Activating SIRT3 in peritoneal mesothelial cells alleviates postsurgical peritoneal adhesion formation by decreasing oxidative stress and inhibiting the NLRP3 inflammasome

Abstract

Peritoneal adhesions (PAs) are a serious complication of abdominal surgery and negatively affect the quality of life of millions of people worldwide. However, a clear molecular mechanism and a standard therapeutic strategy for PAs have not been established. Here, we developed a standardized method to mimic the pathological changes in PAs and found that sirtuin 3 (SIRT3) expression was severely decreased in adhesion tissues, which was consistent with our bioinformatics analysis and patient adhesion tissue analysis. Thus, we hypothesized that activating SIRT3 could alleviate postsurgical PAs. Sirt3-deficient (Sirt3−/−) mice exhibited many more PAs after standardized abdominal surgery. Furthermore, compared with wild-type (Sirt3+/+) mice, Sirt3-deficient (Sirt3−/−) mice showed more prominent reactive oxygen species (ROS) accumulation, increased levels of inflammatory factors, and exacerbated mitochondrial damage and fragmentation. In addition, we observed NLRP3 inflammasome activation in the adhesion tissues of Sirt3−/− but, not Sirt3+/+ mice. Furthermore, mesothelial cells sorted from Sirt3−/− mice exhibited impaired mitochondrial bioenergetics and redox homeostasis. Honokiol (HKL), a natural compound found in several species of the genus Magnolia, could activate SIRT3 in vitro. Then, we demonstrated that treatment with HKL could reduce oxidative stress and the levels of inflammatory factors and suppress NLRP3 activation in vivo, reducing the occurrence of postsurgical PAs. In vitro treatment with HKL also restored mitochondrial bioenergetics and promoted mesothelial cell viability under oxidative stress conditions. Taken together, our findings show that the rescue of SIRT3 by HKL may be a new therapeutic strategy to alleviate and block postsurgical PA formation.

Activation of Sirtuin3 by honokiol ameliorates alveolar epithelial cell senescence in experimental silicosis via the cGAS-STING pathway

“…Although its role in the antagonism towards senescence has been demonstrated, the anti-aging mechanism of HKL is still unclear. Recently, HKL has been reported to prevent senescence via sirt3 activation [ 13 ] and decrease renal inflammation and fibrosis via regulation of mitochondrial dynamics and the NF-κb/TGF-β1/Smad signaling pathway [ 14 ]. Sirtuin 3 (sirt3), as a mitochondrial deacetylase, is a vital antiaging molecule and antioxidant through deacetylating and activating SOD2 [ 15 ].…”

Angelica acutiloba Kitagawa flower induces A549 cell pyroptosis via the NF-κB/NLRP3 pathway for anti-lung cancer effects

“…As a result, Caspase-1 actively participates in the process of pyroptosis [ 17 ]. The NLRP3 inflammasome is a complex of at least three proteins: the sensor (NLRP3), the adaptor (ASC), and the effector (pro-caspase-1) [ 18 , 19 ]. It is activated in two ways.…”