Protective effects of catalpol on mitochondria of hepatocytes in cholestatic liver injury

Gao,Xingjuan; Xu,Jiaju; Liu,Hongbo

doi:10.3892/mmr.2020.11337

Protective effects of catalpol on mitochondria of hepatocytes in cholestatic liver injury

Authors:
- Xingjuan Gao
- Jiaju Xu
- Hongbo Liu
View Affiliations

Affiliations: Department of Pediatrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
Published online on: July 13, 2020 https://doi.org/10.3892/mmr.2020.11337
Pages: 2424-2432
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Cholestasis, which is caused by the obstruction of bile flow, can lead to rapid organ injury, cell apoptosis and necrosis of hepatocytes, and may eventually develop into fibrosis and cirrhosis. Oxidative stress and mitochondrial dysfunction are the key pathogenic signs of hepatic cholestasis. Catalpol has pharmacological activities, including antioxidative and anti‑inflammatory effects, and may relieve mitochondrial damage and restore mitochondrial membrane potential. However, the potential roles and mechanisms of catalpol in cholestasis‑induced liver injury are not clear. In the present study, liver function‑related indexes were measured in the serum of mice by commercial kits. In addition, levels of serum inflammatory factors were detected by ELISA. Hematoxylin and eosin staining was performed to observe histopathological changes, and mitochondrial membrane potential was detected using JC‑1 staining. Mitochondrial adenosine triphosphate (ATP), reactive oxygen species (ROS) and malondialdehyde levels were determined using a luciferase reporter kit, flow cytometry and a thiobarbituric acid reactive substance assay kit, respectively. Western blotting was performed to detect the expression levels of apoptosis‑related proteins in liver tissues. The findings revealed that catalpol reduced liver damage caused by cholestasis, improved the mitochondrial membrane potential, and increased the ATP content and glutathione content of cholestasis model mice. Moreover, catalpol also reduced the ROS level, inhibited lipid peroxidation, and regulated oxidative stress and apoptotic protein expression. Thus, the present study preliminarily confirmed that catalpol can reduce liver injury in a mouse model of cholestasis through inhibiting oxidative stress and enhancing mitochondrial membrane potential.

