👤 Zichao Zheng

This study investigates the relationships between melanocortin-4 receptor (MC4R) rs17782313 gene polymorphisms, low-fat diet, aerobic exercise, and the reduction in blood lipid levels in individuals with obesity. A total of 240 adults living with obesity were enrolled to take part in a 12-week program that combined exercises with dietary interventions. Measurements taken included body weight, body mass index (BMI), plasma lipids, fasting insulin (FIN), and insulin resistance (Homeostasis Model Assessment, HOMA-IR). All participants underwent exercise intervention and genotyping. Our findings revealed significant interactions between genotype, sex, and diet in modulating lipid metabolism. Specifically, after the exercise intervention, the mean reduction in BMI in was: CC+CT with low-fat diet: -2.56 ± 1.98 kg/m The CC+CT genotype group, particularly males on a low-fat diet, showed robust improvements in TG, LDL-C, and insulin resistance markers. However, HDL-C responses were inconsistent across subgroups. Notably, males with the CC+CT allele exhibited the most pronounced benefits in LDL-C reduction and HOMA-IR improvement with a low-fat diet. Show less

This study established a polymerase chain reaction-lateral flow dipstick (PCR-LFD) method for the visual detection of SNP genotypes. Targeting the MC4R gene SNP g.732 C > G, highly specific primers were designed for the mutation site, incorporating a Locked Nucleic Acid (LNA) modification at the 3' terminal nucleotide of the SNP, a BIOTIN modification at the 5' end of the upstream primer, and a fluorescein isothiocyanate (FITC) modification at the 5' end of the downstream primer. The detection primers were used for PCR amplification with the sample, and the reaction system was optimized. The amplification products were subsequently detected using LFD. The results demonstrated that the optimized reaction system and modified primers effectively distinguished among CC, CG, and GG genotypes at the g.732 C > G. Blood samples from 24 Hu sheep were analyzed using the PCR-LFD assay specific to this SNP. The genotyping results from PCR-LFD were completely consistent with those obtained from the mutation analysis of the same blood samples. The PCR-LFD method established in this study did not require genomic DNA extraction; whole blood could be directly used as a template for PCR amplification combined with LFD, enabling on-site visual detection. This positions PCR-LFD as a rapid, simple, and visually interpretable tool for on-site SNP genotyping. Show less

The constitutive activity of melanocortin receptors (MCRs) is integral to several physiological processes. The unliganded cryo-electron microscopy structures of MC1R, MC2R, MC3R, MC4R, and MC5R in complex with G Show less

Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system. Show less

Atherosclerosis, a progressive inflammatory disease and the leading cause of cardiovascular disease (CVD), remains a global health burden due to the lack of effective early therapeutic interventions. Although growing evidence highlights the involvement of plasma proteins in atherogenesis, their causal contributions to disease pathogenesis are poorly understood. To address this gap, we conducted a proteome-wide Mendelian randomization (MR) analysis using cis-pQTLs (cis-protein quantitative trait loci) from the deCODE and UKB-PPP cohorts (~90,000 individuals) as instrumental variables. We integrated colocalization analysis, summary-data-based MR (SMR), and HEIDI tests to systematically prioritize causal plasma proteins. Key findings were replicated in the CARDIOGRAMplusC4D (coronary artery disease, CAD) and FinnGen (CVD) cohorts. Functional validation was performed through phenome-wide association studies (PheWAS), single-cell transcriptomics, histological staining, and ELISA assays to characterize protein expression patterns in specific cell types and tissues. Among 2,711 plasma proteins analyzed, 28 showed strong genetic associations with atherosclerosis. Of these, five proteins (ADK, ANGPTL4, CD4, MGAT1, SYT11) met strict validation criteria through colocalization (posterior probability of colocalization, PP.H4 > 0.8) and SMR. Subsequent replication using MR and PheWAS further confirmed the causal roles of ADK, CALB2, and COMT in CAD and other CVD outcomes. Notably, CALB2 was specifically enriched in mast cells within atherosclerotic plaques and adipose tissue, and plasma levels were significantly elevated in patients with severe carotid artery stenosis (CAS). This study identifies 28 novel therapeutic targets for atherosclerosis using a rigorous multi-omics approach. Our findings establish CALB2 as a promising biomarker and therapeutic target, particularly in severe CAS, by linking genetic evidence to cell-type-specific expression and clinical phenotypes. These insights pave the way for precision medicine approaches in the prevention and treatment of CVD. The online version contains supplementary material available at 10.1186/s12967-025-07269-6. 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

