👤 Guanghui Dong

The etiology of spontaneous abortion (SA) is complex, and the underlying mechanisms remain largely elusive. Environmental toxins have been implicated in the increased occurrence of SA. However, the association between aminomethylphosphonic acid (AMPA) exposure and SA has not yet been established. We found that AMPA, along with the lactate were significantly elevated in villous tissues from SA patients compared to normal controls, with a robust positive correlation between AMPA and lactate concentrations. More importantly, AMPA exposure induced SA in C57BL/6 mice probably through the dysfunctions of human trophoblast cell. Further studies indicated that the L-lactate production which can be induced by AMPA via PPARγ/ANGPTL4 pathway caused similar defects of human trophoblast cells. A global elevation of protein lactylation has been detected in the villous tissues from SA patients as well as AMPA or lactate treated human trophoblast cells. Pan-Kla antibody coimmunoprecipitation coupled with mass spectrometry of AMPA or lactate treated human trophoblast cells revealed JunB, which was reduced in the placenta villus from SA patients and AMPA/lactate treated human trophoblast cells, could be lactylated at lysine (K) 36. JunB K36R mutation abolished JunB lactylation and ameliorated AMPA induced JunB loss via ubiquitination in human trophoblast cells. In comparison to wild type JunB, JunB K36R mutation had better protective roles in AMPA induced trophoblast dysfunctions. In conclusion, our results demonstrate that AMPA exposure promotes lactate production via the PPARγ/ANGPTL4 pathway, which subsequently inhibits the proliferation, migration and invasion of trophoblasts through JunB K38 lactylation, ultimately leading to SA. Show less

Angiopoietin-like protein 4 (ANGPTL4) inhibition is a promising approach to manage atherogenic dyslipidaemia and residual atherosclerotic cardiovascular disease (ASCVD) risk. Human ANGPTL4 loss-of-function (LoF) is associated with reduced plasma triglyceride (TG), remnant cholesterol (RC), and apolipoprotein B (ApoB) levels, and lower risk of type 2 diabetes and ASCVD, without observable safety concerns. However, development of ANGPTL4 inhibitors has been stalled by adverse findings in Angptl4 knockout mice fed a high-saturated-fat diet (HSFD), which show lipid accumulation in mesenteric lymph nodes (MLNs), systemic inflammation, severe adverse clinical signs, and reduced survival. Here, we present the development and preclinical characterisation of MAR001, a humanised monoclonal ANGPTL4 inhibitor antibody. We assessed single-dose MAR001 efficacy in hypertriglyceridemic (HTG) non-human primates (NHPs, n = 4), and safety in two NHP toxicology studies: a 15-week subchronic study with a standard or HSFD (n = 36), and a 9-month chronic study exclusively on an HSFD (n = 24). In HTG monkeys, single-dose MAR001 treatment reduced plasma TG by up to 58%, non-high-density lipoprotein cholesterol by 38%, ApoB by 30%, and RC by 59%. In safety studies, MAR001 was well tolerated without clinically adverse findings with either diet. Animals fed an HSFD exhibited minimal to moderate foamy macrophage formation in MLNs, but importantly, these histological findings did not progress to degeneration, necrosis, inflammation, fibrosis, or other reactive changes, and with no evidence of systemic effects, including no evidence of systemic inflammation or clinical adverse signs. MAR001 improved plasma lipid profiles in NHPs without clinical adversity, even during prolonged HSFD feeding. The favourable NHP safety profile aligns with human ANGPTL4 LoF findings, and contrasts with the severe pathology in mouse knockout models on an HSFD. These findings supported MAR001 clinical studies reported in our concurrent publication, which demonstrated robust lipid improvements without lymphatic pathology. Overall, these findings support continued development of MAR001 as a promising new therapy for ASCVD risk reduction. Marea Therapeutics. Show less

