Generic placeholder image

Current Molecular Pharmacology

Author(s): Guoqing Ren, Gonghao Xu, Renshi Li, Haifeng Xie, Zhengguo Cui, Lei Wang* and Chaofeng Zhang*

DOI: 10.2174/1874467215666220304094058

DownloadDownload PDF Flyer Cite As
Modulation of Bleomycin-induced Oxidative Stress and Pulmonary Fibrosis by Ginkgetin in Mice via AMPK

Article ID: e040322201686 Pages: 11

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Ginkgetin, a flavonoid extracted from Ginkgo biloba, has been shown to exhibit broad anti-inflammatory, anticancer, and antioxidative bioactivity. Moreover, the extract of Ginkgo folium has been reported on attenuating bleomycin-induced pulmonary fibrosis, but the anti-fibrotic effects of ginkgetin are still unclear. This study was intended to investigate the protective effects of ginkgetin against experimental pulmonary fibrosis and its underlying mechanism.

Methods: In vivo, bleomycin (5 mg/kg) in 50 μL saline was administrated intratracheally in mice. One week after bleomycin administration, ginkgetin (25 or 50 mg/kg) or nintedanib (40 mg/kg) was administrated intragastrically daily for 14 consecutive days. In vitro, the AMPK-siRNA transfection in primary lung fibroblasts further verified the regulatory effect of ginkgetin on AMPK.

Results: Administration of bleomycin caused characteristic histopathology structural changes with elevated lipid peroxidation, pulmonary fibrosis indexes, and inflammatory mediators. The bleomycin- induced alteration was normalized by ginkgetin intervention. Moreover, this protective effect of ginkgetin (20 mg/kg) was equivalent to that of nintedanib (40 mg/kg). AMPK-siRNA transfection in primary lung fibroblasts markedly blocked TGF-β1-induced myofibroblasts transdifferentiation and abolished oxidative stress.

Conclusion: All these results suggested that ginkgetin exerted ameliorative effects on bleomycininduced oxidative stress and lung fibrosis mainly through an AMPK-dependent manner.

Keywords: Ginkgetin, pulmonary fibrosis, oxidative stress, AMPK, Sirtuin 1, NADPH Oxidase 4.

