Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice

Abstract

Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), a chronic liver disease with a significant unmet clinical need. In this study, we examined the protective effects of Garcinia indica extract standardized to contain 20% w/w of Garcinol (GIE) and 95% Curcuminoids w/w from Curcuma longa (Curcuminoids) in a Stelic animal model (STAM) of NASH. The STAM mice developed steatosis, hepatocyte ballooning, and inflammation, which were significantly reduced by the combination of GIE and Curcuminoids, resulting in a lower NAFLD activity score. The treatment reduced fibrosis as observed by Sirius red staining, liver hydroxyproline content and mRnA levels of tGf-β and collagen in the liver. Immunostaining with alpha-smooth muscle actin (α SMA) revealed a significant reduction in hepatic stellate cells. Intriguingly, the combination regimen markedly decreased the mRNA levels of MCP1 and CRP and both mRNA and protein levels of TNF-α. NF-kB, reduced the hepatic and circulating FGF21 levels and altered the nonenzymatic (glutathione) and enzymatic antioxidant markers (Glutathione peroxidase, and superoxide dismutase). Our results suggest that the combination of GIE and Curcuminoids can reduce the severity of NASH by reducing steatosis, fibrosis, oxidative stress, and inflammation. The results suggest that the combinatorial regimen could be an effective supplement to prevent the progression of liver steatosis to inflammation and fibrosis in NASH. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disorders 1,2. It includes the spectrum of liver disease, ranging from benign fatty liver to hepatocellular carcinoma. It is histologically further categorized into the nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL, as the early-stage disease shows the presence of excessive fat in the liver (hepatic steatosis) with no evidence of hepatocellular injury, while NASH is characterized by the accumulation of fat accompanied by infiltration of inflammatory cells and cellular damage, which can progress to cirrhosis, liver failure, and liver cancer 3. NASH is the hepatic manifestation of metabolic disorder and is closely associated with type 2 diabetes, obesity, insulin resistance anda systemic inflammatory state 4-8. Consequently, NASH patients have a higher risk of cardiovascular events and neoplasia, resulting in a higher rate of mortality 9,10. It is usually a silent disease with minimum symptoms, while weight loss, fatigue, and weakness develop as the disease progresses. Although the disease development and progression are still not well elucidated, the most accepted theory to explain the pathogenesis is "multiple-hits hypothesis". The initial hit leads to the development of simple steatosis, while liver cell inflammation and apoptosis are induced by secondary hits, leading to mitochondrial dysfunction, oxidative stress, lipid peroxidation, gut dysbiosis, and Kupffer cell activation, which finally results in NASH 11,12. Presence...

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

“…Besides HCC, future work will aim to determine whether regionally increased histone acetylation can progress the severity of NAFLD to NASH and cirrhosis through dysregulation of genes involved in inflammation and fibrosis. Finally, several drugs undergoing preclinical and clinical trials for reducing liver steatosis and fibrosis in NAFLD will likely impact acetyl-CoA metabolism [ 53 ] and/or histone acetylation [ 54 – 56 ]. Accordingly, we observed that firsocostat [ 57 – 59 ], an acetyl-CoA synthetase inhibitor which blocks the use of acetyl-CoA for DNL, reduces oleic acid-induced ɣH2AX in vitro (Fig.…”

Mechanisms of main components in Curcuma longa L. on hepatic fibrosis based on network pharmacology and molecular docking: A review

“…Many in vitro studies have reported the hepatoprotective, antioxidant, antisteatotic and antilipidemic, anti-inflammatory, anti-fibrotic, antitumor, and cholagogic effects of the main phenolic-based components and curcuminoids in CL. [11][12][13][14]26,27] Unfortunately, the potential targets and mechanisms of CL are still not clear at present. This study comprehensively investigated the therapeutic effect of main components of CL on hepatic fibrosis via network pharmacology.…”

“…[12] Remarkable hepatoprotective, anti-inflammatory, and anti-fibrotic effects of analogs of curcumin and non-curcuminoid constituents have also been reported. [13,14] Despite a series of studies on the biological activities of active components in CL, the potential targets and underlying mechanisms of CL in hepatic fibrosis remain largely unclear. Due to the effects of CL and its bioactives on hepatic fibrosis in researches and a variety of pathological processes involved, we therefore hypothesized that CL possibly exert a treatment effect by acting on multiple pathological processes.…”

Garcinol Encapsulated Ph-Sensitive Biodegradable Nanoparticles: A Novel Therapeutic Strategy for the Treatment of Inflammatory Bowel Disease

“…The introduction of GAR into anti-inflammatory therapy has started recently, although the factors behind its capabilities are still yet to be discovered [ 43 ]. GAR has previously shown to have reduced inflammatory markers like TNF- and NF- B in hepatic inflammation in the steatohepatitis-derived hepatocellular carcinoma of a mouse model (STAM) and LPS-induced inflammation in THP-1 cells in vitro [ 50 ]. The inhibition of inflammation by GAR is expected due to its ability to down-regulate NF- B and cyclooxygenase-2 (COX-2) [ 51 ].…”