View Figures

View References

1	Afonso MB, Rodrigues PM, Simao AL, Ofengeim D, Carvalho T, Amaral JD, Gaspar MM, Cortez-Pinto H, Castro RE, Yuan J, et al: Activation of necroptosis in human and experimental cholestasis. Cell Death Dis. 7:e23902016. View Article : Google Scholar : PubMed/NCBI
2	Vinken M: In vitro prediction of drug-induced cholestatic liver injury: A challenge for the toxicologist. Arch Toxicol. 92:1909–1912. 2018. View Article : Google Scholar : PubMed/NCBI
3	Squires JE and McKiernan P: Molecular mechanisms in pediatric cholestasis. Gastroenterol Clin North Am. 47:921–937. 2018. View Article : Google Scholar : PubMed/NCBI
4	Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, Shneider BL, Picarsic JL, Jacobson TA, Zhang J, et al: Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun. 7:107132016. View Article : Google Scholar : PubMed/NCBI
5	Ommati MM, Farshad O, Niknahad H, Arabnezhad MR, Azarpira N, Mohammadi HR, Haghnegahdar M, Mousavi K, Akrami S, Jamshidzadeh A, et al: Cholestasis-associated reproductive toxicity in male and female rats: The fundamental role of mitochondrial impairment and oxidative stress. Toxicol Lett. 316:60–72. 2019. View Article : Google Scholar : PubMed/NCBI
6	Yin F, Yan J, Zhao Y, Guo KJ, Zhang ZL, Li AP, Meng CY and Guo L: Bone marrow mesenchymal stem cells repair Cr (VI)-injured kidney by regulating mitochondria-mediated apoptosis and mitophagy mediated via the MAPK signaling pathway. Ecotoxicol Environ Saf. 176:234–241. 2019. View Article : Google Scholar : PubMed/NCBI
7	Rajavel T, Packiyaraj P, Suryanarayanan V, Singh SK, Ruckmani K and Pandima Devi K: β-sitosterol targets Trx/Trx1 reductase to induce apoptosis in A549 cells via ROS mediated mitochondrial dysregulation and p53 activation. Sci Rep. 8:20712018. View Article : Google Scholar : PubMed/NCBI
8	Zhao X, Ren X, Zhu R, Luo Z and Ren B: Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria-mediated apoptosis in zebrafish embryos. Aquat Toxicol. 180:56–70. 2016. View Article : Google Scholar : PubMed/NCBI
9	Wang LL, Han L, Ma XL, Yu QL and Zhao SN: Effect of mitochondrial apoptotic activation through the mitochondrial membrane permeability transition pore on yak meat tenderness during postmortem aging. Food Chem. 234:323–331. 2017. View Article : Google Scholar : PubMed/NCBI
10	Xia Z, Wang F, Zhou S, Zhang R, Wang F, Huang JH, Wu E, Zhang Y and Hu Y: Catalpol protects synaptic proteins from beta-amyloid induced neuron injury and improves cognitive functions in aged rats. Oncotarget. 8:69303–69315. 2017. View Article : Google Scholar : PubMed/NCBI
11	Huang JZ, Wu J, Xiang S, Sheng S, Jiang Y, Yang Z and Hua F: Catalpol preserves neural function and attenuates the pathology of Alzheimer's disease in mice. Mol Med Rep. 13:491–496. 2016. View Article : Google Scholar : PubMed/NCBI
12	Gao J, An L, Xu Y and Huang Y: Catalpol exerts an anti-epilepticus effect, possibly by regulating the Nrf2-Keap1-ARE signaling pathway. Med Sci Monit. 24:9436–9441. 2018. View Article : Google Scholar : PubMed/NCBI
13	Lin CM, Wang BW, Fang WJ, Pan CM, Shyu KG and Hou SW: Catalpol ameliorates neointimal hyperplasia in diabetic rats. Planta Med. 85:406–411. 2019. View Article : Google Scholar : PubMed/NCBI
14	Zhang H, Jia R, Wang F, Qiu G, Qiao P, Xu X and Wu D: Catalpol protects mice against Lipopolysaccharide/D-galactosamine-induced acute liver injury through inhibiting inflammatory and oxidative response. Oncotarget. 9:3887–3894. 2018. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Wang C, Jin Y, Yang Q, Meng Q, Liu Q, Dai Y, Cai L, Liu Z and Liu K; Sun H Activating the PGC-1α/TERT pathway by catalpol ameliorates atherosclerosis via modulating ROS production, DNA damage, telomere function, : Implications on mitochondria and telomere link. Oxid Med Cell Longev. 2018:28763502018. View Article : Google Scholar : PubMed/NCBI
16	Park KS: Catalpol reduces the production of inflammatory mediators via PPAR-gamma activation in human intestinal Caco-2 cells. J Natural Med. 70:620–626. 2016. View Article : Google Scholar
17	National Research Council Committee for the Update of the Guide for the C and use of laboratory A, . The National Academies Collection: Reports funded by National Institutes of Health. Guide for the care and use of laboratory Animals. National Academies Press (US) Copyright © 2011, National Academy of Sciences. (Washington (DC)). 2011.PubMed/NCBI
18	Cai Q, Ma T, Li C, Tian Y and Li H: Catalpol protects Pre-myelinating oligodendrocytes against Ischemia-induced oxidative injury through ERK1/2 signaling pathway. Int J Biol Sci. 12:1415–1426. 2016. View Article : Google Scholar : PubMed/NCBI
