Reduced Cx43 Expression Induces Autophagy through Activation of the AMPK-mTOR-ULK1 Signaling Pathway in the Common Bile Duct Ligation Rat Heart.

BACKGROUNDS: This study aimed to investigate the relationship between Cx43 expression and autophagy mediated by the AMPK-mTOR-Ulk1 signaling pathway in jaundice heart. METHODS: In this study, a jaundice model was established in common bile duct ligation (CBDL) rats. Cardiac injury was assessed using various methods including myocardial injury indicators, echocardiography, TEM, HE staining, Masson staining, IHC, and IF. We investigated the regulatory relationship between Cx43, autophagy, and the AMPK-mTOR-ULK pathway in vivo by administering autophagy agonists (Rapa), autophagy inhibitors (3-MA), and Cx43 inhibitors (Gap 26). In vitro, we observed the relationship between autophagy and the AMPK-mTOR-ULK1 pathway in cells by exposing them to the AMPK inhibitor Compound C and the AMPK activator AICAR. RESULTS: We found that CBDL induced autophagy through the AMPK-mTOR-ULK pathway, leading to the inhibition of myocardial dysfunction. Rapamycin pretreatment with CBDL3d exhibited a protective effect against myocardial injury and promoted autophagy. In contrast, 3-MA had no impact. Pretreatment with rapamycin at CBDL2w enhanced autophagy and aggravated cardiac injury; however, inhibition of autophagy using 3-MA attenuated cardiac injury. Cell viability was enhanced by AMPK inhibitors and inhibited by AMPK agonists. In addition, we observed that increased autophagy led to decreased Cx43 expression, which negatively affected cardiac function. CONCLUSIONS: CBDL induces myocardial injury in rats and activates autophagy through the AMPK-mTOR-ULK pathway, resulting in decreased Cx43 protein levels. A moderate increase in early autophagy in CBDL can improve cardiac injury, while late inhibition of autophagy can reduce myocardial injury.

HYPERBILIRUBINEMIA AGGRAVATES RENAL ISCHEMIA REPERFUSION INJURY BY EXACERBATING PINK1-PARKIN-MEDIATED MITOPHAGY.

ABSTRACT: Background: Hyperbilirubinemia is a common perioperative complication, which is associated with acute kidney injury. Bilirubin permeabilizes mitochondrial membranes leading to mitochondrial swelling and dysfunction. In this study, we aimed to determine the association between PINK1-PARKIN-mediated mitophagy and renal ischemia-reperfusion (IR) injury aggravated by hyperbilirubinemia. Methods: A C57BL/6 mouse hyperbilirubinemia model was induced via intraperitoneal injection of bilirubin solution. In addition, a hypoxia/reoxygenation (H/R) injury model of TCMK-1 cells was established. In these models, we determined the effects of hyperbilirubinemia on oxidative stress, apoptosis, mitochondrial damage, and fibrosis. Results:In vitro , colocalization of GFP-LC3 puncta and Mito-Tracker Red showed that the number of mitophagosomes increased in TCMK-1 cells under H/R and bilirubin condition. Silencing of PINK1 or inhibition of autophagy alleviated mitochondrial damage, oxidative stress, and apoptosis in H/R injury aggravated by bilirubin and decreased cell death detected by methyl-thiazolyl-tetrazolium. In vivo , hyperbilirubinemia increased serum creatinine level in the renal IR injury mice model. Hyperbilirubinemia enhanced apoptosis induced by renal IR. In addition, hyperbilirubinemia increased mitophagosomes and autophagosomes and disrupted mitochondrial cristae in the IR kidney. Inhibition of PINK1 or autophagy reduced histological damages by alleviating apoptosis in renal IR injury, aggravated by hyperbilirubinemia. 3-MA or PINK1-shRNA-AAV9 treatment decreased the area of collagen and proteins related to fibrosis in renal IR injury, aggravated by hyperbilirubinemia. Conclusions: We have demonstrated that hyperbilirubinemia aggravated oxidative stress, apoptosis, mitochondrial damage, and fibrosis in renal IR injury by exacerbating PINK1-PARKIN-mediated mitophagy.

Comparison of preoperative neutrophil-lymphocyte, lymphocyte-monocyte, and platelet-lymphocyte ratios in patients with upper urinary tract urothelial carcinoma undergoing radical nephroureterectomy.

PURPOSE: The aim of this study was to investigate the prognostic value of preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) in patients with upper urinary tract urothelial carcinoma (UUTUC). METHODS: We retrospectively analyzed the clinical data of 140 patients with UUTUC who underwent radical nephroureterectomy from January 2005 to December 2011. We plotted receiver operating characteristic curves of NLR, PLR, and LMR for the diagnosis of tumor recurrence. Survival analysis was performed using the Kaplan-Meier method and log-rank test. Independent risk factor analysis was performed using a Cox proportional hazards regression model. RESULTS: Receiver operating characteristic curves showed that NLR was superior to PLR and LMR as a predictive factor in patients with UUTUC undergoing radical nephroureterectomy. Univariate analysis revealed that NLR (P<0.001 and P<0.001), PLR (P=0.01 and P<0.001), and LMR (P<0.001 and P<0.001) were significantly associated with disease-free survival and progression-free survival (PFS), respectively. Multivariate analysis identified NLR and LMR as independent prognostic factors for disease-free survival (P=0.035 and P=0.002) and PFS (P=0.005 and P=0.002), respectively. CONCLUSION: NLR and LMR could be independent predictors of disease-free survival and PFS, and NLR is a superior predictive factor to LMR.