Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction

  • Marwa E. Abdelmageed
  • George S. Shehatou
  • Rami A. Abdelsalam
  • Ghada M. SuddekEmail author
  • Hatem A. Salem
Original Article


Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder considered to be the most predominant form of diabetes throughout the world. This study aimed to investigate the possible effects of cinnamaldehyde (CIN) on insulin signaling pathways in STZ-induced T2D rat model. T2D was originated by feeding rats with a high-fat diet (HFD) plus 25% fructose solution plus streptozotocin (STZ) (35 mg/kg, i.p.). CIN effects were investigated on fasting blood glucose, insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), liver biomarkers, lipid profile, oxidative stress biomarkers, serum advanced glycation end products (AGEs) and its receptors (RAGE) in the aorta, and histopathology of the liver and aorta. Additionally, the mRNA expression of hepatic insulin signaling pathway genes, phosphorylated AKT (serine 473) (P-AKT ser473) level, and aortic nitric oxide synthase3 (eNOS) and NADPH oxidase4 (NOX4) were determined. CIN treatment for 30 days significantly decreased OGTT, ITT, fasting blood glucose, insulin, and HOMA-IR and increased HOMA-β index when compared to diabetic rats. CIN also improved lipid profile and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, serum AGEs, and aortic RAGE. Additionally, CIN treatment significantly decreased hepatic malondialdehyde (MDA), increased hepatic and aortic glutathione (GSH) and superoxide dismutase (SOD), and decreased steatosis and inflammation observed in liver tissue of rats. Additionally, significant elevation in mRNA expression of insulin receptor substrate1 (IRS1), phosphatidylinositol 3-kinase regulatory subunit1 (PI3K-P85 subunit), and AKT serine/threonine kinase2 (AKT2); increased levels of P-AKT ser473 and aortic eNOS; and decrease in mRNA expression of NOX4 were detected in CIN-treated group when compared to diabetic group. This study suggests antidiabetic and antioxidant effects of CIN probably through upregulation of eNOS and IRS1/PI3K/AKT2 signaling pathway and alleviating AGEs, RAGE, and NOX4 elevation.


Cinnamaldehyde Type 2 diabetes Rats Streptozotocin High-fat diet Fructose Oxidative stress Advanced glycation end products Insulin signaling pathway 


Author contribution statement

MA, GS, GMS, and HS designed the research. MA and GS conducted experiments and analyzed data. MA and GMS wrote the manuscript. GS, GMS, and HS revised the manuscript. RA performed pathological assessments. All authors read and approved the manuscript.

Compliance with ethical standards

All institutional and national guidelines for the care and use of laboratory animals were followed.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Alameddine A, Fajloun Z, Bourreau J, Gauquelin-Koch G, Yuan M, Gauguier D, Derbre S, Ayer A, Custaud MA, Navasiolava N (2015) The cardiovascular effects of salidroside in the Goto-Kakizaki diabetic rat model. J Physiol Pharmacol 66:249–257PubMedGoogle Scholar
  2. Anand P, Murali KY, Tandon V, Murthy PS, Chandra R (2010) Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase, phosphoenolpyruvate carboxykinase, and GLUT4 translocation in experimental diabetic rats. Chem Biol Interact 186:72–81PubMedCrossRefGoogle Scholar
  3. Arozal W, Watanabe K, Veeraveedu PT, Ma M, Thandavarayan RA, Suzuki K, Tachikawa H, Kodama M, Aizawa Y (2009) Effects of angiotensin receptor blocker on oxidative stress and cardio-renal function in streptozotocin-induced diabetic rats. Biol Pharm Bull 32:1411–1416PubMedCrossRefGoogle Scholar
