Abstract
Cardiomyocyte inflammatory injury is likely required for cardiomyocytes death under hyperglycemia condition. Resveratrol (Res) is famous for its anti-inflammatory effect. However, there are few reports about the anti-inflammatory effect of Res induced by high glucose in cardiomyocytes. The aim of the present study is to investigate the inflammatory effect of high glucose and the anti-inflammatory effect of Res induced by high glucose in cardiomyocytes. Primary cardiomyocytes were isolated from new born SD rats and high glucose (30 mmol/L) was used as a stimulant for cell injury. Cell viability was assayed by CCK-8 method; protein expression was identified by Western blot or ELISA, respectively. The production of reactive oxygen species (ROS) was observed under a fluorescence microscope. The results indicated that High glucose (30 mmol/L) significantly decreased the cell viability of cardiomyocytes after co-cultivated for 12 h and had a time-dependent manner, and increased IL-1β, IL-6 and TNF-α secretion in cardiomyocytes. The injury effect of high glucose involved in ROS-MAPK-NF-κB signaling pathway. For the reason that antioxidant NAC, ERK1/2, p38 MAPK and NF-κB specific pathway inhibitors was able to abolish the secretion of this inflammatory factors; pretreatment with antioxidant NAC significantly decreased the level of phosphorylated ERK1/2, p38 MAPK and nuclear NF-κB; pretreatment of PD98059 and SB203580 can significantly decrease NF-κB level in nuclei. After treatment with Res 20 μmol/L for 12 h, IL-1β, IL-6 and TNF-α secretion were markedly decreased, and the phosphorylation of ERK1/2, p38 MAPK and NF-κB level were also decreased. All the results showed that Res attenuates high glucose-induced inflammatory injury through ROS-ERK1/2/p38-NF-κB signaling pathway in cardiomyocytes.
Keywords: Resveratrol, high glucose, inflammation, cardiovascular disease, MAPK signaling pathway, NF-κB signaling pathway
Introduction
Cardiovascular disease (CVD) is the most common cause of mortality and morbidity in the world [1-3]. Diabetes Mellitus (DM) which is one of the common disease of CVD seriously affects human health [4,5], and diabetic cardiomyopathy (DCM) is an independent complication of DM. Myocardial fibrosis which is most frequently proposed mechanisms can contribute to DCM development [6-8]. Necrosis or apoptosis or both is a wide accepted concept of cardiomyocytes death that can lead to myocardial fibrosis [9,10]. Research showed that hyperglycemia-induced inflammation and oxidative stress in the heart result in cardiomyocytes death [11-14]. High glucose plays a key role in cardiomyocytes death and the overproduction of pro-inflammatory cytokines (such as TNF-α, IL-1β et al.) induced by high glucose, act as a positive feedback mechanism and also stimulate cardiomyocytes apoptosis, which eventually leads to cardiac dysfunction [15-18].
Resveratrol (Res, chemical structure showed in Figure 6A), a type of polyphenolic phytoalexin contained abundantly in red grapes and wine, has received considerable attention for its ability of preventing illnesses such as CVD [19,20], cancer [21-23], and even slowing the aging process [24,25]. Recently, Res has been proved to have some benefits on DCM [26-28]. However, little is known about the potential mechanisms of Res on high glucose induced cardiomyocytes injury. Hence, the aim of present study was to investigate the protective effect of Res on high glucose-induced inflammation in cardiomyocytes which mainly focus on the anti-inflammatory effect and ROS, MAPK and NF-κB signaling pathway.
Figure 6.
The chemical structure of Res and its effect on the cell viability of cardiomyocytes. A. The chemical structure of Res; B. The cells were incubated with the different concentrations of Res for 12 h; C. The cells were incubated with the concentrations of Res at 20 μmol/L for 0-24 h. Results were from six independent experiments and expressed as mean ± standard errors of mean (SEM).
