Schisandrin B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 hepatocytes

Biological & Pharmaceutical Bulletin

Chiu

2012

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We investigated whether two naturally-occurring prooxidants, namely, schisandrin B (Sch B) and curcumin, and a synthetic prooxidant, menadione, can invariably elicit cyto/hepatoprotective responses against oxidant-induced injury. Results showed that ( )Sch B (a potent enantiomer of Sch B, 15 μM), curcumin (7.5 μM) and menadione (2 μM) induced a similar extent of reactive oxygen species production in AML12 cells. The relative potencies of cytoprotection in vitro were in a descending order of curcumin>menadione>( ) Sch B, which were parallel to the extent of stimulation in cellular reduced glutathione level. We further examined their hepatoprotection in vivo. Pretreatment with Sch B (800 mg/kg) and curcumin (737 mg/kg), but not menadione (344 mg/kg), protected against CCl 4 toxicity, with the degree of protection afforded by Sch B being much larger than that of curcumin. The attenuated hepatoprotection afforded by curcumin may be attributed to its low bioavailability in vivo. This postulation is supported by the findings that intraperitoneal injections of Sch B (400 mg/kg) and curcumin (368 mg/kg) and the long term, low dose treatment with Sch B (20 mg/kg/d 15) and curcumin (18 mg/kg/d 15) induced glutathione antioxidant response and hepatoprotection to similar extents in vivo. The inability of menadione to induce hepatoprotection may be related to its extensive intestinal metabolism and/or hepatotoxicity. Taken together, prooxidants can invariably induce the glutathione antioxidant response and confer cytoprotection in vitro. Whether or not the prooxidant can produce a similar response in vivo would depend on its bioavailability and potential toxic effect.

Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

Prooxidant-Induced Glutathione Antioxidant Response in Vitro and in Vivo: A Comparative Study between Schisandrin B and Curcumin

Biological & Pharmaceutical Bulletin

Chiu

2012

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“…The MAPK activation was followed by enhanced Nrf2 nuclear translocation and the elicitation of a glutathione-dependent anti-oxidant response in cultured hepatocytes and cardiomyocytes. 109,110 In addition, long-term SchB treatment by the oral route increased the expression of Hsp25 and Hsp70 in various rat tissues. 86 A recent study has shown that gomisin N (or ())SchB) enhanced tumour necrosis factor-a-induced apoptosis in Hela cells by suppressing NF-jB signalling.…”

Section: Pharmacological Actions Of Schbmentioning

confidence: 98%

Mitochondrial decay in ageing: ‘Qi‐invigorating’ schisandrin B as a hormetic agent for mitigating age‐related diseases

Chen

2012

Clin Exp Pharma Physio

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1. The mitochondrial free radical theory of ageing (MFRTA) proposes a primary role for mitochondrial reactive oxygen species (ROS) in the ageing process. The reductive hot spot hypothesis of mammalian ageing serves as a supplement to the MFRTA by explaining how the relatively few cells that have lost oxidative phosphorylation capacity due to mitochondrial DNA mutations can be toxic to the rest of the body and result in the development of age-related diseases. 2. Schisandrin B (SchB), which can induce both a glutathione anti-oxidant and a heat shock response via redox-sensitive signalling pathways, is a hormetic agent potentially useful for increasing the resistance of tissues to oxidative damage. The enhanced cellular/mitochondrial anti-oxidant status and heat shock response afforded by SchB can preserve the structural and functional integrity of mitochondria, suggesting a potential role for SchB in ameliorating age-related diseases. 3. Future studies will focus on investigating whether SchB can produce the hormetic response in humans.

“…The glutathione antioxidant system is regulated by nuclear factor erythroid 2-related factor-2 (Nrf2), the principal transcriptional regulator of cellular antioxidant genes, which in turn binds to its corresponding element, namely, the antioxidant response element (ARE), on DNA [100]. A recent study has elucidated the cytoprotective mechanism underlying the Sch-B-induced glutathione antioxidant response in cultured hepatocytes [101]. Sch B is metabolized by cytochrome P 450 with concomitant production of ROS [101].…”

Section: Hepatoprotective Action Of Sch B Against Nafldmentioning

confidence: 99%

Schisandrin B: A Double‐Edged Sword in Nonalcoholic Fatty Liver Disease

Oxidative Medicine and Cellular Longevity

2016

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Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver lesions ranging from hepatic steatosis, nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. The high global prevalence of NAFLD has underlined the important public health implications of this disease. The pathogenesis of NAFLD involves the abnormal accumulation of free fatty acids, oxidative stress, endoplasmic reticulum (ER) stress, and a proinflammatory state in the liver. Schisandrin B (Sch B), an active dibenzooctadiene lignan isolated from the fruit of Schisandra chinensis (a traditional Chinese herb), was found to possess antihyperlipidemic, antioxidant, anti-ER stress, and anti-inflammatory activities in cultured hepatocytes in vitro and in rodent livers in vivo. Whereas a long-term, low dose regimen of Sch B induces an antihyperlipidemic response in obese mice fed a high fat diet, a single bolus high dose of Sch B increases serum/hepatic lipid levels in mice. This differential action of Sch B is likely related to a dose/time-dependent biphasic response on lipid metabolism in mice. The hepatoprotection afforded by Sch B against oxidative stress, ER stress, and inflammation has been widely reported. The ensemble of results suggests that Sch B may offer potential as a therapeutic agent for NAFLD. The optimal dose and duration of Sch B treatment need to be established in order to ensure maximal efficacy and safety when used in humans.