  4. Balasubashini MS, Rukkumani R, Viswanathan P, Menon VP (2004) Ferulic acid alleviates lipid peroxidation in diabetic rats. Phytother Res 18:310–314PubMedCrossRefGoogle Scholar
  5. Bansal P, Paul P, Mudgal J, Nayak PG, Pannakal ST, Priyadarsini KI, Unnikrishnan MK (2012) Antidiabetic, antihyperlipidemic and antioxidant effects of the flavonoid rich fraction of Pilea microphylla (L.) in high fat diet/streptozotocin-induced diabetes in mice. Exp Toxicol Pathol 64:651–658PubMedCrossRefGoogle Scholar
  6. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 83:876–886CrossRefGoogle Scholar
  7. Blevins SM, Leyva MJ, Brown J, Wright J, Scofield RH, Aston CE (2007) Effect of cinnamon on glucose and lipid levels in non insulin-dependent type 2 diabetes. Diabetes Care 30:2236–2237PubMedCrossRefGoogle Scholar
  8. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP (2002) Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 51:2796–2803PubMedCrossRefGoogle Scholar
  9. Cai S, Sun W, Fan Y, Guo X, Xu G, Xu T, Hou Y, Zhao B, Feng X, Liu T (2016) Effect of mulberry leaf (Folium Mori) on insulin resistance via IRS-1/PI3K/Glut-4 signalling pathway in type 2 diabetes mellitus rats. Pharm Biol 54:2685–2691PubMedCrossRefGoogle Scholar
  10. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedCrossRefPubMedCentralGoogle Scholar
  11. Cao H, Polansky MM, Anderson RA (2007) Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Arch Biochem Biophys 459:214–222PubMedCrossRefPubMedCentralGoogle Scholar
  12. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR (1994) Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14:4902–4911PubMedPubMedCentralCrossRefGoogle Scholar
  13. Cho NH, Jang HC, Choi SH, Kim HR, Lee HK, Chan JC, Lim S (2007) Abnormal liver function test predicts type 2 diabetes: a community-based prospective study. Diabetes Care 30:2566–2568PubMedCrossRefPubMedCentralGoogle Scholar
  14. Choi KM, Lee YS, Kim W, Kim SJ, Shin KO, Yu JY, Lee MK, Lee YM, Hong JT, Yun YP, Yoo HS (2014) Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice. J Nutr Biochem 25:201–207PubMedCrossRefPubMedCentralGoogle Scholar
  15. Concepcion NM, Pilar MM, Martin A, Jimenez J, Pilar UM (1993) Free radical scavenger and antihepatotoxic activity of Rosmarinus tomentosus. Planta Med 59:312–314CrossRefGoogle Scholar
  16. Cordero-Herrera I, Martin MA, Bravo L, Goya L, Ramos S (2013) Cocoa flavonoids improve insulin signalling and modulate glucose production via AKT and AMPK in HepG2 cells. Mol Nutr Food Res 57:974–985PubMedCrossRefPubMedCentralGoogle Scholar
  17. Cornelius C, Koverech G, Crupi R, Di PR, Koverech A, Lodato F, Scuto M, Salinaro AT, Cuzzocrea S, Calabrese EJ, Calabrese V (2014) Osteoporosis and Alzheimer pathology: role of cellular stress response and hormetic redox signaling in aging and bone remodeling. Front Pharmacol 5:120PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105:311–320PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cvetkovic T, Mitic B, Lazarevic G, Vlahovic P, Antic S, Stefanovic V (2009) Oxidative stress parameters as possible urine markers in patients with diabetic nephropathy. J Diabetes Complicat 23:337–342PubMedCrossRefPubMedCentralGoogle Scholar
  20. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77CrossRefGoogle Scholar
  21. Farag MR, Alagawany M, Tufarelli V (2017) In vitro antioxidant activities of resveratrol, cinnamaldehyde and their synergistic effect against cyadox-induced cytotoxicity in rabbit erythrocytes. Drug Chem Toxicol 40:196–205PubMedCrossRefPubMedCentralGoogle Scholar
