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Oxidative stress can adversely affect the health status of the body, more specifically by causing intestinal damage by disrupting the permeability of the intestinal barrier. This is closely related to intestinal epithelial cell apoptosis caused by the mass production of reactive oxygen species (ROS). Baicalin (Bai) is a major active ingredient in Chinese traditional herbal medicine that has antioxidant, anti-inflammatory, and anti-cancer properties. The purpose of this study was to explore the underlying mechanisms by which Bai protects against hydrogen peroxide (H2O2)-induced intestinal injury in vitro. Our results indicated that H2O2 treatment caused injury to IPEC-J2 cells, resulting in their apoptosis. However, Bai treatment attenuated H2O2-induced IPEC-J2 cell damage by up-regulating the mRNA and protein expression of ZO-1, Occludin, and Claudin1. Besides, Bai treatment prevented H2O2-induced ROS and MDA production and increased the activities of antioxidant enzymes (SOD, CAT, and GSH-PX). Moreover, Bai treatment also attenuated H2O2-induced apoptosis in IPEC-J2 cells by down-regulating the mRNA expression of Caspase-3 and Caspase-9 and up-regulating the mRNA expression of FAS and Bax, which are involved in the inhibition of mitochondrial pathways. The expression of Nrf2 increased after treatment with H2O2, and Bai can alleviate this phenomenon. Meanwhile, Bai down-regulated the ratio of phosphorylated AMPK to unphosphorylated AMPK, which is indicative of the mRNA abundance of antioxidant-related genes. In addition, knockdown of AMPK by short-hairpin RNA (shRNA) significantly reduced the protein levels of AMPK and Nrf2, increased the percentage of apoptotic cells, and abrogated Bai-mediated protection against oxidative stress. Collectively, our results indicated that Bai attenuated H2O2-induced cell injury and apoptosis in IPEC-J2 cells through improving the antioxidant capacity through the inhibition of the oxidative stress-mediated AMPK/Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Hippocalcin‐like 1 (HPCAL1) is involved in the development of several cancer types. However, our understanding of the HPCAL1 activity in cholangiocarcinoma (CCA) remains limited. Methods: Two microarray datasets were used to screen for differentially expressed genes (DEGs) involved in the development of CCA. The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) database was integrated to determine the prognostic significance of DEGs in CCA. The association between clinical characteristics and HPCAL1 expression levels was initially explored to assess the clinical profile of CCA. The prognostic value of HPCAL1 overexpression in the validation cohort was analyzed, followed by Gene Ontology (GO) term analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of HPCAL1. Results: Three upregulated genes and 10 downregulated genes were detected from two microarray‐based screenings. High expression of HPCAL1 as a poor prognostic factor of CCA was validated using TCGA/GEO integrated database and our database. Univariate and multivariate analyses along with Kaplan–Meier survival analysis showed that high HPCAL1 expression was an independent factor affecting the overall survival and relapse‐free survival in patients with CCA. The high expression of HPCAL1 was significantly associated with cancer antigen 125 (CA‐125) levels, number of tumors, lymph node invasion, and TNM stage. Analysis of the enriched GO terms and KEGG pathways revealed that the high expression of HPCAL1 was involved in the critical biological processes and molecular pathways, including modulation by a host of symbiont processes, the clathrin coat, actinin binding, and Rap1 signaling pathways. Conclusion: HPCAL1 was enriched in CCA in our study and has the potential to be applied in the identification of patients with CCA with an unfavorable prognosis. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore novel targets for hepatocellular carcinoma (HCC) treatment by investigating the role of fatty acid metabolism., Methods: RNA-seq and clinical data of HCC were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatic analyses were employed to identify differentially expressed genes (DEGs) related to prognosis. A signature was then constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression to classify HCC patients from the TCGA database into low-risk and high-risk groups. The predictive performance of the signature was evaluated through principal components analysis (PCA), Kaplan Meier (KM) survival analysis, receiver operating characteristics (ROC) curves, nomogram, genetic mutations, drug sensitivity analysis, immunological correlation analysis, and enrichment analysis. Single-cell maps were constructed to illustrate the distribution of core genes. Immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and western blot were employed to verify the expression of core genes. The function of one core gene was validated through a series of in vitro assays, including cell viability, colony formation, wound healing, trans-well migration, and invasion assays. The results were analyzed in the context of relevant signaling pathways., Results: Bioinformatic analyses identified 15 FAMGs that were related to prognosis. A 4-gene signature was constructed, and patients were divided into high- and low-risk groups according to the signature. The