Angiopoietin-like protein 4 (ANGPTL4) is critical for vascular integrity and reducing inflammation in ischemic and hypoxic brain injuries. However, limited studies have evaluated ANGPTL4's role in acute ischemic stroke (AIS) assessment, and its expression patterns across AIS phases remain unclear. The severity of AIS at admission was assessed using the National Institutes of Health Stroke Scale (NIHSS). The association between serum ANGPTL4 level and the occurrence of AIS was examined using logistic regression analysis. The diagnostic accuracy of serum ANGPTL4 level for AIS severity was assessed using receiver operating characteristic curves. This study included 389 AIS patients and 133 healthy individuals. There was a notable increase in the occurrence of AIS associated with rising serum ANGPTL4 levels (odds ratio [OR] 1.03, 95% confidence interval [CI]: 1.02-1.06; p < 0.001). A higher serum level of ANGPTL4 was also found to be associated with severe AIS, as indicated by an AUC of 0.848. Additionally, we observed significant dynamic changes in ANGPTL4 levels, with a marked decrease at 1 week or 2 weeks after admission compared with the acute phase (the day after admission; both p < 0.001). Our findings suggest a robust association between elevated serum ANGPTL4 levels and the presence and severity of AIS. Importantly, this study is distinguished by its novel focus on the temporal dynamics of ANGPTL4 levels, which underscores its potential as a biomarker for AIS monitoring and provides new insights into AIS pathophysiology. Show less

Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker α-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β. In injury-induced mouse disc degeneration model, fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45 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 potential impact of lifestyle changes such as prolonged fasting on brain health still remains unclear. Neurodegenerative diseases often exhibit two key hallmarks: accumulation of misfolded proteins such as amyloid beta oligomers (AβO) and intracellular cholesterol accumulation. In this study, we investigate how a 36-h fast affects the capacity of isolated high-density lipoproteins (HDLs) to modulate the effects of AβO and excess cholesterol in microglia. HDL from 36-h fasted individuals were significantly more effective in effluxing cholesteryl esters from treated microglia, showing a remarkable 10-fold improvement compared to HDL from the postprandial state. Furthermore, the ability of 36-h fasted HDL to mitigate the reduction of apolipoprotein E secretion in AβO- and cholesterol-loaded microglia surpassed that of postprandial HDL. In exploring differences among HDL parameters from postprandial, overnight fasted, and 36-h fasted individuals, we observed that plasma HDL-cholesterol and apolipoprotein A-I concentrations remained unchanged. However, nuclear magnetic resonance (NMR) analysis revealed reduced total HDL particle count, a decrease in the smallest HDL particles (HDL1, 7.4 nm diameter), and an increase in the largest HDL particles (HDL7, 12 nm) after the 36-h fast. Transmission electron microscopy (TEM) analysis further found an increase in even larger HDL particles (12-14 nm) in 36-h fasted individuals. Targeted mass spectrometry (MS)-based proteomics and glycoproteomics unveiled a reduction in HDL-associated apolipoprotein A-IV and disialylated apolipoprotein C-III content following the 36-h fast. These findings collectively suggest that prolonged fasting induces structural, compositional, and functional alterations in HDL particles, and influences their capacity to attenuate the effects of excess cholesterol and AβO in microglia. Show less

Second-generation antipsychotics (SGAs) are widely used to treat schizophrenia (SCZ), but they often induce metabolic side effects like dyslipidemia and obesity. We conducted genome-wide association studies (GWASs) to identify genetic variants associated with SGA-induced lipid and BMI changes in Chinese SCZ patients. A longitudinal cohort of Chinese SCZ receiving SGAs was followed for up to 18.7 years (mean = 5.7 years, SD = 3.3 years). We analysed the patients' genotypes (N = 669), lipid profiles, and BMI using 19 316 prescription records and 3 917 to 7 596 metabolic measurements per outcome. Linear mixed models were employed to evaluate seven SGAs' random effects on metabolic changes for each patient, followed by GWAS and gene set analyses with Bonferroni and FDR correction. Five SNPs achieved p-value < 5 × 10 Show less

