Activating SIRT3 in peritoneal mesothelial cells alleviates postsurgical peritoneal adhesion formation by decreasing oxidative stress and inhibiting the NLRP3 inflammasome
0
조회
0
다운로드
0
인용
0
참고문헌
초록
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.
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.
참고문헌 (51)
- Arung, W., "Pathophysiology and prevention of postoperative peritoneal adhesions", World J. Gastroenterol, 17, pp.4545~4553 (2011)
- Leclercq, R. M., "Postoperative abdominal adhesions and bowel obstruction. A survey among Dutch general practitioners", Eur. J. Gen. Pract, 21, pp.176~182 (2015)
- Moris, D., "Postoperative abdominal adhesions : clinical significance and advances in prevention and management", J. Gastrointest. Surg, 21, pp.1713~1722 (2017)
- Soltany, S., "Postoperative peritoneal adhesion : an update on physiopathology and novel traditional herbal and modern medical therapeutics", Naunyn Schmiedebergs Arch. Pharmacol, 394, pp.317~336 (2020)
- Mavros, M. N., "Morbidity related to concomitant adhesions in abdominal surgery", J. Surg. Res, 192, pp.286~292 (2014)
- Tang, J., "Peritoneal adhesions: occurrence, prevention and experimental models", Acta Biomater, 116, pp.84~104 (2020)
- Huntington, G. S., "The anatomy of the human peritoneum and abdominal cavity" (2022), DigiCat
- Kastelein, A. W., "Embryology, anatomy, physiology and pathophysiology of the peritoneum and the peritoneal vasculature", Semin. Cell Dev. Biol, 92, pp.27~36 (2019)
- Van Baal, J., "The histophysiology and pathophysiology of the peritoneum", Tissue Cell, 49, pp.95~105 (2017)
- Shang, J., "miR-15a-5p suppresses inflammation and fibrosis of peritoneal mesothelial cells induced by peritoneal dialysis via targeting VEGFA", J. Cell Physiol, 234, pp.9746~9755 (2019)
- Shin, H. -S., "Metformin ameliorates the phenotype transition of peritoneal mesothelial cells and peritoneal fibrosis via a modulation of oxidative stress", Sci. Rep, 7, pp.5690~ (2017)
- Xu, L., "Histone deacetylase 6 inhibition counteracts the epithelial–mesenchymal transition of peritoneal mesothelial cells and prevents peritoneal fibrosis", Oncotarget, 8, pp.88730~88750 (2017)
- Ko, J., "Paricalcitol attenuates TGF-β1–induced phenotype transition of human peritoneal mesothelial cells(HPMCs)via modulation of oxidative stress and NLRP3 inflammasome", FASEB J, 33, pp.3035~3050 (2019)
- Zhang, K., "miRNA589 regulates epithelial-mesenchymal transition in human peritoneal mesothelial cells", J. Biomed. Biotechnol, 2012, pp.673096~ (2012)
- Liu, Q., "A crosstalk between the Smad and JNK signaling in the TGF-β-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells", PLoS ONE, 7, pp.e32009~ (2012)
- Sammour, T., "Peritoneal damage : the inflammatory response and clinical implications of the neuro-immuno-humoral axis", World J. Surg, 34, pp.704~720 (2010)
- DiZerega, G. S., "Peritoneal surgery" (2000), Springer
- Wei, G., "Effect of emodin on preventing postoperative intra-abdominal adhesion formation", Oxid. Med. Cell. Longev, 2017, pp.1740317~ (2017)
- Ahn, B. -H., "A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis", Proc. Natl Acad. Sci. USA, 105, pp.14447~14452 (2008)
- Shi, T., "SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes", J. Biol. Chem, 280, pp.13560~13567 (2005)
- Sundaresan, N. R., "Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice", J. Clin. Invest, 119, pp.2758~2771 (2009)
- Morigi, M., "Sirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injury", J. Clin. Invest, 125, pp.715~726 (2015)