Biliary atresia (BA) is a severe obstructive cholangiopathy of early infancy that progresses to end-stage liver disease without any intervention. The aim of this study was to investigate the impact of drainage obstruction of bile on metabolism-related hepatokines and identify clinical biomarkers of BA. A total of 38 patients with BA and 12 age-matched controls were recruited. Blood samples were obtained for measuring liver function and hepatokine levels. Linear correlations between these changes in hepatokines and bilirubin/bile acid were subsequently examined to explore the hepatokines that may reflect the illness severity. Afterwards, ROC curve analysis was conducted to assess the diagnostic value of the hepatokines. Finally, prognostic analysis of the hepatokines was performed based on early cholangitis, the clearance of jaundice, native liver survival and liver transplantation. The serum concentrations of TB, DB, ALT, AST, GGT, ALP and TBA in patients with BA were all increased compared with those in controls (P < 0.05). The plasma levels of ANGPTL4, HGF, FABP1, FGF21 and FGF23 were elevated in BA patients (P < 0.05), whereas the plasma ANGPTL6 level was decreased in BA patients (P < 0.05). The results of the correlation analysis revealed that ANGPTL6 was negatively linearly correlated with TB and DB and that FGF23 was positively linearly correlated with TBA. ROC curve analysis revealed that the AUC of ANGPTL6 for diagnosing BA was 0.9693, with a sensitivity of 0.8684 and a specificity of 1.0 at an optimal cut-off value of 1140.76 ng/ml. Prognostic analysis revealed that a lower plasma level of ANGPTL6 at KPE was associated with the occurrence of early cholangitis after KPE (P < 0.05). Among all of the hepatokines that were measured in this study, ANGPTL6 may be a potential diagnostic biomarker of BA and may be able to predict the occurrence of early cholangitis. Not applicable. Show less

Respiratory distress syndrome threatens neonates' life. This study probed the predictive value of lung ultrasound scores combined with serum angiopoietin-like protein 4 (ANGPTL4) levels on neonatal respiratory distress syndrome (NRDS) severity and prognosis. The NRDS group (n = 115) and control group (n = 30) were established. In both groups, lung ultrasound scores and serum ANGPTL4 levels, lung ultrasound scores and serum ANGPTL4 levels of newborns with NRDS of different severity, the risk factors affecting the poor prognosis of NRDS neonates, and the value of serum ANGPTL4 levels combined with lung ultrasound scores in determining the severity and prognosis of newborns with NRDS were analyzed. The NRDS groups had higher lung ultrasound scores and serum ANGPTL4 levels, and lower Apgar scores than the control group; lung ultrasound scores and serum ANGPTL4 levels were higher in the moderate and severe groups than in the mild group, and those were higher in the severe group than in the moderate group (all Lung ultrasound scores and serum ANGPTL4 levels are closely related to the severity and prognosis of NRDS neonates, and the combination of the two improves the assessed value of the severity and prognosis of NRDS neonates. The study provided a reference for the disease severity assessment of NRDS and the prediction of its prognosis. Show less

Muscle atrophy, including glucocorticoid-induced muscle wasting from treatments such as dexamethasone (DEX), results in significant reductions in muscle mass, strength and function. This study investigates the potential of lonafarnib, a farnesyltransferase inhibitor, to counteract DEX-induced muscle atrophy by targeting key signalling pathways. We utilized in vitro models with C2C12 myotubes treated with DEX and in vivo models with Caenorhabditis elegans and DEX-treated Sprague-Dawley rats. Myotube morphology was assessed by measuring area, fusion index and diameter. Muscle function was evaluated by grip strength and compound muscle action potential (CMAP) in the gastrocnemius (GC) and tibialis anterior (TA) muscles. Molecular mechanisms were explored through RNA sequencing and Western blotting to assess changes in mitochondrial function and muscle signalling pathways. Lonafarnib (2 μM) significantly improved myotube area (1.49 ± 0.14 × 10 Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings. Show less