Among individuals diagnosed with type 2 diabetes mellitus (T2DM), an abnormal accumulation of visceral fat heightens the cardiovascular risk (CVR), and the major reason for death for these people is atherosclerotic cardiovascular disease (ASCVD). This study aimed to gain further insights into the longitudinal relationship between CVR and visceral fat area (VFA) in patients with T2DM, and to compare the predictive performance of additional abdominal obesity measures and VFA for changes in CVR. This prospective cohort study included 316 patients with T2DM who were followed up for more than one year, and VFA was measured by the bioimpedance method. This study investigated the prospective association between a VFA percentage change (∆VFA, %) and CVR, and evaluated the potential nonlinear relationships between ∆VFA (%) and the increase 10-year ASCVD risk. Furthermore, the area under the pooled curve (AUC) was contrasted for both ∆VFA (%) and other abdominal obesity indices. The excessive VFA loss group showed lower low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), triglyceride-glucose index, LDL-C/HDL-C, brachial-ankle pulse wave velocity, 10-year ASCVD risk, atherogenic index of plasma, TC/HDL-C, and apolipoproteins B/apolipoproteins A-1 than the VFA gain group (all β [Formula: see text] 0, HR [Formula: see text] 1, all P [Formula: see text] 0.05) after covariate controlling. VFA reduction of more than 14.82% led to a reduction in the stated risk. Moreover, ∆VFA (%) demonstrated superior predictive value for changes in ASCVD risk, with an AUC of 0.585 (95% CI: 0.513-0.656), compared to other obesity indices. Excessive VFA reduction improved 10-year ASCVD risk in patients diagnosed with T2DM. VFA was a more effective predictor of 10-year ASCVD risk changes than other abdominal obesity measures. This investigation has been registered with the Chinese Clinical Trial Registry (ChiCTR2400086569). Show less

As inflammatory processes may be involved in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), the first aim of the present study was to determine the clinical characteristics of type 2 diabetes mellitus (T2DM) with distal sensorimotor polyneuorpathy (DSPN). Next goal was to investigate inflammatory biomarkers, insulin-like growth factor- 1 and lipid profile in these patients. Finally, we aimed to compare the renal function in these patients. In a cross-sectional study, we included 160 patients diagnosed with T2DM. The control group was included 22 non-diabetic healthy subjects (HC). The patients with diabetes were divided into four groups, absent (n = 74), mild (n = 38), moderate (n = 24), and severe (n = 24) using a nomogram based on the MNSI features for a DSPN severity grading probability. Patients with moderate and severe DSPN were a little older and had longer duration of diabetes compared to patients with absent and mild DSPNS (p < 0.05). Serum levels of interferon-gamma (INF-γ), interleukin (IL)-1β, IL-4, IL- 6 levels in patients with severe DSPN were significantly higher than HC, absent, mild and moderate of DSPN (p < 0.05). The circulating levels of insulin-like growth factor-1 (IGF-1) were significantly lower in patients with severe DSPN (p < 0.05) compared to absent, mild and moderate of DSPN and HC. Diabetic patients with moderate DSPN showed increased circulating levels of TC, LDL-C, APOB (p < 0.05) compared to HC and patients with absent, mild and severe DSPN. Moreover, APO-A1/APOB was significantly lower in patients with diabetes compared to HC. In addition, patients with severe DSPN showed increased Cystatin C (p < 0.05) compared to HC and absent, mild, and moderate DSPN. Multivariate ordered logistic regression analysis showed that the levels of IL-6 (OR = 3.166, 95%CI 1.461-6.860, p = 0.003, IL-1β(OR = 1.148, 95%CI 1.070-2.232; p = 0.000), TC (OR = 1.174, 95%CI 1.011-1.364; p = 0.035), LDL-C (OR = 1.246, 95%CI 1.098-3.618; p = 0.003), Cystatin C (OR = 1.867, 95%CI 1.245-3.434; p = 0.004), ages (OR = 1.043, 95%CI 1.009-1.078; p = 0.012), and duration of diabetes (OR = 1.157, 95%CI 1.049-1.277; p = 0.004) were positively associated with increasing the odds ration of DSPN in T2DM. Conversely, the level of IGF-1 (OR = 0.922, 95%CI 0.961-0.982; p = 0.000) and ratio of APO-A1/APOB (OR = 0.212, 95%CI 0.078-0.567; p = 0.002) were significantly associated with decreasing the odds ratio of DSPN in T2DM. The levels of inflammatory biomarkers such as INF-γ, IL-1β, IL-4, IL- 6 were increased in patients with severe DSPN in T2DM. Ages, duration of diabetes as well as high circulating levels of IL-6, IL-1β, TC, LDL-C and Cystatin C were positively associated with DSPN in T2DM. Conversely, the level of IGF-1 and the ratio of APOA1/APOB were independent protective factors for DSPN in T2DM. Our results emphasize the importance of addressing issues related to inflammatory biomarkers, lipids and early impaired renal function in T2DM with DSPN, as these may be of potential relevance for deteriorating DSPN. Show less

