing neurodegenerative diseases. Show less

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by pathogenesis involving numerous factors. Recent research has highlighted the significant role of autoimmunity in the initiation and progression of AD, with autoantibodies emerging as a pivotal area of investigation. Nevertheless, the influence of autoantibodies in AD is marked by substantial heterogeneity, they may either mitigate disease progression by clearing pathogenic protein aggregates or exacerbate the pathological process through mechanisms such as the activation of inflammatory responses or the induction of neuronal damage.ObjectiveThis review aims to synthesize the various roles of autoantibodies in AD, examine the factors that influence their functions, and assess their potential application in precision immunotherapy.MethodsPubMed and Web of Science databases were searched for English-language papers (2015-2025). Peer-reviewed human, animal and cell studies, systematic reviews and meta-analyses were screened independently by two reviewers.ResultsA total of 87 studies were selected for inclusion, spanning human, animal, and cellular research. The findings indicated that certain autoantibodies, such as those targeting amyloid-β, tau, or 4-hydroxynonenal, may confer neuroprotective effects. Conversely, other autoantibodies, including those against BACE1, aquaporin-4, or HuD, may exacerbate AD pathology. Importantly, some autoantibodies were found to exhibit dual roles, contingent upon their specific modifications or the context of the disease.ConclusionsAutoantibodies constitute a double-edged immune axis in AD. Their impact hinges on antigen class, disease stage, isotype affinity and glycosylation. Precision strategies-like CAAR-T cell therapy, glycosylation modulation, and affinity optimization-offer therapeutic promise but require further validation. Show less

To explore the mechanism by which BALB/c mice were infected by intraperitoneal injection with TgCtwh3 wild type (TgCtwh3 WT) and TgCtwh3 Δ BALB/c mice injected with TgCtwh3 Δ Our results indicated that the GRA15 Show less

Pathological cardiac hypertrophy is an independent risk factor for heart failure (HF). Early identification and timely treatment are crucial for significantly delaying the progression of HF. Targeted amino acid metabolomics and RNA sequencing (RNA-seq) were combined to explore the underlying mechanism. In vitro, H9c2 cells were stimulated with angiotensin II (Ang II) or were incubated with extra valine after Ang II stimulation. The branched chain alpha-ketoate dehydrogenase kinase (Bckdk) inhibitor 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) and rapamycin were utilized to confirm the role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in this process. A significant accumulation of valine was detected within hypertrophic hearts from spontaneously hypertensive rats (SHR). When branched chain amino acid (BCAA) degradation was increased by BT2, the most pronounced decrease was observed in the valine level (Δ = 0.185 μmol/g, p < 0.001), and cardiac hypertrophy was ameliorated. The role of imbalanced mitochondrial quality control (MQC), including the suppression of mitophagy and excessive mitochondrial fission, was revealed in myocardial hypertrophy. In vitro, high concentrations of valine exacerbated cardiomyocyte hypertrophy stimulated by Any II, resulting in the accumulation of impaired mitochondria and respiratory chain dysfunction. BT2, rapamycin, and mitochondrial division inhibitor 1 (Mdivi-1) all ameliorated MQC imbalance, mitochondrial damage and oxidative stress in hypertensive models with high valine concentration. Valine exacerbated pathological cardiac hypertrophy by causing a MQC imbalance, probably as an early biomarker for cardiac hypertrophy under chronic hypertension. Show less

(Sb,Bi)(S,Se)(Br,I) pnictogen chalcohalides constitute an emerging family of Van der Waals (VdW) semiconductors with remarkable potential for energy-related applications, including photovoltaics (PV), photocatalysis (PC), and photoelectrocatalysis (PEC). These ternary compounds exhibit a quasi-1D orthorhombic crystalline phase, and an electronic structure analogous to lead-halide perovskites, making them promising candidates for sustainable and high-performance energy devices. This study introduces a new versatile and adaptable synthesis methodology, which combines co-evaporation of binary chalcogenides with reactive annealing under high-pressure halide atmospheres, to fabricate the eight (Sb,Bi)(S,Se)(Br,I) chalcohalides. Comprehensive structural, compositional, and optoelectronic analyses reveal a wide bandgap range (1.2-2.2 eV), high absorption coefficients, and anisotropic properties driven by unique ribbon-like morphology. Theoretical and experimental results highlight their high stability, versatile chemical adaptability, and defect-tolerant characteristics. Moreover, the distinct differences in morphology and crystallization between Sb and Bi-based compounds, as well as the influence of chalcogen and halogen elements on the optical and structural properties are discussed. Demonstrations of functional devices, including photocatalytic systems, underscore the practical viability of these materials. This work establishes a foundation for the development of pnictogen chalcohalides as scalable and eco-friendly alternatives for advanced energy applications. Show less

Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk prediction methods for DM patients complicated with TB (DM-TB) are lacking. This study mined transcriptome data of DM-TB patients from the GEO database (GSE181143 and GSE114192) and used differential analysis, weighted gene co-expression network analysis (WGCNA), intersecting immune databases, combined with ten machine learning algorithms, to identify immune biomarkers associated with DM-TB. An early alert model for DM-TB was constructed based on the identified core differentially expressed genes (DEGs) and validated through a prospective cohort study and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for gene expression levels. Furthermore, we performed a detailed immune status analysis of DM-TB patients using the CIBERSORT algorithm. We identified 1090 DEGs associated with DM-TB and further pinpointed CETP (cholesteryl ester transfer protein) (AUC = 0.804, CI: 0.744-0.864), TYROBP (TYRO protein tyrosine kinase binding protein) (AUC = 0.810, CI: 0.752-0.867), and SECTM1 (secreted and transmembrane protein 1) (AUC = 0.811, CI: 0.757-0.864) as immune-related biomarkers for DM-TB patients. An early alert model was developed based on these three genes (AUC = 0.86, CI: 0.813-0.907), with a sensitivity of 0.80829 and a specificity of 0.75758 at a Youden index of 0.56587. External validation using the GSE114192 dataset showed an AUC of 0.901 (CI: 0.847-0.955). Population cohort research and RT-qPCR verified the expression levels of these three genes, demonstrating consistency with trends seen in the training set. KEGG enrichment analysis revealed that NF-κB and MAPK signaling pathways play crucial roles in the DM-TB pathogenic mechanism, and immune infiltration analysis showed significant suppression of certain adaptive immune cells and activation of inflammatory cells in DM-TB patients. This study identified three potential immune-related biomarkers for DM-TB, and the constructed risk assessment model demonstrated significant predictive efficiency, providing an early screening strategy for DM-TB. Show less

Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Bronchial biopsy specimens were obtained from healthy subjects and patients with severe asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). A selective CDH11 antagonist SD133 (100 mg/kg) was given to allergen-exposed mice after airway challenge. The effects of recombinant CDH11 were also tested in vivo, and FGFR1 inhibition was used to explore a possible mechanism for CDH11-induced inflammatory responses in the lung. We detected upregulated expression of CDH11 in the airway mucosa of severe asthma patients when compared with the healthy control. In the OVA/CFA-induced model, though CDH11 expression in the lung remained unchanged, pharmacological antagonism of CDH11 with SD133 dramatically decreased airway neutrophil accumulation, as well as IL-6 production, but had no effect on eosinophilic infiltration, type 2 inflammation (IL-4 and IL-5) nor airway hyperresponsiveness. In the TDI model, pulmonary CDH11 expression was upregulated. Treatment with SD133 inhibited TDI-induced airway hyperresponsiveness and neutrophilic inflammation, decreased IL-6 and TNF-α production, with no effect on airway eosinophil counts and type 2 inflammatory cytokines. In addition, intratracheal instillation of recombinant CDH11 led to neutrophil recruitment in the lungs of mice, which could be attenuated by inhibition of FGFR1 signaling. CDH11 contributes to airway neutrophilic inflammation in severe asthma through the FGFR1 pathway. Show less

