Thioredoxin is implicated in the anti‑apoptotic effects of grape seed proanthocyanidin extract during hyperglycemia

Ren,Xiang; Lu,Heyuan; Wang,Nina; Zhang,Chenghong; Ji,Yunpeng; Cui,Shiqi; Dong,Yichen; Yang,Kaiyuan; Du,Mengyi; Diao,Fengsheng; Kong,Li

doi:10.3892/mmr.2017.7508

Thioredoxin is implicated in the anti‑apoptotic effects of grape seed proanthocyanidin extract during hyperglycemia

Authors:
- Xiang Ren
- Heyuan Lu
- Nina Wang
- Chenghong Zhang
- Yunpeng Ji
- Shiqi Cui
- Yichen Dong
- Kaiyuan Yang
- Mengyi Du
- Fengsheng Diao
- Li Kong
View Affiliations

Affiliations: Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China, Department of Traditional Chinese Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
Published online on: September 18, 2017 https://doi.org/10.3892/mmr.2017.7508
Pages: 7731-7737

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

Diabetic retinopathy has long been recognized as a microvascular disease, however, recent research has indicated that diabetic retinopathy may also be considered a neurodegenerative disease. The elucidation of the molecular mechanisms underlying the development of diabetic retinopathy is imperative for the development of preventive and treatment strategies for patients with diabetes. In the present study, grape seed proanthocyanidin extract (GSPE) was used to upregulate the expression of thioredoxin (Trx), in order to evaluate its potential as a novel agent for the prevention and treatment of neurodegenerative diseases, including diabetic retinopathy. Hematoxylin and eosin staining was performed to observe the morphology of retinal neurons, whereas flow cytometry and terminal deoxynucleotidyl transferase 2'‑deoxyuridine, 5'‑triphosphate nick‑end labeling were employed to investigate cellular apoptosis. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were performed to assess the mRNA and protein expression of target proteins in order to investigate the underlying molecular mechanisms. In vivo, it was found that the photoreceptor cell was damaged in diabetic mice but following GSPE treatment, the process could be inhibited. In vitro, the results of the current study demonstrated that, under hyperglycemic culture conditions, the expression of 78 kDa glucose‑regulated protein, which is an endoplasmic reticulum stress marker, was upregulated. In addition, the expression of Trx was downregulated and cell apoptosis was enhanced. Notably, treatment with GSPE was revealed to inhibit the neurodegenerative process induced by hyperglycemia. However, treatment with the Trx inhibitor PX12 in combination with GSPE was demonstrated to potentiate apoptosis compared with GSPE treatment alone under hyperglycemic conditions. Furthermore, the protein expression of apoptosis signal‑regulating kinase (ASK) 1 and Trx‑interacting protein (Txnip) was also upregulated by hyperglycemia, whereas GSPE was revealed to counteract this upregulation. In conclusion, the results of the present study indicate that Trx may be implicated in the mechanisms underlying the protective effects of GSPE against hyperglycemia‑induced cell degeneration and apoptosis. The molecular mechanisms may also involve inhibition of the activation of the Trx/ASK1/Txnip signaling pathway.

