Gut microbiota can digest and ferment feed into metabolites to influence the meat quality. Probiotics are used to regulate the gut microbiota. In this study, a total of 360 broilers were assigned to 4 Show more
Gut microbiota can digest and ferment feed into metabolites to influence the meat quality. Probiotics are used to regulate the gut microbiota. In this study, a total of 360 broilers were assigned to 4 treatments (10 broilers per cage): control (Con), low dose of Show less
The 3-hydroxybutyrate dehydrogenase 1 (BDH1) mainly participates in the regulation of milk fat synthesis and ketone body synthesis in mammary epithelial cells. In our previous study, BDH1 was identifi Show more
The 3-hydroxybutyrate dehydrogenase 1 (BDH1) mainly participates in the regulation of milk fat synthesis and ketone body synthesis in mammary epithelial cells. In our previous study, BDH1 was identified as a key candidate gene regulating lipid metabolism in mammary glands of dairy goats by RNA-seq. This study aimed to investigate the effect of BDH1 on lipid metabolism in mammary epithelial cells of dairy goats (GMECs). The results suggest that BDH1 plays a significant role in reducing triacylglycerol content and lipid droplet accumulation in GMECs (p < 0.05). Overexpression of BDH1 significantly decreased the expression of lipid metabolism-related genes (SREBF1 and GPAM) and reduced the levels of C14:0 and C17:1, while increasing FABP3 expression and C10:0 concentration (p < 0.05). Interference with BDH1 significantly increased the expression of SREBF1 and GPAM and the concentration of C14:0, C15:1, and C20:1, but significantly decreased FABP3 and C18:0 (p < 0.05). Treatment of GMECs with β-hydroxybutyric acid (R-BHBA) significantly decreased the expression of FASN, ACACA, LPL, SREBF1, FABP3, ACSL1, GPAM, DGAT1, and triacylglycerol content, while significantly increasing the expression of BDH1 (p < 0.05). Interference with BDH1 rescued the reduction of cellular TAG content and the expression of FASN, LPL, SREBF1, ACSL1, and GPAM in BHBA-treated GMECs. In conclusion, BDH1 negatively regulates lipid metabolism in mammary glands of dairy goats. Furthermore, it may mitigate the inhibitory effect of R-BHBA on lipid metabolism in GMECs. Show less
The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concom Show more
The co-occurrence of plasma cell neoplasm (PCN) and lymphoplasmacytic lymphoma (LPL) is rare, and their clonal relationship remains unclear. To evaluate the clinicopathologic characteristics of concomitant LPL/PCN. Retrospectively analyzed clinical and laboratory data of 14 cases. Three patients initially presented with immunoglobulin (Ig) M paraprotein, 1 with IgG paraprotein, and 10 had simultaneous diagnoses of PCN and LPL. In 13 cases, flow cytometry detected both LPL and PCN in marrow biopsies. Furthermore, immunohistochemistry highlighted the 2 neoplastic populations, demonstrating an increased proportion of plasma cells and their expression of cyclin D1, CD56, and/or a non-IgM isotype restriction. All cases exhibited discordant heavy-chain isotypes between LPL and PCN. Thirteen of the 14 cases (92.9%) had concordant light-chain restrictions between the 2 neoplasms, and the remaining case (7.1%) showed discordant light-chain restrictions. Of the 12 patients with follow-up, 5 were treated with myeloma regimens, 2 with LPL regimens, 3 with combined therapy, and 2 with observation alone. Follow-up ranged from 2 to 146 months (median, 12.5 months). One patient died of PCN progression, one died of comorbidity, and 10 patients were alive with or without disease. Survival analysis showed no significant difference from the control. The discordant heavy-chain isotype restrictions between PCN and LPL suggest biclonal B-cell neoplasms, which is supported by PCN's phenotypic distinction, such as the expression of cyclin D1 and/or CD56. However, our series exhibited a tendency toward concordant light-chain restrictions between the 2 neoplasms, raising the possibility that PCN may evolve from LPL through class switching. Show less
The objective of this study was to evaluate the effects of dietary fatty acids (FA) saturation and lysophospholipids supplementation on growth, meat quality, oxidative stability, FA profiles, and lipi Show more
