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p38 MAPK Inhibitor (SB203580) and Metformin Reduces Aortic Protein Carbonyl and Inflammation in Non-obese Type 2 Diabetic Rats

  • Nuttikarn Nokkaew
  • Podsawee Mongkolpathumrat
  • Ruttanapong Junsiri
  • Supawit Jindaluang
  • Nichagron Tualamun
  • Niya Manphatthanakan
  • Nareumon Saleesee
  • Marisa Intasang
  • Jantira Sanit
  • Punyanuch Adulyaritthikul
  • Kantapich Kongpol
  • Sarawut Kumphune
  • Nitirut NernpermpisoothEmail author
Short Communication
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Abstract

Microvascular and macrovascular diseases are the main causes of morbidity in type 2 diabetes patients through chronic hyperglycaemic condition via oxidative stress and inflammation. Reactive oxygen species (ROS) activate p38 MAPK phosphorylation and inflammation which enhances protein modification by carbonylation. The use of metformin and a p38 MAPK inhibitor is hypothesised to reduce ROS production and inflammation but effects of metformin and p38 MAPK inhibitor (SB203580) on ROS production and inflammation in vascular type 2 diabetes mellitus non-obese (T2DM) have not been investigated. The Goto-Kakizaki rat T2DM model was divided into three groups as T2DM, T2DM treated with 15 mg/kg bw metformin and T2DM treated with 2 mg/kg bw SB203580 for 4 weeks. Rat aortas were isolated and protein carbonyl (PC) contents were measured by spectrophotometric DNPH assay. Aortic IL-1ß level was determined by ELISA. Results showed that aortic PC contents in the T2DM group were significantly higher than in non-diabetic rats. Treatment with metformin or SB203580 significantly reduced PC contents while only metformin significantly reduced IL-1ß levels. Findings indicated that metformin reduced ROS production and inflammation in diabetic vessels and possibly reduce vascular complications in non-obese T2DM.

Keywords

Type 2 diabetes mellitus Vascular complications Protein carbonyl Inflammation Metformin SB203580 

Notes

Acknowledgements

This thesis is sponsored and supported by National Research Council of Thailand. We would like to thank Naresuan University Research endowment fund Grant I.D. Numbers R2559A017, R2560C138. We would like to thank PhD scholarship from Naresuan University for Nuttikarn Nokkaew, Royal Golden Jubilee Ph.D. Program-Thailand Research Fund (TRF) (No. PHD/0087/2556) for Jantira Sanit and (No. PHD/0125/2558) for Kantapitch Kongpol. We are grateful to the Center for Animal Research, Naresuan University for their excellent technical assistance. We would like to thanks ProofRead4Sure service to English proof reading and editing.

