Abstract
Enhancing soluble receptor for advanced glycation endproducts (sRAGE) is considered as a potent strategy for diabetes therapy. sRAGE secretion is regulated by calcium and transient receptor potential canonical (TRPC) channels. However, the role of TRPC channels in diabetes remains unknown. 18β-Glycyrrhetinic acid (18β-GA), produced from liquorice, has shown antidiabetic properties. This study was aimed to investigate the effect of 18β-GA on sRAGE secretion via TRPC channels in high glucose (HG)-induced THP-1 cells. HG treatment enhanced TRPC3 and TRPC6 expression and consequently caused reactive oxygen species (ROS) accumulation mediated through p47 nicotinamide-adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS) associated with uncoupling protein 2 (UCP2) decline and lower sRAGE secretion. Interestingly, 18β-GA showed the dramatic effects similar to Pyr3 or 2-aminoethyl diphenyl borinate inhibitors and effectively reversed HG-elicited mechanisms including that blocking TRPC3 and TRPC6 protein expressions, suppressing intracellular [Ca2+] concentration, decreasing expressions of ROS, p47s, and iNOS, but increasing UCP2 level and promoting sRAGE secretion. Therefore, 18β-GA provides a potential implication to diabetes mellitus and its complications.
Keywords:
18β-glycyrrhetinic acid; THP-1; TRPC; high glucose; sRAGE.
© 2019 International Union of Biochemistry and Molecular Biology.
MeSH terms
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Boron Compounds / pharmacology
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Calcium / metabolism
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Gene Expression Regulation
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Glucose / antagonists & inhibitors*
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Glucose / toxicity
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Glycyrrhetinic Acid / analogs & derivatives*
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Glycyrrhetinic Acid / isolation & purification
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Glycyrrhetinic Acid / pharmacology
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Glycyrrhiza / chemistry*
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Humans
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Hypoglycemic Agents / isolation & purification
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Hypoglycemic Agents / pharmacology*
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Plant Extracts / chemistry
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Pyrazoles / pharmacology
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Receptor for Advanced Glycation End Products / antagonists & inhibitors
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Receptor for Advanced Glycation End Products / genetics*
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Receptor for Advanced Glycation End Products / metabolism
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Signal Transduction
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THP-1 Cells
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TRPC Cation Channels / antagonists & inhibitors
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TRPC Cation Channels / genetics*
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TRPC Cation Channels / metabolism
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TRPC6 Cation Channel / antagonists & inhibitors
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TRPC6 Cation Channel / genetics*
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TRPC6 Cation Channel / metabolism
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Uncoupling Protein 2 / genetics
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Uncoupling Protein 2 / metabolism
Substances
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2-aminoethyl diphenylborinate
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Boron Compounds
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Hypoglycemic Agents
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Plant Extracts
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Pyrazoles
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Reactive Oxygen Species
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Receptor for Advanced Glycation End Products
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TRPC Cation Channels
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TRPC3 cation channel
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TRPC6 Cation Channel
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TRPC6 protein, human
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Ucp2 protein, rat
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Uncoupling Protein 2
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ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate
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sRAGE protein, human
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18alpha-glycyrrhetinic acid
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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NADPH Oxidases
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neutrophil cytosolic factor 1
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Glucose
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Glycyrrhetinic Acid
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Calcium