The objective of this study was to evaluate the effects of dietary fatty acids (FA) saturation and lysophospholipids supplementation on growth, meat quality, oxidative stability, FA profiles, and lipid metabolism of finishing beef bulls. Thirty-two Angus bulls (initial body weight: 623 ± 22.6 kg; 21 ± 0.5 months of age) were used. The experiment was a completely randomized block design with a 2 × 2 factorial arrangement of treatments: 2 diets with FA of different degree of unsaturation [high saturated FA diet (HSFA) vs. high unsaturated FA diet (HUFA)] combined with (0.075%, dry matter basis) and without lysophospholipids supplementation. The bulls were fed a high-concentrate diet (forage to concentrate, 15:85) for 104 d including a 14-d adaptation period and a 90-d data and sample collection period. No interactions were observed between dietary FA and lysophospholipids supplementation for growth and meat quality parameters. A greater dietary ratio of unsaturated FA (UFA) to saturated FA (SFA) from 1:2 to 1:1 led to lower DM intake and backfat thickness, but did not affect growth performance and other carcass traits. Compared with HSFA, bulls fed HUFA had greater shear force in Longissimus thoracis (LT) muscle, but had lower intramuscular fat (IMF) content and SOD content in LT muscle. Compared with HUFA, feeding the HSFA diet up-regulated expression of ACC, FAS, PPARγ, and SCD1, but down-regulated expression of CPT1B. Compared with feeding HSFA, the HUFA diet led to greater concentrations of c9-C18:1 and other monounsaturated FA in LT muscle. Feeding HUFA also led to lower plasma concentrations of cholesterol, but there were no interactions between FA and lysophospholipids detected. Feeding lysophospholipids improved growth and feed conversion ratio and altered meat quality by increasing muscle pH Results indicated that supplementing a high-concentrate diet with lysophospholipids to beef bulls can enhance growth rate, feed efficiency, meat quality, and beneficial FA. Increasing the dietary ratio of UFA to SFA reduced DM intake and backfat thickness without compromising growth, suggesting potential improvements in feed efficiency. Show less
With the development of optical anti-counterfeiting and the increasing demand for high-level information encryption, multimodal luminescence (MML) materials attract much attention. However, the discov Show more
With the development of optical anti-counterfeiting and the increasing demand for high-level information encryption, multimodal luminescence (MML) materials attract much attention. However, the discovery of these multifunctional materials is very accidental, and the versatile host suitable for developing such materials remains unclear. Here, a grossite-type fast ionic conductor CaGa Show less
The aim of this study was to investigate the ameliorative effects of pterostilbene (PTE), a polyphenolic compound, on stress-induced lipid metabolic disorders in the liver of broiler chickens. Six hun Show more
The aim of this study was to investigate the ameliorative effects of pterostilbene (PTE), a polyphenolic compound, on stress-induced lipid metabolic disorders in the liver of broiler chickens. Six hundred healthy, 1-day-old Arbor Acres with similar weight were randomly assigned to five groups, each consisting of eight replicates with 15 broilers per replicate. The groups included: a control group (fed a basal diet), and four groups treated with corticosterone (CORT) at varying dietary levels of PTE supplementation: CORT (0 mg/kg PTE), CORT-PT200 (200 mg/kg PTE), CORT-PT400 (400 mg/kg PTE), and CORT-PT600 (600 mg/kg PTE). The results indicated that PTE administration to corticosterone (CORT)-injected broilers significantly improved weight gain, reduced liver index, and lowered the elevation of serum aspartate aminotransferase, gamma-glutamyl transferase, glucose, total cholesterol, triglycerides, and lipoprotein cholesterol concentrations induced by CORT injection (P<.05), but had no significant effect on serum CORT concentration (P>.05). PTE also significantly reduced the increased rate of abdominal fat deposition induced by CORT, decreased the average size of adipocytes, and downregulated the expression of the FAS gene (P<.05). It reversed the increase in liver total cholesterol, triglycerides, lipoprotein cholesterol, and non-esterified fatty acids content induced by CORT (P<.05). PTE had no significant effect on the expression of the glucocorticoid receptor (P>.05), but significantly upregulated the protein expression of Sirt1 and p-AMPK (P<.05), promoted the expression of lipid autophagy genes MAP1LC3B and lipolytic genes LPL, but inhibited the expression of fatty acid synthesis genes SREBP-1c, ACC, and SCD (P<.05). The addition of PTE to the diet alleviated CORT-induced oxidative stress and inflammation by enhancing T-SOD and GSH-Px activities, reducing MDA content, inhibiting p-NF-κB p65 and NLRP3 expression and the release of TNF-α and IL-1β in the serum, and increasing IL-4 content (P<.05). Overall, dietary PTE effectively regulates lipid metabolism and antioxidant status, offering a potential strategy to mitigate stress-induced metabolic disruptions in broilers. Show less
Dysregulated lipid metabolism promotes the progression of various cancer types, including breast cancer. The present study aimed to explore the lipidomic profiles of patients with breast cancer, provi Show more