- Kurundkar, D., "SIRT3 diminishes inflammation and mitigates endotoxininduced acute lung injury", JCI Insight, 4, pp.e120722~ (2019)
- Torrens-Mas, M., "SIRT3 : oncogene and tumor suppressor in cancer", Cancers(Basel), 9, pp.90~ (2017)
- Dessai, A. S., "Transcriptional repression of SIRT3 potentiates mitochondrial aconitase activation to drive aggressive prostate cancer to the bone", Cancer Res, 81, pp.50~63 (2021)
- Wan, X., "Cisplatin inhibits SIRT3-deacetylation MTHFD2 to disturb cellular redox balance in colorectal cancer cell", Cell Death Dis, 11, pp.649~ (2020)
- Xia, C., "Metformin combined with nelfinavir induces SIRT3", mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice, 2019, pp.848, 62~69
- Sarrica, A., "Safety and toxicology of magnolol and honokiol", Planta Med, 84, pp.1151~1164 (2018)
- Pillai, V. B., "Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3", Nat. Commun, 6, pp.1~16 (2015)
- Ong, C. P., "Honokiol : a review of its anticancer potential and mechanisms", Cancers(Basel), 12, pp.48~ (2020)
- Banik, K., "Honokiol for cancer therapeutics : a traditional medicine that can modulate multiple oncogenic targets", Pharmacol. Res, 144, pp.192~209 (2019)
- Talarek, S., "N europrotective effects of honokiol : from chemistry to medicine", Biofactors, 43, pp.760~769 (2017)
- Woodbury, A., "Neuro-modulating effects of honokiol:a review", Front. Neurol, 4, pp.130~ (2013)
- Frezza, C., "Organelle isolation : functional mitochondria from mouse liver, muscle and cultured filroblasts", Nat. Protoc, 2, pp.287~295 (2007)
- Nair, S. K., "Role of proteolytic enzyme in the prevention of postoperative intraperitoneal adhesions", Arch. Surg, 108, pp.849~853 (1974)
- Swanson, K. V., "The NLRP3 inflammasome: molecular activation and regulation to therapeutics", Nat. Rev. Immunol, 19, pp.477~489 (2019)
- He, Y., "Mechanism and regulation of NLRP3 inflammasome activation", Trends Biochem. Sci, 41, pp.1012~1021 (2016)
- Zhou, R., "A role for mitochondria in NLRP3inflammasome activation", Nature, 469, pp.221~225 (2011)
- Caron, N. S., "Therapeutic approaches to Huntington disease : from the bench to the clinic", Nat. Rev. Drug Discov, 17, pp.729~750 (2018)
- Lee, J., "SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease", Aging cell, 17, pp.e12679~ (2018)
- Lee, J. J., "Inhibition of epithelial cell migration and Src", FAK signaling by SIRT3, 2018, pp.115, 7057~7062
- Schwer, B., "Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2", Proc. Natl Acad. Sci. USA, 103, pp.10224~10229 (2006)
- Kanneganti, T. -D., "Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin", Nalp3, 2006, pp.440, 233~236
- Allen, I. C., "The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA", Immunity, 30, pp.556~565 (2009)
- Jia, Y., "Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway", Redox Biol, 32, pp.101534~ (2020)
- Perry, J. F. Jr, "Intestinal obstruction caused by adhesions: a review of 388 cases", Ann. Surg, 142, pp.810~816 (1955)
- Szigetvari, I., "Association of previous abdominal surgery and significant adhesions in laparoscopic sterilization patients", J. Reprod. Med, 34, pp.465~466 (1989)
- Zindel, J., "Primordial GATA6 macrophages function as extravascular platelets in sterile injury", Science, 371, pp.eabe0595~ (2021)
- Tsai, J. M., "Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers", Sci. Transl. Med, 10, pp.eaan6735~ (2018)
- Foster, D. S., "Elucidating the fundamental fibrotic processes driving abdominal adhesion formation", Nat. Commun, 11, pp.1~18 (2020)
- Liu, X., "Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1", Acta Pharm. Sin. B, 10, pp.812~824 (2020)