The HSP90 inhibitor 17-DMAG alleviates primary biliary cholangitis via cholangiocyte necroptosis prevention.

Cholangiocyte death accompanied by the progression of primary biliary cholangitis (PBC) has not yet been thoroughly investigated. Thus, we are aimed to explore the role of HSP90 and a potential treatment strategy in cholangiocyte necroptosis. First, we detected the expression of HSP90 and necroptotic markers in liver tissues from patients and mice with PBC by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR). Then, the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), was administered by intraperitoneal injection to evaluate its therapeutic effect for PBC by IHC, real-time PCR, and western blotting. Human intrahepatic bile duct epithelial cells (HIBECs) were induced to necroptosis by toxic bile acid and lipopolysaccharide (LPS) treatment, and evaluated via Cell Counting Kit-8 and flow cytometry assays. Additionally, 17-DMAG, cycloheximide, and a proteasome inhibitor were used to evaluate the role of HSP90 in cholangiocyte necroptosis. We found that the expression of HSP90 was elevated in the cholangiocytes of patients and mice with PBC, along with higher expressions of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated-MLKL (p-MLKL). Proinflammatory cytokines and antibody levels of the E2 subunit of pyruvate dehydrogenase complex decreased after treatment with 17-DMAG in PBC mice. Meanwhile, RIPK1, RIPK3, phosphorylated-RIPK3, MLKL, and p-MLKL protein expressions decreased with 17-DMAG treatment. In vitro, 17-DMAG and necrostatin-1 prevented glycochenodeoxycholic acid and LPS-induced necroptosis of HIBECs. Immunoprecipitation and high-performance liquid chromatography-mass spectrometry analysis showed that RIPK1 combined with HSP90. Additionally, the 17-DMAG treatment reduced the RIPK1 half-life. Overall, 17-DMAG might be a potential therapeutic agent for PBC via cholangiocyte necroptosis prevention by accelerating RIPK1 degradation.

Hepatocyte TGF-ß Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

Transforming growth factor beta (TGF-ß) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-ß signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGF-ß receptor II-deficient (Tgfbr2ΔHEP ) and Tgfbr2flox/flox mice. In addition, browning of white adipose tissue (WAT) was induced by administration of CL-316,243 (a ß3-adrenergic agonist) or cold exposure for 7 days. Compared with Tgfbr2 flox/flox mice, Tgfbr2ΔHEP mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2ΔHEP mice were due to the increase of mitochondrial oxidative phosphorylation in the liver and white-to-beige fat conversion. A further mechanistic study revealed that exosomal let-7b-5p derived from hepatocytes was robustly elevated after stimulation with palmitic acid and TGF-ß. Indeed, let-7b-5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD-fed Tgfbr2ΔHEP mice. Moreover, 3T3-L1 cells internalized hepatocyte-derived exosomes. An in vitro experiment demonstrated that let-7b-5p overexpression increased hepatocyte fatty acid transport and inhibited adipocyte-like cell thermogenesis, whereas let-7b-5p inhibitor exerted the opposite effects. Conclusion: Hepatocyte TGF-ß-let-7b-5p signaling promotes HFD-induced steatosis and obesity by reducing mitochondrial oxidative phosphorylation and suppressing white-to-beige fat conversion. This effect of hepatocyte TGF-ß signaling in metabolism is partially associated with exosomal let-7b-5p.

Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1-Dependent Manner in Mice.

Hepatic ischemia/reperfusion (I/R) is a major challenge for liver surgery and specific severe conditions of chronic liver disease. Current surgical and pharmacological strategies are limited to improve liver function after hepatic I/R injury. Thus, an in-depth understanding of the liver I/R mechanism is pivotal to develop new therapeutic methods. The cellular repressor of E1A-stimulated genes (Creg), a key regulator of cellular proliferation, exerts protective roles in cardiovascular diseases and participates in lipid accumulation and inflammatory response in the liver. However, the role of Creg in hepatic I/R remains largely unknown. A genetic engineering technique was used to explore the function of Creg in hepatic I/R injury. Hepatocyte-specific Creg knockout (CregΔHep ) and transgenic mice were generated and subjected to hepatic I/R injury, as were the controls. Creg in hepatocytes prevented against liver I/R injury by suppressing cell death and inflammation. In vitro studies were performed using primary hepatocytes isolated from CregΔHep that were challenged by hypoxia/reoxygenation insult. These cells exhibited more cell death and inflammatory cytokines production similar to observations in vivo. Moreover, further molecular experiments showed that Creg suppressed mitogen-activated protein kinase (MAPK) signaling by inhibiting TAK1 (TGF-ß-activated kinase 1) phosphorylation. Inhibiting TAK1 by 5Z-7-ox or mutating the TAK1-binding domain of Creg abolished the protective role of Creg indicating that Creg binding to TAK1 was required for prevention against hepatic I/R injury. Conclusion: These data demonstrate that Creg prevents hepatocytes from liver I/R injury. The Creg-TAK1 interaction inhibited the phosphorylation of TAK1 and the activation of MAPK signaling, which protected against cell death and inflammation during hepatic I/R injury.

