Baisheng Sun, Lina Bai, Qinglin Li+5 more · 2024 · Toxicology in vitro : an international journal published in association with BIBRA · Elsevier · added 2026-04-24
Sepsis-induced acute lung injury (ALI) is a life-threatening disease. Macrophage pyroptosis has been reported to exert function in ALI. We aimed to investigate the mechanisms of ANGPTL4-mediated cell Show more
Sepsis-induced acute lung injury (ALI) is a life-threatening disease. Macrophage pyroptosis has been reported to exert function in ALI. We aimed to investigate the mechanisms of ANGPTL4-mediated cell pyroptosis in sepsis-induced ALI, thus providing new insights into the pathogenesis and prevention and treatment measures of sepsis-induced ALI. In vivo animal models and in vitro cell models were established by cecal ligation and puncture (CLP) method and lipopolysaccharide-induced macrophages RAW264.7. ANGPTL4 was silenced in CLP mice or macrophages, followed by the determination of ANGPTL4 expression in bronchoalveolar lavage fluid (BALF) or macrophages. Lung histopathology was observed by H&E staining, with pathological injury scores evaluated and lung wet and dry weight ratio recorded. M1/M2 macrophage marker levels (iNOS/CD86/Arg1), inflammatory factor (TNF-α/IL-6/IL-1β/iNOS) expression in BALF, cell death and pyroptosis, NLRP3 inflammasome, cell pyroptosis-related protein (NLRP3/Cleaved-caspase-1/caspase-1/GSDMD-N) levels, NF-κB pathway activation were assessed by RT-qPCR/ELISA/flow cytometry/Western blot, respectively. ANGPTL4 was highly expressed in mice with sepsis-induced ALI, and ANGPTL4 silencing ameliorated sepsis-induced ALI in mice. In vivo, ANGPTL4 silencing repressed M1 macrophage polarization and macrophage pyroptosis in mice with sepsis-induced ALI. In vitro, ANGPTL4 knockout impeded LPS-induced activation and pyroptosis of M1 macrophages and hindered LPS-induced activation of the NF-κB pathway in macrophages. Knockdown of ANGPTL4 blocks the NF-κB pathway activation, hinders macrophage M1 polarization and pyroptosis, thereby suppressing sepsis-induced ALI. Show less
Reducing production costs while producing high-quality livestock and poultry products is an ongoing concern in the livestock industry. The addition of oil to livestock and poultry diets can enhance fe Show more
Reducing production costs while producing high-quality livestock and poultry products is an ongoing concern in the livestock industry. The addition of oil to livestock and poultry diets can enhance feed palatability and improve growth performance. Emulsifiers can be used as potential feed supplements to improve dietary energy utilization and maintain the efficient productivity of broilers. Therefore, further investigation is warranted to evaluate whether dietary emulsifier supplementation can improve the efficiency of fat utilization in the diet of yellow-feathered broilers. In the present study, the effects of adding emulsifier to the diet on lipid metabolism and the performance of yellow-feathered broilers were tested. A total of 240 yellow-feasted broilers (21-day-old) were randomly divided into 4 groups (6 replicates per group, 10 broilers per replicate, half male and half female within each replicate). The groups were as follows: the control group (fed with basal diet), the group fed with basal diet supplemented with 500 mg/kg emulsifier, the group fed with a reduced oil diet (reduced by 1%) supplemented with 500 mg/kg emulsifier, and the group fed with a reduced oil diet supplemented with 500 mg/kg emulsifier. The trial lasted for 42 days, during which the average daily feed intake, average daily gain, and feed-to-gain ratio were measured. Additionally, the expression levels of lipid metabolism-related genes in the liver, abdominal fat and each intestinal segment were assessed. The results showed that compared with the basal diet group, (1) The average daily gain of the basal diet + 500 mg/kg emulsifier group significantly increased (P < 0.05), and the half-even-chamber rate was significantly increased (P < 0.05); (2) The mRNA expression levels of Cd36, Dgat2, Apob, Fatp4, Fabp2, and Mttp in the small intestine were significantly increased (P < 0.05). (3) Furthermore, liver TG content significantly decreased (P < 0.05), and the mRNA expression level of Fasn in liver was significantly decreased (P < 0.05), while the expression of Apob, Lpl, Cpt-1, and Pparα significantly increased (P < 0.05). (4) The mRNA expression levels of Lpl and Fatp4 in adipose tissue were significantly increased (P < 0.05), while the expression of Atgl was significantly decreased (P < 0.05). (5) Compared with the reduced oil diet group, the half-evading rate and abdominal fat rate of broilers in the reduced oil diet + 500 mg/kg emulsifier group were significantly increased (P < 0.05), and the serum level of LDL-C increased significantly (P < 0.05)0.6) The mRNA expression levels of Cd36, Fatp4, Dgat2, Apob, and Mttp in the small intestine were significantly increased (P < 0.05). 