View Figures

View References

1	Garcia-Huerta P, Troncoso-Escudero P, Jerez C, Hetz C and Vidal RL: The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases? Brain Res. 1649:173–180. 2016. View Article : Google Scholar : PubMed/NCBI
2	Shah SZ, Zhao D, Khan SH and Yang L: Unfolded protein response pathways in neurodegenerative diseases. J Mol Neurosci. 57:529–537. 2015. View Article : Google Scholar : PubMed/NCBI
3	van Dijk HW, Verbraak FD, Kok PH, Stehouwer M, Garvin MK, Sonka M, DeVries JH, Schlingemann RO and Abramoff MD: Early neurodegeneration in the retina of type 2 diabetic patients. Invest Ophthalmol Vis Sci. 53:2715–2719. 2012. View Article : Google Scholar : PubMed/NCBI
4	Simó R and Hernández C: European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR): Neurodegeneration in the diabetic eye: New insights and therapeutic perspectives. Trends Endocrinol Metab. 25:23–33. 2014. View Article : Google Scholar : PubMed/NCBI
5	Yamagishi S, Fukami K and Matsui T: Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: A novel marker of vascular complications in high-risk patients for cardiovascular disease. Int J Cardiol. 185:263–268. 2015. View Article : Google Scholar : PubMed/NCBI
6	Sánchez-Chávez G, Hernández-Ramírez E, Osorio-Paz I, Hernández-Espinosa C and Salceda R: Potential role of endoplasmic reticulum stress in pathogenesis of diabetic retinopathy. Neurochem Res. 41:1098–1106. 2016. View Article : Google Scholar : PubMed/NCBI
7	Zeng XS, Jia JJ and Ma LF: Gensenoside Rb1 protects rat PC12 cells from oxidative stress-induced endoplasmic reticulum stress: The involvement of thioredoxin-1. Mol Cell Biochem. 410:239–246. 2015. View Article : Google Scholar : PubMed/NCBI
8	Weinberg E, Maymon T and Weinreb M: AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress. J Mol Endocrinol. 52:67–76. 2014.PubMed/NCBI
9	Laurent TC, Moore EC and Reichard P: Enzymatic synthesis of deoxyribonucleotides. Iv. Isolation and characterization of thioredoxin, the hydrogen donor from escherichia coli B. J Biol Chem. 239:3436–3444. 1964.PubMed/NCBI
10	Huh KH, Cho Y, Kim BS, Do JH, Park YJ, Joo DJ, Kim MS and Kim YS: The role of thioredoxin 1 in the mycophenolic acid-induced apoptosis of insulin-producing cells. Cell Death Dis. 4:e7212013. View Article : Google Scholar : PubMed/NCBI
11	Zeng XS, Jia JJ, Kwon Y, Wang SD and Bai J: The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radic Biol Med. 67:10–18. 2014. View Article : Google Scholar : PubMed/NCBI
12	Li SG, Ding YS, Niu Q, Xu SZ, Pang LJ, Ma RL, Jing MX, Feng GL, Liu JM and Guo SX: Grape seed proanthocyanidin extract alleviates arsenic-induced oxidative reproductive toxicity in male mice. Biomed Environ Sci. 28:272–280. 2015.PubMed/NCBI
13	Chen S, Zhu Y, Liu Z, Gao Z, Li B, Zhang D, Zhang Z, Jiang X, Liu Z, Meng L, et al: Grape seed proanthocyanidin extract ameliorates diabetic bladder dysfunction via the activation of the Nrf2 pathway. PLoS One. 10:e01264572015. View Article : Google Scholar : PubMed/NCBI
14	Kong L, Tanito M, Huang Z, Li F, Zhou X, Zaharia A, Yodoi J, McGinnis JF and Cao W: Delay of photoreceptor degeneration in tubby mouse by sulforaphane. J Neurochem. 101:1041–1052. 2007. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Tarozzi A, Angeloni C, Malaguti M, Morroni F, Hrelia S and Hrelia P: Sulforaphane as a potential protective phytochemical against neurodegenerative diseases. Oxid Med Cell Longev. 2013:4150782013. View Article : Google Scholar : PubMed/NCBI
17	Simó R and Hernández C: Novel approaches for treating diabetic retinopathy based on recent pathogenic evidence. Prog Retin Eye Res. 48:160–180. 2015. View Article : Google Scholar : PubMed/NCBI
18	Zhang X, Wang N, Barile GR, Bao S and Gillies M: Diabetic retinopathy: Neuron protection as a therapeutic target. Int J Biochem Cell Biol. 45:1525–1529. 2013. View Article : Google Scholar : PubMed/NCBI
19	Sohn EH, van Dijk HW, Jiao C, Kok PH, Jeong W, Demirkaya N, Garmager A, Wit F, Kucukevcilioglu M, van Velthoven ME, et al: Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proc Natl Acad Sci USA. 113:E2655–E2664. 2016; View Article : Google Scholar : PubMed/NCBI
20	Oakes SA and Papa FR: The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 10:173–194. 2015. View Article : Google Scholar : PubMed/NCBI
21	Placido AI, Pereira CM, Duarte AI, Candeias E, Correia SC, Carvalho C, Cardoso S, Oliveira CR and Moreira PI: Modulation of endoplasmic reticulum stress: An opportunity to prevent neurodegeneration? CNS Neurol Disord Drug Targets. 14:518–533. 2015. View Article : Google Scholar : PubMed/NCBI
22	Liu H, Cao MM, Wang Y, Li LC, Zhu LB, Xie GY and Li YB: Endoplasmic reticulum stress is involved in the connection between inflammation and autophagy in type 2 diabetes. Gen Comp Endocrinol. 210:124–129. 2015. View Article : Google Scholar : PubMed/NCBI
23	Sönmez MF and Tascioglu S: Protective effects of grape seed extract on cadmium-induced testicular damage, apoptosis, and endothelial nitric oxide synthases expression in rats. Toxicol Ind Health. 32:1486–1494. 2016. View Article : Google Scholar : PubMed/NCBI
24	Wei J, Shi Y, Hou Y, Ren Y, Du C, Zhang L, Li Y and Duan H: Knockdown of thioredoxin-interacting protein ameliorates high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells. Cell Signal. 25:2788–2796. 2013. View Article : Google Scholar : PubMed/NCBI
25	Ishaq M, Kumar S, Varinli H, Han ZJ, Rider AE, Evans MD, Murphy AB and Ostrikov K: Atmospheric gas plasma-induced ROS production activates TNF-ASK1 pathway for the induction of melanoma cancer cell apoptosis. Mol Biol Cell. 25:1523–1531. 2014. View Article : Google Scholar : PubMed/NCBI