  22. Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502PubMedPubMedCentralGoogle Scholar
  23. Govindaraj J, Sorimuthu PS (2015) Rosmarinic acid modulates the antioxidant status and protects pancreatic tissues from glucolipotoxicity mediated oxidative stress in high-fat diet: streptozotocin-induced diabetic rats. Mol Cell Biochem 404:143–159PubMedCrossRefGoogle Scholar
  24. Guo Z, Zhang R, Li J, Xu G (2012) Effect of telmisartan on the expression of adiponectin receptors and nicotinamide adenine dinucleotide phosphate oxidase in the heart and aorta in type 2 diabetic rats. Cardiovasc Diabetol 11:94PubMedPubMedCentralCrossRefGoogle Scholar
  25. Hermans MP, Levy JC, Morris RJ, Turner RC (1999) Comparison of tests of beta-cell function across a range of glucose tolerance from normal to diabetes. Diabetes 48:1779–1786PubMedCrossRefGoogle Scholar
  26. Huang JS, Lee YH, Chuang LY, Guh JY, Hwang JY (2015) Cinnamaldehyde and nitric oxide attenuate advanced glycation end products-induced the Jak/STAT signaling in human renal tubular cells. J Cell Biochem 116:1028–1038PubMedCrossRefPubMedCentralGoogle Scholar
  27. Huang XL, He Y, Ji LL, Wang KY, Wang YL, Chen DF, Geng Y, OuYang P, Lai WM (2017) Hepatoprotective potential of isoquercitrin against type 2 diabetes-induced hepatic injury in rats. Oncotarget 8:101545–101559PubMedPubMedCentralGoogle Scholar
  28. Islam MS, Loots dT (2009) Experimental rodent models of type 2 diabetes: a review. Methods Find Exp Clin Pharmacol 31:249–261PubMedCrossRefPubMedCentralGoogle Scholar
  29. Kahn BB (1998) Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92:593–596PubMedCrossRefGoogle Scholar
  30. Kanai F, Ito K, Todaka M, Hayashi H, Kamohara S, Ishii K, Okada T, Hazeki O, Ui M, Ebina Y (1993) Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of PI3-kinase. Biochem Biophys Res Commun 195:762–768PubMedCrossRefGoogle Scholar
  31. Kang MK, Chung WB, Hong SK, Kim OR, Ihm SH, Chang K, Seung KB (2016) Effects of candesartan cilexetil and amlodipine orotate on receptor for advanced glycation end products expression in the aortic wall of Otsuka Long-Evans Tokushima Fatty (OETFF) type 2 diabetic rats. Arch Pharm Res 39:565–576PubMedCrossRefGoogle Scholar
  32. Kar A, Choudhary BK, Bandyopadhyay NG (2003) Comparative evaluation of hypoglycaemic activity of some Indian medicinal plants in alloxan diabetic rats. J Ethnopharmacol 84:105–108PubMedCrossRefGoogle Scholar
  33. Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA (2003) Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care 26:3215–3218PubMedCrossRefGoogle Scholar
  34. Khare P, Jagtap S, Jain Y, Baboota RK, Mangal P, Boparai RK, Bhutani KK, Sharma SS, Premkumar LS, Kondepudi KK, Chopra K, Bishnoi M (2016) Cinnamaldehyde supplementation prevents fasting-induced hyperphagia, lipid accumulation, and inflammation in high-fat diet-fed mice. Biofactors 42:201–211PubMedGoogle Scholar
  35. Kilhovd BK, Berg TJ, Birkeland KI, Thorsby P, Hanssen KF (1999) Serum levels of advanced glycation end products are increased in patients with type 2 diabetes and coronary heart disease. Diabetes Care 22:1543–1548PubMedCrossRefGoogle Scholar
  36. Kumar SA, Magnusson M, Ward LC, Paul NA, Brown L (2015) Seaweed supplements normalise metabolic, cardiovascular and liver responses in high-carbohydrate, high-fat fed rats. Mar Drugs 13:788–805PubMedPubMedCentralCrossRefGoogle Scholar
  37. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci U S A 107:15565–15570PubMedPubMedCentralCrossRefGoogle Scholar