7) The mRNA expression levels of Fasn and Acc were significantly decreased in the liver (P < 0.05), while the mRNA expression levels of Lpin1, Dgat2, Apob, Lpl, Cpt-1, and Pparα were significantly increased (P < 0.05). These results suggest that dietary emulsifier can enhance the fat utilization efficiency of broilers by increasing the small intestinal fatty acid uptake capacity, inhibiting hepatic fatty acid synthesis and promoting hepatic TG synthesis and transport capacity. This study provides valuable insights for the potential use of emulsifier supplementation to improve the performance of broiler chickens. Show less
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients fr Show more
The neuronal ceroid lipofuscinoses (NCLs) comprise a group of inherited neurodegenerative disorders with thirteen NCL-disease causing genes ceroid lipofuscinosis neuronal ( We recruited 14 patients from 13 unrelated families who carried biallelic variants in the We detected 21 variants in three Patients with variants in the three Show less
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted eff Show more
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ Show less
Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therap Show more
Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. Aberrant metabolism, a key hallmark of human cancers, plays a crucial role in tumor progression, therapeutic responses and TNBC-related death. However, the underlying mechanisms are not fully understood. In this study, we delineate a previously unrecognized role of aberrant glucose metabolism in regulating the turnover of Snail1, which is a key transcriptional factor of epithelial-mesenchymal transition (EMT) and critically contributes to the acquisition of stemness, metastasis and chemo-resistance. Mechanistically, we demonstrate that AMP-activated protein kinase (AMPK), when activated in response to glucose deprivation, directly phosphorylates Snail1 at Ser11. Such a phosphorylation modification of Snail1 facilitates its recruitment of the E3 ligase FBXO11 and promotes its degradation, thereby suppressing stemness, metastasis and increasing cellular sensitivity to chemotherapies in vitro and in vivo. Clinically, histological analyses reveal a negative correlation between p-AMPKα and Snail1 in TNBC specimens. Taken together, our findings establish a novel mechanism and functional significance of AMPK in linking glucose status to Snail1-dependent malignancies and underscore the potential of AMPK agonists as a promising therapeutic strategy in the management of TNBC. Show less
Dyslipidemia plays a very important role in the occurrence and development of cardiovascular disease (CVD). Genetic factors, including single nucleotide polymorphisms (SNPs), are one of the main risks Show more
Dyslipidemia plays a very important role in the occurrence and development of cardiovascular disease (CVD). Genetic factors, including single nucleotide polymorphisms (SNPs), are one of the main risks of dyslipidemia. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is not only the rate-limiting enzyme step of endogenous cholesterol production, but also the therapeutic target of statins. We investigated 405 Han Chinese and 373 Uyghur people who took statins for a period of time, recorded their blood lipid levels and baseline data before and after oral statin administration, and extracted DNA from each subject for SNP typing of In this study, for rs17671591, the CC We found that Show less
Acute lung injury is a critical life-threatening complication of pulmonary and cardiac surgery with a high rate of morbidity and mortality. Fibroblast growth factor 21 (FGF21) has been reported to pla Show more
