Devabattula Geetanjali, Bakchi Bulti, Sharma Anamika, Panda Biswajit, Madhavi Venkata, Godugu Chandraiah
Department of Biological Sciences (Pharmacology & Toxicology), National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Telangana 500037, India.
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Telangana 500037, India.
Biochem Pharmacol. 2025 Feb;232:116723. doi: 10.1016/j.bcp.2024.116723. Epub 2024 Dec 17.
Silent mating-type information regulation 2 homology 3 (SIRT3) is a member of the sirtuins family expressed in mitochondria performs deacetylation of metabolic enzymes and promotes longevity. 7-hydroxy-3-(4'-methoxyphenyl) coumarin (C12) is a small molecule first ever known for its direct activation of SIRT3. SIRT3 performs its function by balancing the redox system by activating manganese superoxide dismutase (MnSOD) and 8-Oxoguanine glycosylase (OGG1). For the first time, we reported that activation of SIRT3 by C12 attenuated bleomycin (BLM)-)-induced acute lung injury and pulmonary fibrosis. C12 prevented the oxidative stress and injury caused by BLM in alveolar epithelial cells (BEAS-2B) in in vitro and inhibited the fibrosis in transforming growth factor-beta (TGF-β) induced fibrosis in fibroblasts (MRC-5). Additionally, activation of SIRT3 by C12 in vivo mice model alleviated BLM-induced inflammation, collagen accumulation, cellular infiltration, and restoration of alveolar architecture by inhibiting TGF-β, smooth muscle actin (α-SMA), collagen-1A, collagen-3A, and mesenchymal markers. The protective effect of C12 was through activation of MnSOD and OGG1 in both in vitro and in vivo models suggesting C12 can be a potent SIRT3 activator and helps to treat fibrotic-related diseases.
沉默交配型信息调节因子2同源物3（SIRT3）是沉默调节蛋白家族的成员，在线粒体中表达，可使代谢酶去乙酰化并促进长寿。7-羟基-3-（4'-甲氧基苯基）香豆素（C12）是首个已知可直接激活SIRT3的小分子。SIRT3通过激活锰超氧化物歧化酶（MnSOD）和8-氧代鸟嘌呤糖基化酶（OGG1）来平衡氧化还原系统，从而发挥其功能。我们首次报道，C12激活SIRT3可减轻博来霉素（BLM）诱导的急性肺损伤和肺纤维化。C12在体外可预防BLM对肺泡上皮细胞（BEAS-2B）造成的氧化应激和损伤，并在体外抑制成纤维细胞（MRC-5）中转化生长因子-β（TGF-β）诱导的纤维化。此外，在体内小鼠模型中，C12激活SIRT3可通过抑制TGF-β、平滑肌肌动蛋白（α-SMA）、胶原蛋白-1A、胶原蛋白-3A和间充质标志物，减轻BLM诱导的炎症、胶原蛋白积累、细胞浸润，并恢复肺泡结构。C12的保护作用是通过在体外和体内模型中激活MnSOD和OGG1实现的，这表明C12可能是一种有效的SIRT3激活剂，有助于治疗纤维化相关疾病。