Pulmonary nodule with diameters ranging 8-30 mm has a high occurrence rate, and distinguishing benign from malignant nodules can greatly improve the patient outcome of lung cancer. However, sensitive and specific liquid-biopsy methods have yet to achieve satisfactory clinical goals. We enrolled three cohorts and a total of 185 patients diagnosed with benign (BE) and malignant (MA) pulmonary nodules. Utilizing data-independent acquisition (DIA) mass spectrometry, we quantified plasma proteome from these patients. We then performed logistic regression analysis to classify benign from malignant nodules, using cohort 1 as discovery data set and cohort 2 and 3 as independent validation data sets. We also developed a targeted multi-reaction monitoring (MRM) method to measure the concentration of the selected six peptide markers in plasma samples. We quantified a total of 451 plasma proteins, with 15 up-regulated and 5 down-regulated proteins from patients diagnosed as having malignant nodules. Logistic regression identified a six-protein panel comprised of APOA4, CD14, PFN1, APOB, PLA2G7, and IGFBP2 that classifies benign and malignant nodules with improved accuracy. In cohort 1, the area under curve (AUC) of the training and testing reached 0.87 and 0.91, respectively. We achieved a sensitivity of 100%, specificity of 40%, positive predictive value (PPV) of 62.5%, and negative predictive value (NPV) of 100%. In two independent cohorts, the 6-biomarker panel showed a sensitivity, specificity, PPV, and NPV of 96.2%, 35%, 65.8%, and 87.5% respectively in cohort 2, and 91.4%, 54.2%, 74.4%, and 81.3% respectively in cohort 3. We performed a targeted LC-MS/MS method to quantify plasma concentration of the six peptides and applied logistic regression to classify benign and malignant nodules with AUC of the training and testing reached 0.758 and 0.751, respectively. Our study identified a panel of plasma protein biomarkers for distinguishing benign from malignant pulmonary nodules that worth further development into a clinically valuable assay. Show less

Liver diseases are a major contributor to both morbidity and mortality. Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal. The use of floxed rat resource has rapidly increased, but the liver-specific Cre rat lines for studying liver diseases and interested genes are limited, especially in a spatially and temporally restricted manner. RNA sequencing and real-time polymerase chain reaction (PCR) were used to screen and confirm the presence of liver-specific genes. Apoa4-Cre rats and Cyp2c11-Cre rats were produced by CRISPR/Cas9 knockin. Rosa26-imCherry rats were employed to hybridize with the Cre rats to obtain the Apoa4-Cre/Rosa26-imCherry and Cyp2c11-Cre/Rosa26-imCherry rats. The temporal and spatial patterns of Cre expression were determined by the observation of red fluorescence on tissue sections. Hematoxylin-eosin stain was used to evaluate the liver histopathologic changes. The blood biochemical analysis of several liver enzymes and liver lipid profile was performed to evaluate the liver function of Cre rats. Apoa4 and Cyp2c11 were identified as two liver-specific genes. Apoa4-Cre and Cyp2c11-Cre rats were produced and hybridized with Rosa26-imCherry rats. The red fluorescence indicated that the Cre recombinases were specially expressed in the juvenile and adult liver and not in other organs of two hybridized rats. All the blood biochemical parameters except low-density lipoprotein (LDL) did not change significantly in the Cre rats. No histological alterations were detected in the livers of the Cre rats. Liver-specific Apoa4-Cre and Cyp2c11-Cre rats have been established successfully and could be used to study gene knockout, specifically in juvenile and adult liver. Show less

Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanisms of carcinogenesis. Here, we developed geMER to identify candidate driver genes genome-wide by detecting mutation enrichment regions within coding and non-coding elements. We subsequently designed a pipeline to identify a core driver gene set (CDGS) that broadly promotes carcinogenesis across multiple cancers. CDGS comprising 25 genes for 25 cancers displayed instability in DNA aberrations. Variants within the TTN enrichment region may influence the folding of the I-set domain by altering local polarity or side-chain chemistry properties of amino acids, potentially disrupting its antigen-binding capacity in LUAD. Multi-omics analysis revealed that APOB emerged as a candidate oncogene in LIHC, whose genetic alterations within the enrichment region may activate key TFs, upregulate DNA methylation levels, modulate critical histone modifications, and enhance transcriptional activity in the HepG2 and A549 cell lines compared to Panc1. Additionally, CDGS mutation status was an independent prognostic factor for the pan-cancer cohort. High-risk patients tended to develop an immunosuppressive microenvironment and demonstrated a higher likelihood of responding to ICI therapy. Finally, we provided a user-friendly web interface to explore candidate driver genes using geMER ( http://bio-bigdata.hrbmu.edu.cn/geMER/ ). Show less

