Shaohui Tang

Cuproptosis, a copper-triggered cell death pathway, holds therapeutic potential for cancers, but its regulatory mechanisms in hepatocellular carcinoma (HCC) remain undefined. Despite SEC14L3’s known roles in cellular signaling, its involvement in HCC progression and cuproptosis regulation is unclear. Here, we reveal that SEC14L3 expression is downregulated in HCC cells and tissues and correlates with advanced stages and poor prognosis. Copper-induced cuproptosis inhibits HCC cell viability, and SEC14L3 positively modulates cuproptosis in HCC cells by promoting DLAT lipoylation and its oligomerization. Mechanistically, SEC14L3-mediated cuproptosis suppressed HCC growth via the ERK/YY1/FDX1 axis both in vitro and in vivo. Additionally, copper enhanced the SEC14L3 expression, which in turn regulated ERK/YY1/FDX1 axis. Our findings show that copper-mediated SEC14L3 promotes cuproptosis via ERK/YY1/FDX1 axis, thereby inhibiting HCC growth. These insights provide a mechanistic foundation for targeting cuproptosis, advancing the development of SEC14L3-driven therapeutic strategies for HCC.

To address the need for a simple model to predict ≥ F2 fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, a study utilized data from 791 biopsy-proven MASLD patients from the NASH Clinical Research Network and Jinan University First Affiliated Hospital. The data were divided into training and internal testing sets through randomized stratified sampling. A multivariable logistic regression model using key categorical variables was developed to identify ≥ F2 fibrosis. External validation was performed using data from the FLINT trial and multiple centers in China. The DA-GAG score, incorporating diabetes, age, GGT, aspartate aminotransferase/ platelet ratio, and globulin/ total protein ratio, demonstrated superior performance in distinguishing ≥ F2 fibrosis with an area under the receiver operating characteristic curve of 0.79 in training and over 0.80 in testing datasets. The DA-GAG score efficiently identifies MASLD patients with ≥ F2 fibrosis, significantly reducing the medical burden.

The insulin-like growth factor 2 (IGF2) and H19 are overexpressed in hepatocellular carcinoma (HCC). IGF2-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in IGF2 and H19 overexpression regulation and its role in HCC. Firstly, the effect of miR-483-5p on the expression of IGF2 and H19, and the binding of miR-483-5p to IGF2/H19 enhancer were evaluated in HCC cells. Next, miR-483-5p-mediated IGF2/H19 enhancer activation and its mechanism were investigated in HCC cells. Then, the mechanism by which active IGF2/H19 enhancer mediated by miR-483-5p activate IGF2/H19 promoters was studied in HCC cells. Finally, the effect of MED1 on the expression of IGF2/H19 as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p was evaluated. Mir-483-5p up-regulated IGF2 P2 mRNA-P4 mRNA and H19 expression by binding to IGF2/H19 enhancer resulting in IGF2/H19 enhancer activation in HCC cells. Mechanistically, miR-483-5p increased recruitment of Ago1 and Ago2 at IGF2/H19 enhancer and then activated transcription of IGF2/H19 eRNA by RNA polymerase II and p300, which further induced chromatin loops formation between IGF2/H19 enhancer and IGF2/H19 promoters to activate IGF2/H19 promoters via IGF2/H19 eRNA-MED1-IGF2/H19 promoters complex in HCC cells. In this process, MED1 promoted chromatin loops formation as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p. miR-483-5p-mediated activating of IGF2/H19 enhancer up-regulates IGF2/H19 expression via DNA loops, thereby promoting the malignant progression of HCC.

The dysregulation of exosomal microRNAs (miRNAs) plays a crucial role in the development and progression of cancer. This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer (GC) and the underlying mechanisms. The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics. Next, the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues, and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments. Then, the effect of miR-4256 on its downstream target genes HDAC5/p16^INK4a was studied in GC cells, and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation (ChIP). Additionally, the role of the miR-4256/HDAC5/p16^INK4a axis in GC was studied using in vitro and in vivo experiments. Finally, the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments. miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues; in vitro and in vivo results showed that miR-4256 promoted GC growth and progression. Mechanistically, miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells, and then restrained the expression of p16^INK4a through the epigenetic modulation of HDAC5 at the p16^INK4a promoter. Furthermore, miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells. Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16^INK4a axis, which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.