This study aimed to elucidate the correlations among dyslipidemia, immune function, and clinical outcomes in patients with acute-on-chronic liver failure (ACLF), with particular emphasis on the clinical significance of lipid metabolism and cellular immune parameters in hepatitis B virus-associated ACLF (HBV-ACLF). A retrospective analysis was conducted on 803 patients with HBV-ACLF admitted to the Shanghai Public Health Clinical Center from January 2014 to January 2024. Patients were stratified into deceased (n = 414) and survival (n = 389) groups based on clinical outcomes. Clinical baseline data, lipid metabolic indices, and cellular immune parameters were collected. The Spearman correlation coefficient was utilized to assess the correlation between lipid metabolic indices and cellular immune parameters, and a multivariate Cox proportional hazards model was applied to analyze risk factors for mortality. Compared to the survival group, lipid metabolism indices in the deceased group were significantly reduced (P < 0.05). Lipid metabolism indices, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (APOA1), apolipoprotein B (APOB), total cholesterol (TC), and triglycerides (TG), demonstrated significant negative correlations with the severity of liver failure (P < 0.05). Correlation analysis with lymphocyte subset counts revealed positive correlations between low-density lipoprotein, TG, TC, APOB, and CD3 + T cells, CD4 + T cells, CD8 + T cells, and CD45 + T cells (P < 0.05). APOA1 and HDL-C were positively correlated with B cells and NK cells (P < 0.05). TG and APOB showed significant negative correlations with the CD4/CD8 ratio (P < 0.05). Multivariate Cox analysis identified age, creatinine, total bilirubin, international normalized ratio (INR), hepatic encephalopathy, and hepatorenal syndrome as independent risk factors affecting the short-term prognosis of HBV-ACLF, while sodium, APOA1, and APOB were identified as independent protective factors for ACLF (HR = 0.984, 95% CI: 0.974-0.995, P < 0.001, HR = 0.267,95% CI: 0.120-0.596, P = 0.001, HR = 0.486, 95% CI: 0.282-0.838, P = 0.010). Patients with HBV-ACLF exhibit decreased levels of TC, TG, LDL-C, HDL-C, APOA1, and APOB. These alterations in serum lipid profiles are associated with immune dysfunction and disease progression in HBV-ACLF. Notably, APOA1 and APOB serve as protective factors against 90-day mortality in hospitalized ACLF patients. Further investigation is warranted to elucidate the relationship between lipid metabolism disturbances and peripheral immunity in ACLF. Show less

Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. http://www. gov; Unique Identifier: NCT05621070. Show less