Materials and methods
Chemicals and animals
Res was from National Food and Drug Testing Institute (Beijing, China). RPMI 1640 Medium and fetal bovine serum (FBS) were purchased from Gibco (Grand Island, NY, USA). Penicillin and streptomycin were from Beijing Solarbio Science & Technology Co., Ltd. (Beijing, China). CCK-8 was purchased from Invitrogen (Carlsbad, CA, USA). Protein quantification kit was from Beyotime (Jiangsu, China). 2’,7’-dichlorodihydrofluororescein diacetate (DCFH-DA), ERK1/2, phospho-ERK1/2, JNK and phospho-JNK antibodies were obtained from Beyotime (Jiangsu, China). Phospho-p38 and p38 antibodies were from Cell Signaling Technology (Danvers, MA, USA). NF-κB and Lambin b1 antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). HRP-conjugated secondary antibodies were purchased from the Zhongshan Company (Beijing, China).
Sprague-Dawley (SD) rats (Between 3-7 days old) were provided by the experimental animal center of Beijing. The animal experiment was according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (National Institutes of Health Publication No. 85-23, revised in 1996). Primary cardiomyocytes were from new born SD rats according to previous methods [29]. The purity of cultured cardiomycoytes were 98% as evaluated by immunofluoresence staining using cardiac muscle sarcomeric aactin antibody (Abcam, Cambridge, MA, USA) and showed in Supplementary Figure 1. Cardiomyocytes were kept in the 1% FBS for 12 h prior to the experiment, and then stimulated by high glucose (30 mmol/L). In the Res treatment experiments, Cardiomyocytes were exposed to high glucose (30 mmol/L) for 12 h after pretreated with the Res for 1 h.
CCK-8 assay
The CCK-8 method was used to detect the cell viability of cardiomyocytes after indicated treatment in 96-well plates. The experimental protocol as follow: After indicated treatment, 10 μL CCK-8 solution was added to each well and followed by a further 4 h incubation at 37°C. The optical density was measured at 450 nm by a micro-plate reader (Molecular Devices, Sunnyvale, CA, USA). The mean optical density of 6 wells was used to calculate the cell viability percentage.
Enzyme-linked immunosorbent assay (ELISA)
Cardiomyocytes were cultured in 96-well plate and stimulated with high glucose for 12 h. Then, the supernatant was collected and levels of IL-1β, IL-6 and TNF-α in the supernatant were assayed by ELISA kit specific for rat IL-1β, IL-6 and TNF-α.
Measurement of intracellular reactive oxygen species (ROS)
The levels of Intracellular ROS were determined by oxidative conversion of cell-permeable DCFH-DA to fluorescent DCF. After indicated treatments, DCFH-DA (10 μmol/L) in FBS-free DMEM was added to the 6 well plate and the cells were incubated for 20 min at 37°C. Then, the 6 well plate were washed three times with FBS-free DEME and DCF fluorescence was measured by using a fluorescent microscope (BX50-FLA; Olympus, Tokyo, Japan). Mean fluorescence intensity (MFI) from six random fields was analyzed using Image J 1.41 software (National Institutes of Health, Bethesda, MD, USA), and MFI was used to represent the amount of ROS.
Western blot
After indicated treatment, the cells were washed twice by ice-cold PBS (pH 7.4) and lysed by lysis buffer supplemented with protease inhibitor cocktail and phosphatase inhibitors (Roche, Basel, Switzerland) 100 μL per well of a 6-well plate. Concentration of the protein was measured by BCA protein assay kit (Bio-Rad, Hercules, CA, USA). Equal amount of the protein (30 μg) was loaded, separated by 10% SDS-PAGE, and blotted onto PVDF membrane (0.45 μm, GE Healthcare, Buckinghamshire, UK). The membranes were incubated with anti-ERK1/2 (1:1500), anti-phophos-ERK1/2 (1:800) or anti-p38 (1:1500), anti-phophos-p38 (1:800), anti-JNK (1:1000), anti-phophos-JNK (1:600), anti-NF-κB (1:500), antiLamin B1 (1:1000) antibodies at 4°C overnight. After washed three times, the membranes were incubated with the relevant second HRP-conjugated antibodies (1:3000) for 3 h and then the immune complexes were enhanced by chemiluminescence.
Statistical analyses
The results are represented as means ± standard errors of mean (SEM). Statistical analysis was performed by Steer-Dwass or Mann-Whitney multiple comparison test. This was performed by using Graphpad Prism 6.0 (GraphPad Software, Inc. La Jolla, CA). P<0.05 was considered statistically significant.
