Regulation on SIRT1-PGC-1α/Nrf2 pathway together with selective inhibition of aldose reductase makes compound hr5F a potential agent for the treatment of diabetic complications

Zhihua Wang; Sheng Yuan; Yanbing Li; Zhe Zhang; Wei Xiao; Dan Tang; Kaihe Ye; Zhijun Liu; Congcong Wang; Yixiong Zheng; Hong Nie; Heru Chen

doi:10.1016/j.bcp.2018.01.034

Regulation on SIRT1-PGC-1α/Nrf2 pathway together with selective inhibition of aldose reductase makes compound hr5F a potential agent for the treatment of diabetic complications

Biochem Pharmacol. 2018 Apr:150:54-63. doi: 10.1016/j.bcp.2018.01.034. Epub 2018 Jan 31.

Authors

Zhihua Wang¹, Sheng Yuan², Yanbing Li², Zhe Zhang¹, Wei Xiao¹, Dan Tang¹, Kaihe Ye¹, Zhijun Liu¹, Congcong Wang³, Yixiong Zheng³, Hong Nie⁴, Heru Chen⁵

Affiliations

¹ College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
² College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China.
³ College of Agriculture, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, PR China.
⁴ College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China. Electronic address: tnieh@jnu.edu.cn.
⁵ College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China. Electronic address: thrchen@jnu.edu.cn.

PMID: 29371030
DOI: 10.1016/j.bcp.2018.01.034

Abstract

(R,E)-N-(3-(2-acetamido-3-(benzyloxy) propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide (hr5F) was design-synthesized based on bioactivity focus strategy as a potential agent to treat diabetic complicates. With in vitro enzyme assay, it is confirmed that hr5F is an effective ALR2 inhibitor with IC₅₀ value of 2.60 ± 0.15 nM, and selectivity index of 86.0 over ALR1, which is a little bit better than the reference Epalrestat (Epa). hr5F inhibits the increase of ALR2 enzyme activity and expression in human lens epithelial cells (HLECs) induced by high glucose. By applying western blot, it was found that hr5F alleviates the high glucose-induced superoxide overproduction insults by regulating SIRT1-PGC-1α/Nrf2 pathway, together with regulating NRF-1, mtTFA, Bax/Bcl-2 to ameliorate cell apoptosis. The in vivo effects of hr5F on short term streptozocin (STZ)-induced diabetic mice confirm the same functions disclosed in vitro. All the evidences support that hr5F may serve as a promising agent in the treatment of diabetic complications with close efficacy and broader indication than the reference Epa.

Keywords: Aldose reductase inhibitor; Antioxidant; Diabetic complications; Nrf2; ROS; Sirt1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldehyde Reductase / antagonists & inhibitors
Aldehyde Reductase / metabolism*
Animals
Cells, Cultured
Diabetes Complications / drug therapy
Diabetes Complications / metabolism
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Experimental / metabolism*
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Female
Humans
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use*
Male
Mice
NF-E2-Related Factor 2 / physiology*
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / physiology*
Signal Transduction / drug effects
Signal Transduction / physiology
Sirtuin 1 / physiology*
Treatment Outcome

Substances

Enzyme Inhibitors
Hypoglycemic Agents
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Aldehyde Reductase
Sirt1 protein, mouse
Sirtuin 1