Mulberry granules protect against diabetic cardiomyopathy through the AMPK/Nrf2 pathway

Liu,Yang; Zhao,Yan-Bo; Wang,Si-Wang; Zhou,Yu; Tang,Zhi-Shu; Li,Feng

doi:10.3892/ijmm.2017.3050

Mulberry granules protect against diabetic cardiomyopathy through the AMPK/Nrf2 pathway

Authors:
- Yang Liu
- Yan-Bo Zhao
- Si-Wang Wang
- Yu Zhou
- Zhi-Shu Tang
- Feng Li
View Affiliations

Affiliations: School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712000, P.R. China, Department of Emergency, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Department of Natural Medicine, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Otorhinolaryngology, The People's Hospital of Ankang, Ankang, Shaanxi 725000, P.R. China, Department of Traditional Chinese Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: July 3, 2017 https://doi.org/10.3892/ijmm.2017.3050
Pages: 913-921

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mulberry granules (MLD) is a traditional Chinese medicine prescription that has been used in the treatment of diabetes for many years. Recently, we found that MLD protected the heart from diabetes-associated cardiomyopathy when it was used to treat diabetes. However, the beneficial effects and possible mechanism remain unknown. To elucidate these effects, an experimental myocardial ischemia/reperfusion (MI/R) injury model in diabetes rats was used in this study. Male C57BL/6 mice were injected with streptozotocin to induce diabetes. The mice were pretreated with MLD for one month, and then exposed to 30 min of ischemia followed by 24 h of reperfusion. Infarct size, heart function and various cytokines in the heart were assessed. Expression of AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2‑related factor 2 (Nrf2) were investigated by western blotting. In vitro, MLD signiﬁcantly cleared oxygen-free radicals in DPPH and luminol chemiluminescence models. In vivo, fasting blood glucose, fasting blood insulin and lipids were significantly decreased by MLD. The results showed that MLD improved the cardiac function and decreased myocardial infarct size in the diabetic mice subjected to MI/R. In addition, upon pretreatment with MLD before MI/R treatment, GSH, SOD, CAT and GR were significantly increased in a dose-dependent manner. Pretreatment with MLD also significantly induced the expression of Nrf2, and the cardioprotective effects of MLD were abolished in Nrf2-knockout mice. Furthermore, we also found that AMPK increase is upstream and was required for Nrf2 activation mediated by MLD. In conclusion, MLD protects against diabetic-associated cardiomyopathy by suppressing oxidative stress induced by hyperglycemia and MI/R through the AMPK/Nrf2 signaling pathway.

