Effects of thymosin β4 on oxygen‑glucose deprivation and reoxygenation‑induced injury

Ji,Hua; Xu,Linhao; Wang,Zheng; Fan,Xinli; Wu,Lihui

doi:10.3892/ijmm.2018.3369

Effects of thymosin β4 on oxygen‑glucose deprivation and reoxygenation‑induced injury

Authors:
- Hua Ji
- Linhao Xu
- Zheng Wang
- Xinli Fan
- Lihui Wu
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Affiliations: Department of Basic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China, Department of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang 310053, P.R. China
Published online on: January 9, 2018 https://doi.org/10.3892/ijmm.2018.3369
Pages: 1749-1755

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Abstract

Cerebral ischemia causes severe brain injury and results in selective neuronal death through programmed cell death mechanisms, including apoptosis and autophagy. Minimizing neuronal injury has been considered a hot topic among clinicians. The present study elucidated the effect of thymosin β4 (Tβ4) on neuronal death induced by cerebral ischemia/reperfusion in PC12 cells that were subjected to oxygen‑glucose deprivation and reoxygenation (OGD/R). The survival, apoptotic and autophagy rates of PC12 cells were investigated. Tβ4 pre‑conditioning prior to OGD/R was performed to evaluate PC12‑cell viability and the protective mechanisms of Tβ4. Tβ4 significantly increased cell survival after OGD/R. Tβ4 inhibited the release of lactate dehydrogenase, downregulated malondialdehyde and upregulated the activities of glutathione peroxidase and superoxide dismutase. In addition, Tβ4 attenuated OGD/R‑associated decreases in the expression of P62 and the anti‑apoptotic protein B‑cell lymphoma‑2, as well as the upregulation of autophagy mediators, including autophagy‑related protein‑5 and the ratio of microtubule‑associated protein 1 light chain 3 (LC3) II vs. LC3 I. These results suggested that Tβ4 effectively inhibits cell apoptosis and autophagy induced by OGD/R. To the best of our knowledge, the present study was the first to report on the antioxidant, anti‑apoptotic and anti‑autophagic effects of Tβ4 in neuronal‑like PC12 cells. These results suggested that Tβ4 may be explored as a potential treatment for cerebral ischemia.

