title: Thioredoxin-mimetic peptides (TXM) inhibit inflammatory pathways associated with high-glucose and oxidative stress.
abstract: Impaired insulin signaling and the associated insulin-resistance in liver, adipose tissue, and skeletal muscle, represents a hallmark of the pathogenesis of type 2-diabetes-mellitus. Here we show that in the liver of db/db mice, a murine model of obesity, type 2 diabetes, and dyslipidemia, the elevated activities of mitogen-activated protein kinases (MAPK; ERK1/2 and p38MAPK), and Akt/PKB are abolished by rosiglitazone-treatment, which normalizes blood glucose in db/db mice. This is unequivocal evidence of a functional link between the activation of the MAPK specific inflammatory-pathway and high-blood sugar. A similar reduction in ERK1/2, p38MAPK, and Akt activities but without affecting blood-glucose was observed in the liver of db/db mice treated with a molecule that mimics the action of thioredoxin, called thioredoxin-mimetic peptide (TXM). N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3) is a free radical scavenger, a reducing and denitrosylating reagent that protects the cells from early death induced by inflammatory pathways. TXM-CB3 also lowered MAPK signaling activated by the disruption of the thioredoxin-reductase-thioredoxin (Trx-TrxR) redox-system and restored Akt activity in rat hepatoma FAO cells. Similarly, two other TXM-peptides, N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13; DY70), and N-Acetyl-Cys-γGlu-Cys-Cys-amide (TXM-CB16; DY71), lowered insulin- and oxidative stress-induced ERK1/2 activation, and rescued HepG2 cells from cell death. The potential impact of TXM-peptides on inhibiting inflammatory pathways associated with high-glucose could be effective in reversing low-grade inflammation. TXM-peptides might also have the potential to improve insulin resistance by protecting from posttranslational modifications like nitrosylation.
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Katia
authors.initials: K
authors.lastname: Lejnev
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Khomsky
authors.affiliation: Lilly Research Labs DC0522, Eli Lilly & Co, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Krister
authors.initials: K
authors.lastname: Bokvist
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Mistriel-Zerbib
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Tahel
authors.initials: T
authors.lastname: Naveh
authors.affiliation: Lilly Research Labs DC0522, Eli Lilly & Co, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Thomas Bradley
authors.initials: TB
authors.lastname: Farb
authors.affiliation: Lilly Research Labs DC0522, Eli Lilly & Co, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Alsina-Fernandez
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address: daphne.atlas@mail.huji.ac.il.
authors.forename: Daphne
authors.initials: D
authors.lastname: Atlas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D013879:Thioredoxins / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C510899:N-acetyl-Cys-Gly-Pro-Cys-amide; D009842:Oligopeptides; D010455:Peptides; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013879:Thioredoxins; D051057:Proto-Oncogene Proteins c-akt; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Akt/PKB; Diabetes; ERK1/2; Insulin receptor; Insulin receptors; Oxidative stress; Thioredoxin mimetics