View Figures

View References

1	Pappachan JM, Varughese GI, Sriraman R and Arunagirinathan G: Diabetic cardiomyopathy: pathophysiology, diagnostic evaluation and management. World J Diabetes. 4:177–189. 2013.PubMed/NCBI
2	Galderisi M: Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography. J Am Coll Cardiol. 48:1548–1551. 2006. View Article : Google Scholar : PubMed/NCBI
3	Ayaz M, Ozdemir S, Ugur M, Vassort G and Turan B: Effects of selenium on altered mechanical and electrical cardiac activities of diabetic rat. Arch Biochem Biophys. 426:83–90. 2004. View Article : Google Scholar : PubMed/NCBI
4	Ceriello A: New insights on oxidative stress and diabetic complications may lead to a 'causal' antioxidant therapy. Diabetes Care. 26:1589–1596. 2003. View Article : Google Scholar : PubMed/NCBI
5	Vassort G and Turan B: Protective role of antioxidants in diabetes-induced cardiac dysfunction. Cardiovasc Toxicol. 10:73–86. 2010. View Article : Google Scholar : PubMed/NCBI
6	Cai L and Kang YJ: Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol. 1:181–193. 2001. View Article : Google Scholar
7	Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 404:787–790. 2000. View Article : Google Scholar : PubMed/NCBI
8	Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, et al: High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 49:1939–1945. 2000. View Article : Google Scholar : PubMed/NCBI
9	Cai L: Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications. Curr Med Chem. 14:2193–2203. 2007. View Article : Google Scholar : PubMed/NCBI
10	Arabshahi-D S, Vishalakshi Devi D and Urooj A: Evaluation of antioxidant activity of some plant extracts and their heat, pH and storage stability. Food Chem. 100:1100–1105. 2007. View Article : Google Scholar
11	Shibata Y, Kume N, Arai H, Hayashida K, Inui-Hayashida A, Minami M, Mukai E, Toyohara M, Harauma A, Murayama T, et al: Mulberry leaf aqueous fractions inhibit TNF-alpha-induced nuclear factor kappaB (NF-kappaB) activation and lectin-like oxidized LDL receptor-1 (LOX-1) expression in vascular endothelial cells. Atherosclerosis. 193:20–27. 2007. View Article : Google Scholar
12	Du J, He ZD, Jiang RW, Ye WC, Xu HX and But PP: Antiviral flavonoids from the root bark of Morus alba L. Phytochemistry. 62:1235–1238. 2003. View Article : Google Scholar : PubMed/NCBI
13	Pan G and Lou C: Isolation of an 1-aminocyclopropane-1-carboxylate oxidase gene from mulberry (Morus alba L.) and analysis of the function of this gene in plant development and stresses response. J Plant Physiol. 165:1204–1213. 2008. View Article : Google Scholar
14	Sun F, Shen L and Ma Z: Screening for ligands of human aromatase from mulberry (Mori alba L.) leaf by using high-performance liquid chromatography/tandem mass spectrometry. Food Chem. 126:1337–1343. 2011. View Article : Google Scholar
15	El-Beshbishy HA, Singab AN, Sinkkonen J and Pihlaja K: Hypolipidemic and antioxidant effects of Morus alba L. (Egyptian mulberry) root bark fractions supplementation in cholesterol-fed rats. Life Sci. 78:2724–2733. 2006. View Article : Google Scholar
16	Enkhmaa B, Shiwaku K, Katsube T, Kitajima K, Anuurad E, Yamasaki M and Yamane Y: Mulberry (Morus alba L.) leaves and their major flavonol quercetin 3-(6-malonylglucoside) attenuate atherosclerotic lesion development in LDL receptor-deficient mice. J Nutr. 135:729–734. 2005.PubMed/NCBI
17	Gulcin I: Antioxidant properties of resveratrol: a structure-activity insight. Innov Food Sci Emerg. 11:210–218. 2010. View Article : Google Scholar
18	Banu S, Greenway GM and Wheatley RA: Luminol chemiluminescence inducedby immobilised xanthine oxidase. Anal Chim Acta. 541:89–95. 2005. View Article : Google Scholar
19	Huang XL, Wang W and Zhou YW: Protective effect of epimedium flavonoids injection on experimental myocardial infarction rats. Zhongguo Zhong Xi Yi Jie He Za Zhi. 26:68–71. 2006.In Chinese. PubMed/NCBI
20	Trachanas K, Sideris S, Aggeli C, Poulidakis E, Gatzoulis K, Tousoulis D and Kallikazaros I: Diabetic cardiomyopathy: from pathophysiology to treatment. Hellenic J Cardiol. 55:411–421. 2014.PubMed/NCBI
21	Aneja A, Tang WH, Bansilal S, Garcia MJ and Farkouh ME: Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med. 121:748–757. 2008. View Article : Google Scholar : PubMed/NCBI
22	Arrington CB, Dowse BR, Bleyl SB and Bowles NE: Non-synonymous variants in pre-B cell leukemia homeobox (PBX) genes are associated with congenital heart defects. Eur J Med Genet. 55:235–237. 2012. View Article : Google Scholar : PubMed/NCBI
23	Ustinova EE, Barrett CJ, Sun SY and Schultz HD: Oxidative stress impairs cardiac chemoreflexes in diabetic rats. Am J Physiol Heart Circ Physiol. 279:H2176–H2187. 2000.PubMed/NCBI
24	Gao X, Ohlander M, Jeppsson N, Björk L and Trajkovski V: Changes in antioxidant effects and their relationship to phytonutrients in fruits of sea buckthorn (Hippophae rhamnoides L.) during maturation. J Agric Food Chem. 48:1485–1490. 2000. View Article : Google Scholar : PubMed/NCBI
25	Rains JL and Jain SK: Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med. 50:567–575. 2011. View Article : Google Scholar
26	Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD and Yamamoto M: Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 13:76–86. 1999. View Article : Google Scholar : PubMed/NCBI
27	Ma Q, Kinneer K, Bi Y, Chan JY and Kan YW: Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem J. 377:205–213. 2004. View Article : Google Scholar
28	He X, Chen MG, Lin GX and Ma Q: Arsenic induces NAD(P)H quinone oxidoreductase I by disrupting the Nrf2•Keap1•Cul3 complex and recruiting Nrf2•Maf to the antioxidant response element enhancer. J Biol Chem. 281:23620–23631. 2006. View Article : Google Scholar : PubMed/NCBI
29	Hardie DG: AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 25:1895–1908. 2011. View Article : Google Scholar : PubMed/NCBI
30	Sriwijitkamol A, Ivy JL, Christ-Roberts C, DeFronzo RA, Mandarino LJ and Musi N: LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training. Am J Physiol Endocrinol Metab. 290:E925–E932. 2006. View Article : Google Scholar