Dysregulated lipid metabolism promotes the progression of various cancer types, including breast cancer. The present study aimed to explore the lipidomic profiles of patients with breast cancer, providing insights into the correlation between lipid compositions and tumor subtypes characterized by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Briefly, 30 patients with breast cancer were categorized into four groups based on their HR and HER2 status: HR+ no HER2 expression (HER2-0), HR+ HER2-low; HR+ HER2-positive (pos) and HR- HER2-pos. The lipidomic profiles of these patients were analyzed using high-throughput liquid chromatography-mass spectrometry. The data were processed through principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and random forest (RF) classification to assess the lipidomic variations and significant lipid features among these groups. The profiles of the lipids, particularly triglycerides (TG) such as TG(16:0-18:1-18:1)+NH Show less
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiolo Show more
Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. This study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings. Show less
Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, it Show more
Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, its protective mechanism on the central nervous system (CNS) is not clear. The present study initially evaluated the possible mechanism of PNS to improve cognitive dysfunction due to chronic sleep deprivation (CSD). In the present study, we used a modified multi-platform aquatic environment sleep deprivation method to induce a cognitively impaired rat model, and explored the mechanism of action of PNS by integrating serum metabolomics and network pharmacology, which was further verified by molecular docking and experiments. The results showed that PNS significantly shortened the escape latency, increased the target quadrant time and the number of traversing platforms, and attenuated the inflammatory damage in the hippocampal Cornu Ammonis 1 (CA1) region in CSD rats. The non-targeted metabolomics results indicated that 35 biomarkers significantly altered following PNS therapy intervention, with metabolic pathways enriched for the effects of One carbon pool by folate, Riboflavin metabolism, Glycerophospholipid metabolism, Sphingolipid metabolism, Glycerolipid metabolism, Arachidonic acid metabolism, and Tryptophan metabolism. In addition, network pharmacology identified 234 potential targets for PNS intervention in CSD with cognitive impairment. Metabolite-response-enzyme-gene network was constructed by MetaScape and matched with the network pharmacology results to identify a total of five shared targets (LPL, GPAM, HSD11B1, HSD11B2, and SULT2A1) and two metabolic pathways (Sphingolipid metabolism and Steroid hormone biosynthesis). The results of molecular docking revealed that the five active ingredients had good binding ability with the five core targets. qPCR analysis confirmed the ability of PNS to modulate the above five targets. The combination of metabolomics and network analysis provides a scientific basis for promoting the clinical application of PNS in cognitive impairment. Show less
Two-coordinate coinage metal complexes have been exploited for various applications. Herein, a new donor-metal-acceptor (D-M-A) complex PZI-Au-TOT, using bulky pyrazine-fused N-heterocyclic carbene (P Show more
Two-coordinate coinage metal complexes have been exploited for various applications. Herein, a new donor-metal-acceptor (D-M-A) complex PZI-Au-TOT, using bulky pyrazine-fused N-heterocyclic carbene (PZI) and trioxytriphenylamine (TOT) ligands, was synthesized. PZI-Au-TOT displays decent thermally activated delayed fluorescence (TADF) with a quantum yield of 93 % in doped film. The crystals of PZI-Au-TOT show simultaneous TADF, polymorphism, and linearly polarized luminescence (LPL). The polymorph-dependent emission properties with widely varied peaks from 560 to 655 nm are attributed to different packing modes in terms of isolated monomers, discrete π-π stacked dimers or dimer PLUS. Two well-defined microcrystals of PZI-Au-TOT exhibit linearly polarized thermally activated delayed fluorescence with a degree of polarization up to 0.64. This work demonstrates that the molecular rotational flexibility of D-M-A type complexes endows an integration of multiple functions into one complex through manipulation of supramolecular aggregation. This type of complexes is expected to serve as a versatile platform for the fabrication of crystal materials for advanced photonic applications. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and ga Show more