Author Contributions

NN, PM and SK conceived and designed the experiments; NN, RJ, SJ, NT, NM, NS, MI, JS, PA, and KK performed the experiments; NN, PM and SK analyzed the data; SK contributed reagents/materials/analysis tools; NN, NN and SK wrote and prepared the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Boffetta P, McLerran D, Chen Y, Inoue M, Sinha R, He J, et al. Body mass index and diabetes in Asia: a cross-sectional pooled analysis of 900,000 individuals in the Asia cohort consortium. PLoS ONE. 2011;6(6):e19930.  https://doi.org/10.1371/journal.pone.0019930.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ali MK, Narayan KMV, Tandon N. Diabetes and coronary heart disease: current perspectives. Indian J Med Res. 2010;132(5):584–97.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34(31):2436–43.  https://doi.org/10.1093/eurheartj/eht149.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev. 2002;23(5):599–622.  https://doi.org/10.1210/er.2001-0039.CrossRefPubMedGoogle Scholar
  5. 5.
    Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98.  https://doi.org/10.1038/nri2925.CrossRefPubMedGoogle Scholar
  6. 6.
    Pollack RM, Donath MY, LeRoith D, Leibowitz G. Anti-inflammatory agents in the treatment of diabetes and its vascular complications. Diabetes Care. 2016;39(Suppl 2):S244–52.  https://doi.org/10.2337/dcS15-3015.CrossRefPubMedGoogle Scholar
  7. 7.
    Araújo AA, Pereira ASBF, Medeiros CACX, Brito GAC, Leitão RFC, Araújo LS, et al. Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS ONE. 2017;12(8):e0183506.  https://doi.org/10.1371/journal.pone.0183506.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kumphune S, Chattipakorn S, Chattipakorn N. Roles of p38-MAPK in insulin resistant heart: evidence from bench to future bedside application. Curr Pharm Des. 2013;19(32):5742–54.CrossRefGoogle Scholar
  9. 9.
    Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A. Protein carbonylation in human diseases. Trends Mol Med. 2003;9(4):169–76.CrossRefGoogle Scholar
  10. 10.
    Robbins N, Thompson A, Mann A, Blomkalns AL. Isolation and excision of murine aorta; a versatile technique in the study of cardiovascular disease. J Vis Exp. 2014;93:52172.  https://doi.org/10.3791/52172.CrossRefGoogle Scholar
  11. 11.
    Maneewong K, Mekrungruangwong T, Luangaram S, Thongsri T, Kumphune S. Combinatorial determination of ischemia modified albumin and protein carbonyl in the diagnosis of NonST-elevation myocardial infarction. Indian J Clin Biochem. 2011;26(4):389–95.  https://doi.org/10.1007/s12291-011-0118-2.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wang Z, Yang Y, Xiang X, Zhu Y, Men J, He M. Estimation of the normal range of blood glucose in rats. Wei sheng yan jiu J Hyg Res. 2010;39(2):133–7.Google Scholar
  13. 13.
    Association AD. 2. Classification and diagnosis of diabetes. Diabetes Care. 2017;40(Supplement 1):S11–24.CrossRefGoogle Scholar
  14. 14.
    Son SM. Reactive oxygen and nitrogen species in pathogenesis of vascular complications of diabetes. Diabetes Metab. 2012;36(3):190–8.  https://doi.org/10.4093/dmj.2012.36.3.190.CrossRefGoogle Scholar
  15. 15.
    Sasaki S, Inoguchi T. The role of oxidative stress in the pathogenesis of diabetic vascular complications. Diabetes Metab. 2012;36(4):255–61.  https://doi.org/10.4093/dmj.2012.36.4.255.CrossRefGoogle Scholar
  16. 16.
    Sarkar P, Kar K, Mondal MC, Chakraborty I, Kar M. Elevated level of carbonyl compounds correlates with insulin resistance in type 2 diabetes. Ann Acad Med Singap. 2010;39(12):909.PubMedGoogle Scholar
  17. 17.
    Bigagli E, Raimondi L, Mannucci E, Colombi C, Bardini G, Rotella C, et al. Lipid and protein oxidation products, antioxidant status and vascular complications in poorly controlled type 2 diabetes. Br J Diabetes Vasc Dis. 2012;12(1):33–9.CrossRefGoogle Scholar
  18. 18.
    Herder C, Illig T, Rathmann W, Martin S, Haastert B, Muller-Scholze S, et al. Inflammation and type 2 diabetes: results from KORA Augsburg. Gesundheitswesen. 2005;67(Suppl 1):S115–21.  https://doi.org/10.1055/s-2005-858252.CrossRefPubMedGoogle Scholar
  19. 19.
    Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang Z-Y, Yamauchi T, et al. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Investig. 1999;103(2):185–95.  https://doi.org/10.1172/JCI3326.CrossRefPubMedGoogle Scholar
  20. 20.
    Westermann D, Rutschow S, Van Linthout S, Linderer A, Bucker-Gartner C, Sobirey M, et al. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia. 2006;49(10):2507–13.  https://doi.org/10.1007/s00125-006-0385-2.CrossRefPubMedGoogle Scholar
  21. 21.
    Shi Q, Cheng L, Liu Z, Hu K, Ran J, Ge D, et al. The p38 MAPK inhibitor SB203580 differentially modulates LPS-induced interleukin 6 expression in macrophages. Cent Eur J Immunol. 2015;40(3):276–82.  https://doi.org/10.5114/ceji.2015.54586.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Association of Clinical Biochemists of India 2019

Authors and Affiliations

  • Nuttikarn Nokkaew
    • 1
    • 2
  • Podsawee Mongkolpathumrat
    • 1
    • 2
  • Ruttanapong Junsiri
    • 2
  • Supawit Jindaluang
    • 2
  • Nichagron Tualamun
    • 2
  • Niya Manphatthanakan
    • 2
  • Nareumon Saleesee
    • 2
  • Marisa Intasang
    • 2
  • Jantira Sanit
    • 1
    • 2
  • Punyanuch Adulyaritthikul
    • 1
    • 2
  • Kantapich Kongpol
    • 1
    • 2
  • Sarawut Kumphune
    • 1
    • 2
    • 4
  • Nitirut Nernpermpisooth
    • 1
    • 2
    • 3
    Email author
  1. 1.Biomedical Research Unit in Cardiovascular Sciences (BRUCS), Faculty of Allied Health SciencesNaresuan UniversityPhitsanulokThailand
  2. 2.Graduate Program in Biomedical Sciences, Faculty of Allied Health SciencesNaresuan UniversityPhitsanulokThailand
  3. 3.Department of Cardio-Thoracic Technology, Faculty of Allied Health SciencesNaresuan UniversityPhitsanulokThailand
  4. 4.Department of Medical Technology, Faculty of Allied Health SciencesNaresuan UniversityPhitsanulokThailand

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