Results
High glucose decrease the cell viability of cardiomyocytes
Figure 1A showed that the cell viability of cardiomyocytes were significantly inhibited by glucose at 30 mmol/L for 12 h and showed a concentration dependent fashion; the result in Figure 1B indicated a time-dependent manner when subjected to glucose at 30 mmol/L. However, cells were exposed to mannitol, an osmotic control, did not influence the growth rate of the cardiomyocytes. This suggested that high glucose inhibited cell viability was not a consequence of high osmolarity (showed in Figure 1C and 1D).
Figure 1.
The effect of high glucose treatment on cell viability of cardiomyocytes. A. The cells were incubated with different concentrations of glucose for 12 h; B. The cells were incubated with the concentrations of glucose at 30 mmol/L for 0, 6, 12, 24 h; C. The cells were incubated with different concentrations of mannitol for 12 h; D. Cells were subjected to the concentrations of mannitol at 24.4 mmol/L for 0, 6, 12, 24 h. Results were from six independent experiments and expressed as mean ± standard errors of mean (SEM), **P<0.01 vs. control.
High glucose induces inflammatory cytokines expression in cardiomyocytes
The IL-1β, IL-6 and TNF-α were tested by ELISA kit. As shown in Figure 2A-C that IL-1β, IL-6 and TNF-α proteins in supernate of the DMEM were significantly increased after exposure to glucose at 30 mmol/L for 12 h in compared with control. However, cells were exposed to mannitol at 24.4 mmol/L did not influence the secretion of inflammatory factors of the cardiomyocytes. This suggested that high glucose increased the secretion of IL-1β, IL-6 and TNF-α was not a consequence of high osmolarity.
Figure 2.
High glucose increases the proteins secretion of IL-1β, IL-6 and TNF-α in cardiomyocytes. The cells were subjected to high glucose at 30 mmol/L for 12 h, then, the proteins expression of IL-1β, IL-6 and TNF-α were identified by ELISA, respectively. A-C: IL-1β, IL-6 and TNF-α proteins expression. Results were from six independent experiments for ELISA, and expressed as mean ± standard errors of mean (SEM), **P<0.01 vs. control.
ROS, MAPK and NF-κB signaling pathway involve in the inflammatory effect of high glucose in cardiomyocytes
As shown in Figure 3A that high glucose treatment was able to increase the generation of intracellular ROS in cardiomyocytes. The results from western blot showed that the phosphorylated ERK and phosphorylated p38 proteins expression were increased as well as activating NF-κB in cardiomyocytes after the stimulation with glucose at 30 mmol/L for 12 h (Figure 3B, 3C, 3E). Whereas the phosphorylation of JNK was no obvious change (Figure 3D). However, cells were exposed to mannitol at 24.4 mmol/L did not affect the level of the above proteins of the cardiomyocytes. This suggested that high glucose increased the expression of phosphorylated ERK and phosphorylated p38 and activating NF-κB was not a consequence of high osmolarity.
Figure 3.
ROS, MAPK and NF-κB signaling pathway involve in the inflammatory effect of high glucose in cardiomyocytes. The cells were subjected to high glucose at 30 mmol/L or mannitol at 24.4 mmol/L for 12 h, then, the detection of ROS was by laser scanning confocal microscope (A, 600×); expression of the phosphorylation of ERK1/2, JNK and p38 and NF-κB were assayed by Western blot (B-E). Results were from six independent experiments for ROS detection, and three independent experiments for western blot. Data are expressed as mean ± standard errors of mean (SEM), **P<0.01 vs. control.
Further research by ELISA shown that IL-1β, IL-6 and TNF-α proteins in supernate of the DMEM were significantly decreased after pretreated with PD98059 (ERK1/2 inhibitor) at 1 μmol/L, SB203580 (p38 inhibitor) at 10 μmol/L, PDTC (NF-κB inhibitor) at 100 μmol/L and antioxidant NAC at 10-2 mol/L for 1 h. These results indicated that ROS, MAPK and NF-κB signaling pathway involve in the inflammatory effect of high glucose in cardiomyocytes (Figure 4A-C).
Figure 4.
