Empagliflozin activates Wnt/ß-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome.

OBJECTIVES: Cardiorenal syndrome type-3 (CRS-3) is an abrupt worsening of cardiac function secondary to acute kidney injury. Mitochondrial dysfunction is a key pathological mechanism of CRS-3, and empagliflozin can improve mitochondrial biology by promoting mitophagy. Here, we assessed the effects of empagliflozin on mitochondrial quality surveillance in a mouse model of CRS-3. METHODS: Cardiomyocyte-specific FUNDC1-knockout (FUNDC1CKO) mice were subjected to CRS-3 prior to assessment of mitochondrial homeostasis in the presence or absence of empagliflozin. RESULTS: CRS-3 model mice exhibited lower heart function, increased inflammatory responses and exacerbated myocardial oxidative stress than sham-operated controls; however, empagliflozin attenuated these alterations. Empagliflozin stabilized the mitochondrial membrane potential, suppressed mitochondrial reactive oxygen species production, increased mitochondrial respiratory complex activity and restored the oxygen consumption rate in cardiomyocytes from CRS-3 model mice. Empagliflozin also normalized the mitochondrial morphology, mitochondrial dynamics and mitochondrial permeability transition pore opening rate in cardiomyocytes. Cardiomyocyte-specific ablation of FUN14 domain-containing protein 1 (FUNDC1) in mice abolished the protective effects of empagliflozin on mitochondrial homeostasis and myocardial performance. Empagliflozin activated ß-catenin and promoted its nuclear retention, thus increasing FUNDC1-induced mitophagy in heart tissues; however, a ß-catenin inhibitor reversed these effects. CONCLUSIONS: In summary, empagliflozin activated Wnt/ß-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance, ultimately improving mitochondrial function and cardiac performance during CRS-3. Thus, empagliflozin could be considered for the clinical management of heart function following acute kidney injury.

Thromboelastography Parameters as Predictors for Long-Term Survival in Critically Ill Patients.

Thromboelastography (TEG) is used for monitoring abnormal blood coagulation in critically ill patients. However, the correlation between TEG parameters and long-term survival in these patients is unknown. We aimed to quantify the effect of TEG on long-term survival of critically ill patients. Critically ill patients undergoing TEG were retrospectively examined. Baseline patient characteristics and coagulation function indexes were compared. Cox regression, receiver-operating characteristic curve analysis, and Kaplan-Meier survival estimate curve were performed. We included 167 critically ill patients. Clot formation speed (K) and reaction time (R) were higher, whereas maximum amplitude (MA) and angle were lower in the mortality group than in the survival group (P < .01). All TEG parameters were risk factors for 2-year survival in critically ill patients (P < .01). The area under the curve of MA for predicting 2-year survival was 0.756 (95% confidence interval: 0.670-0.841). The Kaplan-Meier survival estimate curve analysis showed that MA predicted 2-year survival of critically ill patients(P < .01). Maximum amplitude can effectively predict 2-year survival of critically ill patients, indicating the influence of the coagulation system on these patients.

Peri-operative use of sorafenib in liver transplantation: a time-to-event meta-analysis.

AIM: To evaluate whether the application of sorafenib during the peri-operative period of liver transplantation improves prognosis in liver cancer patients. METHODS: We searched PubMed, EMBASE and MEDLINE for eligible articles. A total of 4 studies were found that fulfilled the previously agreed-upon standards. We then performed a systematic review and meta-analysis on the enrolled trials that met the inclusion criteria. RESULTS: Out of the 104 studies identified in the database, 82 were not clinical experiments, and 18 did not fit the inclusion standards. Among the remaining 4 articles, only 1 was related to the preoperative use of sorafenib, whereas the other 3 were related to its postoperative use. As the heterogeneity among the 4 studies was high, with an I(2) of 86%, a randomized effect model was applied to pool the data. The application of sorafenib before liver transplantation had a hazard ratio (HR) of 3.29 with a 95% confidence interval (CI) of 0.33-32.56. The use of sorafenib after liver transplantation had an HR of 1.44 (95%CI: 0.27-7.71). The overall pooled HR was 1.68 (95%CI: 0.41-6.91). CONCLUSION: The results showed that the use of sorafenib during the peri-operative period of liver transplantation did not improve patient survival significantly. In fact, sorafenib could even lead to a worse prognosis, as its use may increase the hazard of poor survival.