L‑carnitine alleviates oxidative stress‑related damage via MAPK signaling in human lens epithelial cells exposed to H2O2

Li,Xiaoxia; Meng,Fanlan; Li,Hua; Hua,Xia; Wu,Li'an; Yuan,Xiaoyong

doi:10.3892/ijmm.2019.4283

L‑carnitine alleviates oxidative stress‑related damage via MAPK signaling in human lens epithelial cells exposed to H2O2

Authors:
- Xiaoxia Li
- Fanlan Meng
- Hua Li
- Xia Hua
- Li'an Wu
- Xiaoyong Yuan
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Affiliations: Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, P.R. China, Department of Ophthalmology, Tianjin Orbit Research Institute, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China, Xi'an No. 4 Hospital, Shaanxi Ophthalmic Medical Center, Affiliated Guangren Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: July 22, 2019 https://doi.org/10.3892/ijmm.2019.4283
Pages: 1515-1522

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Abstract

L‑carnitine (LC) is well known for its antioxidative properties. The present study aimed to evaluate the effects of LC on human lens epithelial cells (HLECs) and to analyze its regulatory mechanism in cataractogenesis. HLE B‑3 cells were cultured with hydrogen peroxide (H2O2) and were pretreated with or without LC. The Cell Counting kit‑8 assay was used to determine cell viability. Reactive oxygen species (ROS) assay kit was used to measure the cellular ROS production induced by H2O2 and LC. In addition, reverse transcription‑quantitative PCR and western blot analysis were performed to detect the expression levels of oxidative damage markers and antioxidant enzymes. Notably, ROS overproduction was observed upon exposure to H2O2, whereas LC supplementation markedly decreased ROS levels through activation of the antioxidant enzymes forkhead box O1, peroxiredoxin 4 and catalase. Furthermore, LC suppressed the expression of apoptosis‑associated genes (caspase-3) and inflammation‑associated genes [interleukin (IL)1, IL6, IL8 and cyclooxygenase‑2]. Conversely, LC promoted proliferating cell nuclear antigen, cyclin‑dependent kinase (CDK)2 and CDK4 expression, which may increase proliferation of HLECs that were incubated with H2O2. In addition, epithelial‑mesenchymal transition occurred upon ROS accumulation, whereas the effects of H2O2 on AQP1 and vimentin expression were reversed upon LC supplementation. Notably, this study revealed that LC restored the oxidant/antioxidant balance and protected against cell damage through the mitogen‑activated protein kinase signaling pathway. In conclusion, LC may serve a protective role in curbing oxidative damage and therefore may be considered a potential therapeutic agent for the treatment of cataracts.