  38. Lakshmanan AP, Watanabe K, Thandavarayan RA, Sari FR, Harima M, Giridharan VV, Soetikno V, Kodama M, Aizawa Y (2011) Telmisartan attenuates oxidative stress and renal fibrosis in streptozotocin induced diabetic mice with the alteration of angiotensin-(1-7) mas receptor expression associated with its PPAR-gamma agonist action. Free Radic Res 45:575–584PubMedCrossRefGoogle Scholar
  39. Li XW, Hao W, Liu Y, Yang JR (2014) Effect of sequoyitol on expression of NOX4 and eNOS in aortas of type 2 diabetic rats. Yao Xue Xue Bao 49:329–336PubMedGoogle Scholar
  40. Li XD, Gu LW, Ran QS, Zhou P, Zhan XL, Li CH, Jiang TL (2016) Protective effects of three phenylallyl compounds from Guizhi decoction ox-LDL-induced oxidative stress injury of human brain microvascular endothelial cells. Zhongguo Zhong Yao Za Zhi 41:2315–2320PubMedGoogle Scholar
  41. Luo C, Yang H, Tang C, Yao G, Kong L, He H, Zhou Y (2015) Kaempferol alleviates insulin resistance via hepatic IKK/NF-kappaB signal in type 2 diabetic rats. Int Immunopharmacol 28:744–750PubMedCrossRefGoogle Scholar
  42. Lv C, Yuan X, Zeng HW, Liu RH, Zhang WD (2017) Protective effect of cinnamaldehyde against glutamate-induced oxidative stress and apoptosis in PC12 cells. Eur J Pharmacol 815:487–494PubMedCrossRefGoogle Scholar
  43. Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474PubMedCrossRefGoogle Scholar
  44. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419PubMedCrossRefGoogle Scholar
  45. Mokashi P, Bhatt LK, Khanna A, Pandita N (2017) Swertisin rich fraction from Enicostema littorale ameliorates hyperglycemia and hyperlipidemia in high-fat fed diet and low dose streptozotacin induced type 2 diabetes mellitus in rats. Biomed Pharmacother 96:1427–1437PubMedCrossRefGoogle Scholar
  46. Monnier VM, Cerami A (1981) Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 211:491–493PubMedCrossRefGoogle Scholar
  47. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ (2002) Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol 16:1931–1942PubMedCrossRefGoogle Scholar
  48. Nair S, Gagnon J, Pelletier C, Tchoukanova N, Zhang J, Ewart HS, Ewart KV, Jiao G, Wang Y (2017) Shrimp oil extracted from the shrimp processing waste reduces the development of insulin resistance and metabolic phenotypes in diet-induced obese rats. Appl Physiol Nutr Metab 42:841–849PubMedCrossRefGoogle Scholar
  49. Nattrass M, Bailey CJ (1999) New agents for type 2 diabetes. Baillieres Best Pract Res Clin Endocrinol Metab 13:309–329PubMedCrossRefGoogle Scholar
  50. Nour OAA, Shehatou GSG, Rahim MA, El-Awady MS, Suddek GM (2018) Cinnamaldehyde exerts vasculoprotective effects in hypercholestrolemic rabbits. Naunyn Schmiedebergs Arch Pharmacol 391:1203–1219PubMedCrossRefPubMedCentralGoogle Scholar
  51. Ohaeri OC (2001) Effect of garlic oil on the levels of various enzymes in the serum and tissue of streptozotocin diabetic rats. Biosci Rep 21:19–24PubMedCrossRefGoogle Scholar
  52. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358PubMedCrossRefGoogle Scholar
  53. Paneni F, Costantino S, Cosentino F (2014) Insulin resistance, diabetes, and cardiovascular risk. Curr Atheroscler Rep 16:419PubMedCrossRefPubMedCentralGoogle Scholar
  54. Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y (2004) Cinnamon extract prevents the insulin resistance induced by a high-fructose diet. Horm Metab Res 36:119–125PubMedCrossRefGoogle Scholar
  55. Ramasamy R, Yan SF, Schmidt AM (2009) RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts. J Leukoc Biol 86:505–512PubMedCrossRefPubMedCentralGoogle Scholar
