Cyclocarya paliurus ethanol leaf extracts protect against diabetic cardiomyopathy in db/db mice via regulating PI3K/Akt/NF-κB signaling

  • Yang Wang
  • Xiaojie Zheng
  • Longyu Li
  • Hong Wang
  • Keyuan Chen
  • Mingjie Xu
  • Yiwei Wu
  • Xueli Huang
  • Meiling Zhang
  • Xiaoxia Ye
  • Tunhai Xu
  • Rongchang Chen
  • Yindi Zhu
Keywords: Cyclocarya paliurus, diabetic cardiomyopathy, inflammation, PI3K/Akt, NF-κB

Abstract

Background: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes that can lead to significant mortality. Cyclocarya paliurus is a tree, the leaves of which are often utilized to prevent and treat diabetes mellitus. Whether C. paliurus leaves can prevent or treat DCM, however, it remains to be formally assessed. The present study was therefore designed to assess the ability of C. paliurus to protect against DCM in db/db mice.

Methods: Male wild-type (WT) and db/db mice were administered C. paliurus ethanol leaf extracts (ECL) or appropriate vehicle controls daily via gavage, and levels of blood glucose in treated animals were assessed on a weekly basis. After a 10-week treatment, the levels of cardiac troponin I (cTn-I), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), aspartate transaminase (AST), total triglycerides (TG), and total cholesterol (TC) in serum were measured. Activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in heart tissues were detected. Hematoxylin-eosin (HE) and Masson staining were conducted. The protein expression that related with oxidative stress and inflammatory reaction was evaluated by Western blotting.

Results: Compared with WT mice, the TG, TC, and blood glucose levels in db/db mice increased significantly, which were reduced by ECL treatment. Compared with WT mice, the levels of LDH, CK-MB, AST, and cTn-I in serum and MDA in heart tissues of db/db mice increased significantly. Activities of SOD, GSH-Px, and CAT in heart tissues of db/db mice decreased significantly. The levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) in heart tissues of db/db mice increased remarkably. However, ECL treatment improved the above pathological changes significantly. ECL alleviated pathological injury and fibrosis in heart tissues of mice. Western blotting showed that ECL increased Bcl-2 level and decreased Bax, cle-caspase-3, and clecaspase- 9 expression. Furthermore, ECL inhibited NF-κB nuclear translocation and increased PI3K and p-Akt expressions.

Conclusion: Our results indicate that ECL treatment can markedly reduce pathological cardiac damage in db/ db mice through antiapoptotic, antifibrotic, and anti-inflammatory mechanisms. Specifically, this extract was able to suppress NF-κB activation via the PI3K/Akt signaling pathway. Given its diverse activities and lack of significant side effects, ECL may thus have therapeutic value for the treatment of DCM.

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References


  1. International Diabetes Federation. IDF diabetes atlas globally. 8th ed. Brussels:IDF; 2017.

  2. Zheng J, Cheng J, Zheng S, Zhang L, Guo XH, Zhang JQ, et al. Physical exercise and its protective effects on diabetic cardiomyopathy: what is the evidence? Front Endocrinol 2018; 9: 729. doi: 10.3389/fendo.2018.00729

  3. Evangelista I, Nuti R, Picchioni T, Dotta F, Palazzuoli A. Molecular dysfunction and phenotypic derangement in diabetic cardiomyopathy. Int J Mol Sci 2019; 20(13): 3264. doi: 10.3390/ijms20133264

  4. Filardi T, Ghinassi B, Di Baldassarre A, Tanzilli G, Morano S, Lenzi A, et al. Cardiomyopathy associated with diabetes: the central role of the cardiomyocyte. Int J Mol Sci 2019; 20(13): 3299. doi: 10.3390/ijms20133299

  5. Liang ES, Liu X, Du ZH, Yang RX, Zhao YX. Andrographolide ameliorates diabetic cardiomyopathy in mice by blockage of oxidative damage and NF-kappaB-mediated inflammation. Oxid Med Cell Longev 2018; 2018: 9086747. doi: 10.1155/2018/9086747

  6. Wu HK, Liu G, He YL, Da J, Xie BQ. Obeticholic acid protects against diabetic cardiomyopathy by activation of FXR/Nrf2 signaling in db/db mice. Eur J Pharmacol 2019; 858: 172393. doi: 10.1016/j.ejphar.2019.05.022

  7. Quinaglia T, Oliveira DC, Matos-Souza JR, Sposito AC. Diabetic cardiomyopathy: factual or factoid? Rev Assoc Med Bras 2019; 65(1): 61–9. doi: 10.1590/1806-9282.65.1.69

  8. Wang YH, Cai L. Diabetes/obesity-related inflammation, cardiac cell death and cardiomyopathy. J Cent South Univ 2006; 31(6): 814–18. doi: 10.3321/j.issn:1672-7347.2006.06.003