ROS, ERK1/2, p38 and NF-κB signaling pathway involve in the inflammatory effect of high glucose in cardiomyocytes. The cells were pretreatment with antioxidant NAC, ERK1/2, p38 or NF-κB specific pathway inhibitor respectively for 1 h, and then subjected to high glucose at 30 mmol/L for 12 h, then, the proteins expression of IL-1β, IL-6 and TNF-α were identified by ELISA, respectively. A-C: IL-1β, IL-6 and TNF-α proteins expression. Results were from six independent experiments for ELISA, and expressed as mean ± standard errors of mean (SEM), **P<0.01 vs. control.
The inflammatory effect induced by high glucose via ROS-MAPK-NF-κB signaling pathway in cardiomyocytes
ROS, MAPK and NF-κB participate in the expression of inflammatory cytokines in cardiomyocytes. High glucose-induced inflammation in cardiomyocytes was possibly related to ROS-MAPK-NF-κB signaling. Pretreatment of the cells with 10-2 mol/L NAC (antioxidant) for 1 h was able to inhibit the phosphorylation of ERK1/2 and p38 (Figure 5A, 5B) and also decrease the activation of NF-κB (Figure 5C). This results indicated that ROS are the up-stream of MAPK and NF-κB signaling pathway in the inflammatory effect of high glucose in cardiomyocytes.
Figure 5.
The inflammatory effect induced by high glucose via ROS-MAPK-NF-κB signaling pathway in cardiomyocytes. The cells were subjected to high glucose at 30 mmol/L for 12 h or in combination with the pretreatment of related pathway inhibitor for 1 h, then, the detection of ROS was by laser scanning confocal microscopy (D, F: 600×); expression of p-ERK, p-p38 or NF-κB were assayed by Western blot (A-C, E, G). Results were from six independent experiments for ROS detection and three independent experiments for Western blot and expressed as mean ± standard errors of mean (SEM), **P<0.01 vs. control.
Further study by using 1 μmol/L PD98059 (ERK1/2 inhibitor) and 10 μmol/L SB203580 (p38 inhibitor) to investigate the role of MAPK in the inflammatory effect of high glucose in cardiomyocytes. Data showed that PD98059 and SB203580 was able to inhibit the level of nuclear NF-κB expression (Figure 5E, 5G); however, the expression of ROS was not significantly decreased (Figure 5D, 5F). These data showed that the inflammatory effect induced by high glucose via ROS-MAPK-NF-κB signaling pathway in cardiomyocytes.
The effect of Res on the cell viability cardiomyocytes
Figure 6A showed that Res from 0-40 μmol/L did not affect the cell viability of cardiomyocytes, when treatment with Res at concentration of 20 μmol/L for 0-24 h also showed the same manner.
Res attenuates high glucose-induced cardiomyocytes inflammatory damage through ROS-MAPK-NF-κB signaling pathway
As shown in Figure 7A-C that IL-1β, IL-6 and TNF-α proteins in cardiomyocytes were significantly decreased in the presence of Res 20 μmol/L for 12 h. The levels of inner ROS as well as the expression of the phosphorylation of ERK1/2 and p38 and the activation of NF-κB were notably decreased (Figure 7D-G). These results indicated that the anti-inflammatory effect of Res might be via interfering ROS-MAPK-NF-κB signaling pathway in high glucose-induced inflammation of cardiomyocytes.
Figure 7.
Res decreases proteins expression of IL-1β, IL-6 and TNF-α via ROS-MAPK-NF-κB signaling pathway in Cardiomyocytes. The cells were subjected to high glucose treatment in the absence or presence of Res at 20 μmol/L for 12 h. Then, the detection of ROS was by laser scanning confocal microscopy (D: 600×); protein expressions of IL-1β, IL-6 and TNF-α were identified by ELISA and expression of p-ERK, p-38 or NF-κB were assayed by Western blot. (A-C) IL-1β, IL-6 and TNF-α protein expression; (D-G) ROS, p-ERK, p-38 and NF-κB expression. Results were from six independent experiments for ROS detection and three independent experiments for Western blot and expressed as mean ± standard errors of mean (SEM), **P<0.01 vs. control.
Discussion
DCM is a greater risk for cardiovascular morbidity and mortality. Hyperglycemia has been regarded as the primary pathogenic factor of DCM and also directly damages cardiomyocytes [30,31]. Apoptosis of cardiomyocytes is one of the important outcomes of hyperglycemia-induced inflammation and oxidative stress in the heart [32]. In addition, inflammation with increased cytokine levels in the heart was also found to have an important role in the pathogenic development of DCM [33-36]. High glucose could increase the overexpression of inflammatory cytokines in cardiomyocytes [37,38]. Nonetheless, the molecular mechanisms of high glucose induced-cardiomyocytes inflammatory response remain largely unknown. In the present study, we found that high glucose could increase the secretion of IL-1β, IL-6 and TNF-α in cardiomyocytes.