Acute lung injury is a critical life-threatening complication of pulmonary and cardiac surgery with a high rate of morbidity and mortality. Fibroblast growth factor 21 (FGF21) has been reported to play an important role in protecting vital organs from damage. This study aims to investigate the potential protective role and mechanism of FGF21 in pulmonary ischemia/reperfusion (I/R)-induced acute lung injury. A pulmonary epithelial cell line was treated with hypoxia/regeneration (H/R) in vitro and a mouse model of acute lung injury was induced with pulmonary I/R in vivo. Lung injury after pulmonary I/R was compared between FGF21-konckout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. Circulating levels of FGF21 in mice with pulmonary I/R injury were significantly higher than in those without pulmonary I/R injury. Lung injury was aggravated in FGF21-KO mice compared with WT mice and the administration of FGF21 alleviated lung injury in mouse treated with I/R and pulmonary epithelial cell injury treated with H/R. FGF21 treatment decreased endoplasmic reticulum (ER) stress, Fe Our study reveals that FGF21 protects against pulmonary I/R injury via inhibiting ER stress-induced ferroptosis though FGFR1/PPARδ signaling pathway. Boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for pulmonary IRI. Show less
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal Show more
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy. Show less
Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-re Show more
Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithmsr. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis. A diagnostic model was developed using random forest algorithm and validated by receiver operating characteristic (ROC) curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by quantitative real-time PCR (qRT-PCR). We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P < 0.0001) and interleukins pathway (R = 0.79, P < 0.0001). Furthermore, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes. Show less
Carcass traits are crucial indicators of meat production efficiency. However, the molecular regulatory mechanisms associated with these traits remain unclear. In this study, we conducted comprehensive Show more
Carcass traits are crucial indicators of meat production efficiency. However, the molecular regulatory mechanisms associated with these traits remain unclear. In this study, we conducted comprehensive transcriptomic and genomic analyses on 399 Tiannong partridge chickens to identify key genes and variants associated with carcass traits and to elucidate the underlying regulatory mechanisms. Based on association analyses with the elastic net (EN) model, we identified 12 candidate genes (AMY1A, AP3B2, CEBPG, EEF2, EIF4EBP1, FGFR1, FOXD3, GOLM1, LOC107052698, PABPC1, SERPINB6 and TBC1D16) for 4 carcass-related traits, namely live weight, dressed weight, eviscerated weight, and breast muscle weight. SERPINB6 was identified as the only overlapping gene by 3 analyses, EN model analysis, weighted gene co-expression network analysis and differential expression analysis. Cell-level experiments confirmed that SERPINB6 promotes the proliferation of chicken DF1 cells and primary myoblasts. Further expression genome-wide association study and association analysis indicated that rs317934171 is the critical site that enhances SERPINB6 expression. Furthermore, a dual-luciferase reporter assay proved that gga-miR-1615 targets the 3'UTR of SERPINB6. Collectively, our findings reveal that SERPINB6 serves as a novel gene for chicken carcass traits by promoting fibroblast and myoblast proliferation. Additionally, the downstream variant rs317934171 regulates SERPINB6 expression. These results identify a new target gene and molecular marker for the molecular mechanisms of chicken carcass traits. Show less
RNA-binding proteins (RBPs) are powerful and versatile regulators in living creatures, playing fundamental roles in organismal development, metabolism, and various diseases by the regulation of gene e Show more
RNA-binding proteins (RBPs) are powerful and versatile regulators in living creatures, playing fundamental roles in organismal development, metabolism, and various diseases by the regulation of gene expression at multiple levels. The requirements of deep research on RBP function have promoted the rapid development of RBP-RNA interplay detection methods. Recently, the detection method of fusing RNA modification enzymes (RME) with RBP of interest has become a hot topic. Here, we reviewed RNA modification enzymes in adenosine deaminases that act on RNA (ADAR), terminal nucleotidyl transferase (TENT), and activation-induced cytosine deaminase/ApoB mRNA editing enzyme catalytic polypeptide-like (AID/APOBEC) protein family, regarding the biological function, biochemical activity, and substrate specificity originated from enzyme selves, their domains and partner proteins. In addition, we discussed the RME activity screening system, and the RME mutations with engineered enzyme activity. Furthermore, we provided a systematic overview of the basic principles, advantages, disadvantages, and applications of the RME-based and cross-linking and immunopurification (CLIP)-based RBP target profiling strategies, including targets of RNA-binding proteins identified by editing (TRIBE), RNA tagging, surveying targets by APOBEC-mediated profiling (STAMP), CLIP-seq, and their derivative technology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Processing > RNA Editing and Modification. Show less
