Chrysophanol alleviates myocardial injury in diabetic db/db mice by regulating the SIRT1/HMGB1/NF‑κB signaling pathway

Xue,Peng; Zhao,Jing; Zheng,Aibin; Li,Lin; Chen,Huaqin; Tu,Wenjuan; Zhang,Ning; Yu,Zhangbin; Wang,Qiuwei; Gu,Meng

doi:10.3892/etm.2019.8083

Chrysophanol alleviates myocardial injury in diabetic db/db mice by regulating the SIRT1/HMGB1/NF‑κB signaling pathway

Authors:
- Peng Xue
- Jing Zhao
- Aibin Zheng
- Lin Li
- Huaqin Chen
- Wenjuan Tu
- Ning Zhang
- Zhangbin Yu
- Qiuwei Wang
- Meng Gu
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Affiliations: Department of Pediatrics, Changzhou Children's Hospital of Nantong Medical University, Changzhou, Jiangsu 213003, P.R. China, Department of Pediatrics, Nanjing Maternity and Child Health Care Hospital of Nanjing Medical University, Nangjing, Jiangsu 210004, P.R. China
Published online on: October 7, 2019 https://doi.org/10.3892/etm.2019.8083
Pages: 4406-4412
Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Myocardial injury induced by diabetes has become an increasing health problem. Chrysophanol (CHR) has been widely studied as a potential treatment for many diseases due to its anti‑inflammatory effects, but has not been investigated in regard to diabetes‑induced myocardial injury. The present study evaluated the myocardial protective effects of CHR in C57BL/KsJ‑db/db diabetic mice. C57BL/KsJ‑db/db and C57BLKS/J mice were treated with vehicle, metformin (100 mg/kg/day) or CHR (50 or 100 mg/kg/day) for 28 days. An oral glucose tolerance test was performed to detect blood glucose levels. Blood lipids, triglycerides, total cholesterol, myocardial function‑associated enzymes, namely creatine kinase (CK) and lactate dehydrogenase (LDH), and insulin levels were analyzed. TNF‑α, interleukin (IL)‑1β and IL‑6 inflammatory cytokine levels in serum and myocardial tissues were determined by ELISA. Expression of silent information regulator l (SIRT1) and high mobility group box 1/NF‑κB pathway‑associated proteins in myocardial tissues were measured by western blot analysis and immunohistochemistry. CHR treatment at both concentrations markedly decreased blood lipid and serum insulin levels, and inhibited the myocardial enzymes CK and LDH. CHR also significantly ameliorated the cardiac pathological changes in diabetic mice. The inflammatory cytokine levels that were increased in C57BL/KsJ‑db/db diabetic mice were downregulated by CHR treatment. CHR also increased SIRT1 protein expression and inhibited activation of the HMGB1/NF‑κB pathway. In conclusion, the present study indicates that CHR effectively protected against diabetic myocardial injury via regulation of SIRT1 and the HMGB1/NF‑κB signaling pathway.