The activation of inflammatory effect via multi pathway, and oxidative damage to cardiomyocytes is of sever in DCM [39,40]. ROS are both the important second messenger and the direct participant of oxidative stress. The recent researches show that ROS play an important role in high glucose elicited the expression of inflammatory factors. Pro-treatment with antioxidant NAC at 10 mmol/L can significantly inhibit the secretion of IL-1β, IL-6 and TNF-α in cardiomyocytes.
MAPK and NF-κB signaling also play a pivotal role in inflammation [41-43]. The activation of NF-κB is responsible for the expressions of many inflammatory cytokines. Our result exhibited that MAPK and NF-κB was involved in the expression of IL-1β, IL-6 and TNF-α protein induced by high glucose, since the selective PD98059 (ERK1/2 inhibitor), SB203580 (p38 inhibitor) and NF-κB inhibitor PDTC significantly blocked the expression of IL-1β, IL-6 and TNF-α proteins in cardiomyocytes.
Previous researches have indicated that Res has a various protective effects against inflammation, CVD, aging and cancer. In the present study, we demonstrated that high glucose was able to increase the level of ROS and the anti-inflammatory effect of Res mainly by blocking the expression of ROS. MAPK and NF-κB signaling pathway is also a target of Res. Our current research also showed that high glucose was able to increase the expression of the phosphorylation of p38 and ERK1/2 and NF-κB in cardiomyocytes, and the anti-inflammatory effect of Res via mediating MAPK-NF-κB signaling pathway for the reason that the function of Res is similar to the specific inhibitor of P38, ERK1/2 and NF-κB signaling pathway.
In conclusion, the present study demonstrates that high glucose induced the expression of IL-1β, IL-6 and TNF-α protein via ROS-MAPK-NF-κB signal pathway in cardiomyocytes. And the anti-inflammatory effect of Res might be via interfering ROS-MAPK-NF-κB signal pathway in cardiomyocytes. These provide the new evidence for the potential inflammatory effect of high glucose and a strategy of dealing with high glucose induced inflammation.
Disclosure of conflict of interest
None.
Supporting Information
References
- 1.Patel P, Ordunez P, DiPette D, Escobar MC, Hassell T, Wyss F, Hennis A, Asma S, Angell S Standardized Hypertension Treatment and Prevention Network. Improved blood pressure control to reduce cardiovascular disease morbidity and mortality: the standardized hypertension treatment and prevention project. J Clin Hypertens (Greenwich) 2016;18:1284–1294. doi: 10.1111/jch.12861. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Wadhera RK, Steen DL, Khan I, Giugliano RP, Foody JM. A review of low-density lipoprotein cholesterol, treatment strategies, and its impact on cardiovascular disease morbidity and mortality. J Clin Lipidol. 2016;10:472–489. doi: 10.1016/j.jacl.2015.11.010. [DOI] [PubMed] [Google Scholar]
- 3.Winkel P, Hilden J, Hansen JF, Kastrup J, Kolmos HJ, Kjøller E, Jensen GB, Skoog M, Lindschou J, Gluud C CLARICOR trial group. Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10 years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol. 2015;182:459–465. doi: 10.1016/j.ijcard.2015.01.020. [DOI] [PubMed] [Google Scholar]
