title: Suppression of dimerumic acid on hepatic fibrosis caused from carboxymethyl-lysine (CML) by attenuating oxidative stress depends on Nrf2 activation in hepatic stellate cells (HSCs).
abstract: Hyperglycemia facilitates the formation of advanced glycation end-products (AGEs) in type-2 diabetes. Evidence indicates that carboxymethyl-lysine (CML) is highly prevalent in diabetes, resulting in hepatic fibrosis. The current study was designed to evaluate the effects of dimerumic acid (DMA) identified from Monascus-fermented products on receptor for AGEs (RAGE) signal and hepatic stellate cells (HSCs) activation by CML treatment. We found that DMA (50 μM) eliminated collagen generation, mRNA expressions of α-smooth muscle actin (α-SMA), platelet-derived growth factor-β receptor (PDGF-βR), and procollagen 1a1 (proCol-1a1) in CML (100 μg/ml)-treated HSCs, and these effects were similar to allyl isothiocyanate (AITC; 50 μM). In addition, the suppression of α-SMA, PDGF-βR, proCol-1a1 by DMA were abolished while nuclear factor-erythroid 2-related factor 2 (Nrf2) silence in CML-treated HSCs. These findings suggested that DMA and AITC increased Nrf2 and glutamate-cysteine ligase (GCL) activities thereby inhibiting oxidative stress caused by CML and showing anti-fibrogentic effect in HSCs.
authors.affiliation: Department of Biochemical Science & Technology, College of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.
authors.forename: Bao-Hong
authors.initials: BH
authors.lastname: Lee
authors.forename: Wei-Hsuan
authors.initials: WH
authors.lastname: Hsu
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Hsu
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Pan
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D054659:Diketopiperazines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D000199:Actins; D000975:Antioxidants; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D054659:Diketopiperazines; D006877:Hydroxamic Acids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C544013:alpha-smooth muscle actin, mouse; C552122:dimerumic acid; C048496:N(6)-carboxymethyllysine; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases; D008239:Lysine
keywords: Advanced glycation end-products (AGEs); Carboxymethyl-lysine (CML); Dimerumic acid (DMA); Hepatic fibrosis; Nuclear factor-erythroid 2-related factor 2 (Nrf2)