SIRT3 alleviates sepsis-induced acute lung injury by inhibiting pyroptosis via regulating the deacetylation of FoxO3a.

OBJECTIVE: This study mainly analyzes the mechanism of SIRT3 alleviating sepsis-induced acute lung injury (ALI) by regulating the deacetylation of FoxO3a and inhibiting pyroptosis. METHODS: SIRT3-overexpressing and silenced BEAS-2B cells were used to evaluate the effect of SIRT3 on apoptosis in LPS-treated lung epithelial cells. FoxO3a-silenced BEAS-2B cells were also used to verify the mechanism by which SIRT3 inhibited oxidative stress and pyroptosis in vitro in ALI. 3-TYP was used to inhibit the deacetylation function of SIRT3 in vivo. Pyroptosis was assessed by detecting GSDMD-N and LDH efflux. RESULTS: In CLP-induced ALI mice, GSDMD-N and LDH levels were elevated, pyroptosis was induced. Silencing of SIRT3 exacerbated oxidative stress, NLRP3 activation and pyroptosis, and inhibited the deacetylation of FoxO3a. Overexpression of SIRT3 attenuated pyroptosis, induced deacetylation and restored the expression of FoxO3a and MnSOD. Silencing FoxO3a aggravated pyroptosis. Overexpression of SIRT3 restored the reduced FoxO3a expression and suppressed pyroptosis. 3-TYP blocked the promotion of FoxO3a by SIRT3 and the inhibitory effect of SIRT3 on pyroptosis. CONCLUSION: The reduction of SIRT3 in sepsis caused hyperacetylation of FoxO3a, which in turn exacerbates oxidative stress and induces pyroptosis of ALI. Increasing the level of SIRT3 promotes FoxO3a through deacetylation, thereby inhibiting pyroptosis and relieving ALI.

Effects of ß-blockers therapy on the 28-day and 3-year survival rates of end-stage renal disease patients with cardiovascular disease: a retrospective cohort study.

Background: ß-blockers have been used in the treatment of end-stage renal disease (ESRD) patients and cardiovascular disease (CVD) patients, separately. However, the effects of ß-blockers on ESRD patients with CVD have not been fully investigated. This study sought to investigate the effects of ß-blockers therapy on the 28-day and 3-year survival rates of ESRD patients with pre-existing CVD who were admitted to the intensive care unit (ICU). Methods: After excluding patients without CVD, receiving a kidney transplant, not admitted to the ICU, and with missing baseline data, this cohort study included 1081 ESRD participants with CVD from the Medical Information Mark for Intensive Care III database. Baseline characteristics, including demographic data and clinical data, were collected. The outcomes were 28-day and 3-year survival rates of the patients. At the 28-day of ICU hospitalization, patients had a mean inpatient hospital stay of 24.7 days. At 3-year, the patients had a median survival time of 489.2 days. Univariate and multivariate Cox regression analyses were used to evaluate the effects of ß-blockers therapy on the 28-day and 3-year survival outcomes of ESRD patients with CVD. Results: The 28-day and 3-year survival rates were 82.8% and 37.9%, respectively. The mean age of the all patients was 68 years, and 642 were male. After adjusting for age, race, hyperlipidemia, dialysis, simplified acute physiological score (SAPS) II, sequential organ failure assessment (SOFA) score, glucocorticoid, hemoglobin, diabetes, hypertension, the 28-day survival rate of the ESRD patients with CVD requiring intensive care who received ß-blockers therapy was higher than that of the patients who did not receive the treatment. Similarly, after adjusting for age, race, hyperlipidemia, dialysis, SAPS II, SOFA score, glucocorticoid, hemoglobin, diabetes, hypertension, creatinine, the long-term survival rate of the patients who received ß-blockers therapy was also higher than that of those who did not. Conclusions: ß-blockers therapy was associated with increased 28-day and 3-year survival rates in ESRD patients with CVD requiring intensive care. Our findings may provide a theoretical basis for the prognostic impact of ß-blockers therapy among patients with ESRD and CVD who were admitted to the ICU.

Downregulation of tripartite motif protein 11 attenuates cardiomyocyte apoptosis after ischemia/reperfusion injury via DUSP1-JNK1/2.

Currently, the prevention of ischemic diseases such as myocardial infarction associated with ischemia/reperfusion (I/R) injury remains to be a challenge. Thus, this study was designed to explore the effects of tripartite motif protein 11 (TRIM11) on cardiomyocytes I/R injury and its underlying mechanism. Cardiomyocytes AC16 were used to establish an I/R injury cell model. After TRIM11 downregulation in I/R cells, cell proliferation (0, 12, 24, and 48 h) and apoptosis at 48 h as well as the related molecular changes in oxidative stress-related pathways was detected. Further, after the treatment of TRIM11 overexpression, SP600125, or DUSP1 overexpression, cell proliferation, apoptosis, and related genes were detected again. As per our findings, it was determined that TRIM11 was highly expressed in the cardiomyocytes AC16 after I/R injury. Downregulation of TRIM11 was determined to have significantly reduced I/R-induced proliferation suppression and apoptosis. Besides, I/R-activated c-Jun N-terminal kinase (JNK) signaling and cleaved caspase 3 and Bax expression were significantly inhibited by TRIM11 downregulation. In addition, the overexpression of TRIM11 significantly promoted apoptosis in AC16 cells, and JNK1/2 inhibition and DUSP1 overexpression potently counteracted the induction of TRIM11 overexpression in AC16 cells. These suggested that the downregulation of TRIM11 attenuates apoptosis in AC16 cells after I/R injury probably through the DUSP1-JNK1/2 pathways.