title: Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes.
abstract: BACKGROUND
  Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG).
  
  
  RESULTS
  Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 μM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucose-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW.
  
  
  CONCLUSIONS
  Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2-regulated antioxidant enzymes in cardiomyocytes exposed to HG.
authors: Department of Pediatrics, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC; Department of Biological Science & Technology College of Life Sciences, China Medical University, Taichung, Taiwan, ROC.
authors: Cheng-Yen
authors: CY
authors: Tsai
authors: Chien-Chung
authors: CC
authors: Wang
authors: Tung-Yuan
authors: TY
authors: Lai
authors: Han-Nien
authors: HN
authors: Tsu
authors: Chung-Hsing
authors: CH
authors: Wang
authors: Hsin-Yueh
authors: HY
authors: Liang
authors: Wei-Wen
authors: WW
authors: Kuo
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D005737:Garlic; D005947:Glucose / Q000633:toxicity; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D000498:Allyl Compounds; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D013440:Sulfides; C042577:diallyl trisulfide; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: 2′,7′-dichlorofluorescein diacetate; Apo; Apoptosis; BW; DADS; DAS; DATS; DCF; DCFH-DA; DHE; DTT; Diallyl trisulfide (DATS); GSK3β; HG; HO-1; Hyperglycemia; Keap1; NG; Nrf2; Nuclear factor E2-related factor 2 (Nrf2); OSCs; ROS; Reactive oxygen species (ROS); SAPKs; SOD; STZ; TBARS; TUNEL; TXN-1; apocynin; body weight; dially trisulfide; diallyl disulfide; diallyl sulfide; dichlorofluorescein; dihydroethidium; dithiothreitol; glycogen synthase kinase 3β; heme oxygenase 1; high glucose; kelch-like ECH-associated protein 1; normal glucose; nuclear factor erythroid 2-related factor 2; organosulfur compounds; reactive oxygen species; streptozotocin; stress-activated protein kinases; superoxide dismutases; terminal deoxynucleotide transferase-mediated dUTP Nick End Labeling; thiobarbituric acid reactive substances; thioredoxin-1; γ-glutamylcysteine synthetase; γGCS