Objective: We aimed to investigate the effect of Cyclocarya paliurus leaves extracts (CP) on glucose and blood lipid metabolism and its relationship with intestinal flora in type 2 diabetes mellitus (T2DM) patients.Methods: In this open-label, 84-day randomized controlled trial, a total of 38 T2DM patients were randomly assigned to the CP group or the Glipizide group (G group) in a 2:1 ratio. T2DM-associated metabolic phenotypes, gut microbiota and metabolites including short-chain fatty acids (SCFAs) and bile acids (BAs) were detected.Results: At the end of intervention, CP, like Glipizide, significantly improved HbA1c level and other glucose metabolism parameters (fasting plasma glucose (FBG), 2-hour post-meal blood glucose (2hPBG), the area under curve of oral glucose tolerance test glucose (OGTT glucose AUC)). Moreover, CP also resulted in the significant improvement in the levels of blood lipid and blood pressure. Notably, the improvement in blood lipid(triglycerides (TG) and high-density lipoprotein cholesterol (HDL-c)) and blood pressure (diastolic blood pressure (DBP)) was significantly greater in the CP group compared with the G group. Furthermore, the liver and kidney function parameters did not significantly change in both CP group and the G group over the 84-day period. Additionally, the enrichment of potentially beneficial bacteria (Faecalibacterium and Akkermansia), SCFAs and unconjugated BAs and the depletion of potential pathogenic bacteria (Prevotella_9) and conjugated BAs were observed in the CP group, while the abundances of the gut microbial were kept stable in the G group after intervention.Conclusion: CP displays a more beneficial effect in the alleviation of T2DM-associated metabolic phenotypes than glipizide by regulating gut microbiota and metabolites in T2DM patients, with no significant effects on liver and kidney function.

Few studies have thoroughly assessed the efficacy and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD). Therefore, this systematic review and meta‑analysis was performed to further evaluate this association. PubMed, Embase, and the Cochrane databases were searched until April 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of VDZ in the treatment of IBD were included. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome using a random effects model. A total of 12 RCTs, including 4,865 patients, met the inclusion criteria. In the induction phase, VDZ was more effective than placebo for patients with ulcerative colitis and Crohn's disease (CD) in clinical remission (RR=2.09; 95% CI=1.66‑2.62) and clinical response (RR=1.54; 95% CI=1.34‑1.78). In the maintenance therapy group, VDZ reached higher clinical remission (RR=1.98; 95% CI=1.58‑2.49) and clinical response (RR=1.78; 95% CI=1.40‑2.26) rates compared with the placebo group. VDZ particularly improved clinical remission (RR=2.07; 95% CI=1.48‑2.89) and clinical response (RR=1.84; 95% CI=1.54‑2.21) in patients with TNF antagonist failure. In terms of corticosteroid‑free remission, VDZ was also more effective than placebo in patients with IBD (RR=1.98; 95% CI=1.51‑2.59). In Crohn's patients, VDZ was more effective than placebo in terms of mucosal healing (RR=1.78; 95% CI=1.27‑2.51). With respect to adverse events, VDZ significantly reduced the risk of IBD exacerbation compared with the placebo (RR=0.60; 95% CI=0.39‑0.93; P=0.023). However, when compared with the placebo, VDZ increased the risk of nasopharyngitis in patients with CD (RR=1.77; 95% CI=1.01‑3.10; P=0.045). No significant differences in other adverse events were observed. Although there might be underlying risk, such as selection bias, in the present study it can be safely concluded that VDZ is a safe and effective biological agent for IBD, particularly for patients with TNF antagonist failure.

