Berberine enhances the radiosensitivity of hepatoma cells by Nrf2 pathway.

You X ，Cao X ，Lin Y 《-》

Fangchinoline suppresses hepatocellular carcinoma by regulating ROS accumulation via the TRIM7/Nrf2 signaling pathway.

Dysregulation of redox homeostasis is associated with developing hepatocellular carcinoma (HCC). Oxidative stress (OS) is distinguished by the accumulation of ROS, which plays a variety of roles in cancer pathology. Fangchinoline (FAN), a bis-benzylisoquinoline alkaloid, has anti-cancer pharmacological activity. However, the regulatory mechanism of FAN on OS and whether it can inhibit HCC by mediating OS are still unclear. This paper aims to explore the effectiveness of FAN in preventing HCC via regulating OS and identify the underlying molecular mechanisms. We used the primary HCC mouse model and hepatoma cell line to explore the suppressive effect of FAN on hepatocarcinogenesis. To study the role of ROS in the anti-hepatocarcinoma effect of FAN in cell model and mouse model. The mechanism of FAN-induced nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation was studied through various techniques, including generation of Nrf2 and tripartite motif containing 7 (TRIM7) gene overexpressing or knockdown cell model, co-immunoprecipitation, immunohistochemistry and subcutaneous tumor xenograft models constructed by the stable TRIM7-overexpression HLE cells, etc. RESULTS: We showed that FAN significantly inhibited cell proliferation and hepatocarcinogenesis in HCC cells and primary HCC mouse model. The FAN-induced mitochondrial dysfunction promoted ROS accumulation, and using N-Acetylcysteine to clear ROS reversed the anti-HCC effects of FAN. We observed that FAN is capable of activating the Nrf2 pathway. This effect was thought to be due to the fact that, in response to the FAN-induced OS, the cancer cells created a feedback loop to stable Nrf2 via depressing the K48-linkage ubiquitination of it, which was caused by reduced binding of kelch-like ECH-associated protein 1 (Keap1) and Nrf2 and elevated TRIM7 expression. Indeed, overexpression of TRIM7 suppressed the anti-hepatocarcinoma effect of FAN. The study determines the anti-liver cancer effect of FAN and first describes the positive regulatory effect of TRIM7 on Nrf2 signaling. We reveal that TRIM7/Nrf2 signaling served as a target of FAN-induced ROS accumulation in HCC, which helps to clarify the mechanism of action of FAN against HCC and provides a theoretical basis for FAN as an anti-cancer drug.

Liu Y ，Wang Y ，Wang J ，Wang X ，Chen L ，Han T ，Lian H ，Gan M ，Wang J ... -  《-》

Xiaoai Jiedu recipe reduces cell survival and induces apoptosis in hepatocellular carcinoma by stimulating autophagy via the AKT/mTOR pathway.

The Xiaoai Jiedu recipe (XJR) is a traditional Chinese medicine formulation used in clinical settings to treat liver cancer. It has shown promising effectiveness by combining herbal and animal-derived ingredients, offering a new approach to cancer treatment. However, its mechanism of action is poorly understood. The molecular processes underlying the inhibitory effects of the XJR on hepatocellular cancer (HCC) were investigated. The primary chemical components of XJR and associated disease targets relevant to HCC were anticipated and compiled using a database. The potential targets and processes by which XJR influenced HCC were investigated using GO and KEGG enrichment analyses, as well as protein-protein interaction (PPI) networks. Transmission electron microscopy, laser confocal microscopy, and Western blotting were used to evaluate autophagy, while CCK-8 assays measured cell viability and Western blotting and flow cytometry evaluated apoptosis. In vivo assays were conducted employing an HCC xenograft mouse model. Network pharmacology analysis identified 456 intersecting targets between XJR and HCC. The top five active components are quercetin, cholesterol, jaceosidine, eupafolin, and oleanolic acid. The key targets include TP53, AKT1, IL6, EGFR, SRC, HSP90AA1, TNF, IL1B, MYC, and CASP3. Additionally, the autophagy pathway was found to be one of the main pathways through which XJR intervenes in HCC. The increased quantity of autophagosomes and autolysosomes, the overexpression of Beclin1 and LC3A/B-II proteins, and the downregulation of P62 all suggest that XJR stimulated autophagy in HCC cells. Functional tests employing pathway-specific activators and inhibitors and siRNA-based knockdown demonstrated that XJR promoted autophagy by blocking AKT/mTOR signaling. Furthermore, XJR reduced the viability of HCC cells and promoted apoptosis by upregulating apoptosis proteins. Autophagy inhibitors and Beclin1 silencing reversed these effects. Research conducted in vivo showed that XJR activated autophagy through the AKT/mTOR axis, thereby markedly reducing tumor growth and inducing tumor cell demise. These studies show that XJR activates autophagy in both cellular and animal models to induce apoptosis and decrease HCC cell proliferation, as shown by network pharmacology and verification assays. Further, these findings provide experimental evidence that the anti-tumor activity of XJR involves autophagy stimulation.

Ji Y ，Li L ，Li W ，Li L ，Ma Y ，Li Q ，Chen X ，Zhao W ，Zhu H ，Huo J ，Wu M ... -  《-》

Glycyrrhizin alleviates BoAHV-1-induced lung injury in guinea pigs by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway.