Patients with schizophrenia (SCZ) face multiple health challenges due to the complication of chronic diseases and psychiatric disorders. Among these, cardiovascular comorbidities are the leading cause of their life expectancy being 15-20 years shorter than that of the general population. Identifying comorbidity patterns and uncovering differences in immune and metabolic function are crucial steps toward improving prevention and management strategies. A retrospective cross-sectional study was conducted using electronic medical records of inpatients discharged between 2015 and 2024 from a municipal psychiatric hospital in China. The study included patients diagnosed with Schizophrenia, Schizotypal, and Delusional Disorders (SSDs) (ICD-10: F20-F29). Comorbidity patterns were identified through latent class analysis (LCA) based on the 20 most common comorbid conditions among SSD patients. To investigate differences in peripheral blood metabolic and immune function, linear regression or generalized linear models were applied to 44 laboratory test indicators collected during the acute episode. The Benjamini-Hochberg method was used for p-value correction, and the false discovery rate (FDR) was calculated, with statistical significance set at FDR < 0.05. Among 3,697 inpatients with SSDs, four distinct comorbidity clusters were identified: SSDs only (Class 1), High-Risk Metabolic Multisystem Disorders (Class 2, n = 39), Low-Risk Metabolic Multisystem Disorders (Class 3, n = 573), and Sleep Disorders (Class 4, n = 205). Compared to Class 1, Class 2 exhibited significantly elevated levels of apolipoprotein A (ApoA; β = 90.62), apolipoprotein B (ApoB; β = 0.181), mean platelet volume (MPV; β = 0.994), red cell distribution width-coefficient of variation (RDW-CV; β = 1.182), antistreptolysin O (ASO; β = 276.80), and absolute lymphocyte count (ALC; β = 0.306), along with reduced apolipoprotein AI (ApoAI; β = -0.173) and hematocrit (HCT; β = -35.13). Class 3 showed moderate increases in low-density lipoprotein cholesterol (LDL-C; β = 0.113), MPV (β = 0.267), white blood cell count (WBC; β = 0.476), and absolute neutrophil count (ANC; β = 0.272), with decreased HCT (β = -9.81). Class 4 was characterized by elevated aggregate index of systemic inflammation (AISI; β = 81.07), neutrophil-to-lymphocyte ratio (NLR; β = 0.465), and systemic inflammation response index (SIRI; β = 0.346), indicating a heightened inflammatory state. The comorbidity patterns of patients with SCZ can be distinctly classified. During the acute episode, those with comorbid metabolic disorders exhibit a higher risk of cardiovascular diseases and immune system abnormalities, while patients with comorbid sleep disorders present a pronounced systemic inflammatory state and immune dysfunction. This study provides a basis for the chronic disease management and anti-inflammatory treatment, while also offering objective biomarker insights for transdiagnostic research. Show less

The association between low-density lipoprotein (LDL) cholesterol and increased mortality risk has been well-documented, yet apolipoprotein B (apoB) is regarded as a more precise risk indicator. However, a comprehensive analysis integrating both markers in relation to mortality risk remains unreported. This study aimed to investigate the relationship between LDL cholesterol levels and mortality across varying apoB concentrations within the general population. Data from 15,380 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) were utilized to construct Cox regression models and apply restricted cubic splines, assessing the association between LDL cholesterol and mortality across distinct apoB stratifications. The study cohort had a median (IQR) age of 46.0 (32.0, 60.0) years, with 7949 (51.8%) males. During a median follow-up of 101.0 months (IQR: 67-137), 1771 (8.8%) all-cause mortality events were observed; 443 (2.1%) deaths were attributed to cardiovascular diseases, while 109 (0.5%) resulted from cerebrovascular diseases. Low apoB and LDL-cholesterol levels were independently linked to an elevated risk of all-cause and cardiovascular mortality. Compared with participants having apoB <90 mg/dL and LDL-cholesterol levels between 100-129 mg/dL, those with LDL-cholesterol <70 mg/dL (HR, 1.81; 95%CI: 1.39-2.36) and 70-99 mg/dL (HR, 1.28; 95%CI: 1.01-1.62) demonstrated a higher risk of all-cause mortality. Additionally, reduced apoB levels contributed to an increased risk of cardiovascular mortality among individuals with low LDL-cholesterol levels. Low apoB and LDL-cholesterol levels were associated with heightened all-cause and cardiovascular mortality risk in the general population. Conversely, high apoB and low LDL-cholesterol levels did not correlate with increased mortality risk. Show less