  9. Sun LJ, Qiao W, Xiao YJ, Cui L, Wang X, Ren WD. Naringin mitigates myocardial strain and the inflammatory response in sepsis-induced myocardial dysfunction through regulation of PI3K/AKT/NF-kappaB pathway. Int Immunopharmacol 2019; 75: 105782. doi: 10.1016/j.intimp.2019.105782

  10. Laddha AP, Kulkarni YA. Tannins and vascular complications of diabetes: an update. Phytomedicine 2019; 56: 229–45. doi: 10.1016/j.phymed.2018.10.026

  11. Borghetti G, Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic cardiomyopathy: current and future therapies. Beyond glycemic control. Front Physiol 2018; 9: 1514. doi: 10.3389/fphys.2018.01514

  12. Tian JF, Zhao YK, Liu YF, Liu Y, Chen KJ, Lyu SZ. Roles and mechanisms of herbal medicine for diabetic cardiomyopathy: current status and perspective. Oxid Med Cell Longev 2017; 8214541. doi: 10.1155/2017/8214541

  13. Pang B, Zhao LH, Zhou Q, Zhao TY, Wang H, Gu CJ, et al. Application of berberine on treating type 2 diabetes mellitus. Int J Endocrinol 2015; 2015: 905749. doi: 10.1155/2015/905749

  14. Flora of China editorial committee: Flora of China. Beijing: Science Press; 1999.

  15. Liu Y, Wang TL, Fang SZ, Zhou MM, Qin J. Responses of morphology, gas exchange, photochemical activity of photosystem II, and antioxidant balance in Cyclocarya paliurus to light spectra. Front Plant Sci 2018; 9: 1704. doi: 10.3389/fpls.2018.01704

  16. Fang ZJ, Shen SN, Wang JM, Wu YJ, Zhou CX, Mo JX, et al. Triterpenoids from Cyclocarya paliurus that enhance glucose uptake in 3T3-L1 adipocytes. Molecules 2019; 24(1): 187. doi: 10.3390/molecules24010187

  17. Zhou MM, Lin Y, Fang SZ, Liu Y, Shang XL. Phytochemical content and antioxidant activity in aqueous extracts of Cyclocarya paliurus leaves collected from different populations. Peer J 2019; 7: e6492. doi: 10.7717/peerj.6492

  18. Wang ZJ, Xie JH, Yang YJ, Zhang F, Wang SN, Wu T, et al. Sulfated Cyclocarya paliurus polysaccharides markedly attenuates inflammation and oxidative damage in lipopolysaccharide-treated macrophage cells and mice. Sci Rep 2017; 7: 40402. doi: 10.1038/srep40402

  19. Riehle C, Bauersachs J. Of mice and men: models and mechanisms of diabetic cardiomyopathy. Basic Res Cardiol 2018; 114(1): 2. doi: 10.1007/s00395-018-0711-0

  20. Kim E, Shin JH, Seok PR, Kim MS, Yoo SH, Kim Y. Phyllodulcin, a natural functional sweetener, improves diabetic metabolic changes by regulating hepatic lipogenesis, inflammation, oxidative stress, fibrosis, and gluconeogenesis in db/db mice. J Funct Foods 2018; 42: 1–11. doi: 10.1016/j.jff.2017.12.038

  21. Zhang B, Zhang JY, Zhang CY, Zhang XL, Ye JX, Kuang SH, et al. Notoginsenoside R1 protects against diabetic cardiomyopathy through activating estrogen receptor alpha and its downstream signaling. Front Pharmacol 2018; 9: 1227. doi: 10.3389/fphar.2018.01227

  22. Bi YM, Wu YT, Chen L, Tan ZB, Fan HJ, Xie LP, et al. 3,5-Dicaffeoylquinic acid protects H9C2 cells against oxidative stress-induced apoptosis via activation of the PI3K/Akt signaling pathway. Food Nutr Res 2018; 62: 1423. doi: 10.29219/fnr.v62.1423

  23. Othman AI, El-Sawi MR, El-Missiry MA, Abukhalil MH. Epigallocatechin-3-gallate protects against diabetic cardiomyopathy through modulating the cardiometabolic risk factors, oxidative stress, inflammation, cell death and fibrosis in streptozotocin-nicotinamide-induced diabetic rats. Biomed Pharmacother 2017; 94: 362–73. doi: 10.1016/j.biopha.2017.07.129

  24. Meyerovich K, Ortis F, Cardozo AK. The non-canonical NF- κB pathway and its contribution to β-cell failure in diabetes. J Mol Endocrinol 2018; 61(2): F1–6. doi: 10.1530/JME-16-0183

  25. Jia GH, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res 2018; 122(4): 624–38. doi: 10.1161/CIRCRESAHA.117.311586

  26. Jiang KF, Guo SH, Yang CH, Yang J, Chen Y, Shaukat A, et al. Barbaloin protects against lipopolysaccharide (LPS)-induced acute lung injury by inhibiting the ROS-mediated PI3K/AKT/NF-kappaB pathway. Int Immunopharmacol 2018; 64: 140–50. doi: 10.1016/j.intimp.2018.08.023