Varicellovirus bovinealpha 1 (BoAHV-1) is a significant pathogen responsible for respiratory disease in cattle, capable of inducing lung damage independently or co-infection with bacteria. The widespread spread of BoAHV-1 in cattle herds has caused substantial economic losses to the cattle industry. The pathogenic mechanisms of BoAHV-1 are often relevant to robust inflammatory responses, increased oxidative burden, and the initiation of apoptosis. Glycyrrhizin (GLY) is a small-molecule triterpenoid saponin compound obtained from the herb liquorice, which has a broad spectrum of pharmacological properties such as antiviral, anti-inflammatory, and antioxidant effects. Furthermore, GLY regulates lung physiology by modulating oxidative stress, inflammatory response, and cell apoptosis through interference with the NF-κB/NLRP3 and Nrf2/HO-1 Signaling pathways. However, the potential of GLY to mitigate lung injury induced by BoAHV-1 and its underlying mechanism remains unclear. Therefore, in this study, we investigated the protective effect of GLY against pulmonary injury induced by BoAHV-1 in a guinea pig model by reducing viral load and suppressing the inflammatory response, oxidative stress, and apoptosis. The results of this study demonstrated that GLY exerted a protective effect against BoAHV-1-induced lung injury in guinea pigs. Specifically, GLY reduced the levels of pro-inflammatory cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and interleukin (IL)-8 in guinea pig tissues while suppressing the expression of Caspase-1. Additionally, GLY reduced BoAHV-1 load and the number of TUNEL-positive lung cells in guinea pig lungs while inhibiting Caspase 3 protein expression. Furthermore, GLY significantly enhanced lung antioxidant capacity by increasing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity while simultaneously reducing malondialdehyde (MDA) levels. Lung histological observation and score further validated the protective effect of GLY on BoAHV-1-induced lung injury. Furthermore, we observed that the expression of phosphorylated NF-κB p65 (p-NF-κB p65) and NLRP3 proteins in the lung tissue of BoAHV-1-infected guinea pigs decreased after GLY treatment while the expression of Nrf2 and HO-1 proteins increased. These results indicated that GLY inhibited the NF-κB/NLRP3 Signaling pathway and activated the Nrf2/HO-1 Signaling pathway during BoAHV-1 infection. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Ultimately, our findings demonstrated that GLY alleviates BoAHV-1-induced inflammation response, oxidative stress, and cell apoptosis by inhibiting the NF-κB/NLRP3 Signaling pathway and activating the Nrf2/HO-1 Signaling pathway to protect guinea pigs from lung injury caused by BoAHV-1. Importantly, this study provides a compelling argument for the GLY in combating respiratory disease in cattle caused by BoAHV-1.

Guo B ，Wang H ，Zhang Y ，Wang C ，Zhang H ，Zhao Y ，Qin J ... -  《-》

Targeting autophagy in HCC treatment: exploiting the CD147 internalization pathway.

Chemotherapy resistance in liver cancer is a major clinical issue, with CD147 playing a vital role in this process. However, the specific mechanisms underlying these processes remain largely unknown. This study investigates how CD147 internalization leads to cytoprotective autophagy, contributing to chemotherapy resistance in hepatocellular carcinoma (HCC). Utilizing bioinformatics methods for KEGG pathways enrichment and screening key molecules associated with chemotherapy resistance through analyses of GEO and TCGA databases. An overexpression/knockdown system was used to study how CD147 internalization leads to autophagy in vitro and in vivo. The process was observed using microscopes, and molecular interactions and autophagy flux were analyzed. Analyzing the internalization of CD147 intracellular domains and the interaction with G3BP1 in clinical chemotherapy recurrence HCC tissues by immunohistochemistry, tissue immunofluorescence, and mass spectrometry. A tumor xenograft mice model was used to study cytoprotective autophagy induced by CD147 and test the effectiveness of combining cisplatin with an autophagy inhibitor in nude mice models. In our study, we identified the tumor-associated membrane protein CD147, which implicated in chemoresistance lysosome pathways, by evaluating its protein degree value and betweenness centrality using Cytoscape. Our findings revealed that CD147 undergoes internalization and interacts with G3BP1 following treatment with cisplatin and methyl-β-cyclodextrin, forming a complex that is transported to lysosomes via Rab7A. Notably, higher doses of cisplatin enhanced CD147-mediated lysosomal transport while concurrently inhibiting SG assembly. The CD147-G3BP1 complex additionally inhibits mTOR activity, promoting autophagy and augmenting chemoresistance in hepatoma cells. In vivo studies investigations and analyses of clinical samples revealed that elevated internalization of CD147 is associated with chemotherapy recurrence in liver cancer and the maintenance of stem cells. Mice experiments found that the combined administration of cisplatin and hydroxychloroquine enhanced the efficacy of treatment. This study reveals that CD147 internalization and CD147-G3BP1 complex translocation to lysosomes induce cytoprotective autophagy, reducing chemotherapy sensitivity by suppressing mTOR activity. It is also shown that chemotherapy drugs combined with autophagy inhibitors can improve the therapeutic effect of cancer, providing new insights into potential targeted therapeutic approaches in treating HCC.

Qian M ，Wan Z ，Liang X ，Jing L ，Zhang H ，Qin H ，Duan W ，Chen R ，Zhang T ，He Q ，Lu M ，Jiang J ... -  《Cell Communication and Signaling》