To assess the value of preoperative peripheral blood inflammatory and nutritional parameters in distinguishing between benign and malignant parotid gland tumors. A retrospective analysis was conducted on 79 patients with malignant parotid gland tumors and 79 patients with benign parotid gland tumors who were treated at the Second Hospital of Dalian Medical University from January 2015 to December 2024. Preoperative levels of total protein (TP), prealbumin (PA), albumin (Alb), albumin-to-globulin ratio (AGR), apolipoprotein A1-to-apolipoprotein B ratio (ApoA1/ApoB), and platelet-to-lymphocyte ratio (PLR) were compared between the malignant and benign tumor groups. The diagnostic value of these parameters in differentiating between benign and malignant parotid tumors was evaluated. The ApoA1/ApoB ratio and PLR were significantly higher in the malignant tumor group compared to the benign tumor group (P < .05). Conversely, TP, Alb, PA, and AGR were significantly lower in the malignant tumor group than in the benign tumor group (P < .05). Binary logistic regression analysis identified TP, PA, AGR, and ApoA1/ApoB as independent risk factors for parotid malignancy (P < .05). The optimal cut-off values for diagnosing parotid malignancy were 65.75 for TP, 248.46 for PA, 1.55 for AGR, and 1.45 for ApoA1/ApoB. Preoperative peripheral blood inflammatory and nutritional markers may serve as valuable indicators for differentiating between benign and malignant parotid gland tumors, providing a potential adjunctive diagnostic tool. However, further large-scale studies are required to validate these findings. Show less

To investigate the correlation between uric acid (UA), lipid levels, and preeclampsia (PE), as well as their effect on pregnancy outcome in women in late pregnancy. A retrospective analysis was conducted on the clinical data from 126 pregnant women with PE who were admitted to the First Affiliated Hospital of Xi'an Medical University from June 2021 to January 2024 (research group). Additionally, clinical data from 130 healthy pregnant women who gave birth during the same period were served as controls. General information, UA levels, blood lipid levels [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), free fatty acids (FFA), lipoprotein-a (Lp-a), apolipoprotein-a1 (ApoA1), apolipoprotein B (ApoB), LDL-C/HDL-C, and ApoA1/ApoB] and pregnancy outcomes were compared between the two groups. A logistic regression model was used to identify the influencing factors for PE. The predictive value of UA and lipid levels for PE diagnosis and prognosis was evaluated using receiver operating characteristic (ROC) curve analysis. No significant differences were observed between the groups in terms of age, parity, mode of delivery, neonatal gender, gestational cardiac disease, HDL-C, FFA, ApoA1, or ApoA1/ApoB (all P>0.05). However, the research group exhibited significantly higher body mass index (BMI), prevalence of gestational diabetes, and gestational hypertension, UA, TC, TG, LDL-C, Lp-a, ApoB, and LDL-C/HDL-C ratio compared to the control group, but lower neonatal weight (all P<0.05). Furthermore, the research group had a higher incidence of gestational diabetes, gestational hypertension, postpartum hemorrhage, fetal growth retardation, preterm delivery, and neonatal asphyxia (all P<0.05). Multivariate logistic regression analysis identified BMI, neonatal weight, UA, TC, TG, and LDL-C as independent influencing factors for PE. ROC curve analysis demonstrated high diagnostic accuracy for BMI (AUC=0.835), neonatal weight (AUC=0.755), UA (AUC=0.765), TC (AUC=0.706), and LDL-C (AUC=0.792) in predicting PE. Maternal BMI, neonatal weight, serum UA, TC, TG, and LDL-C levels are risk factors for the development of PE. Among these, BMI, neonatal weight, serum UA, TC, and LDL-C levels have a high predictive value for PE and can serve as valuable indicators for its early prediction and management. Show less