- 4.Ding Y, Sun X, Shan PF. MicroRNAs and cardiovascular disease in diabetes mellitus. Biomed Res Int. 2017;2017:4080364. doi: 10.1155/2017/4080364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Fox CS, Golden SH, Anderson C, Bray GA, Burke LE, de Boer IH, Deedwania P, Eckel RH, Ershow AG, Fradkin J, Inzucchi SE, Kosiborod M, Nelson RG, Patel MJ, Pignone M, Quinn L, Schauer PR, Selvin E, Vafiadis DK American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research, and the American Diabetes Association. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2015;132:691–718. doi: 10.1161/CIR.0000000000000230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ding WY, Liu L, Wang ZH, Tang MX, Ti Y, Han L, Zhang L, Zhang Y, Zhong M, Zhang W. FPreceptor gene silencing ameliorates myocardial fibrosis and protects from diabetic cardiomyopathy. J Mol Med (Berl) 2014;92:629–640. doi: 10.1007/s00109-013-1119-9. [DOI] [PubMed] [Google Scholar]
- 7.Wang L, Li J, Li D. Losartan reduces myocardial interstitial fibrosis in diabetic cardiomyopathy rats by inhibiting JAK/STAT signaling pathway. Int J Clin Exp Pathol. 2015;8:466–473. [PMC free article] [PubMed] [Google Scholar]
- 8.Zou C, Liu X, Xie R, Bao Y, Jin Q, Jia X, Li L, Liu R. Deferiprone attenuates inflammation and myocardial fibrosis in diabetic cardiomyopathy rats. Biochem Biophys Res Commun. 2017;486:930–936. doi: 10.1016/j.bbrc.2017.03.127. [DOI] [PubMed] [Google Scholar]
- 9.Guo X, Xue M, Li CJ, Yang W, Wang SS, Ma ZJ, Zhang XN, Wang XY, Zhao R, Chang BC, Chen LM. Protective effects of triptolide on TLR4 mediated autoimmune and inflammatory response induced myocardial fibrosis in diabetic cardiomyopathy. J Ethnopharmacol. 2016;193:333–344. doi: 10.1016/j.jep.2016.08.029. [DOI] [PubMed] [Google Scholar]
- 10.Zhu Z, Hu X. HMGB1 induced endothelial permeability promotes myocardial fibrosis in diabetic cardiomyopathy. Int J Cardiol. 2017;227:875. doi: 10.1016/j.ijcard.2015.11.024. [DOI] [PubMed] [Google Scholar]
- 11.Bliksoen M, Mariero LH, Torp MK, Baysa A, Ytrehus K, Haugen F, Seljeflot I, Vaage J, Valen G, Stenslokken KO. Extracellular mtDNA activates NF-kappaB via toll-like receptor 9 and induces cell death in cardiomyocytes. Basic Res Cardiol. 2016;111:42. doi: 10.1007/s00395-016-0553-6. [DOI] [PubMed] [Google Scholar]
- 12.Lee J, Lee S, Lee CY, Seo HH, Shin S, Choi JW, Kim SW, Park JC, Lim S, Hwang KC. Adipose-derived stem cell-released osteoprotegerin protects cardiomyocytes from reactive oxygen species-induced cell death. Stem Cell Res Ther. 2017;8:195. doi: 10.1186/s13287-017-0647-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Takatani-Nakase T, Katayama M, Matsui C, Hanaoka K, van der Vlies AJ, Takahashi K, Nakase I, Hasegawa U. Hydrogen sulfide donor micelles protect cardiomyocytes from ischemic cell death. Mol Biosyst. 2017;13:1705–1708. doi: 10.1039/c7mb00191f. [DOI] [PubMed] [Google Scholar]
- 14.Tsai CY, Wen SY, Cheng SY, Wang CH, Yang YC, Viswanadha VP, Huang CY, Kuo WW. Nrf2 activation as a protective feedback to limit cell death in high glucose-exposed cardiomyocytes. J Cell Biochem. 2017;118:1659–1669. doi: 10.1002/jcb.25785. [DOI] [PubMed] [Google Scholar]
- 15.Adams B, Mapanga RF, Essop MF. Partial inhibition of the ubiquitin-proteasome system ameliorates cardiac dysfunction following ischemia-reperfusion in the presence of high glucose. Cardiovasc Diabetol. 2015;14:94. doi: 10.1186/s12933-015-0258-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Choi HY, Park JH, Jang WB, Ji ST, Jung SY, Kim da Y, Kang S, Kim YJ, Yun J, Kim JH, Baek SH, Kwon SM. High glucose causes human cardiac progenitor cell dysfunction by promoting mitochondrial fission: role of a GLUT1 blocker. Biomol Ther (Seoul) 2016;24:363–370. doi: 10.4062/biomolther.2016.097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ji L, Liu Y, Zhang Y, Chang W, Gong J, Wei S, Li X, Qin L. The antioxidant edaravone prevents cardiac dysfunction by suppressing oxidative stress in type 1 diabetic rats and in high-glucose-induced injured H9c2 cardiomyoblasts. Can J Physiol Pharmacol. 2016;94:996–1006. doi: 10.1139/cjpp-2015-0587. [DOI] [PubMed] [Google Scholar]
