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// Jimin Kim 1, 2 , Su-Hyun Shin 1, 2 , Jong-Koo Kang 3 and Jae Wha Kim 1, 2 1 Cell Factory Research Center, Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 2 Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Republic of Korea 3 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea Correspondence to: Jae Wha Kim, email: wjkim@kribb.re.kr Keywords: HX-1171; Nrf2 activator; beta cell; diabetes; hyperglycemia Received: July 17, 2017 Accepted: September 04, 2017 Epub: March 23, 2018 Published: May 11, 2018 ABSTRACT Streptozotocin (STZ) acts specifically on pancreatic beta cells, inducing cell destruction and cell dysfunction, resulting in diabetes. Many studies have reported that nuclear factor-erythroid 2-related factor 2 (Nrf2), a main regulator of antioxidant expression, prevents and improves diabetes-related diseases. In this study, we investigated the antidiabetic effect of the newly discovered Nrf2 activator, HX-1171, in the STZ-induced diabetic mouse model. HX-1171 enhanced insulin secretion by reducing STZ-induced cell apoptosis, and decreased intracellular reactive oxygen species (ROS) generation by upregulating the expression of antioxidant enzymes through Nrf2 activation in INS-1 pancreatic beta cells. In STZ-induced diabetic mice, HX-1171 administration significantly lowered blood glucose levels and restored blood insulin levels. In the STZ-only injected mice, the pancreatic islets showed morphological changes and loss of function, whereas the HX-1171-treated group was similar to that of the control group. These results suggest that HX-1171 may be developed as a promising therapeutic agent for diabetes-related diseases.

Yo Han Kim,1 Hee Youn Choi,1 Shi Hyang Lee,1 Hyeong-Seok Lim,1 Tokutaro Miki,2 Jong-Koo Kang,3 Kyoung-Goo Han,4 Kyun-Seop Bae1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2Nippon Hypox Laboratories Inc., Yamanashi, Japan; 3College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea; 4Biotoxtech Co., Ltd, Cheongju, Republic of Korea Background: HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers. Methods: A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Results: Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63–1.50 hours and slowly eliminated with a terminal half-life of 21.12–40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine. Conclusion: HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing. Keywords: HX-1171, antioxidant, pharmacokinetics, tolerability, healthy subjects&nbsp