  27. Deng LH, Lei JD, He J, Liu J, Wang LY, Zhang R, et al. Evaluation on genotoxicity and teratogenicity of aqueous extract from Cyclocarya paliurus leaves. The Scientific World J 2014; 2014: 498134. doi: 10.1155/2014/498134

  28. Zheng GT, Yin ZQ. Research progress on development in Cyclocarya paliurus. World Latest Med Info 2019; 19(43):123–4. doi: 10.19613/j.cnki.1671-3141.2019.43.058

  29. Yaribeygi H, Atkin SL, Simental-Mendia LE, Barreto GE, Sahebkar A. Anti-inflammatory effects of resolvins in diabetic nephropathy: mechanistic pathways. J Cell Physiol 2019; 234(9): 14873–82. doi: 10.1002/jcp.28315

  30. Li MC, Murabito A, Ghigo A, Hirsch E. PI3Ks in diabetic cardiomyopathy. J Cardiovasc Pharm 2017; 70(6): 422–9. doi: 10.1097/FJC.0000000000000511

  31. Karbasforooshan H, Karimi G. The role of SIRT1 in diabetic cardiomyopathy. Biomed Pharmacother 2017; 90: 386–92. doi: 10.1016/j.biopha.2017.03.056

  32. Cao XY, Liu D, Xia Y, Cai TG, He Y, Liu JL. A novel polysaccharide from Lentinus edodes mycelia protects MIN6 cells against high glucose-induced damage via the MAPKs and Nrf2 pathways. Food Nutr Res 2019; 63: 1598. doi: 10.29219/fnr.v63.1598

  33. Sifuentes-Franco S, Padilla-Tejeda DE, Carrillo-Ibarra S, Miranda-Diaz AG. Oxidative stress, apoptosis, and mitochondrial function in diabetic nephropathy. Int J Endocrinol 2018; 2018: 1875870. doi: 10.1155/2018/1875870

  34. Fuentes-Antras J, Ioan AM, Tunon J, Egido J, Lorenzo O. Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol 2014; 2014: 847827. doi: 10.1155/2014/847827

  35. Sangweni NF, Dludla PV, Mosa RA, Kappo AP, Opoku A, Muller CJF, et al. Lanosteryl triterpenes from Protorhus longifolia as a cardioprotective agent: a mini review. Heart Fail Rev 2019; 24(1): 155–66. doi: 10.1007/s10741-018-9733-9

  36. Frati G, Schirone L, Chimenti I, Yee D, Biondi-Zoccai G, Volpe M, et al. An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy. Cardiovasc Res 2017; 113(4): 378–88. doi: 10.1093/cvr/cvx011

  37. Brignall R, Moody AT, Mathew S, Gaudet S. Considering abundance, affinity, and binding site availability in the NF-kappaB target selection puzzle. Front Immuno 2019; 10: 609. doi: 10.3389/fimmu.2019.00609

  38. Du L, Li JK, Zhang XT, Wang LF, Zhang WM, Yang M, et al. Pomegranate peel polyphenols inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4/NF-kappaB pathway activation. Food Nutr Res 2019; 63: 3392. doi: 10.29219/fnr.v63.3392

  39. Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP. The role of oxidative stress and NF-kappaB activation in late diabetic complications. Biofactors 2008; 10(2–3): 157–67. doi: 10.1002/biof.5520100211

  40. Palomer X, Salvadó L, Barroso E, Vázquez-Carrera M. An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. Int J Cardiol 2013; 168(4): 3160–72. doi: 10.1016/j.ijcard.2013.07.150

  41. Yudushkin I. Getting the Akt together: guiding intracellular Akt activity by PI3K. Biomole 2019; 9(2): 67. doi: 10.3390/biom9020067

  42. Ghoneum A, Said N. PI3K-AKT-mTOR and NFkappaB pathways in ovarian cancer: implications for targeted therapeutics. Cancers 2019; 11(7): 949. doi: 10.3390/cancers11070949

  43. Chen SP, Zhou YQ, Liu DQ, Zhang W, Manyande A, Guan XH, et al. PI3K/Akt pathway: a potential therapeutic target for chronic pain. Curr Pharm Design 2017; 23(12): 1860–68. doi: 10.2174/1381612823666170210150147

Published
2020-08-31
How to Cite
Wang, Y., Zheng, X., Li, L., Wang, H., Chen, K., Xu, M., Wu, Y., Huang, X., Zhang, M., Ye, X., Xu, T., Chen, R., & Zhu, Y. (2020). <em>Cyclocarya paliurus</em&gt; ethanol leaf extracts protect against diabetic cardiomyopathy in db/db mice via regulating PI3K/Akt/NF-κB signaling. Food & Nutrition Research, 64. https://doi.org/10.29219/fnr.v64.4267
Section
Original Articles