high-risk group exhibited a poorer prognosis compared to the low-risk group in both the training (P < 0.001) and validation (P = 0.020) sets. Furthermore, the risk score was identified as an independent predictor of OS (P < 0.001, HR = 8.005). The incorporation of the risk score and clinicopathologic features into a nomogram enabled the effective prediction of patient prognosis. The model was able to effectively predict the immune microenvironment, drug sensitivity to chemotherapy, and gene mutation for each group. Single-cell maps demonstrated that FAMGs in the model were distributed in tumor cells. Enrichment analyses revealed that the cell cycle, fatty acid β oxidation and PPAR signaling pathways were the most significant pathways. Among the four key prognostically related FAMGs, Spermine Synthase (SMS) was selected and validated as a potential oncogene affecting cell cycle, PPAR-γ signaling pathway and fatty acid β oxidation in HCC., Conclusions: The risk characteristics based on FAMGs could serve as independent prognostic indicators for predicting HCC prognosis and could also serve as evaluation criteria for gene mutations, immunity, and chemotherapy drug therapy in HCC patients. Meanwhile, targeted fatty acid metabolism could be used to treat HCC through related signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The endocannabinoid system (ECS) is dysregulated in various liver diseases. Previously, we had shown that the major endocannabinoid 2-arachidonoyl glycerol (2-AG) promoted tumorigenesis of intrahepatic cholangiocarcinoma (ICC). However, biosynthesis regulation and clinical significance of 2-AG remain elusive. In the present study, we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in patients with ICC samples as well as in thioacetamide-induced orthotopic rat ICC model. Moreover, we found that diacylglycerol lipase β (DAGLβ) was the principal synthesizing enzyme of 2-AG that significantly upregulated in ICC. DAGLβ promoted tumorigenesis and metastasis of ICC in vitro and in vivo and positively correlated with clinical stage and poor survival in patients with ICC. Functional studies showed that activator protein-1 (AP-1; heterodimers of c-Jun and FRA1) directly bound to the promoter and regulated transcription of DAGLβ , which can be enhanced by lipopolysaccharide (LPS). miR-4516 was identified as the tumor-suppressing miRNA of ICC that can be significantly suppressed by LPS, 2-AG, or ectopic DAGLβ overexpression. FRA1 and STAT3 were targets of miR-4516 and overexpression of miRNA-4516 significantly suppressed expression of FRA1 , SATA3 , and DAGLβ . Expression of miRNA-4516 was negatively correlated with FRA1 , SATA3 , and DAGLβ in patients with ICC samples. Our findings identify DAGLβ as the principal synthesizing enzyme of 2-AG in ICC. DAGLβ promotes oncogenesis and metastasis of ICC and is transcriptionally regulated by a novel AP-1/DAGLβ/miR4516 feedforward circuitry. NEW & NOTEWORTHY Dysregulated endocannabinoid system (ECS) had been confirmed in various liver diseases. However, regulation and function of 2-arachidonoyl glycerol (2-AG) and diacylglycerol lipase β (DAGLβ) in intrahepatic cholangiocarcinoma (ICC) remain to be elucidated. Here, we demonstrated that 2-AG was enriched in ICC, and DAGLβ was the principal synthesizing enzyme of 2-AG in ICC. DAGLβ promotes tumorigenesis and metastasis in ICC via a novel activator protein-1 (AP-1)/DAGLβ/miR4516 feedforward circuitry.

Aims: Dilated cardiomyopathy (DCM) is defined as a serious cardiac disorder caused by the presence of left ventricular dilatation and contractile dysfunction in the absence of severe coronary artery disease and abnormal loading conditions. The incidence of cardiac death is markedly higher in patients with DCM with pulmonary hypertension (PH) than in DCM patients without PH. No previous studies have constructed a predictive model to predict PH in patients with DCM., Methods: Data from 218 DCM patients (68.3% man; mean age 57.33) were collected. Patients were divided into low, intermediate and high PH-risk groups based on the echocardiographic assessment at the tricuspid regurgitation peak velocity (TRV) in conjunction with the presence of echocardiographic signs from at least two different categories. Basic information, vital signs, comorbidities and biochemical data of each patient were determined. The impact of each parameter on PH probability was analysed by univariable and multivariable analyses, the data from which were employed to establish a predictive model. Finally, the discriminability, calibration ability and clinical efficacy of the model were verified for both the modelling group and the external validation group., Results: We successfully applied a history of chronic obstructive pulmonary disease (COPD) or chronic bronchitis, systolic murmur (SM) at the tricuspid area, SM at the apex and brain natriuretic peptide (BNP) level to establish a model for predicting PH probability in DCM. The model was proven to have high accuracy and good discriminability (area under the receiver operating characteristic curve 0.889), calibration ability and clinical application value., Conclusions: A model for predicting PH probability in patients with DCM was successfully established. The new model is reliable for predicting PH probability in DCM and has good clinical applicability., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)