- 18.Yan J, Young ME, Cui L, Lopaschuk GD, Liao R, Tian R. Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. Circulation. 2009;119:2818–2828. doi: 10.1161/CIRCULATIONAHA.108.832915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ahmet I, Tae HJ, Lakatta EG, Talan M. Longterm low dose dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in chronic heart failure in rats. Can J Physiol Pharmacol. 2017;95:268–274. doi: 10.1139/cjpp-2016-0512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Cho S, Namkoong K, Shin M, Park J, Yang E, Ihm J, Thu VT, Kim HK, Han J. Cardiovascular protective effects and clinical applications of resveratrol. J Med Food. 2017;20:323–334. doi: 10.1089/jmf.2016.3856. [DOI] [PubMed] [Google Scholar]
- 21.Chatterjee A, Ronghe A, Padhye SB, Spade DA, Bhat NK, Bhat HK. Antioxidant activities of novel resveratrol analogs in breast cancer. J Biochem Mol Toxicol. 2018;32 doi: 10.1002/jbt.21925. [DOI] [PubMed] [Google Scholar]
- 22.Fenner A. Prostate cancer: resveratrol inhibits the AR. Nat Rev Urol. 2017;14:642. doi: 10.1038/nrurol.2017.159. [DOI] [PubMed] [Google Scholar]
- 23.Jiang Z, Chen K, Cheng L, Yan B, Qian W, Cao J, Li J, Wu E, Ma Q, Yang W. Resveratrol and cancer treatment: updates. Ann N Y Acad Sci. 2017;1403:59–69. doi: 10.1111/nyas.13466. [DOI] [PubMed] [Google Scholar]
- 24.Abharzanjani F, Afshar M, Hemmati M, Moossavi M. Short-term high dose of quercetin and resveratrol alters aging markers in human kidney cells. Int J Prev Med. 2017;8:64. doi: 10.4103/ijpvm.IJPVM_139_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kou X, Chen N. Resveratrol as a natural autophagy regulator for prevention and treatment of Alzheimer’s disease. Nutrients. 2017;9 doi: 10.3390/nu9090927. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Bagul PK, Deepthi N, Sultana R, Banerjee SK. Resveratrol ameliorates cardiac oxidative stress in diabetes through deacetylation of NFkB-p65 and histone 3. J Nutr Biochem. 2015;26:1298–1307. doi: 10.1016/j.jnutbio.2015.06.006. [DOI] [PubMed] [Google Scholar]
- 27.Bagul PK, Dinda AK, Banerjee SK. Effect of resveratrol on sirtuins expression and cardiac complications in diabetes. Biochem Biophys Res Commun. 2015;468:221–227. doi: 10.1016/j.bbrc.2015.10.126. [DOI] [PubMed] [Google Scholar]
- 28.Huang JP, Huang SS, Deng JY, Chang CC, Day YJ, Hung LM. Insulin and resveratrol act synergistically, preventing cardiac dysfunction in diabetes, but the advantage of resveratrol in diabetics with acute heart attack is antagonized by insulin. Free Radic Biol Med. 2010;49:1710–1721. doi: 10.1016/j.freeradbiomed.2010.08.032. [DOI] [PubMed] [Google Scholar]
- 29.Xiao T, Zhang Y, Wang Y, Xu Y, Yu Z, Shen X. Activation of an apoptotic signal transduction pathway involved in the upregulation of calpain and apoptosis-inducing factor in aldosterone-induced primary cultured cardiomyocytes. Food Chem Toxicol. 2013;53:364–370. doi: 10.1016/j.fct.2012.12.022. [DOI] [PubMed] [Google Scholar]
- 30.Arkat S, Umbarkar P, Singh S, Sitasawad SL. Mitochondrial peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in diabetic cardiomyopathy. Free Radic Biol Med. 2016;97:489–500. doi: 10.1016/j.freeradbiomed.2016.06.019. [DOI] [PubMed] [Google Scholar]