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1	Matsumaru Y, Ishikawa E, Yamamoto T and Matsumura A: Recent trends in neuro-endovascular treatment for acute ischemic stroke, cerebral aneurysms, carotid stenosis, and brain arteriovenous malformations. Neurol Med Chir (Tokyo). 57:253–260. 2017. View Article : Google Scholar
2	Rocha-Ferreira E, Kelen D, Faulkner S, Broad KD, Chandrasekaran M, Kerenyi Á, Kato T, Bainbridge A, Golay X, Sullivan M, et al: Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model. J Neuroinflammation. 14:442017. View Article : Google Scholar : PubMed/NCBI
3	Li N, Yuan Q, Cao XL, Zhang Y, Min ZL, Xu SQ, Yu ZJ, Cheng J, Zhang C and Hu XM: Opposite effects of HDAC5 and p300 on MRTF-A-related neuronal apoptosis during ischemia/reperfusion injury in rats. Cell Death Dis. 8:e26242017. View Article : Google Scholar : PubMed/NCBI
4	Goldstein AL, Hannappel E and Kleinman HK: Thymosin beta4: Actin-sequestering protein moonlights to repair injured tissues. Trends Mol Med. 11:421–429. 2005. View Article : Google Scholar : PubMed/NCBI
5	Kim S and Kwon J: Thymosin beta 4 improves dermal burn wound healing via downregulation of receptor of advanced glycation end products in db/db mice. Biochim Biophys Acta. 1840:3452–3459. 2014. View Article : Google Scholar : PubMed/NCBI
6	Marks ED and Kumar A: Thymosin β4: Roles in development, repair, and engineering of the cardiovascular system. Vitam Horm. 102:227–249. 2016. View Article : Google Scholar
7	Zhu J, Song J, Yu L, Zheng H, Zhou B, Weng S and Fu G: Safety and efficacy of autologous thymosin β4 pre-treated endothelial progenitor cell transplantation in patients with acute ST segment elevation myocardial infarction: A pilot study. Cytotherapy. 18:1037–1042. 2016. View Article : Google Scholar : PubMed/NCBI
8	Guarnera G, DE Rosa A and Camerini R: Thymosin beta-4 and venous ulcers: Clinical remarks on a European prospective, randomized study on safety, tolerability, and enhancement on healing. Ann N Y Acad Sci. 1112:407–412. 2007. View Article : Google Scholar : PubMed/NCBI
9	Choi SY, Noh MR, Kim DK, Sun W and Kim H: Neuroprotective function of thymosin-beta and its derivative peptides on the programmed cell death of chick and rat neurons. Biochem Biophys Res Commun. 362:587–593. 2007. View Article : Google Scholar : PubMed/NCBI
10	Popoli P, Pepponi R, Martire A, Armida M, Pèzzola A, Galluzzo M, Domenici MR, Potenza RL, Tebano MT, Mollinari C, et al: Neuroprotective effects of thymosin beta4 in experimental models of excitotoxicity. Ann N Y Acad Sci. 1112:219–224. 2007. View Article : Google Scholar : PubMed/NCBI
11	Morris DC, Cui Y, Cheung WL, Lu M, Zhang L, Zhang ZG and Chopp M: A dose-response study of thymosin β4 for the treatment of acute stroke. J Neurol Sci. 345:61–67. 2014. View Article : Google Scholar : PubMed/NCBI
12	Xiong Y, Mahmood A, Meng Y, Zhang Y, Zhang ZG, Morris DC and Chopp M: Treatment of traumatic brain injury with thymosin β4 in rats. J Neurosurg. 114:102–115. 2011. View Article : Google Scholar
13	Santra M, Chopp M, Zhang ZG, Lu M, Santra S, Nalani A, Santra S and Morris DC: Thymosin β4 mediates oligodendrocyte differentiation by upregulating p38 MAPK. Glia. 60:1826–1838. 2012. View Article : Google Scholar : PubMed/NCBI
14	Northington FJ, Chavez-Valdez R and Martin LJ: Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol. 69:743–758. 2011. View Article : Google Scholar : PubMed/NCBI
15	Huang J and Klionsky DJ: Autophagy and human disease. Cell Cycle. 6:1837–1849. 2007. View Article : Google Scholar : PubMed/NCBI
16	Levine B, Mizushima N and Virgin HW: Autophagy in immunity and inflammation. Nature. 469:323–335. 2011. View Article : Google Scholar : PubMed/NCBI
17	Oh BM, Lee SJ, Cho HJ, Park YS, Kim JT, Yoon SR, Lee SC, Lim JS, Kim BY, Choe YK and Lee HG: Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer. Cell Death Dis. 8:e30532017. View Article : Google Scholar : PubMed/NCBI
18	Nixon RA: Autophagy in neurodegenerative disease: Friend, foe or turncoat? Trends Neurosci. 29:528–535. 2006. View Article : Google Scholar : PubMed/NCBI
19	Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, Kawahara N, Kuida K, Nagata S, Kominami E, et al: Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol. 172:454–469. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ginet V, Puyal J, Clarke PG and Truttmann AC: Enhancement of autophagic flux after neonatal cerebral hypoxia-ischemia and its region-specific relationship to apoptotic mechanisms. Am J Pathol. 175:1962–1974. 2009. View Article : Google Scholar : PubMed/NCBI
21	Tabakman R, Jiang H, Levine RA, Kohen R and Lazarovici P: Apoptotic characteristics of cell death and the neuroprotective effect of homocarnosine on pheochromocytoma PC12 cells exposed to ischemia. J Neurosci Res. 75:499–507. 2004. View Article : Google Scholar : PubMed/NCBI
22	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
23	Dai R, Zhang S, Duan W, Wei R, Chen H, Cai W, Yang L and Wang Q: Enhanced autophagy contributes to protective effects of GM1 ganglioside against Aβ1-42-induced neurotoxicity and cognitive deficits. Neurochem Res. 42:2417–2426. 2017. View Article : Google Scholar : PubMed/NCBI
24	Rabinowitz JD and White E: Autophagy and metabolism. Science. 330:1344–1348. 2010. View Article : Google Scholar : PubMed/NCBI
25	Rubinsztein DC, DiFiglia M, Heintz N, Nixon RA, Qin ZH, Ravikumar B, Stefanis L and Tolkovsky A: Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy. 1:11–22. 2005. View Article : Google Scholar
26	Rami A, Langhagen A and Steiger S: Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis. 29:132–141. 2008. View Article : Google Scholar
27	Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, et al: Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury. Autophagy. 12:410–423. 2016. View Article : Google Scholar : PubMed/NCBI
28	Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B and Sadoshima J: Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 100:914–922. 2007. View Article : Google Scholar : PubMed/NCBI
29	Geng J and Klionsky DJ: Direct quantification of autophagic flux by a single molecule-based probe. Autophagy. 13:639–641. 2017. View Article : Google Scholar : PubMed/NCBI
30	Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, et al: Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell. 51:618–631. 2013. View Article : Google Scholar : PubMed/NCBI
31	Song S, Tan J, Miao Y, Li M and Zhang Q: Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress. J Cell Physiol. 232:2977–2984. 2017. View Article : Google Scholar : PubMed/NCBI
32	Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, Geneste O and Kroemer G: BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L). Autophagy. 3:374–376. 2007. View Article : Google Scholar : PubMed/NCBI
33	Du Y and Ji X: Bcl-2 down-regulation by small interfering RNA induces Beclin1-dependent autophagy in human SGC-7901 cells. Cell Biol Int. 38:1155–1162. 2014. View Article : Google Scholar : PubMed/NCBI