Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

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The adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of cellular energy. Once activated, it switches on catabolic pathways generating adenosine triphosphate (ATP), while switching off biosynthetic pathways consuming ATP. Pharmacological activation of AMPK by metformin holds a therapeutic potential to reverse metabolic abnormalities such as type 2 diabetes and nonalcoholic fatty liver disease. In addition, altered metabolism of tumor cells is widely recognized and AMPK is a potential target for cancer prevention and/or treatment. Panax ginseng is known to be useful for treatment and/or prevention of cancer and metabolic diseases including diabetes, hyperlipidemia, and obesity. In this review, we discuss the ginseng extracts and ginsenosides that activate AMPK, we clarify the various mechanisms by which they achieve this, and we discuss the evidence that shows that ginseng or ginsenosides might be useful in the treatment and/or prevention of metabolic diseases and cancer.

Beneficial effect of eugenol on fatty liver was examined in hepatocytes and liver tissue of high fat diet (HFD)-fed C57BL/6J mice. To induce a fatty liver, palmitic acid or isolated hepatocytes from HFD-fed Sprague-Dawley (SD) rats were used in vitro studies, and C57BL/6J mice were fed HFD for 10 weeks. Lipid contents were markedly decreased when hepatocytes were treated with eugenol for up to 24 h. Gene expressions of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes were suppressed but those of lipolysis-related proteins were increased. As a regulatory kinase for lipogenic transcriptional factors, the AMP-activated protein kinase (AMPK) signaling pathway was examined. Protein expressions of phosphorylated Ca 2 -calmodulin dependent protein kinase kinase (CAMKK), AMPK and acetyl-CoA carboxylase (ACC) were significantly increased and those of phosphorylated mammalian target of rapamycin (mTOR) and p70S6K were suppressed when the hepatocytes were treated with eugenol at up to 100 µM. These effects were all reversed in the presence of specific inhibitors of CAMKK, AMPK or mTOR. In vivo studies, hepatic triglyceride (TG) levels and steatosis score were decreased by 45% and 72%, respectively, in eugenoltreated mice. Gene expressions of fibrosis marker protein such as α-smooth muscle actin (α-SMA), collagen type I (Col-I) and plasminogen activator inhibitor-1 (PAI-1) were also significantly reduced by 36%, 63% and 40% in eugenol-treated mice. In summary, eugenol may represent a potential intervention in populations at high risk for fatty liver.Key words eugenol; fatty liver; fibrosis; AMP-activated protein kinase; sterol regulatory element binding protein Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver ailment worldwide.1) While hepatic steatosis is often asymptomatic, it can progress to non-alcoholic steatohepatitis (NASH). If untreated, NASH can progress to cirrhosis and increased risk of early mortality.2) Obesity and insulin resistance, as seen in type 2 diabetes mellitus (T2DM), and hypertriglyceridemia are well-documented risk factors for NAFLD.3) These factors are key targets for prevention and therapy of NAFLD tends to focus on addressing the obesity or insulin resistance rather than NAFLD itself. NAFLD in the hepatic steatosis (HS) phase can be reversed by lifestyle modification, while NASH is more difficult to treat. Thus, preventing the progression of HS to NASH is of primary importance. Lifestyle recommendations for NAFLD are generally limited to losing weight through energy restriction and/or increasing physical activity, which is often to fail to hold on to them. With this notion, phytochemicals obtained from medicinal plants or foods are attracting alternative options for the treatment of NAFLD and prevention to progress to NASH.

The inhibitory effect of betulinic acid (BA) on hepatic glucose production was examined in HepG2 cells and high fat diet (HFD)-fed ICR mice. BA significantly inhibited the hepatic glucose production (HGP) and gene expression levels of PGC-1α, PEPCK, and G6Pase. BA activated AMPK and suppressed the expression level of phosphorylated CREB. These effects were all abolished in the presence of compound C (an AMPK inhibitor). Moreover, inhibition of AMPK by overexpression of dominant negative AMPK prevented BA from suppression of HGP, indicating that the inhibitory effect of BA on HGP is AMPK-dependent. In addition, BA markedly phosphorylated CAMKK, and phosphorylation of AMPK and ACC, and suppression of HGP were all reversed in the presence of STO-609 (a CAMKK inhibitor), suggesting that CAMKK is an upstream kinase for AMPK. In an animal study, HFD-fed ICR mice were orally administered with 5 or 10 mg of BA per kg (B5 and B10) for three weeks. Plasma glucose, triglyceride, and the insulin resistance index of the B10 group were decreased by 34%, 59%, and 38%, respectively. In a pyruvate tolerance test, pyruvate-induced glucose excursion was decreased by 27% when mice were pretreated with 10 mg/kg of BA. In summary, BA effectively ameliorates hyperglycemia through inhibition of hepatic gluconeogenesis via modulating the CAMKK-AMPK-CREB signaling pathway.