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1	Mäkimattila S, Virkamäki A, Groop PH, Cockcroft J, Utriainen T, Fagerudd J and Yki-Järvinen H: Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation. 94:1276–1282. 1996. View Article : Google Scholar : PubMed/NCBI
2	Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U and Shaw JE: Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 103:137–149. 2014. View Article : Google Scholar : PubMed/NCBI
3	Brownlee M: The pathobiology of diabetic complications: A unifying mechanism. Diabetes. 54:1615–1625. 2005. View Article : Google Scholar : PubMed/NCBI
4	Giacco F and Brownlee M: Oxidative stress and diabetic complications. Circ Res. 107:1058–1070. 2010. View Article : Google Scholar : PubMed/NCBI
5	Adeyemi DO, Ukwenya VO, Obuotor EM and Adewole SO: Anti-hepatotoxic activities of Hibiscus sabdariffa L. in animal model of streptozotocin diabetes-induced liver damage. BMC Complement Altern Med. 14:2772014. View Article : Google Scholar : PubMed/NCBI
6	Dias AS, Porawski M, Alonso M, Marroni N, Collado PS and González-Gallego J: Quercetin decreases oxidative stress, NF-kappaB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats. J Nutr. 135:2299–2304. 2005. View Article : Google Scholar : PubMed/NCBI
7	Matafome P, Nunes E, Louro T, Amaral C, Crisóstomo J, Rodrigues L, Moedas AR, Monteiro P, Cipriano A and Seiça R: A role for atorvastatin and insulin combination in protecting from liver injury in a model of type 2 diabetes with hyperlipidemia. Naunyn Schmiedebergs Arch Pharmacol. 379:241–251. 2009. View Article : Google Scholar : PubMed/NCBI
8	Wellen KE and Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest. 115:1111–1119. 2005. View Article : Google Scholar : PubMed/NCBI
9	Finkel T, Deng CX and Mostoslavsky R: Recent progress in the biology and physiology of sirtuins. Nature. 460:587–591. 2009. View Article : Google Scholar : PubMed/NCBI
10	Lai T, Wen X, Wu D, Su G, Gao Y, Chen C, Wu W, Lv Y, Chen Z, Lv Q, et al: SIRT1 protects against urban particulate matter-induced airway inflammation. Int J Chron Obstruct Pulmon Dis. 14:17412019. View Article : Google Scholar : PubMed/NCBI
11	Lee JH, Moon JH, Lee YJ and Park SY: SIRT1, a Class III histone deacetylase, regulates LPS-induced inflammation in human keratinocytes and mediates the anti-inflammatory effects of hinokitiol. J Invest Dermatol. 137:1257–1266. 2017. View Article : Google Scholar : PubMed/NCBI
12	Harris HE, Andersson U and Pisetsky DS: HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol. 8:195–202. 2012. View Article : Google Scholar : PubMed/NCBI
13	Yang H, Wang H, Chavan SS and Andersson U: High mobility group box protein 1 (HMGB1): The prototypical endogenous danger molecule. Mol Med 1(Suppl 21). S6–S12. 2015. View Article : Google Scholar
14	Kornblit B, Munthe-Fog L, Madsen HO, Strøm J, Vindeløv L and Garred P: Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome. Crit Care. 12:R832008. View Article : Google Scholar : PubMed/NCBI
15	Xueyang D, Zhanqiang M, Chunhua M and Kun H: Fasudil, an inhibitor of Rho-associated coiled-coil kinase, improves cognitive impairments induced by smoke exposure. Oncotarget. 7:78764–78772. 2016. View Article : Google Scholar : PubMed/NCBI
16	Komers R: Rho kinase inhibition in diabetic kidney disease. Br J Clin Pharmacol. 76:551–559. 2013.PubMed/NCBI
17	Lu CC, Yang JS, Huang AC, Hsia TC, Chou ST, Kuo CL, Lu HF, Lee TH, Wood WG and Chung JG: Chrysophanol induces necrosis through the production of ROS and alteration of ATP levels in J5 human liver cancer cells. Mol Nutr Food Res. 54:967–976. 2010. View Article : Google Scholar : PubMed/NCBI
18	Kim SJ, Kim MC, Lee BJ, Park DH, Hong SH and Um JY: Anti-Inflammatory activity of chrysophanol through the suppression of NF-kappaB/caspase-1 activation in vitro and in vivo. Molecules. 15:6436–6451. 2010. View Article : Google Scholar : PubMed/NCBI
19	Wen Q, Mei L, Ye S, Liu X, Xu Q, Miao J, Du S, Chen D, Li C and Li H: Chrysophanol demonstrates anti-inflammatory properties in LPS-primed RAW 264.7 macrophages through activating PPAR-γ. Int Immunopharmacol. 56:90–97. 2018. View Article : Google Scholar : PubMed/NCBI
20	Shiezadeh F, Mousavi SH, Amiri MS, Iranshahi M, Tayarani-Najaran Z and Karimi G: Cytotoxic and apoptotic potential of rheum turkestanicum janisch root extract on human cancer and normal cells. Iran J Pharm Res. 12:811–819. 2013.PubMed/NCBI
21	Chang SJ, Huang SH, Lin YJ, Tsou YY and Lin CW: Antiviral activity of Rheum palmatum methanol extract and chrysophanol against Japanese encephalitis virus. Arch Pharm Res. 37:1117–1123. 2014. View Article : Google Scholar : PubMed/NCBI
22	Zhi-Yun LI, Ming Z, Wei JI, et al: Protective effect of chrysophanol on hypoxic injury of rat adrenal medulla pheochromocytoma cells. Chin J Cerebrovascular Dis. 9:418–427. 2012.(In Chinese).
23	Zhang J, Yang S, Chen F, Li H and Chen B: Ginkgetin aglycone ameliorates LPS-induced acute kidney injury by activating SIRT1 via inhibiting the NF-κB signaling pathway. Cell Biosci. 7:442017. View Article : Google Scholar : PubMed/NCBI
24	Qi Z, Zhang Y, Qi S, Ling L, Gui L, Yan L, Lv J and Li Q: Salidroside inhibits HMGB1 acetylation and release through upregulation of SirT1 during inflammation. Oxid Med Cell Longev. 2017:98215432017. View Article : Google Scholar : PubMed/NCBI
25	Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature. 414:813–820. 2001. View Article : Google Scholar : PubMed/NCBI
26	Gerrity RG, Natarajan R, Nadler JL and Kimsey T: Diabetes-induced accelerated atherosclerosis in swine. Diabetes. 50:1654–1665. 2001. View Article : Google Scholar : PubMed/NCBI
27	He Q, Pu J, Yuan A, Yao T, Ying X, Zhao Y, Xu L, Tong H and He B: Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc Diabetol. 13:1492014. View Article : Google Scholar : PubMed/NCBI
28	Bujak M and Frangogiannis NG: The role of IL-1 in the pathogenesis of heart disease. Arch Immunol Ther Exp (Warsz). 57:165–176. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ohsuzu F: The roles of cytokines, inflammation and immunity in vascular diseases. J Atheroscler Thromb. 11:313–321. 2004. View Article : Google Scholar : PubMed/NCBI
30	Tanaka T, Narazaki M and Kishimoto T: IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 6:a0162952014. View Article : Google Scholar : PubMed/NCBI
31	Yang H and Tracey KJ: Targeting HMGB1 in inflammation. Biochim Biophys Acta. 1799:149–156. 2010. View Article : Google Scholar : PubMed/NCBI
32	Andersson U and Tracey KJ: HMGB1 Is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 29:139–162. 2011. View Article : Google Scholar : PubMed/NCBI
33	Lotze MT and Tracey KJ: High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nat Rev Immunol. 5:331–342. 2005. View Article : Google Scholar : PubMed/NCBI
34	Kauppinen A, Suuronen T, Ojala J, Kaarniranta K and Salminen A: Antagonistic crosstalk between NF-kB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal. 25:1939–1948. 2013. View Article : Google Scholar : PubMed/NCBI
35	Salem ML, Hossain MS and Nomoto K: Mediation of the immunomodulatory effect of beta-estradiol on inflammatory responses by inhibition of recruitment and activation of inflammatory cells and their gene expression of TNF-alpha and IFN-gamma. Int Arch Allergy Immunol. 121:235–245. 2000. View Article : Google Scholar : PubMed/NCBI