Clostridium butyricum (CB) is a spore-forming, gram-positive and obligate anaerobic rod bacterium. CB can modulate the composition of the gut microbiome and promote the growth of beneficial microbes in the intestine by generating short-chain fatty acids (SCFAs), which in turn protect against colitis and prevents the formation of inflammatory-associated colorectal cancer (CRC) by ameliorating colon inflammatory processes. Yet, it remains unclear whether the culture and supernatant of CB could directly influence inflammatory CRC in mice. In this study, azoxymethane (AOM)+dextran sodium sulphate (DSS) was used to induce CRC model in C57BL/6 mice. Next, the serum levels of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), and cytokines TNF-α, were measured and the pathohistological examination of the large intestine was performed. Both CB culture and supernatant were found to have anti-inflammatory properties. Subsequently, Western blot and Real-Time Quantitative PCR (RT-qPCR) revealed that CB and supernatant regulate the NF-κB/p65 pathway to inhibit the development and progression of inflammatory CRC in AOM+DSS-treated mice, which could be due to the high levels of butyric acid in the supernatant.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent hepatic pathology worldwide. However, the precise molecular mechanisms for NAFLD are still not sufficiently explained. Recently, a new mode of cell death (cuproptosis) is found. However, the relationship between NAFLD and cuproptosis remains unclear. We analyzed three public datasets (GSE89632, GSE130970, and GSE135251) to identify cuproptosis-related genes stably expressed in NAFLD. Then, we performed a series of bioinformatics analyses to explore the relationship between NAFLD and cuproptosis-related genes. Finally, 6 high-fat diet- (HFD-) induced NAFLD C57BL/6J mouse models were established to carry out transcriptome analysis. The results of gene set variation analysis (GSVA) revealed that the cuproptosis pathway was abnormally activated to a certain degree ( in GSE89632, in GSE130970, in GSE135251), and the principal component analysis (PCA) of the cuproptosis-related genes showed that the NAFLD group separated from the control group, with the first two principal components accounting for 58.63%-74.88% of the variation. Among three datasets, two cuproptosis-related genes (DLD and PDHB, or 0.001) were stably upregulated in NAFLD. Additionally, both DLD ( ) and PDHB ( ) had favorable diagnostic properties, and the multivariate logistics regression model further improved the diagnostic properties ( ). NADH, flavin adenine dinucleotide, and glycine targeted DLD, and pyruvic acid and NADH targeted PDHB in the DrugBank database. The DLD and PDHB were also associated with clinical pathology, especially with steatosis (DLD, ; PDHB, ) and NAFLD activity score (DLD, ; PDHB,

Background: Omega-3 polyunsaturated fatty acids are known to be associated with numbers of health benefits, and which can be uptake from fish. The aim of this study was to evaluate the current evidence of associations between consumption of fish and diverse health outcomes. Here, we performed an umbrella review to summarize the breadth, strength, and validity of the evidence derived from meta-analyses and systematic reviews of fish consumption on all health outcomes. Methods: The methodological quality of the included meta-analyses and the quality of the evidence were assessed by the Assessment of Multiple Systematic Reviews (AMSTAR) and the grading of recommendations, assessment, development, and evaluation (GRADE) tools, respectively. The umbrella review identified 91 meta-analyses with 66 unique health outcomes, of which 32 outcomes were beneficial, 34 showed nonsignificant associations and only one was harmful (myeloid leukemia). Results: A total of 17 beneficial associations [all-cause mortality, prostate cancer mortality, cardiovascular disease (CVD) mortality, esophageal squamous cell carcinoma (ESCC), glioma, non-Hodgkin lymphoma (NHL), oral cancer, acute coronary syndrome (ACS), cerebrovascular disease, metabolic syndrome, age-related macular degeneration (AMD), inflammatory bowel disease (IBD), Crohn’s disease (CD), triglycerides, vitamin D, high-density lipoprotein (HDL)-cholesterol, and multiple sclerosis (MS)], and eight nonsignificant associations [colorectal cancer (CRC) mortality, esophageal adenocarcinoma (EAC), prostate cancer, renal cancer, ovarian cancer, hypertension, ulcerative colitis (UC), and rheumatoid arthritis (RA)] were evaluated as moderate/high quality of evidence. According to dose-response analyses, consumption of fish, especially fatty types, seems generally safe at one-two servings per week and could exert protective effects. Conclusions: Fish consumption is often associated with a variety of health outcomes, both beneficial and harmless, but only about 34% of the associations were graded as based on a moderate/high quality of evidence, and additional multicenter high quality randomized controlled trials (RCTs) with a large sample size are needed to verify these findings in the future.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Copper metabolism plays an important role in the pathogenesis of NAFLD. However, the relationship between serum/hepatic copper concentration and NAFLD is still debated. A literature search was performed using electronic databases to find publications up to September 2022, where the relationship between serum/hepatic copper or ceruloplasmin concentration and NAFLD was evaluated. Finally, 6 articles with 9 unique outcomes involving 2,607 NAFLD patients and 1,441 non-NAFLD normal individuals were included. The pooled results showed that hepatic copper concentration was significantly decreased in NAFLD patients (SMD = −0.98, 95% CI = [−1.21; −0.74], p < 0.0001), and the sensitivity analysis also confirmed this. Nevertheless, serum copper (SMD = −0.02, 95% CI = [−0.32; 0.28], p = 0.88) and ceruloplasmin (SMD = −0.03, 95% CI = [−0.69; 0.63], p = 0.93) were not associated with NAFLD. This meta-analysis revealed that low hepatic copper concentration was found in NAFLD patients and serum copper and ceruloplasmin were not associated with NAFLD. Larger cohort studies and related trials are needed to further validate the result of this meta-analysis in the future.