Lipoprotein subclasses and high-density lipoprotein (HDL) functions are associated with atherosclerotic cardiovascular disease (ASCVD), but researches on them in patients with nephrotic syndrome (NS) are limited. The aims of this study were (1) to analyze the changes in quantity and quality of lipoprotein in patients with idiopathic nephrotic syndrome (INS) and patients in remission from NS, and (2) to evaluate the lipid-related atherosclerotic risk in these patients. 51 patients with idiopathic nephrotic syndrome (NS group), 72 NS patients with complete remission (NS remission group), and 80 healthy controls (control group) were recruited. The levels of conventional lipids, lipoprotein subclasses, including VLDL, IDL (C, B, A), LDL (LDL1-7), HDL (large, intermediate, small) and HDL cholesterol efflux capacity (CEC), were measured and compared across the three groups. Conventional lipid parameters [TG, TC, LDL-C, apo-B and Lp(a)] and lipoprotein subclasses (VLDL, IDL-C, IDL-B, LDL-2 and sdLDL) were higher in NS group when compared to NS remission group and control group (P < 0.05). CEC in NS group was significantly lower than that in control group [21.0 (18.3-27.2) % vs 25.7 (23.3-28.9) %] (P < 0.001) and improved to 22.8 (20.6-23.7) % in NS remission group with the disease recovery. Proatherogenic changes in conventional lipid parameters, lipoprotein subclasses and HDL-CEC were observed in patients with NS, suggesting that more rigorous lipid regulation strategies may help reduce cardiovascular disease risk in patients with NS. Show less

Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD. A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq). G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus. This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD. Show less

As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, particularly atherosclerosis, remain unclear. This study aimed to explore the effects of IL-38 on atherosclerosis progression and its mechanisms in regulating macrophage function during the atherosclerotic process. To evaluate the therapeutic potential of IL-38 in atherosclerosis, we performed histopathological examinations and biochemical analyses in vivo. In vitro, we used primary bone marrow-derived macrophages (BMDMs) stimulated with oxidized low-density lipoprotein (ox-LDL) to assess the anti-inflammatory effects of IL-38 and quantified its impact on ox-LDL-induced macrophage polarization. To further elucidate the specific mechanisms by which IL-38 regulates macrophage function, we conducted mRNA sequencing and validated downstream regulatory signaling pathways. IL-38 exhibited therapeutic potential in atherosclerosis by reducing atherosclerotic plaque formation, modulating plaque composition, suppressing the production of proinflammatory cytokines within plaques, and potentially regulating macrophage cholesterol metabolism. Moreover, IL-38 exerted significant anti-inflammatory effects on macrophages both in vivo and in vitro. Notably, it inhibited the polarization of macrophages toward the proinflammatory M1-like phenotype in both settings. Additionally, IL-38 impeded the phosphorylation and nuclear translocation of p65 in BMDMs and reduced ox-LDL-induced macrophage apoptosis. IL-38 holds therapeutic potential for atherosclerosis, as it alleviates disease progression, inhibits macrophage polarization toward the M1-like phenotype, suppresses nuclear factor-κB (NF-κB) signaling activation, and reduces macrophage apoptosis. This study provides new insights into the anti-inflammatory mechanisms by which IL-38 mitigates atherosclerosis. Show less

Metabolic reprogramming is a hallmark of cancer; however, the mechanisms driving metabolic heterogeneity across diverse cell types in the tumor microenvironment remain poorly understood. Most existing methods predict metabolic states at the pathway level but rarely map reaction-level alterations to their upstream regulators, thereby constraining both interpretability and translational relevance. We developed MetroSCREEN, a reference-guided computational framework that infers reaction-level metabolic flux propensity and nominates upstream regulators from bulk and single-cell transcriptomes. MetroSCREEN uses a fast enrichment-based procedure to quantify reaction-level metabolic activity. To characterize metabolic regulons, it integrates intrinsic gene-regulatory signals with extrinsic cell-cell interaction cues, then applies a robust multi-evidence ranking scheme to combine these information sources, and finally employs a constraint-based causal discovery module to infer regulatory directionality. MetroSCREEN accurately predicts reaction-level metabolic activities and their upstream regulators, as demonstrated using paired transcriptomic-metabolomic datasets from the cancer cell lines. We further validated predicted regulators with in-house single-cell CRISPR screens in PC9 cells targeting metabolic regulators. Applying MetroSCREEN to a pan-cancer single-cell atlas of more than 700,000 fibroblasts and myeloid cells across 36 cancer types, we identified ZNF281 and STAT1 as key regulators of collagen metabolism, which is elevated in extracellular-matrix-associated fibroblasts and macrophages at tumor margins. By contrast, APOE and KLF7 regulate sphingolipid metabolism and antigen presentation in macrophages. Leveraging extensive tumor profiles, MetroSCREEN also delineates metabolic subtypes and regulators associated with patient survival and response to immunotherapy. MetroSCREEN is a robust and scalable approach for characterizing metabolic heterogeneity and pinpointing metabolic regulators at single-cell resolution, unveiling novel antitumor targets for future metabolic interventions. The source codes of MetroSCREEN is available at the Github site https://github.com/wanglabtongji/MetroSCREEN . Show less