Neovascular age-related macular degeneration (nAMD) is an advanced stage of AMD and is associated with an increased risk of visual impairment. Disturbances in lipid metabolism have been proposed as a major contributing factor to the pathogenesis of AMD. This study aims to investigate whether lipid profiles in the serum and components of dyslipidemia can be used as indicators for predicting progression to nAMD. A retrospective analysis was conducted involving 125 participants with nAMD. 125 non-AMD controls, matched by age, sex, and BMI, were incorporated into the study. The comparative analysis between the groups involved six lipid biomarkers in the serum: HDL-C, LDL-C TG, TC, ApoA1, and ApoB. Moreover, the existence of dyslipidemia and its constituents was assessed through t-tests, as well as univariate and multivariable logistic regression models. Individuals with nAMD exhibited significantly higher serum HDL-C (P = 0.02) compared to the controls without AMD. Furthermore, the concentrations of ApoB were significantly less in the nAMD cohort (P < 0.01) when compared to the control group. During the investigation of the correlation between levels of serum HDL-C (P < 0.01) and serum ApoB (P < 0.01) with nAMD through logistic regression analysis, notable findings indicated a significant association between both variables and nAMD. However, by multivariate logistic regression analysis, neither serum HDL-C nor serum ApoB was an independent risk factor for nAMD. While individuals with nAMD demonstrated elevated serum HDL-C and reduced serum ApoB levels, these lipid markers may not be suitable as biomarkers for monitoring or preventing nAMD. Show less

Duchenne muscular dystrophy (DMD) is a serious, progressive neuromuscular condition that predominantly impacts male individuals, marked by progressive muscle weakness resulting from mutations in the dystrophin gene (DMD) encoding dystrophin. DMD is a primary muscle disorder that often presents with secondary abnormalities in lipid metabolism and decreased bone mineral density. Although disturbances in circulating lipid profiles and skeletal health have been observed in individuals with DMD, their relationship remains underexplored.This study aimed to investigate the potential association between lipid metabolic disturbances and spinal bone mineral density in patients with DMD by combining clinical lipid levels and bone density with transcriptomic pathway analysis of DMD muscle tissue. Retrospective analysis was performed on 219 genetically confirmed DMD patients and 99 age-matched healthy controls. Healthy controls with a family history of genetic disorders were excluded. Clinical data included lipid profiles (triglycerides [TGs], remnant cholesterol [RC]); bone mineral density of the lumbar spine was evaluated using Dual-energy X-ray absorptiometry (DXA); and corticosteroid use, including treatment status, dose, and duration. Patients were stratified by corticosteroid exposure. Restricted cubic splines and multivariable regression models were applied to explore potential relationships between lipid parameters and bone mineral density. Bioinformatic analyses were performed on RNA sequencing data from muscle biopsy samples from patients with DMD (GSE38417 dataset) and an independent validation cohort (GSE6011 dataset), focusing on pathways related to lipid metabolism and osteoclast differentiation. Patients with DMD had higher TG, RC, and apolipoprotein B (ApoB) levels and lower high-density lipoprotein cholesterol (HDL-C) levels than healthy controls (P < 0.05). Elevated TG and RC levels were associated with reduced spine bone mineral density, independent of corticosteroid use. The bioinformatic analyses identified key pathways, including sphingolipid metabolism and osteoclast differentiation, as well as hub genes such as FCGR2B, C1QA, which are involved in lipid regulation and bone remodeling. Lipid abnormalities, particularly elevated TG and RC levels, were significantly associated with lower bone mineral density in patients with DMD. These findings suggest that lipid abnormalities are involved in bone health impairment in DMD, warranting further studies to confirm the association. Show less

Scatophagus argus is a highly valuable aquaculture fish. Its artificial breeding faces problems in the induction of high quality eggs, thus necessitating studies on the regulation of ovarian development. As the centre of nutrient metabolism in fish, the liver provides the material basis for ovarian development. However, the molecular mechanism of the liver in ovarian development in S. argus is still unclear. In this study, a transcriptome analysis of adult S. argus livers at different stages of ovarian development (stages II, III and IV) was performed. 410, 1025 and 1867 differentially expressed genes (DEGs) were obtained between stages II and III, stages II and IV and stages III and IV, respectively. In GO and KEGG analyses, DEGs were mostly involved in vitellogenesis and egg envelope formation (e.g., erα, erβ1, vtga, vtgb, vtgc, zp3, zp4a and zp4b), lipid metabolism and energy metabolism (e.g., dagt1, dagt2, lpl, apob, hk1, acly, ogdh, pc, and fbp1), and hormone signaling (e.g., lepa and igfbp1). Additionally, genes that were significantly upregulated in the liver at stage IV of ovarian development, compared to stages II and III, were markedly enriched in steroid biosynthesis and metabolism pathways. These findings provide clues to understanding the mechanisms of liver action in teleost ovarian development. Show less