19	Xu D, Wang L, Jiang Z, Zhao G, Hassan HM, Sun L, Fan S, Zhou Z, Zhang L and Wang T: A new hypoglycemic mechanism of catalpol revealed by enhancing MyoD/MyoG-mediated myogenesis. Life Sci. 209:313–323. 2018. View Article : Google Scholar : PubMed/NCBI
20	Zeng YF, Wang R, Bian Y, Chen WS and Peng L: Catalpol attenuates IL-1β induced matrix catabolism, apoptosis and inflammation in rat chondrocytes and inhibits cartilage degeneration. Med Sci Monit. 25:6649–6659. 2019. View Article : Google Scholar : PubMed/NCBI
21	Lin C, Lu Y, Yan X, Wu X, Kuai M, Sun X, Chen Q, Kong X, Liu Z, Tang Y, et al: Catalpol protects glucose-deprived rat embryonic cardiac cells by inducing mitophagy and modulating estrogen receptor. Biomed Pharmacother. 89:973–982. 2017. View Article : Google Scholar : PubMed/NCBI
22	Sun W, Gao Y, Ding Y, Cao Y, Chen J, Lv G, Lu J, Yu B, Peng M, Xu H, et al: Catalpol ameliorates advanced glycation end product-induced dysfunction of glomerular endothelial cells via regulating nitric oxide synthesis by inducible nitric oxide synthase and endothelial nitric oxide synthase. IUBMB Life. 71:1268–1283. 2019. View Article : Google Scholar : PubMed/NCBI
23	Ma X, Wen JX, Gao SJ, He X, Li PY, Yang YX, Wei SZ, Zhao YL and Xiao XH: Paeonia lactiflora Pall. regulates the NF-κB-NLRP3 inflammasome pathway to alleviate cholestasis in rats. J Pharm Pharmacol. 70:1675–1687. 2018. View Article : Google Scholar : PubMed/NCBI
24	Wang L, Cao F, Zhu LL, Liu P, Shang YR, Liu WH, Dong X, Bao HD, Gong P and Wang ZY: Andrographolide impairs alpha-naphthylisothiocyanate-induced cholestatic liver injury in vivo. J Natural Med. 73:388–396. 2019. View Article : Google Scholar
25	Wagner M and Trauner M: Recent advances in understanding and managing cholestasis. F1000Research. 5:F1000 Faculty Rev–705. 2016. View Article : Google Scholar
26	Heidari R and Niknahad H: The role and study of mitochondrial impairment and oxidative stress in cholestasis. Methods Mol Biol. 1981:117–132. 2019. View Article : Google Scholar : PubMed/NCBI
27	Baud O, Li J, Zhang Y, Neve RL, Volpe JJ and Rosenberg PA: Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. Eur J Neurosci. 20:1713–1726. 2004. View Article : Google Scholar : PubMed/NCBI
28	Javadov S, Karmazyn M and Escobales N: Mitochondrial permeability transition pore opening as a promising therapeutic target in cardiac diseases. J Pharmacol Exp Ther. 330:670–678. 2009. View Article : Google Scholar : PubMed/NCBI
29	Zhang XL, Jiang B, Li ZB, Hao S and An LJ: Catalpol ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Pharmacol Biochem Behav. 88:64–72. 2007. View Article : Google Scholar : PubMed/NCBI
30	Bi J, Wang XB, Chen L, Hao S, An LJ, Jiang B and Guo L: Catalpol protects mesencephalic neurons against MPTP induced neurotoxicity via attenuation of mitochondrial dysfunction and MAO-B activity. Toxicol In Vitro. 22:1883–1889. 2008. View Article : Google Scholar : PubMed/NCBI
31	Riddle A, Luo NL, Manese M, Beardsley DJ, Green L, Rorvik DA, Kelly KA, Barlow CH, Kelly JJ, Hohimer AR and Back SA: Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury. J Neurosc. 26:3045–3055. 2006. View Article : Google Scholar
32	Xiong Y, Shi L, Wang L, Zhou Z, Wang C, Lin Y, Luo D, Qiu J and Chen D: Activation of sirtuin 1 by catalpol-induced down-regulation of microRNA-132 attenuates endoplasmic reticulum stress in colitis. Pharmacol Res. 123:73–82. 2017. View Article : Google Scholar : PubMed/NCBI
33	Antus B: Oxidative stress markers in sputum. Oxid Med Cell Longev. 2016:29304342016. View Article : Google Scholar : PubMed/NCBI
34	Shaker RA, Abboud SH, Assad HC and Hadi N: Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. BMC Oharmacol Toxicol. 19:32018. View Article : Google Scholar
35	Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, Aghaei F, Esfandiari A, Azarpira N and Niknahad H: Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. Biomed Pharmacother. 97:1086–1095. 2018. View Article : Google Scholar : PubMed/NCBI
36	Sharanek A, Burban A, Ciriaci N and Guillouzo A: Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics. Toxicol In Vitro. 58:51–59. 2019. View Article : Google Scholar : PubMed/NCBI
37	Xu YJ, Yu ZQ, Zhang CL, Li XP, Feng CY, Lei K, He WX and Liu D: Protective effects of ginsenosides on 17[Formula: See text]-Ethynyelstradiol-Induced intrahepatic cholestasis via anti-oxidative and anti-inflammatory mechanisms in rats. Am J Chin Med. 45:1613–1629. 2017. View Article : Google Scholar : PubMed/NCBI