Toxicology 290 (2011) 14–21 Contents lists available at ScienceDirect Toxicology j ourna l h o me page: www.elsevier.com/locate/toxicol Hepato-protective effects of loganin, iridoid glycoside from Corni Fructus, against hyperglycemia-activated signaling pathway in liver of type 2 diabetic db/db mice Chan Hum Park a , Takashi Tanaka b , Ji Hyun Kim a , Eun Ju Cho c , Jong Cheol Park d , Naotoshi Shibahara a , Takako Yokozawa a,e,∗ a Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan b Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyou-cho, Nagasaki 852-8521, Japan c Department of Food Science and Nutrition, Pusan National University, 30 Jangjeon-dong, Geumjeong-gu, Busan 609-735, Republic of Korea d Department of Oriental Medicine Resources and Research Institute of Korean Oriental Medicines, Sunchon National University, 413 Jungang-ro, Jeonnam 540-742, Republic of Korea e Organization for Promotion of Regional Collaboration, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan a r t i c l e i n f o Article history: Received 20 July 2011 Received in revised form 4 August 2011 Accepted 6 August 2011 Available online 12 August 2011 Keywords: Loganin Type 2 diabetes Oxidative stress Inflammation Apoptosis Liver a b s t r a c t Accumulating evidence indicates that uncontrolled diabetes leads to the progression of diabetic compli- cations such as liver disorder. The present study was carried out to elucidate the protective role of loganin extracted from Corni Fructus against hepatic oxidative stress caused by type 2 diabetes. Loganin (20 or 100 mg/kg body weight/day, p.o.) was administered every day for 8 weeks to db/db mice, and its effect was assessed on comparison with vehicle-treated db/db and m/m mice. The administration of loganin led to a decrease in glucose and elevation of leptin in serum. The diabetic oxidative stress was attenu- ated by loganin through inhibitions of reactive oxygen species production and lipid peroxidation in the serum and liver. The expression of proteins induced by oxidative stress was significantly up-regulated in the liver of diabetic db/db mice; however, the expressions of both Nox-4 and p22 phox were decreased significantly by loganin administration. Loganin showed a crucial effect in the inflammation-activated signaling pathway through the regulation of NF-B, COX-2, and iNOS. It was also found to regulate the anti-inflammatory factors Nrf-2 and HO-1 in hepatic tissue. Moreover, expression of MCP-1 was signifi- cantly down-regulated in the loganin-treated db/db mice. Furthermore, loganin administration showed a protective effect against apoptosis by the regulation of Bcl-2 and cytochrome c. The present study demonstrated that the administration of loganin isolated from Corni Fructus had a protective effect against hepatic oxidative stress under type 2 diabetes through regulations of protein expressions related to oxidative stress, inflammation, and apoptosis. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Changes in life style and diet have resulted in increasing rates of obesity, and obesity has been considered as an important causative factor for several diseases such as type 2 diabetes, hyperten- sion, cardiovascular disease, various infectious diseases, and cancer worldwide (Hu et al., 2001). Among these kinds of problems related to obesity, the most devastating may be type 2 diabetes. Type 2 diabetes, a complex metabolic disorder, is a major health prob- lem associated with high morbidity and mortality, and results in considerable health-care costs (Narayan et al., 2000). At present, 285 million people around the world have been diagnosed with diabetes mellitus, and the number is expected to grow to 438 million by 2030. By far, the largest proportion is derived from ∗ Corresponding author at: Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Tel.: +81 76 434 7631; fax: +81 76 415 8841. E-mail address: yokozawa@inm.u-toyama.ac.jp (T. Yokozawa). type 2 diabetes, which accounts for more than 90% of diabetes (Doria et al., 2008; Zimmet, 2010). In light of these findings, pre- vention and the implementation of intervention for people with type 2 diabetes should become a public health priority world- wide. Type 2 diabetes is considered to be preceded by a long period of insulin resistance which is characterized by reduced responsive- ness to normal circulating concentrations of insulin (Weyer et al., 2001). In particular, hepatic insulin resistance is a principal com- ponent of type 2 diabetes. Decreased insulin sensitivity in the liver leads to elevated hepatic glucose production, hyperinsulinemia, - cell stress, and hyperglycemia (Michael et al., 2000). Besides, insulin resistance is accompanied by the intracellular production of free radicals, consequently causing elevated oxidative stress in the tis- sues of organs (Evans et al., 2003). This indicates that there is a strong association between the degree of oxidative stress and risk of developing insulin resistance. Insulin resistance can play a pri- mary role in the development of complications of type 2 diabetes, especially liver disorder. 0300-483X/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2011.08.004