This study aimed to evaluate the impact of combining high-intensity statins with CETP inhibitors on lipid levels, as well as to explore their potential clinical significance. We conducted a comprehensive search of relevant studies in the PubMed, Embase, Cochrane Library, and Web of Science databases. The Cochrane Risk of Bias Tool RoB 2.0 was employed to evaluate the quality of the included studies. Statistical analyses were carried out using STATA 15 software, with primary outcomes being high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Out of 2,552 records, 7 studies were included in the final analysis. The findings revealed that the combination of high-intensity statins with CETP inhibitors significantly raised HDL-C levels (SMD 2.47 [1.77, 3.18], p < 0.001) and lowered LDL-C levels (SMD -1.75 [-2.19, -1.31], p < 0.001). Compared to statin monotherapy, the combination of high-intensity statins and CETP inhibitors resulted in a more pronounced increase in HDL-C and ApoAI, while reducing LDL-C, triglycerides (TG), and ApoB levels, without increasing the incidence of adverse events. Show less

We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete tolerogenic adjuvant that acts systemically to form an active vaccine in situ with endogenous pathogenic autoantigens. This active vaccine suppresses autoimmunity by expanding antigen-specific Treg cells in affected tissues. In a mouse model of atherosclerosis, 8206 successfully targeted all three analyzed pathogenic autoantigens (ApoB, HSP60, and HMGB1) and inhibited disease progression. These findings suggest that 8206 can potentially serve as a universal treatment vaccine for autoimmune diseases by eliminating the need for exogenous immunogens, with implications for broad applications in immunotherapy. Show less

To investigate the relationship between dyslipidemia and intervertebral disc degeneration (IVDD). A total of 269 patients with lumbar disc herniation (Grade III-VIII using the modified Pfirrmann Grading Systems and Total End Plate Damage Score (TEPS) III-VI grade) and 269 patients with lumbar vertebral fracture (LVF, Grade I-II using the modified Pfirrmann Grading Systems and TEPS I-II grade) were enrolled in this study. The total cholesterol level (TC), low-density lipoprotein-cholesterol level (LDL-C), triglyceride level (TG), high-density lipoprotein-cholesterol level (HDL-C), nonHDL-C, ApoB level, ApoB A1 level and arteriosclerosis index (AI) were measured. The 269 patients with single-level LDH who underwent surgery were assigned to the disc herniation group (DH) and 269 patients who underwent surgical treatment for lumbar vertebral fracture during the same period were enrolled as the control group. The participants in the control group were selected randomly and matched for sex. The analysis revealed that the levels of TC, TG, LDL, nonHDL-C, APOB, and APOA1 in patients with LDH were significantly higher compared with those in the controls. The proportion of high-TC, borderline high-total cholesterol, high LDL-C, high-TG, borderline high LDL-C, high APO B, high arteriosclerosis index (AI), and high-ApoB/ApoA1 in the LDH group was significantly higher relative to that of the control group. The ratio of TC/HDL-C, TG/HDL-C, LDL-C/HDL-C, nonHDL-C/HDL-C, and ApoB/ApoA1 in the LDH group was significantly higher compared with that of the control group. Multivariate logistic regression analysis showed that the levels of serum TG, Apo B/ApoA1 ratio, atherogenic index(AI), labour intensity, and age were positively associated with the risk of LDH and were independent risk factors predicting IVDD development. Overall, this study indicates that age, labour intensity, TG, ApoB/ApoA1 ratio and atherogenic index (AI) may increase the risk of IVDD. The levels of TC, TG, LDL-C, nonHDL-C, Apo B, and atherogenic index (AI) may be related to the degree of cartilage endplate (CEP) and intervertebral disc degeneration (IVDD). Moreover, dyslipidemia may be a useful predictor of IVDD. Show less