In recent years, metal-organic framework (MOF) materials with long persistent luminescence (LPL) have inspired extensive attention and presented various applications in security systems, information a Show more
In recent years, metal-organic framework (MOF) materials with long persistent luminescence (LPL) have inspired extensive attention and presented various applications in security systems, information anticounterfeiting, and biological imaging fields. However, obtaining LPL materials with ultralong lifetime remains challenging. Halogen atoms, as nonmetallic elements existing in the frameworks, can not only induce the heavy-atom effect, effectively enhancing spin-orbit coupling and promoting intersystem crossing (ISC) processes, but also suppress non-radiative transition of the triplet states through the intra- and intermolecular interactions. Specifically, fluorine atoms with the strongest electronegativity may form intermolecular aggregate interlockings through halogen-bonding interactions that restrict molecular motions and vibrations, thereby improving phosphorescent lifetime. With the aforementioned considerations, two distinct types of MOFs with/without fluorine atoms (namely, Ca-MOF and 5FCa-MOF) were synthesized. Notably, by introducing fluorine atoms into MOFs, fluorine-induced intermolecular aggregate interlockings effectively enhanced the phosphorescent lifetime of 5FCa-MOF exceeding 264 ms compared to that of Ca-MOF (103.94 ms). Remarkably, both MOFs displayed bright LPL to the naked eye after removal of the irradiation source, especially 5FCa-MOF which can last for about 2 s. By introducing fluorine atoms, 5FCa-MOF exhibits greatly enhanced ISC with a rate constant up to 4.1 × 10 Show less
Non-obstructive azoospermia (NOA) is a major contributor of male infertility. Herein, we used existing datasets to identify novel biomarkers for the diagnosis and prognosis of NOA, which could have gr Show more
Non-obstructive azoospermia (NOA) is a major contributor of male infertility. Herein, we used existing datasets to identify novel biomarkers for the diagnosis and prognosis of NOA, which could have great significance in the field of male infertility. NOA datasets were obtained from the Gene Expression Omnibus (GEO) database. CIBERSORT was utilized to analyze the distributions of 22 immune cell populations. Hub genes were identified by applying weighted gene co-expression network analysis (WGCNA), machine learning methods, and protein-protein interaction (PPI) network analysis. The expression of hub genes was verified in external datasets and was assessed by receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) was applied to explore the important functions and pathways of hub genes. The mRNA-microRNA (miRNA)-transcription factors (TFs) regulatory network and potential drugs were predicted based on hub genes. Single-cell RNA sequencing data from the testes of patients with NOA were applied for analyzing the distribution of hub genes in single-cell clusters. Furthermore, testis tissue samples were obtained from patients with NOA and obstructive azoospermia (OA) who underwent testicular biopsy. RT-PCR and Western blot were used to validate hub gene expression. Two immune-related oxidative stress hub genes ( It appears that Show less
Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for develop Show more
