In vitro and in vivo inhibition of aldose reductase and advanced glycation end products by phloretin, epigallocatechin 3-gallate and [6]-gingerol.
Hyperglycemic stress activates polyol pathway and aldose reductase (AR) key enzyme responsible for generating secondary complications during diabetes. In this study the therapeutic potential of phloretin, epigallocatechin 3-gallate (EGCG) and [6]-gingerol were evaluated for anti-glycating and AR inhibitory activity in vitro and in vivo systems. Human retinal pigment epithelial (HRPE) cells were induced with high glucose supplemented with the phloretin, EGCG and [6]-gingerol. Aldose reductase activity, total advanced glycation end products (AGEs) and enzyme inhibitor kinetics were assessed. Male C57BL/6J mice were randomly assigned to one of the different treatments (bioactive compounds at 2 concentrations each) with either a low fat diet or high fat diet (HFD). After sixteen weeks, AGE accumulation and AR activity was determined in heart, eyes and kidney. High glucose induced toxicity decreased cell viability compared to the untreated cells and AR activity increased to 2-5 folds from 24 to 96h. Pre-treatment of cells with phloretin, EGCG and [6]-gingerol improved cell viability and inhibited AR activity. The enzyme inhibition kinetics followed a non-competitive mode of inhibition for phloretin and EGCG whereas [6]-gingerol indicated uncompetitive type of inhibition against AR. Data from the animal studies showed high plasma glucose levels in HFD group over time, compared to the low fat diet. HFD group developed cataract and AR activity increased to 4 folds compared to the group with low fat diet. Administration of EGCG, phloretin and [6]-gingerol significantly reduced blood sugar levels, AGEs accumulation, and AR activity. These findings could provide a basis to consider using the selected dietary components alone or in combination with other therapeutic approaches to prevent diabetes-related complications in humans.
Department of Human Nutrition, College of Health Sciences, Qatar University, Doha 2713, Qatar.
Chethan
C
Sampath
Laboratory for Functional Foods and Human Health, Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC 28081, United States.
Shengmin
S
Sang
Department of Human Nutrition, College of Health Sciences, Qatar University, Doha 2713, Qatar. Electronic address: ahmedna@qu.edu.qa.
Mohamed
M
Ahmedna
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003930:Diabetic Retinopathy / Q000097:blood / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology; D010693:Phloretin / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors
D015415:Biomarkers; D001786:Blood Glucose; D002396:Catechols; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D002392:Catechin; C007845:gingerol; C045651:epigallocatechin gallate; D000449:Aldehyde Reductase; D010693:Phloretin
Aldose reductase; Bioactive compounds; Diabetes; Enzyme kinetics; Functional foods