Diabetic nephropathy (DN) is the most intractable complication of diabetes. Despite decades of research, accurate diagnostic markers and effective therapeutic drugs are still elusive. Abnormal copper metabolism is also implicated in diabetes and its complications. This study aims to identify copper metabolism-related biomarkers and potential drugs for DN. DN datasets and copper metabolism-related genes (CMGs) were obtained from Gene Expression Omnibus (GEO) and GeneCards. Differentially expressed CMGs (DE-CMGs) were identified using the limma package and the Venn algorithm. Functional enrichment analysis and protein-protein interaction (PPI) network were performed to identify candidate hub genes. The single gene with an area under the receiver operating characteristic (ROC) curve > 0.7 was identified as a potential diagnostic biomarker of DN. Finally, these biomarkers were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in high-glucose-treated human proximal tubular (HK-2) cells. These validated hub genes were used to construct a combined prediction model, confirmed by additional GSE30528 and GSE30529 datasets. The correlation analysis between the expression level of the hub genes and the estimated glomerular filtration rate (eGFR) was carried out. Additionally, immune cell infiltration and potential target drugs were investigated for these biomarkers. Five hub genes associated with copper metabolism, namely CD36, CCL2, CASP3, LPL, and APOC3, were identified as biomarkers for the early diagnosis of DN. Utilizing multiple biomarkers enhanced diagnostic accuracy and specificity. CD36, CCL2, and CASP3 correlated negatively with eGFR levels, while LPL and APOC3 correlated positively. Additionally, these hub genes were significantly linked to various immune cell types, including macrophages M1 and M2, T cells, gamma delta resting dendritic cells, neutrophils, and NK cells. Furthermore, 15 agents targeting these biomarkers were retrieved from the DrugBank database. Our study identified key genes possibly related to copper metabolism in the pathological mechanism of DN that could serve as novel targets for the diagnosis and therapy of DN. Show less

Gastric cancer (GC) exhibits marked heterogeneity, patients with identical stage receive divergent outcomes. Metabolic reprogramming and aging are pivotal in reshaping the tumor microenvironment. However, their interplay in GC prognosis remains unexplored. We analyzed RNA-seq and clinical data from The Cancer Genome Atlas Program and Gene Expression Omnibus databases. Using univariate Cox, LASSO, and multivariate Cox regression, we identified candidate genes and constructed a prognostic signature. Immune contexture, genomic alterations and drug sensitivity were compared between high- and low-risk group. The metabolic and aging related risk score, comprising 4 genes (GNAI1, GSTA1, APOC3, and LOX), was developed. Validation across multiple cohorts confirmed its robust prognostic performance. The model also effectively stratified patients into distinct risk subgroups with differential immune profiles and responses to immunotherapy. Notably, high-risk patients showed reduced sensitivity to common chemotherapeutic agents but may benefit from targeting the PI3K/mTOR pathway. Metabolic and aging related risk score serves as a promising tool for individualized risk assessment and therapeutic guidance in GC, warranting further clinical validation. Show less

Prior research has highlighted the significant roles of circulating retinol, retinol-binding protein 4 (RBP4), and apolipoprotein C (ApoC) in metabolic health. This study investigates the joint association of retinol and RBP4 with metabolic syndrome (MetS) and examines the potential mediating role of ApoCs in these relationships. This prospective study included 3,009 and 2,724 participants with baseline serum retinol and RBP4 data, respectively. Over a 9-year follow-up among 2,621 participants, 1,136, 127, 696, and 662 were categorized into MetS-free, recovered, incident MetS, and persistent MetS groups, respectively. Midway through the study, ApoC1-4 levels were measured in 2316 participants. Adjusted odds ratios (95% CIs) for the highest (vs. lowest) tertile of retinol and RBP4 levels were 3.63 (2.69-4.92) and 5.64 (4.05-7.92) for 9-year persistent MetS, respectively. The corresponding hazard ratios (95% CIs) were 1.67 (1.39-2.01) and 1.67(1.38, 2.03) for incident MetS, and 0.65 (0.41-1.03) and 0.44 (0.28, 0.70) for recovered MetS (all P-trends<.05). A synergistic association of retinol and RBP4 with MetS risk was observed for persistent MetS. Higher levels of retinol or RBP4 were associated with increased concentrations of ApoC1-4, which were linked to a greater risk of incident and persistent MetS. A newly developed composite score (ApoCS), derived from ApoC1-4 levels, explained 30.5% and 24.5% of the association between retinol or RBP4 and MetS, with ApoC2 and ApoC3 contributing predominantly to this connection. Our study identified notable positive correlations between serum retinol and RBP4 levels and MetS progression, explained by increases in circulating ApoC2 and ApoC3 within a Chinese cohort. Show less

