Download PDF
Planta Med 2020; 86(12): 876-883
DOI: 10.1055/a-1203-0452
Biological and Pharmacological Activity
Original Papers

Syzygium aromaticum Reduces Diabetes-induced Glucotoxicity via the NRF2/Glo1 Pathway

Moon Ho Do
1   Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun, Jeollabuk-do, Republic of Korea
,
Jiwon Choi
1   Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun, Jeollabuk-do, Republic of Korea
,
Yoonsook Kim
1   Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun, Jeollabuk-do, Republic of Korea
,
Sang Keun Ha
1   Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun, Jeollabuk-do, Republic of Korea
2   Division of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea
,
Guijae Yoo
1   Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun, Jeollabuk-do, Republic of Korea
,
Jinyoung Hur
1   Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-Gun, Jeollabuk-do, Republic of Korea
2   Division of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea
› Author AffiliationsSupported by: Korea Food Research Institute E0164400-04
› Further Information
Also available at
    Permissions and Reprints

Abstract

Advanced glycation end products and methylglyoxal are known to show increased levels in diabetic conditions and induce diverse metabolic disorders. However, the antiglycation ability of the bark of Syzygium aromaticum is not yet studied. In this study, we determined the inhibitory effects of S. aromaticum on AGE formation. Moreover, S. aromaticum showed breakage and inhibitory ability against the formation of AGE-collagen crosslinks. In SV40 MES13 cells, treatment with the S. aromaticum extract significantly ameliorated MG-induced oxidative stress as well as cytotoxicity. Furthermore, in the S. aromaticum extract-treated group, there was a reduction in levels of several diabetic markers, such as blood glucose, kidney weight, and urinary albumin to creatinine ratio in streptozotocin-induced diabetic rats. Treatment with the S. aromaticum extract significantly increased the expression of nuclear factor erythroid 2-related factor 2, a transcription factor involved in the expression of antioxidant enzymes. Moreover, the treatment significantly upregulated the expression of glyoxalase 1 and downregulated the expression of receptor for AGEs. These results suggest that the S. aromaticum extract might ameliorate diabetes-induced renal damage by inhibiting the AGE-induced glucotoxicity and oxidative stress through the Nrf2/Glo1 pathway.