  56. Reaven GM (1995) Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473–486PubMedCrossRefPubMedCentralGoogle Scholar
  57. Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, Reaven GM (2000) A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49:1390–1394PubMedCrossRefPubMedCentralGoogle Scholar
  58. Rubino F, Marescaux J (2004) Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg 239:1–11PubMedPubMedCentralCrossRefGoogle Scholar
  59. Saleh S, El-Maraghy N, Reda E, Barakat W (2014) Modulation of diabetes and dyslipidemia in diabetic insulin-resistant rats by mangiferin: role of adiponectin and TNF-alpha. An Acad Bras Cienc 86:1935–1948PubMedCrossRefPubMedCentralGoogle Scholar
  60. Schaalan M, El-Abhar HS, Barakat M, El-Denshary ES (2009) Westernized-like-diet-fed rats: effect on glucose homeostasis, lipid profile, and adipocyte hormones and their modulation by rosiglitazone and glimepiride. J Diabetes Complicat 23:199–208PubMedCrossRefPubMedCentralGoogle Scholar
  61. Schmidt AM, Yan SD, Yan SF, Stern DM (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 1498:99–111PubMedCrossRefGoogle Scholar
  62. Sepici-Dincel A, Acikgoz S, Cevik C, Sengelen M, Yesilada E (2007) Effects of in vivo antioxidant enzyme activities of myrtle oil in normoglycaemic and alloxan diabetic rabbits. J Ethnopharmacol 110:498–503PubMedCrossRefPubMedCentralGoogle Scholar
  63. Shimoda I, Koizumi M, Shimosegawa T, Shishido T, Ono T, Sato K, Ishizuka J, Toyota T (1993) Physiological characteristics of spontaneously developed diabetes in male WBN/Kob rat and prevention of development of diabetes by chronic oral administration of synthetic trypsin inhibitor (FOY-305). Pancreas 8:196–203PubMedCrossRefGoogle Scholar
  64. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 52:313–320PubMedCrossRefPubMedCentralGoogle Scholar
  65. Subash BP, Prabuseenivasan S, Ignacimuthu S (2007) Cinnamaldehyde—a potential antidiabetic agent. Phytomedicine 14:15–22CrossRefGoogle Scholar
  66. Subash-Babu P, Alshatwi AA, Ignacimuthu S (2014) Beneficial antioxidative and antiperoxidative effect of cinnamaldehyde protect streptozotocin-induced pancreatic beta-cells damage in Wistar rats. Biomol Ther (Seoul) 22:47–54CrossRefGoogle Scholar
  67. Sylow L, Kleinert M, Pehmoller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE (2014) Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance. Cell Signal 26:323–331PubMedCrossRefPubMedCentralGoogle Scholar
  68. Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D’Agati VD (2000) Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol 11:1656–1666PubMedPubMedCentralGoogle Scholar
  69. Thandavarayan RA, Watanabe K, Ma M, Gurusamy N, Veeraveedu PT, Konishi T, Zhang S, Muslin AJ, Kodama M, Aizawa Y (2009) Dominant-negative p38alpha mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus. Am J Physiol Heart Circ Physiol 297:H911–H919PubMedCrossRefPubMedCentralGoogle Scholar
  70. Veerapur VP, Prabhakar KR, Thippeswamy BS, Bansal P, Srinivasan KK, Unnikrishnan MK (2012) Antidiabetic effect of Ficus racemosa Linn. stem bark in high-fat diet and low-dose streptozotocin-induced type 2 diabetic rats: a mechanistic study. Food Chem 132:186–193PubMedCrossRefGoogle Scholar
  71. Vlassara H, Uribarri J (2014) Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr Diab Rep 14:453PubMedPubMedCentralCrossRefGoogle Scholar
  72. Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495CrossRefGoogle Scholar