Clinical studies have indicated a comorbidity between sepsis and kidney diseases. Individuals with specific mutations that predispose them to kidney conditions are also at an elevated risk for developing sepsis, and vice versa. This suggests a potential shared genetic etiology that has not been fully elucidated. Summary statistics data on exposure and outcomes were obtained from genome-wide association meta-analysis studies. We utilized these data to assess genetic correlations, employing a pleiotropy analysis method under the composite null hypothesis to identify pleiotropic loci. After mapping the loci to their corresponding genes, we conducted pathway analysis using Generalized Gene-Set Analysis of GWAS Data (MAGMA). Additionally, we utilized MAGMA gene-test and eQTL information (whole blood tissue) for further determination of gene involvement. Further investigation involved stratified LD score regression, using diverse immune cell data, to study the enrichment of SNP heritability in kidney-related diseases and sepsis. Furthermore, we employed Mendelian Randomization (MR) analysis to investigate the causality between kidney diseases and sepsis. In our genetic correlation analysis, we identified significant correlations among BUN, creatinine, UACR, serum urate, kidney stones, and sepsis. The PLACO analysis method identified 24 pleiotropic loci, pinpointing a total of 28 nearby genes. MAGMA gene-set enrichment analysis revealed a total of 50 pathways, and tissue-specific analysis indicated significant enrichment of five pairs of pleiotropic results in kidney tissue. MAGMA gene test and eQTL information (whole blood tissue) identified 33 and 76 pleiotropic genes, respectively. Notably, genes This study lays the groundwork for shared etiological factors between kidney and sepsis. The confirmed pleiotropic loci, shared pathogenic genes, and enriched pathways and immune cells have enhanced our understanding of the multifaceted relationships among these diseases. This provides insights for early disease intervention and effective treatment, paving the way for further research in this field. Show less
Nonalcoholic steatohepatitis (NASH) is a prominent cause of liver-related death that poses a threat to global health and is characterized by severe hepatic steatosis, lobular inflammation, and balloon Show more
Nonalcoholic steatohepatitis (NASH) is a prominent cause of liver-related death that poses a threat to global health and is characterized by severe hepatic steatosis, lobular inflammation, and ballooning degeneration. To date, no Food and Drug Administration-approved medicine is commercially available. The Chaihu Guizhi Ganjiang Decoction (CGGD) shows potential curative effects on regulation of blood lipids and blood glucose, mitigation of organism inflammation, and amelioration of hepatic function. However, the overall regulatory mechanisms underlying its effects on NASH remain unclear. This study aimed to investigate the efficiency of CGGD on methionine- and choline-deficient (MCD)-induced NASH and unravel its underlying mechanisms. A NASH model of SD rats was established using an MCD diet for 8 weeks, and the efficacy of CGGD was evaluated based on hepatic lipid accumulation, inflammatory response, and fibrosis. The effects of CGGD on the intestinal barrier, metabolic profile, and differentially expressed genes (DEGs) profile were analyzed by integrating gut microbiota, metabolomics, and transcriptome sequencing to elucidate its mechanisms of action. In MCD-induced NASH rats, pathological staining demonstrated that CGGD alleviated lipid accumulation, inflammatory cell infiltration, and fibrosis in the hepatic tissue. After CGGD administration, liver index, liver weight, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) contents, liver triglycerides (TG), and free fatty acids (FFAs) were decreased, meanwhile, it down-regulated the level of proinflammatory mediators (TNF-α, IL-6, IL-1β, MCP-1), and up-regulated the level of anti-inflammatory factors (IL-4, IL-10), and the expression of liver fibrosis markers TGFβ, Acta2, Col1a1 and Col1a2 were weakened. Mechanistically, CGGD treatment altered the diversity of intestinal flora, as evidenced by the depletion of Allobaculum, Blautia, norank_f_Erysipelotrichaceae, and enrichment of the probiotic genera Roseburia, Lactobacillus, Lachnoclostridium, etc. The colonic histopathological results indicated that the gut barrier damage recovered in the CGGD treatment group, and the expression levels of colonic short-chain fatty acids (SCFAs)-specific receptors FFAR2, FFAR3, and tight junction (TJs) proteins ZO-1, Occludin, Claudin-1 were increased compared with those in the model group. Further metabolomic and transcriptomic analyses suggested that CGGD mitigated the lipotoxicity caused by glycerophospholipid and eicosanoid metabolism disorders by decreasing the levels of PLA2G4A, LPCAT1, COX2, and LOX5. In addition, CGGD could activate the inhibitory lipotoxic transcription factor PPARα, regulate the proteins of FABP1, APOC2, APOA2, and LPL to promote fatty acid catabolism, and suppress the TLR4/MyD88/NFκB pathway to attenuate NASH. Our study demonstrated that CGGD improved steatosis, inflammation, and fibrosis on NASH through enhancing intestinal barrier integrity and alleviating PPARα mediated lipotoxicity, which makes it an attractive candidate for potential new strategies for NASH prevention and treatment. Show less
