Xiaobin Zao

Background: Current treatments for cirrhosis-a progressive disease marked by fibrosis and inflammation-are limited and non-specific. Jinqiancao granules (JQC), a traditional Chinese medicine used for hepatobiliary diseases, could provide a promising new therapeutic approach. Purpose: The objective of this study is to explore the therapeutic effects and potential molecular mechanisms of JQC on CCl ₄ -induced liver cirrhosis in mice, and to analyze its effects on the liver-gut axis, including liver pathology, the intestinal barrier, and gut microbiota. Methods: To investigate the therapeutic effects of JQC and its impact on the liver-gut axis, a mouse model of liver cirrhosis was established by intraperitoneal injection of carbon tetrachloride (CCl ₄ ). The mice were allocated into four groups: the control group (without CCl ₄ induction and receiving normal saline), the model group (CCl ₄ -induced and receiving normal saline), and the two treatment groups which received JQC via gavage at either 500 mg/kg (JQC-H) or 250 mg/kg (JQC-L) after CCl ₄ induction. Upon completion of the treatment, all mice were euthanized to collect serum, fecal samples, liver, and intestinal tissues for subsequent analysis. The assessments encompassed histopathology (H&E, Masson, Picro Sirius Red), immunohistochemistry, immunofluorescence, molecular biology (ELISA, Western blot, qRT-PCR), transcriptomics, and 16S rRNA sequencing. Results: JQC ameliorated CCl ₄ -induced liver cirrhosis in mice by improving liver function and suppressing fibrosis, inflammation, and oxidative stress. Mechanistically, it modulated the PI3K-AKT pathway and restored gut-liver axis homeostasis. This was evidenced by intestinal barrier repair (including upregulation of ZO-1 and occludin, and reduction of LPS) and correction of microbial dysbiosis, specifically enriching beneficial bacteria, such as Bacteroidota and Akkermansia, that correlated negatively with liver injury. Conclusion: This study demonstrates that JQC mitigates liver cirrhosis in mice by modulating the gut-liver axis, enhancing the intestinal barrier, and inhibiting the PI3K-AKT signaling pathway. These results propose JQC as a promising therapeutic candidate, warranting further clinical translation.

BACKGROUND UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in glucuronic acid metabolism and acts as a key mediator in several cancer developmental signaling pathways. AIM To offer a more systematic and comprehensive elucidation of the involvement of UGDH in the onset and progression of various malignancies. METHODS The role of UGDH in cancer was investigated via public databases. The data were analyzed via various R packages and websites, including TISIDB, cBioPortal, STRING, Cytoscape, GSCALite, and CancerSEA. A rat hepatocellular carcinoma (HCC) model was established via the intraperitoneal injection of diethylnitrosamine. Hematoxylin-eosin staining, Masson staining, Ki67 and UGDH immunohistochemical staining, and ARG1 immunofluorescence staining of liver tissues were performed. Real-time quantitative PCR and Western blotting were used to detect UGDH expression. The UGDH gene was knocked down in Huh7 cells, and CCK8 and nude mouse tumor xenograft assays were performed. RESULTS High UGDH expression is associated with poor clinical outcomes in HCC, lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma patients and is differentially expressed across molecular and immune subtypes. UGDH is primarily involved in the pentose and glucuronate interconversion pathway. Its expression is positively correlated with T helper, Tcm, and Th2 cells in most cancers. Moreover, experimental results demonstrated that UGDH expression is elevated in HCC tissues and that its downregulation inhibits HCC cell proliferation. CONCLUSION Our study revealed that UGDH could be a valuable prognostic biomarker and potential therapeutic target in many cancers, especially liver and lung cancer. UGDH could promote HCC cell proliferation, potentially by modulating the pentose and glucuronate interconversion pathways.

