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Introduction
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, with high rates of morbidity and mortality worldwide (1). NAFLD is characterized by excessive lipid accumulation in hepatocytes, and is considered as the origin of cirrhosis (2). The pathogenesis of NAFLD remains unclear and the ‘two hit theory’ was proposed for the pathogenic mechanism. Briefly, lipid accumulation in the liver associated with obesity and insulin resistance (IR) was reported as the ‘first hit theory’ in patients with NAFLD. This results in hepatic steatosis and can provides sufficient reaction conditions for oxidative stress, increasing the susceptibility of hepatocytes to endogenous and exogenous damage. The ‘second hit theory’ involves hepatic oxidative stress and lipid peroxidation, and the secretion of inflammatory cytokines, which mediates the pathological progression of steatosis to inflammation, fibrosis and necrosis in liver cells (3,4). Notably, 20–30% of adults suffer from NAFLD and it has been suggested that it may become the leading cause of liver transplantation within the next few decades (5). NAFLD is closely associated with the growing epidemic of obesity and cardiovascular mortality, and NAFLD-associated complications are a major cause of death (6,7). At present, there is no effective drug for treating NAFLD in clinical practice. Some antioxidants, insulin sensitizers and lipid-lowering drugs have been applied in clinical trials for the treatment of NAFLD/non-non-alcoholic steatosis (NASH) (8,9).
As an active ingredient of Daphne Koreana Nakai (10), daphnetin (DAP; Fig. 1) has notable antioxidative, anti-inflammatory and anticoagulant activities (10–12). Generally, coumarin compounds markedly lower blood glucose and lipid levels, and protect the liver against oxidative stress and inflammation. (13,14). Recently, Lv et al (12) reported that DAP could ameliorate mitochondrial dysfunction and cell death by upregulating nuclear factor-like 2 (Nrf2)-associated antioxidant signaling pathways and reducing the expression of kelch-like epichlorohydrin related protein-1, thus enhancing the expression of antioxidant reaction elements and alleviating oxidative damage-associated toxicity (12). Yu et al reported that proinflammatory mediators induced by lipopolysaccharides or β-amyloid, including interleukin-1 and tumor necrosis factor-α, could be inhibited by DAP. DAP may also regulate a series of intracellular signaling pathways, including IκB kinase, mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) to reduce the microglial activation and proinflammatory response (15). Therefore, we proposed that DAP...