- 31.Han DN, Zhang DH, Wang LP, Zhang YS. Protective effect of beta-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress. Peptides. 2013;44:120–126. doi: 10.1016/j.peptides.2013.03.028. [DOI] [PubMed] [Google Scholar]
- 32.Guleria RS, Choudhary R, Tanaka T, Baker KM, Pan J. Retinoic acid receptor-mediated signaling protects cardiomyocytes from hyperglycemia induced apoptosis: role of the renin-angiotensin system. J Cell Physiol. 2011;226:1292–1307. doi: 10.1002/jcp.22457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Pan Y, Wang Y, Zhao Y, Peng K, Li W, Wang Y, Zhang J, Zhou S, Liu Q, Li X, Cai L, Liang G. Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy. Diabetes. 2014;63:3497–3511. doi: 10.2337/db13-1577. [DOI] [PubMed] [Google Scholar]
- 34.Suzuki H, Kayama Y, Sakamoto M, Iuchi H, Shimizu I, Yoshino T, Katoh D, Nagoshi T, Tojo K, Minamino T, Yoshimura M, Utsunomiya K. Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. Diabetes. 2015;64:618–630. doi: 10.2337/db13-1896. [DOI] [PubMed] [Google Scholar]
- 35.Tschope C, Walther T, Escher F, Spillmann F, Du J, Altmann C, Schimke I, Bader M, Sanchez-Ferrer CF, Schultheiss HP, Noutsias M. Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J. 2005;19:2057–2059. doi: 10.1096/fj.05-4095fje. [DOI] [PubMed] [Google Scholar]
- 36.Vulesevic B, McNeill B, Giacco F, Maeda K, Blackburn NJ, Brownlee M, Milne RW, Suuronen EJ. Methylglyoxal-induced endothelial cell loss and inflammation contribute to the development of diabetic cardiomyopathy. Diabetes. 2016;65:1699–1713. doi: 10.2337/db15-0568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Wada T, Kenmochi H, Miyashita Y, Sasaki M, Ojima M, Sasahara M, Koya D, Tsuneki H, Sasaoka T. Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by highfat and high-fructose diet. Endocrinology. 2010;151:2040–2049. doi: 10.1210/en.2009-0869. [DOI] [PubMed] [Google Scholar]
- 38.Xu W, Chen J, Lin J, Liu D, Mo L, Pan W, Feng J, Wu W, Zheng D. Exogenous H2S protects H9c2 cardiac cells against high glucose-induced injury and inflammation by inhibiting the activation of the NF-kappaB and IL-1beta pathways. Int J Mol Med. 2015;35:177–186. doi: 10.3892/ijmm.2014.2007. [DOI] [PubMed] [Google Scholar]
- 39.Liu Q, Wang S, Cai L. Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage. J Diabetes Investig. 2014;5:623–634. doi: 10.1111/jdi.12250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Zhang C, Zhang L, Chen S, Feng B, Lu X, Bai Y, Liang G, Tan Y, Shao M, Skibba M, Jin L, Li X, Chakrabarti S, Cai L. The prevention of diabetic cardiomyopathy by non-mitogenic acidic fibroblast growth factor is probably mediated by the suppression of oxidative stress and damage. PLoS One. 2013;8:e82287. doi: 10.1371/journal.pone.0082287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Akanda MR, Park BY. Involvement of MAPK/NF-kappaB signal transduction pathways: camellia japonica mitigates inflammation and gastric ulcer. Biomed Pharmacother. 2017;95:1139–1146. doi: 10.1016/j.biopha.2017.09.031. [DOI] [PubMed] [Google Scholar]
- 42.Guo RM, Xu WM, Lin JC, Mo LQ, Hua XX, Chen PX, Wu K, Zheng DD, Feng JQ. Activation of the p38 MAPK/NF-kappaB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells. Mol Med Rep. 2013;8:603–608. doi: 10.3892/mmr.2013.1554. [DOI] [PubMed] [Google Scholar]
- 43.Jeon YJ, Kim BH, Kim S, Oh I, Lee S, Shin J, Kim TY. Rhododendrin ameliorates skin inflammation through inhibition of NF-kappaB, MAPK, and PI3K/Akt signaling. Eur J Pharmacol. 2013;714:7–14. doi: 10.1016/j.ejphar.2013.05.041. [DOI] [PubMed] [Google Scholar]
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