Traumatic brain injury (TBI) is more common than ever and is becoming a global public health issue. A variety of secondary brain injuries occur after TBI, including ferroptosis characterized by iron-dependent lipid peroxidation. Gallic acid is a kind of traditional Chinese medicine, which has many biological effects such as anti-inflammatory and antioxidant. We further investigated whether Gallic acid can improve the neurological impairment caused by ferroptosis after TBI by targeting APOC3. Weighted gene coexpression network analyses (WGCNA) and 3 kinds of machine-learning algorithms were used to find the potential biomarkers. Then the HERB database was used to select the Chinese herb that acted on the target gene APOC3. Finally, we selected Gallic acid as a drug targeting APOC3 and verified by Western blotting. The effect of Gallic acid on the improvement of neurological function was studied by Nissl staining and FJB staining. Finally, the effect of Gallic acid on the cognitive ability of TBI mice was explored through behavioral experiments. Gallic acid can inhibit the expression level of APOC3 and thus inhibit the level of ferroptosis after TBI. It can also reduce the degeneration of nerve tissue by inhibiting ferroptosis and improve the neurological function deficit. The behavioral experiment proved that Gallic acid can alleviate the behavioral cognitive impairment caused by TBI. Gallic acid can reduce ferroptosis by inhibiting APOC3, and then alleviate neurological impairment after TBI. Show less

It remains controversial whether lipids affect osteoporosis (OP) or bone mineral density (BMD), and causality has not been established. This study aimed to investigate the genetic associations between lipids, novel non-statin lipid-lowering drug target genes, and OP and BMD. Mendelian randomization (MR) method was used to explore the genetic associations between 179 lipid species and OP, BMD. Drug-target MR analysis was used to explore the causal associations between angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C3 (APOC3) inhibitors on BMD. The IVW results with Bonferroni correction indicated that triglyceride (TG) (51:3) (OR = 1.0029; 95% CI: 1.0014-1.0045; P = 0.0002) and TG (56:6) (OR = 1.0021; 95% CI: 1.0008-1.0033; P = 0.0011) were associated with an increased risk of OP; TG (51:2) (OR = 0.9543; 95% CI: 0.9148-0.9954; P = 0.0298) was associated with decreased BMD; and ANGPTL3 inhibitor (OR = 1.1342; 95% CI: 1.0393-1.2290; P = 0.0093) and APOC3 inhibitor (OR = 1.0506; 95% CI: 1.0155-1.0857; P = 0.0058) was associated with increased BMD. MR analysis indicated causal associations between genetically predicted TGs and OP and BMD. Drug-target MR analysis showed that ANGPTL3 and APOC3 have the potential to serve as novel non-statin lipid-lowering drug targets to treat or prevent OP. Show less

It is unclear whether the different Alzheimer's disease (AD) progression trajectories of apolipoprotein E (APOE) ɛ4 carriers is reflected by blood phosphorylated tau (p-tau) analytes. We assessed longitudinal trajectories in plasma p-tau181, 217, and 231, in amyloid beta-positive (A+) and negative (A-) APOE ɛ4 carriers (E+) or non-carriers (E-). We included 2039 participants from the observational Translational Biomarkers in Aging and Dementia (TRIAD) and Alzheimer's Disease Neuroimaging Initiative cohorts, categorized into 840 A-E-, 251 A-E+, 386 A+E4-, and 616 A+E4+. Longitudinal data were available for 1045 participants. In TRIAD, ALZpath p-tau217 (β = 0.45, p = 0.02) and p-tau217+ These findings suggest p-tau217 as a marker of faster progression in APOE ɛ4 carriers, highlighting its potential in disease stratification. Blood phosphorylated tau (p-tau)217 increases faster in apolipoprotein E (APOE) ɛ4 carriers with amyloid pathology. p-tau181 and p-tau231 do not increase faster in APOE ɛ4 carriers. APOE ɛ4 carriership does not change p-tau in individuals without amyloid pathology. Show less