To investigate the regulatory role of MACF1 and its upstream transcriptional control in focal adhesion remodeling and tumor progression in lung adenocarcinoma (LUAD). We employed in vitro loss- and gain-of-function assays using shRNA-mediated knockdown and ectopic overexpression of MACF1 and NR2F1 in LUAD cell lines (H1299 and Calu-3). Cell proliferation, adhesion, and migration were assessed by CCK-8, EdU, crystal violet, and Transwell assays. In vivo tumor growth and metastasis were evaluated using subcutaneous and tail vein xenograft models in nude mice. RNA-seq and GSEA were performed to identify MACF1-regulated pathways, followed by nuclear-cytoplasmic fractionation, dual-luciferase reporter assays, and immunofluorescence to assess WNT/β-catenin activity. ChIP-qPCR and ChIP-seq data from ENCODE were used to validate NR2F1 binding to the MACF1 promoter. MACF1 knockdown significantly suppressed LUAD cell proliferation, DNA replication, adhesion, and migration, and reduced tumor burden and lung metastases in vivo. Mechanistically, MACF1 activated WNT/β-catenin signaling by promoting CTNNB1 nuclear translocation, which upregulated focal adhesion genes (Paxillin, FAK, ITGB1). CTNNB1 agonist TWS119 restored focal adhesion in MACF1-deficient cells. Bioinformatic prediction and ChIP validation identified NR2F1 as a transcription factor directly targeting the MACF1 promoter. NR2F1 deficiency reduced MACF1 expression and phenocopied its functional loss, while MACF1 overexpression rescued the impaired phenotype. Our study uncovers a previously unrecognized NR2F1-MACF1-WNT axis that drives focal adhesion formation and LUAD progression. Targeting this regulatory circuit may offer new avenues for anti-metastatic therapy in lung adenocarcinoma. 1. NR2F1 is identified as a direct upstream transcription factor that activates MACF1 expression in LUAD. 2. MACF1 promotes LUAD cell proliferation, adhesion, and migration by enhancing focal adhesion assembly. 3. MACF1 activates the WNT/CTNNB1 signaling cascade, facilitating CTNNB1 nuclear translocation and downstream target expression. 4. Loss of MACF1 impairs focal adhesion formation and metastatic potential both in vitro and in xenograft and tail vein models. 5. The NR2F1-MACF1-WNT axis represents a novel regulatory circuit driving LUAD metastasis and offers potential therapeutic targets. Show less
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA i Show more
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA in tumor diagnosis have gradually attracted the attention of researchers. However, methylation detection, which is more advantageous than mutation detection in tumor diagnosis, has not been widely practiced in EV DNA, and its value in PCa diagnosis also remains underexplored. This study aims to establish and optimize an EV DNA methylation detection system and evaluate its diagnostic and classification potential for PCa. We characterized EV DNA biological properties, optimized pretreatment strategies, validated its correlation with genomic DNA methylation, and explored urine EV DNA methylation targets in 86 benign prostatic hyperplasia (BPH) and 109 PCa patients across three cohorts (screening: 30 BPH/33 PCa; training: 27 BPH/30 PCa; validation: 29 BPH/46 PCa). Heterogeneous biological characteristics were observed among DNA from different subtypes of EV, but methylation profiles remained consistent across subtypes and post-DNase I treatment. EV DNA accurately reflected the methylation state of source cell genomic DNA. By combining our screening results with data from the TCGA database and previously reported, we developed a panel consisting of 667 PCa-specific methylation targets for detection. Among these, six methylation sites (MACF1、LINC01359-1、LINC01359-2、ADCY4、GAPLINC、C19orf25) demonstrated high diagnostic value for PCa, enabling construction of PCa and aggressive PCa differential diagnosis model with AUCs up to 0.74 and 0.91 respectively. The diagnostic value of these six markers was further confirmed using methylight PCR in the validation cohort which also displayed promising performance as a tool for diagnosing PCa. This study highlights the potential of urine EV DNA methylation as a novel diagnostic marker for PCa and lays a foundation for future EV DNA research. Show less
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expr Show more
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of Two de novo heterozygous and eight biallelic Show less
The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidate Show more