Prognostic significance of CXCR7 in cancer patients: a meta-analysis.

BACKGROUND: CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in a variety of tumors. Nevertheless, whether CXCR7 can be used as a tumor prognosis marker has not been systematically assessed. The current meta-analysis was performed to obtain an accurate evaluation of the relationship between CXCR7 level and the prognosis of cancer patients. METHODS: Embase, Web of Science, and PubMed were systematically searched according to a defined search strategy up to June 11, 2018. Then, the required data were extracted from all qualified studies which were screened out based on the defined inclusion and exclusion criteria. Finally, the hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the prognostic significance of CXCR7 in tumor patients. RESULTS: A total of 28 original research studies comprising 33 cohorts and 5685 patients were included in this meta-analysis. The results showed that CXCR7 overexpression was significantly related to worse overall survival (OS) (HR 1.72; 95% CI 1.49-1.99), disease-free survival (DFS) (HR 5.58; 95% CI 3.16-9.85), progression-free survival (PFS) (HR 2.83; 95% CI 1.66-4.85) and recurrence-free survival (RFS) (HR 1.58; 95% CI 1.34-1.88) in cancer patients. Furthermore, for certain types of cancer, significant associations between higher CXCR7 expression and worse OS of glioma (HR 1.77; 95% CI 1.43-2.19), breast cancer (HR 1.45; 95% CI 1.28-1.63), esophageal cancer (HR 2.72; 95% CI 1.11-6.66) and pancreatic cancer (HR 1.46; 95% CI 1.12-1.90) were found. However, for lung cancer and hepatocellular cancer, there was no significant relationship between CXCR7 expression level and OS, (HR 2.40; 95% CI 0.34-17.07) and (HR 1.37; 95% CI 0.84-2.24) respectively. CONCLUSIONS: Increased CXCR7 level could predict poor prognosis of tumor patients and might be regarded as a novel prognostic biomarker for tumor patients.

Prognostic significance of CXCL5 expression in cancer patients: a meta-analysis.

BACKGROUND: CXCL5 is a member of the CXC-type chemokine family, which has been found to play important roles in tumorigenesis and cancer progression. Recent studies have demonstrated that CXCL5 could serve as a potential prognostic biomarker for cancer patients. However, the prognostic value of CXCL5 is still controversial. METHODS: We systematically searched PubMed, Embase and Web of Science to obtain all relevant articles investigating the prognostic significance of CXCL5 expression in cancer patients. Hazards ratios (HR) with corresponding 95% confidence intervals (CI) were pooled to estimate the association between CXCL5 expression levels with survival of cancer patients. RESULTS: A total of 15 eligible studies including 19 cohorts and 5070 patients were enrolled in the current meta-analysis. Our results demonstrated that elevated expression level of CXCL5 was significantly associated with poor overall survival (OS) (pooled HR 1.70; 95% CI 1.36-2.12), progression-free survival (pooled HR 1.65; 95% CI 1.09-2.49) and recurrence-free survival (pooled HR 1.49; 95% CI 1.15-1.93) in cancer patients. However, high or low expression of CXCL5 made no difference in predicting the disease-free survival (pooled HR 0.63; 95% CI 0.11-3.49) of cancer patients. Furthermore, we found that high CXCL5 expression was associated with reduced OS in intrahepatic cholangiocarcinoma (HR 1.91; 95% CI 1.31-2.78) and hepatocellular carcinoma (HR 1.87; 95% CI 1.55-2.27). However, there was no significant association between expression level of CXCL5 with the OS in lung cancer (HR 1.25; 95% CI 0.79-1.99) and colorectal cancer (HR 1.16; 95% CI 0.32-4.22, p = 0.826) in current meta-analysis. CONCLUSIONS: In conclusion, our meta-analysis suggested that elevated CXCL5 expression might be an adverse prognostic marker for cancer patients, which could help the clinical decision making process.