Key words

Syzygium aromaticum - Myrtaceae - diabetes - AGEs - Nrf2


Publication History

Received: 17 February 2020

Accepted after revision: 12 June 2020

Article published online:
09 July 2020

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Kerkeni M, Saïdi A, Bouzidi H, Yahya SB, Hammami M. Elevated serum levels of AGEs, sRAGE, and pentosidine in Tunisian patients with severity of diabetic retinopathy. Microvasc Res 2012; 84: 378-383
    CrossrefPubMedSearch in Google Scholar
  • 2 Zhu D, Wang L, Zhou Q, Yan S, Li Z, Sheng J, Zhang W. (+)-Catechin ameliorates diabetic nephropathy by trapping methylglyoxal in type 2 diabetic mice. Mol Nutr Food Res 2014; 58: 2249-2260
    CrossrefPubMedSearch in Google Scholar
  • 3 Jin X, Yao T, Zhou Z, Zhu J, Zhang S, Hu W, Shen C. Advanced glycation end products enhance macrophages polarization into M1 phenotype through activating RAGE/NF-κB pathway. Biomed Res Int 2015; 2015: 732450 doi:10.1155/2015/732450
    PubMedSearch in Google Scholar
  • 4 Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5: 194-222
    CrossrefPubMedSearch in Google Scholar
  • 5 Lin JA, Wu CH, Lu CC, Hsia SM, Yen GC. Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression. Mol Nutr Food Res 2016; 60: 1850-1864
    CrossrefPubMedSearch in Google Scholar
  • 6 Schalkwijk C, Stehouwer CD. Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications and other age-related diseases. Physiol Rev 2019; 100: 407-461
    CrossrefPubMedSearch in Google Scholar
  • 7 Zhou Q, Cheng KW, Gong J, Li ET, Wang M. Apigenin and its methylglyoxal-adduct inhibit advanced glycation end products-induced oxidative stress and inflammation in endothelial cells. Biochem Pharmacol 2019; 166: 231-241
    CrossrefPubMedSearch in Google Scholar
  • 8 Moraru A, Wiederstein J, Pfaff D, Fleming T, Miller AK, Nawroth P, Teleman AA. Elevated levels of the reactive metabolite methylglyoxal recapitulate progression of type 2 diabetes. Cell Metabol 2018; 27: 926-934
    CrossrefPubMedSearch in Google Scholar
  • 9 Giacco F, Du X, DʼAgati VD, Milne R, Sui G, Geoffrion M, Brownlee M. Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes 2014; 63: 291-299
    CrossrefPubMedSearch in Google Scholar
  • 10 Hanssen NM, Stehouwer CD, Schalkwijk CG. Methylglyoxal stress, the glyoxalase system, and diabetic chronic kidney disease. Curr Opin Nephrol Hypertens 2019; 28: 26-33
    CrossrefPubMedSearch in Google Scholar
  • 11 Liu YW, Liu XL, Kong L, Zhang MY, Chen YJ, Zhu X, Hao YC. Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/ARE/glyoxalase-1 pathway mediated by phosphorylation regulation. Biomed Pharmacother 2019; 109: 2145-2154
    CrossrefPubMedSearch in Google Scholar
  • 12 Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res 2016; 118: 1808-1829
    CrossrefPubMedSearch in Google Scholar
  • 13 Pulikottil S, Nath S. Potential of clove of Syzygium aromaticum in development of a therapeutic agent for periodontal disease: a review. South Afr Dental J 2015; 70: 108-115
    PubMedSearch in Google Scholar
  • 14 Issac A, Gopakumar G, Kuttan R, Maliakel B, Krishnakumar I. Safety and anti-ulcerogenic activity of a novel polyphenol-rich extract of clove buds (Syzygium aromaticum L). Food Funct 2015; 6: 842-852
    CrossrefPubMedSearch in Google Scholar
  • 15 Sompong W, Adisakwattana S. Inhibitory effect of herbal medicines and their trapping abilities against methylglyoxal-derived advanced glycation end-products. BMC Complement Altern Med 2015; 15: 394
    CrossrefPubMedSearch in Google Scholar
  • 16 Al-Sowygh ZH, Ghani SMA, Sergis K, Vohra F, Akram Z. Peri-implant conditions and levels of advanced glycation end products among patients with different glycemic control. Clin Implant Dent Relat Res 2018; 20: 345-351
    CrossrefPubMedSearch in Google Scholar
  • 17 Nigro C, Leone A, Raciti GA, Longo M, Mirra P, Formisano P, Beguinot F, Miele C. Methylglyoxal-glyoxalase 1 balance: the root of vascular damage. Int J Mol Sci 2017; 18: 188
    CrossrefPubMedSearch in Google Scholar
  • 18 Berlanga J, Cibrian D, Guillén I, Freyre F, Alba JS, Lopez-Saura P, Merino N, Aldama A, Quintela AM, Triana ME, Montequin JF, Ajamieh H, Urquiza D, Ahmed N, Thornalley PJ. Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. Clin Sci (Lond) 2005; 109: 83-95
    CrossrefPubMedSearch in Google Scholar
  • 19 Al Maruf A, Lip H, Wong H, OʼBrien PJ. Protective effects of ferulic acid and related polyphenols against glyoxal or methylglyoxal-induced cytotoxicity and oxidative stress in isolated rat hepatocytes. Chem Biolo Interact 2015; 234: 96-104
    CrossrefPubMedSearch in Google Scholar
  • 20 Wada J, Makino H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 2016; 12: 13-26
    CrossrefPubMedSearch in Google Scholar
  • 21 Rasch R, Dørup J. Quantitative morphology of the rat kidney during diabetes mellitus and insulin treatment. Diabetologia 1997; 40: 802-809
    CrossrefPubMedSearch in Google Scholar
  • 22 Hoefield RA, Kalra PA, Baker PG, Sousa I, Diggle PJ, Gibson MJ, OʼDonoghue DJ, Middleton RJ, New JP. The use of eGFR and ACR to predict decline in renal function in people with diabetes. Nephrol Dial Transplant 2010; 26: 887-892
    CrossrefPubMedSearch in Google Scholar
  • 23 Jensen T, Vistisen D, Fleming T, Nawroth P, Rossing P, Jørgensen M, Lauritzen T, Sandbaek A, Witte DR. Methylglyoxal is associated with changes in kidney function among individuals with screen-detected Type 2 diabetes mellitus. Diabet Med 2016; 33: 1625-1631
    CrossrefPubMedSearch in Google Scholar
  • 24 Rodrigues L, Matafome P, Crisóstomo J, Santos-Silva D, Sena C, Pereira P, Seiça R. Advanced glycation end products and diabetic nephropathy: a comparative study using diabetic and normal rats with methylglyoxal-induced glycation. J Physiol Biochem 2014; 70: 173-184
    CrossrefPubMedSearch in Google Scholar
  • 25 Reiniger N, Lau K, McCalla D, Eby B, Cheng B, Lu Y, Qu W, Quadri N, Ananthakrishnan R, Furmansky M, Rosario R, Song F, Rai V, Weinberg A, Friedman R, Ramasamy R, DʼAgati V, Schmidt AM. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes 2010; 59: 2043-2054
    CrossrefPubMedSearch in Google Scholar
  • 26 Tomino Y, Hagiwara S, Gohda T. AGE–RAGE interaction and oxidative stress in obesity-related renal dysfunction. Kidney Int 2011; 80: 133-135
    CrossrefPubMedSearch in Google Scholar
  • 27 Chen XL, Dodd G, Thomas S, Zhang X, Wasserman MA, Rovin BH, Kunsch C. Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol 2006; 290: H1862-H1870
    CrossrefPubMedSearch in Google Scholar
  • 28 Xue M, Rabbani N, Momiji H, Imbasi P, Anwar MM, Kitteringham N, Park BK, Souma T, Moriguchi T, Yamamoto M, Thornalley PJ. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation. Biochem J 2012; 443: 213-222
    CrossrefPubMedSearch in Google Scholar
  • 29 Zhang S, Liang X, Zheng X, Huang H, Chen X, Wu K, Wang B, Ma S. Glo1 genetic amplification as a potential therapeutic target in hepatocellular carcinoma. Int J Clin Exp Pathol 2014; 7: 2079-2090
    PubMedSearch in Google Scholar
  • 30 Do M, Hur J, Choi J, Kim Y, Park HY, Ha S. Spatholobus suberectus ameliorates diabetes-induced renal damage by suppressing advanced glycation end products in db/db mice. Int J Mol Sci 2018; 19: 2774
    CrossrefPubMedSearch in Google Scholar