The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidated. This study aims to examine the prognostic significance of genes associated with immune-stromal scores and to explore their underlying mechanisms in ccRCC. Data from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) were subjected to analysis to compute immune and stromal scores utilizing the ESTIMATE algorithm. The weighted gene co-expression network analysis (WGCNA) was employed to identify gene modules associated with these scores. Differentially expressed genes were assessed using the limma package. Prognostic biomarkers were subsequently identified through univariate, LASSO, and multivariate Cox regression analyses, culminating in the development of a risk score model. Gene expression was confirmed in ccRCC cell lines (786-O, Caki-1) and tumor tissues. Functional assays, such as wound healing and Transwell assays, were employed to evaluate tumor invasion and migration. The prognostic accuracy was assessed through ROC curve analysis, and a nomogram integrating risk scores with clinical variables was constructed. Analyses of immune infiltration, human leukocyte antigen (HLA) expression, immune checkpoint expression, immunophenoscore (IPS), tumor immune dysfunction and exclusion (TIDE) scores, and responses to six targeted therapies were conducted across different risk groups. Twelve critical prognostic markers, including CAPRIN1, CXCR3, FERMT3, HAPLN3, HBP1, MACF1, MPEG1, OSCAR, STAT1, UBA7, VAMP1, and VSIG4, were identified. The risk score model exhibited a high degree of predictive accuracy for survival outcomes in ccRCC. Immune profiling revealed significant differences in the TME between risk groups, with high-risk patients displaying elevated expression of HLA and immune checkpoints. Drug sensitivity analyses suggested that high-risk patients had a better response to erlotinib, temsirolimus, axitinib, and sunitinib, whereas low-risk patients demonstrated greater sensitivity to pazopanib. Variability in immunotherapy responsiveness between groups was observed based on IPS and TIDE analyses. This study highlights the prognostic value and TME-related mechanisms of immune-stromal score signatures in ccRCC, developing a risk score model and nomogram for predicting patient prognosis. Show less
To investigate the dynamic genetic regulatory mechanisms of CD4 This study integrated context-specific expression quantitative trait locus analysis, Mendelian randomization, colocalization analysis, s Show more
To investigate the dynamic genetic regulatory mechanisms of CD4 This study integrated context-specific expression quantitative trait locus analysis, Mendelian randomization, colocalization analysis, single-cell RNA sequencing, and qPCR experimental validation. A systematic investigation was conducted on gene expression and genetic variation in CD4 The study identified multiple genes demonstrating a causal relationship with OSA risk, such as The immune regulation mediated by CD4 Show less
To evaluate potential genetic causal relationships between chronic pain subtypes like migraine and multi-site chronic pain (MCP) and their impact on breast cancer occurrence and survival rates. The as Show more
To evaluate potential genetic causal relationships between chronic pain subtypes like migraine and multi-site chronic pain (MCP) and their impact on breast cancer occurrence and survival rates. The association between chronic pain and breast cancer was reported before, yet the causal nature between them remained uncertain. Data on chronic pain and breast cancer were sourced from publicly available European genome-wide association study (GWAS) datasets. Genetic association between chronic pain and breast cancer phenotypes was assessed using linkage disequilibrium genetic correlation (LDSC). Colocalization analysis further identified potential shared causal variation. Based on Inverse variance weighted method, 2-sample Mendelian Randomization (MR) was conducted to investigate causal associations between migraine, MCP, and breast cancer or breast cancer survival. Sensitive analysis was conducted to ensure the absence of heterogeneity and horizontal pleiotropy. LDSC demonstrated significant genetic correlations between migraine and both estrogen receptor-negative (ER-) and overall breast cancer, while also revealing a notable genetic association between MCP and ER- and ER+ breast cancer, as well as overall breast cancer. Through colocalization analysis, potential involvement of rs2183271, located in MLLT10 gene, in regulating MCP and ER+ breast cancer was identified. MR analysis revealed the association between migraine and elevated risk of ER- breast cancer (IVW, P = 4.95 × 10 Our results provided new insights into the role of migraine and MCP in breast cancer, paving the way for targeted preventive strategies and future investigations. Show less
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People wit Show more
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. Show less
Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of ca Show more
Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. In this study, we found that carbohydrate-responsive element-binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment. Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS/STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the tumor microenvironment and proposes ChREBP as a potential immunotherapeutic target in cancer. ChREBP induces a choline-deprived tumor microenvironment and promotes chemokine secretion to facilitate immune evasion, suggesting targeting ChREBP as a therapeutic approach to improve the efficacy of immunotherapy. Show less
The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, t Show more
The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, the biological basis for the association between childhood obesity and adult cholelithiasis is poorly understood, which poses a challenge for preventing adult cholelithiasis in specific biological pathways. Summary statistics of genome-wide association studies (GWASs) of childhood age-specific body mass index (BMI) at 12 time points and adult cholelithiasis derived from FinnGen were used in this study, with the former covering data from birth to 8 years. Linkage disequilibrium score regression (LDSC) analyses were used to assess the genetic correlations of age-specific childhood BMI to cholelithiasis. Two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses were utilized to explore the causal associations. As downstream analyses, summary-based Mendelian randomization (SMR) analyses, transcriptome-wide association studies (TWAS), and Bayesian colocalization were conducted to discover the shared transcriptomic signals. The GWAS summary statistics of cholelithiasis from the UK Biobank were used for sensitivity analyses. LDSC analyses revealed significant genetic correlations between 11 age-specific childhood BMIs and adult cholelithiasis (except for birth BMI). Two-sample MR and MVMR analyses indicated causal relationships between birth BMI and BMI at 8 months, 1.5 years, 7 years, and 8 years after birth and adult cholelithiasis. SMR, TWAS, and colocalization analyses identified MLXIPL as the strongest overlapping signal between age-specific BMI and adult cholelithiasis. This study provides new evidence on the relationships between childhood obesity and adult cholelithiasis, highlighting the role of early intervention for obesity in childhood at key time points. MLXIPL gene expression was identified as a potential biological pathway, suggesting potential therapeutic targets and precise intervention strategies for childhood obesity and adult cholelithiasis. Show less
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injur Show more
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injured hepatocytes evoke fibrogenic responses in HSCs. However, intrahepatocyte players that modulate such cell-to-cell communications remain poorly defined. In this study, hepatic ChREBPα is found to be reduced in mouse models of chemical-induced liver fibrosis as well as in three groups of human patients with liver fibrosis. Chrebpα-LKO mice are highly sensitive to both chemical (CCL4 and TAA) and bile duct ligation (BDL)-induced liver injury and developed more advanced liver fibrosis without affecting liver lipid content. Hepatocyte ChREBPα overexpression suppressed the activation of HSCs in an in vitro medium transfer experiment in part via inhibiting the expression of profibrogenic factors THBS1 and CTGF. RNA-Seq analysis revealed that E2F1, a novel effector of TGFβ-mediated fibrogenic pathway, is highly induced in the liver of Chrebpα-LKO mice. Hepatic knockdown of E2F1 ameliorated the increased liver fibrosis in mice with hepatic Chrebpα deficiency while reducing the expression of hepatic THBS1 and CTGF. Show less
Mi Cheong Cheong, Bryan Mackowiak, Hyung Bum Kim+10 more · 2025 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, thi Show more
Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Show less
Diabetic kidney disease (DKD), characterized by mesangial fibrosis and renal dysfunction, is a major microvascular complication of diabetes. Studies have shown that miRNAs are closely related to the p Show more
Diabetic kidney disease (DKD), characterized by mesangial fibrosis and renal dysfunction, is a major microvascular complication of diabetes. Studies have shown that miRNAs are closely related to the progression of DKD. Therefore, in this study, we aimed to explore whether miR-1225-3p can regulate Smad ubiquitin regulatory factor 2 (SMURF2)-mediated carbohydrate response element binding protein (ChREBP) ubiquitination through Rho GTPase-activating protein 5 (ARHGAP5) to affect fibrosis in DKD. DKD mice were established by intraperitoneally injecting streptozocin (STZ), and a DKD cell model was generated by culturing in media supplemented with 25 mmol/L glucose (high glucose, HG). StarBase was used to predict the target binding sites between