UDP-glucose 6-dehydrogenase (UGDH) is the key enzyme of glucuronic acid metabolism and a key mediator in several cancer developmental signaling pathways. However, the expression and function of UGDH in colorectal cancer (CRC) are unclear. Bioinformatics analysis was conducted to research the expression, diagnosis, prognosis, functional enrichment, genetic alterations, and immune characteristics of UGDH in CRC. Hematoxylin-Eosin staining, KI67 immunohistochemistry staining, and UGDH immunohistochemistry staining of clinical colon tissues were performed. The UGDH gene was knocked down in HCT-8 cells. CCK8 and cell wound scratch assays were further performed in UGDH wild-type and UGDH-knockdown HCT-8 cells. UGDH is markedly downregulated in CRC tissues compared to normal tissues, which predicts a poor prognosis. The lower expression of UGDH is associated with a high gene promoter methylation level and genome deletion. UGDH expression is proportional to immune cell infiltration and immune-related genes. UGDH expression is correlated with the p53 signaling pathway. Knockdown of UGDH in HCT-8 cells promoted their proliferation and migration ability. UGDH could be useful as a valuable prognostic biomarker and potential therapeutic target in CRC. UGDH could inhibit the proliferation and migration of CRC cells.

Background and Aims: In this research, we sought to enhance our comprehension of liver cancer’s genetic architecture by employing Mendelian randomization (MR) techniques to establish causative relationships between particular genetic variations and liver cancer susceptibility. Methods: We integrated data from the public databases with MR analysis to identify differentially expressed genes (DEGs) associated with Hepatocellular Carcinoma (HCC). We conducted functional enrichment analyses to determine the biological processes and signaling cascades associated with the identified DEGs. We also used the CIBERSORT deconvolution method to evaluate immune cell composition in HCC tissues, followed by correlation studies examining relationships between our key genes of interest and various immune cell populations. Additionally, we validated our findings using a rat model of HCC and clinical HCC samples. Results: We obtained two key genes, EHD4 and PPARGC1A, which co-regulated M0 macrophages, suggesting their role in macrophage polarization and tumor progression. In addition, PPARGC1A is associated with resting and activated mast cells, suggesting its involvement in regulating the tumor microenvironment. Detection of rat and clinical samples further confirmed the upregulation of these genes in HCC, supporting their potential as therapeutic targets. Conclusions: Our findings emphasize the significant involvement of EHD4 and PPARGC1A in HCC, specifically regarding their influence on tumor-associated macrophage polarization and broader immune microenvironment modulation. These findings offer new insights into the molecular mechanisms driving HCC and suggest that targeting these genes may provide novel strategies for personalized treatment.

To investigate the therapeutic effects of Chinese medicine Weifuchun (WFC, 胃复春) on gastric fundic gland polyps (FGPs). FGPs organoids were constructed with patients-derived samples. The morphology and size of FGPs organoids were detected using bright-field imaging. Effective components and corresponding potential targets of WFC were screened using multiple open-source databases and research on Traditional Chinese Medicine or compound formulas. Core genes were identified through protein-protein interaction networks. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of the core genes were conducted. The interactions between main components and core targets were analyzed through the FerrDb database. The expressions of core targets were detected by quantitative real-time polymerase chain reaction (qRT-PCR). After WFC treatment, the number and size of FGPs organoids were significantly reduced. Twenty nine active drug components and 162 candidate targets of WFC for treating FGPs were identified, including 37 targets related to ferroptosis. Quercetin, Glaucocalyxin B, Melissoidesin U, Melissoidesin O, Hesperetin, Glaucocalyxin A, Angustifolin, Melissoidesin M, Di-n-octyl phthalate, and beta-sitosterol were identified as the main active compounds. SRC proto-oncogene, non-receptor tyrosine kinase, signal transducer and activator of transcription 3, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta, phosphoinositide-3-kinase regulatory subunit 1, and AKT serine/threonine kinase 1 were identified as the primary targets. KEGG pathways related to carcinogenesis, cell proliferation and metabolism, and oxidative stress. WFC promoted FGPs organoids’ death and could be reversed by ferroptosis inhibitor of Erastin. The qRT-PCR results showed that WFC treatment could regulate the mRNA expression levels of solute carrier family 7 member 11, acyl-CoA synthetase long chain family member 4, and arachidonate 15-lipoxygenase, type B. WFC may exert its therapeutic effects by inducing ferroptosis in FGPs cells.