- 主題一：Role of the chrysophanol on hepatitis B virus X protein-induced hepatic stellate cell fibrosis by regulating endoplasmic reticulum stress and ferroptosis
簡介：Hepatitis B virus X protein (HBx) and hepatic stellate cells (HSCs) are critical for liver fibrosis development. Anti-fibrosis occurs by reversion to quiescent-type HSCs or clearance of HSCs via apoptosis or ferroptosis. This study aims to investigate the ferroptotic effects, endoplasmic reticulum (ER) stress induction, and mechanisms of chrysophanol (isolated from Rheum palmatum rhizomes) in a rat HSC cell line (HSC-T6) and thioacetamide (TAA)-induced liver fibrosis mouse model. In contrast, to further elucidate the pharmacological effect and action mechanism of chrysophanol on liver fibrosis, the technology of high-throughput microarray systems biology was also used to integrate the complex relationships between gene regulation and protein interactions for chrysophanol and establish a molecular marker for liver fibrosis. Our preliminary results demonstrated that analysis of lipid reactive oxygen species, Bip, CHOP, p-IRE1α, GPX4, SLC7A11, α-SMA, and CTGF showed that chrysophanol attenuated
HBx-repressed cell death. Chrysophanol can impair HBx-induced activation of HSCs through ER stress and ferroptosis-dependent and GPX4-independent pathways; however, the relationship between ferroptosis and liver fibrosis caused by HBx remains unclear and further investigations are required.
- 主題二：Role of the inflammatory response of von Hippel-Lindau tumor suppressor gene mutations in the progression of clear-cell renal cell carcinoma via the LCN2-ROS pathway
簡介：Kidney disease and cancer are serious health problems worldwide. Cancer is a systemic disease, and tissue inflammation induces carcinogenesis. Previous studies have shown that mutations in the tumor suppressor gene von Hippel-Lindau (VHL) significantly cause clear-cell renal cell carcinoma (ccRCC) and can result in reactive oxygen species (ROS) overproduction and chronic inflammation. However, due to VHL’s complex cellular functions, the mechanism of this phenomenon remains unconfirmed. Here, we studied VHL’s role in ccRCC formation by developing a novel conditional knockout mouse model that mimicked the features of kidney inflammation and fibrosis that lead to cyst formation and hyperplasia. Additionally, the HK-2 cells and mouse primary renal tubule cells (mRTCs) carrying VHL mutations as models were used to study the effects and underlying molecular mechanisms of ROS accumulation. Further, we studied the role of lipocalin 2 (LCN2) in regulating macrophage recruitment by HK-2 cells. The level of ROS in HK-2 cells in the presence or absence of LCN2 was measured, and it was discovered that the VHL mutation caused ROS overproduction; however, an LCN2 knockdown could reverse the process. Conversely, VHL was found to mediate the in vitro and in vivo expression and secretion of LCN2. Thus, VHL likely affects ROS production in an LCN2-dependent manner. Additionally, our findings suggest that LCN2 sensitizes the inflammatory response of HK-2 cells and the chemotactic abilities of macrophage RAW 264.7 cells. By revealing the regulatory effect of VHL on chronic inflammation in the progression of ccRCC through the LCN2-ROS pathway, our results provide novel insights into the therapeutic target and strategy for attenuating the development of ccRCC.