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1	Nagai N, Ito Y and Takeuchi N: Correlation between hyper-sensitivity to hydrogen peroxide and low defense against Ca(2+) influx in cataractogenic lens of Ihara cataract rats. Biol Pharm Bull. 34:1005–1010. 2011. View Article : Google Scholar : PubMed/NCBI
2	Zuercher J, Neidhardt J, Magyar I, Labs S, Moore AT, Tanner FC, Waseem N, Schorderet DF, Munier FL, Bhattacharya S, et al: Alterations of the 5′ untranslated region of SLC16A12 lead to age-related cataract. Invest Ophthalmol Vis Sci. 51:3354–3361. 2010. View Article : Google Scholar : PubMed/NCBI
3	Chang D, Zhang X, Rong S, Sha Q, Liu P, Han T and Pan H: Serum antioxidative enzymes levels and oxidative stress products in age-related cataract patients. Oxid Med Cell Longev. 2013:5878262013. View Article : Google Scholar : PubMed/NCBI
4	Mok JW, Chang DJ and Joo CK: Antiapoptotic effects of anthocyanin from the seed coat of black soybean against oxidative damage of human lens epithelial cell induced by H₂O₂. Curr Eye Res. 39:1090–1098. 2014. View Article : Google Scholar : PubMed/NCBI
5	Fujii J, Ikeda Y, Kurahashi T and Homma T: Physiological and pathological views of peroxiredoxin 4. Free Radic Biol Med. 83:373–379. 2015. View Article : Google Scholar : PubMed/NCBI
6	Yamada S and Guo X: Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease. Pathol Int. 68:91–101. 2018. View Article : Google Scholar : PubMed/NCBI
7	Kim DH, Park CH, Park D, Choi YJ, Park MH, Chung KW, Kim SR, Lee JS and Chung HY: Ginsenoside Rc modulates Akt/FoxO1 pathways and suppresses oxidative stress. Arch Pharm Res. 37:813–820. 2014. View Article : Google Scholar
8	Kubo E, Shibata T, Singh DP and Sasaki H: Roles of TGF β and FGF signals in the lens: Tropomyosin regulation for posterior capsule opacity. Int J Mol Sci. 19:E30932018. View Article : Google Scholar
9	Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 15:178–196. 2014. View Article : Google Scholar : PubMed/NCBI
10	Schey KL, Petrova RS, Gletten RB and Donaldson PJ: The role of aquaporins in ocular lens homeostasis. Int J Mol Sci. 18:E26932017. View Article : Google Scholar : PubMed/NCBI
11	Dahm R: Dying to see. Sci Am. 291:82–89. 2004. View Article : Google Scholar : PubMed/NCBI
12	Traina G: The neurobiology of acetyl-L-carnitine. Front Biosci (Landmark Ed). 21:1314–1329. 2016. View Article : Google Scholar
13	Nutrients Editorial Office: Erratum: l-Carnitine supplementation in recovery after exercise; Nutrients 2018, 10, 349. Nutrients. 10:E5412018. View Article : Google Scholar
14	Mishra A, Reddy IJ, Gupta PS and Mondal S: L-carnitine mediated reduction in oxidative stress and alteration in transcript level of antioxidant enzymes in sheep embryos produced in vitro. Reprod Domest Anim. 51:311–321. 2016. View Article : Google Scholar : PubMed/NCBI
15	Deng R, Su Z, Hua X, Zhang Z, Li DQ and Pflugfelder SC: Osmoprotectants suppress the production and activity of matrix metalloproteinases induced by hyperosmolarity in primary human corneal epithelial cells. Mol Vis. 20:1243–1252. 2014.PubMed/NCBI
16	Mitchell SL, Uppal K, Williamson SM, Liu K, Burgess LG, Tran V, Umfress AC, Jarrell KL, Cooke Bailey JN, Agarwal A, et al: The carnitine shuttle pathway is altered in patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 59:4978–4985. 2018. View Article : Google Scholar : PubMed/NCBI
17	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
18	Werner E, Wang H and Doetsch PW: Opposite roles for p38MAPK-driven responses and reactive oxygen species in the persistence and resolution of radiation-induced genomic instability. PLoS One. 9:e1082342014. View Article : Google Scholar : PubMed/NCBI
19	Bai J, Yang F, Dong L and Zheng Y: Ghrelin protects human lens epithelial cells against oxidative stress-induced damage. Oxid Med Cell Longev. 2017:19104502017. View Article : Google Scholar : PubMed/NCBI
20	Akasaki Y, Alvarez-Garcia O, Saito M, Caramés B, Iwamoto Y and Lotz MK: FoxO transcription factors support oxidative stress resistance in human chondrocytes. Arthritis Rheumatol. 66:3349–3358. 2014. View Article : Google Scholar : PubMed/NCBI
21	Patel H, Chen J and Kavdia M: Induced peroxidase and cytoprotective enzyme expressions support adaptation of HUVECs to sustain subsequent H₂O₂ exposure. Microvasc Res. 103:1–10. 2016. View Article : Google Scholar
22	Zhu L, Li J, Wu D and Li B: The protective effect of beta-casomor-phin-7 via promoting Foxo1 activity and nuclear translocation in human lens epithelial cells. Cutan Ocul Toxicol. 37:267–274. 2018. View Article : Google Scholar : PubMed/NCBI
23	Shamsi FA, Chaudhry IA, Boulton ME and Al-Rajhi AA: L-carnitine protects human retinal pigment epithelial cells from oxidative damage. Curr Eye Res. 32:575–584. 2007. View Article : Google Scholar : PubMed/NCBI
24	Thrimawithana TR, Rupenthal ID, Räsch SS, Lim JC, Morton JD and Bunt CR: Drug delivery to the lens for the management of cataracts. Adv Drug Deliv Rev. 126:185–194. 2018. View Article : Google Scholar : PubMed/NCBI
25	Yuan X, Marcano DC, Shin CS, Hua X, Isenhart LC, Pflugfelder SC and Acharya G: Ocular drug delivery nanowafer with enhanced therapeutic efficacy. ACS Nano. 9:1749–1758. 2015. View Article : Google Scholar : PubMed/NCBI
26	Zhao C, Fu MJ and Qiu LH: Molecular cloning and functional characterization of cyclin E and CDK2 from penaeus monodon. Genet Mol Res. 15:2016. View Article : Google Scholar
27	Kanska J, Zakhour M, Taylor-Harding B, Karlan BY and Wiedemeyer WR: Cyclin E as a potential therapeutic target in high grade serous ovarian cancer. Gynecol Oncol. 143:152–158. 2016. View Article : Google Scholar : PubMed/NCBI
28	Chou HC, Wen LL, Chang CC, Lin CY, Jin L and Juan SH: From the cover: l-Carnitine via PPARγ- and Sirt1-dependent mechanisms attenuates epithelial-mesenchymal transition and renal fibrosis caused by perfluorooctanesulfonate. Toxicol Sci. 160:217–229. 2017. View Article : Google Scholar : PubMed/NCBI
29	Baierle M, Nascimento SN, Moro AM, Brucker N, Freitas F, Gauer B, Durgante J, Bordignon S, Zibetti M, Trentini CM, et al: Relationship between inflammation and oxidative stress and cognitive decline in the institutionalized elderly. Oxid Med Cell Longev. 2015:8041982015. View Article : Google Scholar : PubMed/NCBI
30	Dogru M, Kojima T, Simsek C and Tsubota K: Potential role of oxidative stress in ocular surface inflammation and dry eye disease. Invest Ophthalmol Vis Sci. 59:DES163–DES168. 2018. View Article : Google Scholar : PubMed/NCBI
31	Hua X, Chi W, Su L, Li J, Zhang Z and Yuan X: ROS-induced oxidative injury involved in pathogenesis of fungal keratitis via p38 MAPK activation. Sci Rep. 7:104212017. View Article : Google Scholar : PubMed/NCBI
32	Xu D, Zhu H, Fu Q, Xu S, Sun W, Chen G and Lv X: Ketamine delays progression of oxidative and damaged cataract through regulating HMGB-1/NF-κB in lens epithelial cells. Immunopharmacol Immunotoxicol. 40:303–308. 2018. View Article : Google Scholar : PubMed/NCBI
33	Jia Z, Song Z, Zhao Y, Wang X and Liu P: Grape seed proanthocyanidin extract protects human lens epithelial cells from oxidative stress via reducing NF-κB and MAPK protein expression. Mol Vis. 17:210–217. 2011.PubMed/NCBI
34	Yao K, Ye P, Zhang L, Tan J, Tang X and Zhang Y: Epigallocatechin gallate protects against oxidative stress-induced mitochondria-dependent apoptosis in human lens epithelial cells. Mol Vis. 14:217–223. 2008.PubMed/NCBI