title: Arachidonic acid and lipoxinA4 attenuate streptozotocin-induced cytotoxicity to RIN5 F cells in vitro and type 1 and type 2 diabetes mellitus in vivo.
abstract: OBJECTIVE
  The aim of this study was to observe whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5 F) cells against streptozotocin (STZ)-induced apoptosis in vitro and type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) in vivo and if so, what would be the mechanism of this action.
  
  
  METHODS
  RIN5 F cells were used for the in vitro study, whereas the in vivo study was performed in Wistar rats. STZ was used to induce apoptosis of RIN5 F cells in vitro and T1- and T2DM in vivo. The effect of PUFAs: γ-linolenic acid (GLA), arachidonic acid (AA) of ω-6 series, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of ω-3 series; cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors and antiinflammatory metabolite of AA and DHA, lipoxin A4 (LXA4), and resolvin D2 and protectin, respectively against STZ-induced cytotoxicity to RIN5 F cells in vitro and LXA4 against T1- and T2DM in vivo was studied. Changes in the antioxidant content, lipid peroxides, nitric oxide, and expression of PDX1, P65, nuclear factor-κb (NF-κb), and IKB genes in STZ-treated RIN5 F cells in vitro and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue of T1- and T2DM and LPCLN2 (lipocalin 2), NF-κb, IKB I in adipose tissue of T2DM after LXA4 treatment were studied. Plasma glucose, insulin, and tumor necrosis factor (TNF)-α levels also were measured in STZ-induced T1- and T2DM Wistar rats.
  
  
  RESULTS
  Among all PUFAs tested, AA and EPA are the most effective against STZ-induced cytotoxicity to RIN5 F cells in vitro. Neither COX nor LOX inhibitors blocked the cytoprotective action of AA in vitro and T1- and T2DM by STZ. LXA4 production by RIN5 F cells in vitro and plasma LXA4 levels in STZ-induced T1- and T2DM animals were decreased by STZ that reverted to normal after AA treatment. AA prevented both T1- and T2DM induced by STZ. Antiinflammatory metabolite of AA and LXA4 prevented both T1- and T2DM induced by STZ. The expression of Pdx1, NF-κb, IKB genes in the pancreas and plasma TNF-α levels in T1- and T2DM; Nrf2, Glut2, COX2, and iNOS proteins in pancreatic tissue of T1DM and LPCLN2, NF-κb, IKB I in adipose tissue of T2DM reverted to normal in LXA4-treated animals.
  
  
  CONCLUSIONS
  Both AA and LXA4 prevented STZ-induced cytotoxicity to RIN5 F cells in vitro and T1- and T2DM in vivo, suggesting that these two bioactive lipids may function as antidiabetic molecules. AA is beneficial against STZ-induced cytotoxicity and T1- and T2DM by enhancing the production of LXA4.
authors.affiliation: BioScience Research Centre, Department of Medicine, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam, India.
authors.forename: Naveen K V
authors.initials: NKV
authors.lastname: Gundala
authors.affiliation: National Institute of Pharmaceutical Education and Research, Hyderabad, India.
authors.forename: Vegi G M
authors.initials: VGM
authors.lastname: Naidu
authors.affiliation: BioScience Research Centre, Department of Medicine, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam, India; UND Life Sciences, Federal Way, Washington. Electronic address: Undurti@hotmail.com.
authors.forename: Undurti N
authors.initials: UN
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D017965:gamma-Linolenic Acid / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D044045:Lipoxins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; C495683:Slc2a2 protein, rat; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; C084010:pancreatic and duodenal homeobox 1 protein; C545423:resolvin D2; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D017965:gamma-Linolenic Acid; D015118:Eicosapentaenoic Acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat
keywords: Antioxidants; Arachidonic acid; Diabetes mellitus; Inflammation; Lipoxin A4; Polyunsaturated fatty acids; Streptozotocin