Activation of Sirtuin 3 by Silybin Attenuates Mitochondrial Dysfunction in Cisplatin-induced Acute Kidney Injury

Abstract

Silybin is a secondary metabolite isolated from the seeds of blessed milk thistle (Silybum marianum) that has anti-inflammatory, antioxidative, antifibrotic, and antitumor properties. Here, we showed that silybin protected against cisplatin-induced acute kidney injury (AKI) by improving mitochondrial function through the regulation of sirtuin 3 (SIRT3) expression. Male SV129 and SIRT3 knockout (KO) mice were administered a single intraperitoneal (i.p.) injection of cisplatin with or without treatment with silybin. Moreover, cultured HK2 cells were used to evaluate mitochondrial morphology and function. Our data suggested that silybin enhanced SIRT3 expression after cisplatin administration both in vivo and in vitro. Silybin treatment improved mitochondrial function and bioenergetics in wild-type, but not SIRT3-defective, cells and mice. Moreover, we demonstrated that silybin markedly attenuated cisplatin-induced AKI and tubular cell apoptosis and improved cell regeneration in a SIRT3-dependent manner. Collectively, these results suggest that silybin is a pharmacological activator of SIRT3 capable of protecting against cisplatin-induced tubular cell apoptosis and AKI by improving mitochondrial function. Thus, silybin could serve as a potential clinical renoprotective adjuvant treatment in cisplatin chemotherapy.

RAGE-dependent mitochondria pathway: a novel target of silibinin against apoptosis of osteoblastic cells induced by advanced glycation end products

“…In the present study, we demonstrated that silibinin protected osteoblasts from AGE-induced apoptosis. Evidence has also suggested that silibinin exerts beneficial effects against mitochondrial damage under pathological conditions 24 , 25 . Our results revealed that the protective effects of silibinin against AGEs-induced apoptosis of osteoblastic cells were achieved via the attenuation of mitochondrial OS and dysfunction, restoration of mitochondrial morphology and aberrant mitochondrial fission/fusion.…”

Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects

“…Pine bark extract with potent anti-oxidant activity attenuates cisplatin-induced kidney injury of rats (Lee et al, 2017 ). Silybin (a main flavonoid of S. marianum ) as a pharmacological activator of SIRT3, has capable of protection against cisplatin-induced tubular cell apoptosis and acute kidney injury by improving mitochondrial function (Li et al, 2017 ). Origanum majorana is commonly known as marjoram in traditional medicine, which possesses anti-oxidant, anti-microbial and anti-inflammatory activities (Leyva-Lopez et al, 2017 ).…”

Antifungal Compounds againstCandidaInfections from Traditional Chinese Medicine

“…Silibinin, the most famous and active compound isolated from Silybum marianum (milk thistle) traditionally used to protect from liver injury, could induce apoptosis related to mitochondrial Ca 2+ influx in C. albicans cells [ 84 , 85 ]. Silibinin could alleviate mitochondrial dysfunction in mice model of cisplatin-induced acute kidney injury through Sirt3 activation, although in vitro proapoptotic effects through inducing ROS production have been also reported [ 86 , 87 ]. The safe profile with silibinin, evidenced by marketed health food and clinical trials, makes silibinin a very promising candidate for antifungal therapies against Candida infections although there is still a long way to go [ 88 ].…”