Cardiac hypertrophy is an independent risk factor and the primary predictor of heart failure (HF). Mitochondria are crucial for the shift from hypertrophy to heart failure. The expression of fibroblast growth factor 21 (FGF21), a cardioprotective factor, is increased in patients with cardiac hypertrophy but fails to prevent heart failure. Additionally, the molecular mechanism through which FGF21 exerts its beneficial effects on hypertrophic myocardial mitochondria remains unclear. Our study investigated the effect of FGF21 on cardiac hypertrophy, elucidating its mechanism of action through the enhancement of mitophagy-mediated cardioprotection. A transverse aortic constriction (TAC) model and a phenylephrine (PE) model were applied to explore the effect and mechanism of FGF21. P62-mediated mitophagy inducer (PMI) and rapamycin (Rapa) were used to confirm that FGF21-regulated mitophagy under overload pressure conditions. FGF21 knockout markedly exacerbated TAC-induced cardiac function damage, mitochondrial damage, and mitophagy impairment. In vitro, FGF21 knockdown aggravated PE-induced cardiomyocyte hypertrophy and mitophagy dysfunction. FGF21 treatment promoted mitophagy in the TAC and PE models, but this effect was abolished in the absence of PTEN-induced putative kinase 1 (PINK1). The increase in PINK1 expression induced by Rapa can rescue impaired cardiac function and mitophagy impairment in FGF21-deficient TAC mice. Similarly, PMI enhances mitophagy, which inhibits damage to cardiac functions. A further study revealed that the expression of fibroblast growth factor receptor 1 (FGFR1) and FGF21 was opposite in heart failure. Knockdown of FGFR1 inhibited FGF21-mediated mitophagy. FGF21 promotes PINK1-mediated mitophagy to attenuate cardiac hypertrophy, and mismatched FGFR1 expression may hamper the beneficial effect of FGF21 on cardiac hypertrophy. Show less

Clinical trials have demonstrated Sodium-glucose cotransporter 2 inhibitors (SGLT2i) antihypertensive effects, yet their underlying mechanisms remain to be fully elucidated. Fibroblast growth factor 21 (FGF21) circulating levels are associated with hypertension in humans. This study aims to investigate the roles of SGLT2i and FGF21 in improving hypertension and their potential mechanisms. A mouse model of Ang II-induced hypertension was established. Wild-type (WT) C57BL/6 mice and FGF21 knockout (FGF21 Show less

Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither the core pathway nor the cellular mechanisms underlying these therapeutic effects are known. Here, morphine-induced conditioned place preference (CPP) in mice as an addiction model and NAc-DBS combined with adeno-associated virus gene delivery for activity-dependent tagging, transgenic and chemogenetic manipulation of recruited neuronal networks are used. It is reported that a cortical-accumbal pathway and local fibroblast growth factor 1 (FGF1) signaling in the medial prefrontal cortex (mPFC) are critical for NAc-DBS to be effective in altering morphine CPP. It is shown that NAc-DBS retrogradely activates mPFC neurons projecting to the NAc, and chemogenetic activation/inhibition of these DBS-activated neuron ensembles in the mPFC reproduces the NAc-DBS effects on CPP. Sustained therapeutic effects accompany reductions in local FGF1 binding to fibroblast growth factor receptor 1 (FGFR1) in these neurons. Additionally, overexpressing FGF1 in the mPFC-NAc pathway abolishes the therapeutic effects of NAc-DBS. These results demonstrate that the mPFC-NAc pathway forms a top-down motif to regulate the therapeutic effects of subcortical DBS on addiction. These results support the potential for addiction treatments involving FGF1 signaling and highlight the mPFC as a target for noninvasive brain stimulation. Show less

Calcified chondroid mesenchymal neoplasm (CCMN) is a recently identified category of soft tissue neoplasms defined by cartilage or cartilaginous matrix formation and We conducted a clinicopathological analysis of five newly identified CCMN cases and reviewed 87 cases documented in PubMed. Next-generation sequencing was used to detect molecular alterations, while clinical, radiological and histopathological features were extensively reviewed. CCMN typically affects adults, presenting as a slow-growing, painless mass in soft tissue. Histologically, CCMN exhibits a chondroid matrix with variable calcification. Molecular analyses in our cases identified CCMN should be considered in the differential diagnosis of soft tissue tumours with chondroid and calcified components. Detecting Show less