The effects of soy isoflavone (SIF) on insulin sensitivity and adipocytokines in high-fat-diet-induced insulin resistant (IR) rats were studied. Male Sprague Dawley rats (n = 80) were randomly assigned into a basal diet fed group and high-fat diet fed group. The high-fat-diet-induced IR rats were assigned into IR model control group and three SIF-treated groups with different dosages. Thirty days later, the fasting blood glucose, insulin and adipocytokines in serum and mRNA expressions of adipocytokines in perirenal white adipose tissue were measured. The Homeostasis Model Assessment of IR was calculated. The administration of 450 mg kg(-1) d(-1) SIF decreased the body weights and depositions of visceral adipose tissue as well as improved insulin resistance in high-fat-diet-induced IR rats. The mechanisms were associated with SIF regulating the expression of adipocytokines, including adiponectin, leptin, resistin and TNF-alpha. SIF supplements may have favourable effects on insulin resistance in high-fat-diet-induced IR rats.
BaCKgRoUND aND aIMS:Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. appRoaCH aND ReSUltS: RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch-like ECH-associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.CoNClUSIoN: These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies. (Hepatology 2020;71:2005-2022.
NRF2 is the master transcriptional activator of cytoprotective genes and Kelch-like ECH-associated protein 1 (Keap1), a biosensor for electrophiles and oxidation, promotes NRF2 degradation in unstressed conditions. SQSTM1/p62, an oncogenic protein aberrantly accumulated in hepatocellular carcinoma (HCC), binds and sequestrates Keap1, leading to the prevention of NRF2 degradation. Here, we show that p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A) is highly expressed in HCC tumors and correlated with aggressive clinicopathological features. RPRD1A competitively interacts with TRIM21, an E3 ubiquitin ligase of p62, resulting in the decrease of p62 ubiquitination and the increased sequestration for Keap1. Therefore, RPRD1A enhances the nuclear translocation of NRF2, which induces gene expression for counteracting oxidative stress, maintaining cancer cells survival, and promoting HCC development. Moreover, disturbing the redox homeostasis of cancer cells by genetic knockdown of RPRD1A sensitizes cancer cells to platinum-induced cell death. Our study reveals RPRD1A is involved in the oxidative stress defense program and highlights the therapeutic benefits of targeting pathways that support antioxidation.
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