  73. Wang Q, Jiang C, Fang S, Wang J, Ji Y, Shang X, Ni Y, Yin Z, Zhang J (2013) Antihyperglycemic, antihyperlipidemic and antioxidant effects of ethanol and aqueous extracts of Cyclocarya paliurus leaves in type 2 diabetic rats. J Ethnopharmacol 150:1119–1127PubMedCrossRefGoogle Scholar
  74. Wang F, Zhou Z, Ren X, Wang Y, Yang R, Luo J, Strappe P (2015) Effect of Ganoderma lucidum spores intervention on glucose and lipid metabolism gene expression profiles in type 2 diabetic rats. Lipids Health Dis 14:49PubMedPubMedCentralCrossRefGoogle Scholar
  75. Wenzel P, Schulz E, Oelze M, Muller J, Schuhmacher S, Alhamdani MS, Debrezion J, Hortmann M, Reifenberg K, Fleming I, Munzel T, Daiber A (2008) AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. Free Radic Biol Med 45:619–626PubMedCrossRefGoogle Scholar
  76. Wilson RD, Islam MS (2012) Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes. Pharmacol Rep 64:129–139PubMedCrossRefGoogle Scholar
  77. Wong WY, Ward LC, Fong CW, Yap WN, Brown L (2017) Anti-inflammatory gamma- and delta-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats. Eur J Nutr 56:133–150PubMedCrossRefGoogle Scholar
  78. Xin G, Honggui L, Hang X, Shihlung W, Hui D, Fuer L, Alex JL, Chaodong W (2012) Glycolysis in the control of blood glucose homeostasis. Acta Pharm Sin B 2:358–367CrossRefGoogle Scholar
  79. Xu Y, Wang L, He J, Bi Y, Li M, Wang T, Wang L, Jiang Y, Dai M, Lu J, Xu M, Li Y, Hu N, Li J, Mi S, Chen CS, Li G, Mu Y, Zhao J, Kong L, Chen J, Lai S, Wang W, Zhao W, Ning G (2013) Prevalence and control of diabetes in Chinese adults. JAMA 310:948–959PubMedCrossRefGoogle Scholar
  80. Yong R, Chen XM, Shen S, Vijayaraj S, Ma Q, Pollock CA, Saad S (2013) Plumbagin ameliorates diabetic nephropathy via interruption of pathways that include NOX4 signalling. PLoS One 8:e73428PubMedPubMedCentralCrossRefGoogle Scholar
  81. Youn HS, Lee JK, Choi YJ, Saitoh SI, Miyake K, Hwang DH, Lee JY (2008) Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem Pharmacol 75:494–502PubMedCrossRefPubMedCentralGoogle Scholar
  82. Yuan X, Han L, Fu P, Zeng H, Lv C, Chang W, Runyon RS, Ishii M, Han L, Liu K, Fan T, Zhang W, Liu R (2018) Cinnamaldehyde accelerates wound healing by promoting angiogenesis via up-regulation of PI3K and MAPK signaling pathways. Lab Investig 98:783–798PubMedCrossRefPubMedCentralGoogle Scholar
  83. Zeng G, Quon MJ (1996) Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98:894–898PubMedPubMedCentralCrossRefGoogle Scholar
  84. Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ (2000) Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101:1539–1545PubMedCrossRefPubMedCentralGoogle Scholar
  85. Zhang W, Xu YC, Guo FJ, Meng Y, Li ML (2008) Anti-diabetic effects of cinnamaldehyde and berberine and their impacts on retinol-binding protein 4 expression in rats with type 2 diabetes mellitus. Chin Med J 121:2124–2128PubMedGoogle Scholar
  86. Zhao H, Zhang M, Zhou F, Cao W, Bi L, Xie Y, Yang Q, Wang S (2016) Cinnamaldehyde ameliorates LPS-induced cardiac dysfunction via TLR4-NOX4 pathway: the regulation of autophagy and ROS production. J Mol Cell Cardiol 101:11–24PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Marwa E. Abdelmageed
    • 1
  • George S. Shehatou
    • 1
  • Rami A. Abdelsalam
    • 2
  • Ghada M. Suddek
    • 1
    Email author
  • Hatem A. Salem
    • 1
  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacyMansoura UniversityMansouraEgypt
  2. 2.Department of Pathology, Faculty of MedicineMansoura UniversityMansouraEgypt

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