miR-1225-3p and ARHGAP5, and a dual-luciferase reporter gene assay was used to verify this relationship. Western blotting, RT-qPCR, flow cytometry, immunoprecipitation, ELISAs, HE staining, and Masson staining were used to detect relevant indicators. ARHGAP5 and SMURF2 expression was decreased, but ChREBP was highly expressed in the renal tissue of DKD mice and HG-induced mouse mesangial cells (MMCs). miR-1225-3p could target and regulate the transcription of ARHGAP5, and an association between ARHGAP5 and SMURF2 was revealed. miR-1225-3p facilitated fibrosis and oxidative stress in MCCs by inhibiting ARHGAP5. In addition, SMURF2 promoted the ubiquitination of HA-ChREBP, and miR-1225-3p facilitated fibrosis and oxidative stress by mediating the ARHGAP5/SMURF2-mediated ubiquitination of ChREBP in MCCs. Furthermore, the miR-1225-3p inhibitor inhibited fibrosis and inflammation in the renal tissues of DKD mice. miR-1225-3p facilitates fibrosis and oxidative stress by mediating ARHGAP5/SMURF2-mediated ubiquitination of ChREBP. Show less
The study aimed to investigate the role of carbohydrate-responsive element-binding protein (ChREBP) in the pathogenesis of pulmonary fibrosis (PF) by assessing its impact on fibrotic protein expressio Show more
The study aimed to investigate the role of carbohydrate-responsive element-binding protein (ChREBP) in the pathogenesis of pulmonary fibrosis (PF) by assessing its impact on fibrotic protein expression, fibroblast proliferation, and apoptosis in lung tissues. The PF model was established using bleomycin, and pathological changes in lung tissues were assessed through histopathological analysis. Expression levels of inflammatory markers and fibrotic proteins, including ChREBP, were measured using Western blot and ELISA. Additionally, human embryonic lung fibroblasts (MRC-5) were transfected with ChREBP overexpression or silencing vectors following TGF-β1 induction to examine changes in cellular behavior, including viability, apoptosis, and fibrotic protein expression. The PF model group showed significant alveolar structural abnormalities and elevated levels of TNF-α, MMP-7 and TGF-β1. ChREBP expression was markedly increased in fibrotic tissues (P < 0.05). In vitro, ChREBP overexpression in MRC-5 cells enhanced fibrotic protein levels, increased cell viability, and reduced apoptosis rates. Conversely, silencing ChREBP reduced fibrotic protein expression, inhibited fibroblast proliferation, and increased apoptosis (P < 0.05). These findings suggest that ChREBP plays a key role in modulating fibrosis-related pathways in PF. ChREBP is substantially upregulated in PF and plays a key role in promoting fibroblast proliferation and inhibiting apoptosis. These findings suggest that targeting ChREBP may present a novel therapeutic strategy for treating pulmonary fibrosis by modulating fibrotic and apoptotic pathways. Show less
The deficiency of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, causes fatty liver. However, its underlying mechanism and physiological significance are not fully understood. Show more
The deficiency of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, causes fatty liver. However, its underlying mechanism and physiological significance are not fully understood. Here we demonstrate that carbohydrate response element-binding protein (ChREBP) mediates lipid metabolic remodeling and promotes progressive triglyceride accumulation against metabolic injury in adult FBP1-deficient liver. Inducible liver-specific deletion of Fbp1 gene caused progressive hepatomegaly and hepatic steatosis, with a marked increase in hepatic de novo lipogenesis (DNL) as well as a decrease in plasma β-hydroxybutyrate levels. Notably, FBP1 deficiency resulted in a persistent activation of ChREBP and its target genes involved in glycolysis, lipogenesis, and fatty acid oxidation, even under fasting conditions. Furthermore, liver-specific ChREBP disruption could markedly restore the phenotypes of enhanced DNL and triglyceride accumulation in FBP1-deficient liver but exacerbated its hepatomegaly and liver injury, which was associated with remarkable energy deficit, impaired mammalian target of rapamycin (mTOR) activation, and increased oxidative stress. Furthermore, metabolomics analysis revealed a robust elevation of phosphoenolpyruvate, phosphoglycerates, phospholipids, and ceramides caused by ChREBP deletion in FBP1-deficient liver. Put together, these results suggest that overactivation of ChREBP pathway mediates liver metabolic remodeling in the absence of FBP1, which contributes to the pathogenesis of progressive hepatic steatosis and provides a protection against liver injury. Thus, our findings point to a beneficial role of ChREBP in metabolic remodeling in the context of excessive gluconeogenic intermediates. Show less