Dyslipidemia has been established as a potential risk factor for venous thromboembolism (VTE) in several observational studies. Statins and novel lipid-modifying agents are being explored for their po Show more
Dyslipidemia has been established as a potential risk factor for venous thromboembolism (VTE) in several observational studies. Statins and novel lipid-modifying agents are being explored for their potential in VTE prevention, encompassing deep vein thrombosis (DVT), and pulmonary embolism (PE). Nonetheless, conclusive evidence supporting the effectiveness remains uncertain. Without definitive proof, the current recommendation of lipid-lowering drugs (LLDs) for preventing VTE, either primarily or secondarily, is not support. An investigation into the impact of 8 classes of LLDs on VTE was conducted using a drug-target Mendelian randomization approach. The drug categories examined included 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), apolipoprotein B, proprotein convertase subtilisin/kexin type 9, Niemann-Pick C1-like 1, lipoprotein lipase (LPL), angiopoietin-like 3, apolipoprotein C3 (APOC3), and peroxisome proliferator-activated receptor alpha. Leveraging genetic variants situated proximate to or within drug-target genes linked with low-density lipoprotein and triglycerides, we acted as proxies for LLDs. The UK Biobank study was the source of data on VTE, PE, and DVT of lower extremities (LEDVT). We employed the inverse-variance weighted method for the core analysis in Mendelian randomization, complemented by sensitivity analysis to investigate horizontal pleiotropy and heterogeneity. Employing genetic proxies to inhibit HMGCR revealed a notable correlation with reduced LEDVT risk (odds ratio [OR]: 0.995, 95% CI: 0.992-0.998, P = .002), VTE (OR: 0.994, 95% CI: 0.988-1.000, P = .033), but a no significant association with PE (OR: 1.000, 95% CI: 0.994-1.002, P = .246). The suppression of APOB was linked with an elevated risk of experiencing LEDVT (OR: 1.002, 95% CI: 1.001-1.004, P = .006), VTE (OR: 1.005, 95% CI: 1.002-1.007, P < .001), and PE (OR: 1.002, 95% CI: 1.000-1.004, P = .031). Similarly, the activation of LPL was associated with increased risks for VTE (OR: 1.003, 95% CI: 1.001-1.005, P = .003) and PE (OR: 1.003, 95% CI: 1.002-1.005, P < .001). Additionally, the inhibition of APOC3 was linked to a higher DVT risk (OR: 1.002, 95% CI: 1.000-1.004, P = .038). Research has shown that HMGCR, out of 8 lipid-lowering drug-targets evaluated, exhibited a significant correlation with VTE and LEDVT, highlighting its potential as an effective target for the treatment or prevention of these conditions. In contrast, APOB, LPL, and APOC3 each contribute to an increased risk of VTE, PE, and LEDVT in various degrees, pharmacovigilance for VTE, PE, and LEDVT risk among users of APOB inhibitors, LPL activation, and APOC3 inhibitors may be warranted. Show less
Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiolo Show more
Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer. Show less
Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poo Show more
Migraine is a common primary headache that has a significant impact on patients' quality of life. The co-occurrence of migraine and depression is frequent, resulting in more complex symptoms and a poorer prognosis. The evidence suggests that depression and migraine comorbidity share a polygenic genetic background. The aim of this study is to identify related genetic variants that contribute to genetic susceptibility to migraine with and without depression in a Chinese cohort. In this case-control study, 263 individuals with migraines and 223 race-matched controls were included. Eight genetic polymorphism loci selected from the GWAS were genotyped using Sequenom's MALDI-TOF iPLEX platform. In univariate analysis, The study indicates that there is an association between Show less
The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. A total of 1,115 type 2 Show more
The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. ANGPTL4 could be a potential marker and therapeutic target for DKD treatment. Show less
This study investigated the effect of dietary lipid levels on growth performance, lipid metabolism, antioxidant capacity, digestive enzyme activity, and metamorphosis rate of bullfrog (
Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this stud Show more
Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34 Show less
To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Ha Show more
To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Han Chinese preschool children from Henan and Guizhou Province of Long-term Health Effects Assessment Project of Infants and Toddlers Nutritional Pack were selected for the study and divided into an overweight and obese group and a normal control group in 2022. rs633715, rs713586, rs11642015 and rs6567160 were genotyped using Kompetitive allele-specific PCR(KASP) technology. The distribution of genotypic polymorphisms was compared using the χ~2 test. The association between the four loci and overweight and obesity in preschool children was analyzed using a multifactorial logistic regression model. The statistical analysis revealed a significant disparity(P<0.05) in the distribution of genotypic polymorphisms of rs633715 and rs6567160 among preschoolers in Henan and Guizhou Province. CC heterozygous mutant and recessive models at rs633715 locus were associated with susceptibility to overweight and obesity in preschool children [OR and 95% CI 2.915(1.163-7.305), and 2.997(1.226-7.323), respectively, both P<0.05]. TC heterozygous mutant and dominant models at rs713586 locus were also associated susceptibility to overweight and obesity in preschool children(OR and 95% CI were 2.362(1.054-5.289)and 2.362(1.054-5.289), respectively, both P<0.05). rs11642015 and rs6567160 loci were not associated with susceptibility to overweight and obesity in preschool children(P>0.05). The result of the analysis of the cumulative effect of rs633715 and rs713586 showed that the number of genotypes carrying the risk genotype was positively associated with the risk of overweight and obesity in preschool children(P₍trend)<0.01). Among Han Chinese preschool children, SEC16B rs633715 and DNAJC27 rs713586 were associated with susceptibility to overweight and obesity in preschool children. Moreover, rs633715 and rs713586 had a cumulative effect on susceptibility to overweight and obesity in preschool children, the number of risk genotypes carried was positively associated with childhood overweight and obesity risk. Show less
no PDFDOI: 10.19813/j.cnki.weishengyanjiu.2024.02.009
Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, pe Show more
Extramammary Paget's disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration such as the vulva, scrotum, penis and perianal regions. Here, we aim to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease landscape. Immunohistochemical staining on the scrotal wall tumor and bone marrow metastasis demonstrated HER2 overexpression. Whole genome sequencing of the tumor and matched blood was performed. Notable copy number gains (log Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen. Show less
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune respo Show more
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent. Show less
The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity Show more
The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells. Show less
Evidence has revealed that oestrogen deprivation-induced osteolysis is microbiota-dependent and can be treated by probiotics. However, the underlying mechanism require further investigation. This stud Show more
Evidence has revealed that oestrogen deprivation-induced osteolysis is microbiota-dependent and can be treated by probiotics. However, the underlying mechanism require further investigation. This study aims to provide additional evidence supporting the use of probiotics as an adjuvant treatment and to explore the pathophysiology of oestrogen-deprived osteolysis. Forty-five SD rats were randomly divided into five groups (n = 9). Rats from four groups were ovariectomised and treated with NS, calcium, probiotics, or calcium + probiotics, while one group underwent a sham operation and was treated with NS. The osteometabolic effects were evaluated, and the mechanistic role of the probiotic supplement was explored. Intragastric administration of Bifidobacterium animalis subsp. lactis LPL-RH (LPL-RH) markedly suppressed osteoclastic activation and bone calcium loss by downregulating TRAP enzymatic activity, the OPG/RANKL ratio, and the downstream signalling pathway RANKL/TRAF6/NF-κB/NFATc1/TRAP in ovariectomised SD rats. LPL-RH also reduced CD4 Collectively, LPL-RH suppressed osteoclastogenesis and osteolysis by modulating type 17 immunity and gut microbiome. Show less