The active ingredients of Traditional Chinese Medicine with diverse structures exhibited anti-inflammatory and lipid lowering functions, demonstrating significant therapeutic effects in inflammatory diseases of atherosclerosis. We incorporate Astaxanthin (AST) and Dihydroartemisinin (DHA) into PLGA NPs to synthesized HA@PLGA@AST/DHA NPs (HPAD NPs) for alleviating atherosclerosis. In vitro assay indicated that the designed HPAD NPs promoted cholesterol efflux of macrophages by enhancing selective lipophagy, which is benefit to lipid antigen degradation. Meanwhile, HPAD NPs regulated T-cell differentiation and crucially induced macrophages from pro-inflammatory M1 type to anti-inflammatory M2 type. In vivo study demonstrated that HPAD NPs decreased the necrotic core dimension and improved plaque stability in ApoE Show less

Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-κB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its degradation through ubiquitin-proteasome and autophagy-lysosomal pathways. BAG3 Show less

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD. Show less

Diabetes constitutes a risk factor for cognitive impairment, whereas insulin resistance serves as the shared pathogenesis underlying both diabetes and cognitive decline. The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin's efficacy in reducing blood sugar levels, improving insulin sensitivity, and ameliorating cognitive impairment in diabetic rats. Additionally, it reduced the required dosage of metformin to one-third of its conventional dose. Transcriptome analysis and 16S rRNA sequencing revealed that the activation of insulin and cyclic-adenosine monophosphate response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathways benefited from the regulation of gut microbiota and the promotion of short-chain fatty acid (SCFA) producers such as Show less

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans. Show less

Cardiovascular diseases are one of the major health threats to humans. Researchers have proposed numerous deep learning-based methods for the automatic analysis of electrocardiogram (ECG), achieving encouraging results. However, many existing methods are limited to task-specific model training and require retraining or full fine-tuning when confronted with a new ECG classification task, thus lacking flexibility in clinical applications. In this study, we propose a Task-Adaptive Classification method for ECG (TAC-ECG) based on cross-modal contrastive learning and low-rank convolutional adapters. TAC-ECG comprises two main phases. In the first phase, inspired by the Contrastive Language-Image Pre-training, we design the Contrastive ECG-Text Pre-training (CETP) to pre-train a robust ECG encoder. In the second phase, the pre-trained ECG encoder is frozen and integrated with a lightweight plug-in, the Low-Rank Convolutional Adapter (LRC-Adapter), forming an extensible ECG classification model. The frozen encoder extracts more discriminative features from the ECG signal, while the LRC-Adapter enables task-specific adaptation. For diverse ECG classification tasks, TAC-ECG only requires training the LRC-Adapter. This mechanism enables TAC-ECG to efficiently perform different ECG classification tasks, significantly reducing resource consumption and deployment costs in multi-tasking scenarios compared to traditional fully fine-tuned methods. We conducted extensive experiments using six different network architectures as ECG encoders. Specifically, we performed ECG classification experiments on four datasets: CPSC2018, Cinc2017, PTB-XL, and Chapman, targeting 9-category, 3-category, 5-category, and 4-category classifications respectively. The TAC-ECG achieved highly competitive results using only approximately 3% of the trainable parameters and approximately 25% of the total parameters compared to the fully fine-tuned method. These results demonstrates the effectiveness and practicality of the TAC-ECG method. The TAC-ECG offers a flexible and efficient method for ECG classification, enabling rapid adaptation to diverse tasks and enhancing clinical diagnostic practicality. Show less