Graphical Abstract

[1]
Reed, E.B.; Ard, S.; La, J.; Park, C.Y.; Culligan, L.; Fredberg, J.J.; Smolyaninova, L.V.; Orlov, S.N.; Chen, B.; Guzy, R.; Mutlu, G.M.; Dulin, N.O. Anti-fibrotic effects of tannic acid through regulation of a sustained TGF-beta receptor signaling. Respir. Res., 2019, 20(1), 168.
[http://dx.doi.org/10.1186/s12931-019-1141-8] [PMID: 31358001]
[2]
Cerri, S.; Spagnolo, P.; Luppi, F.; Richeldi, L. Management of idiopathic pulmonary fibrosis. Clin. Chest Med., 2012, 33(1), 85-94.
[http://dx.doi.org/10.1016/j.ccm.2011.11.005] [PMID: 22365248]
[3]
Feng, F.; Wang, Z.; Li, R.; Wu, Q.; Gu, C.; Xu, Y.; Peng, W.; Han, D.; Zhou, X.; Wu, J.; He, H. Citrus alkaline extracts prevent fibroblast senescence to ameliorate pulmonary fibrosis via activation of COX-2. Biomed. Pharmacother., 2019, 112, 108669.
[http://dx.doi.org/10.1016/j.biopha.2019.108669] [PMID: 30784938]
[4]
Du, M.Y.; Duan, J.X.; Zhang, C.Y.; Yang, H.H.; Guan, X.X.; Zhong, W.J.; Liu, Y.Z.; Li, Z.M.; Cheng, Y.R.; Zhou, Y.; Guan, C.X. Psoralen attenuates bleomycin-induced pulmonary fibrosis in mice through inhibiting myofibroblast activation and collagen deposition. Cell Biol. Int., 2019. Online ahead of print.
[http://dx.doi.org/10.1002/cbin.11205] [PMID: 31329322]
[5]
Li, Q.; Ye, T.; Long, T.; Peng, X. Ginkgetin exerts anti-inflammatory effects on cerebral ischemia/reperfusion-induced injury in a rat model via the TLR4/NF-κB signaling pathway. Biosci. Biotechnol. Biochem., 2019, 83(4), 675-683.
[http://dx.doi.org/10.1080/09168451.2018.1553608] [PMID: 30570395]
[6]
Watson, W.H.; Ritzenthaler, J.D.; Roman, J. Lung extracellular matrix and redox regulation. Redox Biol., 2016, 8, 305-315.
[http://dx.doi.org/10.1016/j.redox.2016.02.005] [PMID: 26938939]
[7]
Ju, K.D.; Kim, H.J.; Tsogbadrakh, B.; Lee, J.; Ryu, H.; Cho, E.J.; Hwang, Y.H.; Kim, K.; Yang, J.; Ahn, C.; Oh, K.H. HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis. Am. J. Physiol. Renal Physiol., 2016, 310(5), F342-F350.
[http://dx.doi.org/10.1152/ajprenal.00204.2015] [PMID: 26661649]
[8]
Song, P.; Zou, M.H. Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems. Free Radic. Biol. Med., 2012, 52(9), 1607-1619.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.01.025] [PMID: 22357101]
[9]
Yang, Y.; Zhao, Z.; Liu, Y.; Kang, X.; Zhang, H.; Meng, M. Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB1-AMP-activated protein kinase signaling. J. Gastroenterol. Hepatol., 2015, 30(3), 609-618.
[http://dx.doi.org/10.1111/jgh.12723] [PMID: 25168399]
[10]
Gamad, N.; Malik, S.; Suchal, K.; Vasisht, S.; Tomar, A.; Arava, S.; Arya, D.S.; Bhatia, J. Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: Pharmacological effects and molecular mechanisms. Biomed. Pharmacother., 2018, 97, 1544-1553.
[http://dx.doi.org/10.1016/j.biopha.2017.11.101] [PMID: 29793317]
[11]
Chu, H.; Jiang, S.; Liu, Q.; Ma, Y.; Zhu, X.; Liang, M.; Shi, X.; Ding, W.; Zhou, X.; Zou, H.; Qian, F.; Shaul, P.W.; Jin, L.; Wang, J. Sirtuin1 protects against systemic sclerosis-related pulmonary fibrosis by decreasing proinflammatory and profibrotic processes. Am. J. Respir. Cell Mol. Biol., 2018, 58(1), 28-39.
[http://dx.doi.org/10.1165/rcmb.2016-0192OC] [PMID: 28800254]
[12]
Liao, Z.; Zhang, J.; Wang, J.; Yan, T.; Xu, F.; Wu, B.; Xiao, F.; Bi, K.; Niu, J.; Jia, Y. The anti-nephritic activity of a polysaccharide from okra (Abelmoschus esculentus (L.) Moench) via modulation of AMPK-Sirt1-PGC-1α signaling axis mediated anti-oxidative in type 2 diabetes model mice. Int. J. Biol. Macromol., 2019, 140(1), 568-576.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.08.149] [PMID: 31442509]
[13]
Zhang, X.; Cai, Y. Effects of Ginkgo biloba leaf extract, shenmai and matrine on a human embryonic lung fibroblast fibrosis model. Exp. Ther. Med., 2018, 16(5), 4289-4295.
[http://dx.doi.org/10.3892/etm.2018.6698] [PMID: 30344702]
[14]
Zhang, L.; Liu, J.; Geng, T. Ginkgetin aglycone attenuates the apoptosis and inflammation response through nuclear factor-kB signaling pathway in ischemic-reperfusion injury. J. Cell. Biochem., 2018, 120, 8078-8085.
[http://dx.doi.org/10.1002/jcb.28086] [PMID: 30582212]
[15]
Tian, Z.; Tang, C.; Wang, Z. Neuroprotective effect of ginkgetin in experimental cerebral ischemia/reperfusion via apoptosis inhibition and PI3K/Akt/mTOR signaling pathway activation. J. Cell. Biochem., 2019, 120(10), 18487-18495.
[http://dx.doi.org/10.1002/jcb.29169] [PMID: 31265179]
[16]
Cao, J.; Tong, C.; Liu, Y.; Wang, J.; Ni, X.; Xiong, M.M. Ginkgetin inhibits growth of breast carcinoma via regulating MAPKs pathway. Biomed. Pharmacother., 2017, 96, 450-458.
[http://dx.doi.org/10.1016/j.biopha.2017.09.077] [PMID: 29031204]
[17]
Jeon, Y.J.; Jung, S.N.; Yun, J.; Lee, C.W.; Choi, J.; Lee, Y.J.; Han, D.C.; Kwon, B.M. Ginkgetin inhibits the growth of DU-145 prostate cancer cells through inhibition of STAT3 activity. Cancer Sci., 2015, 106(4), 413-420.
[http://dx.doi.org/10.1111/cas.12608] [PMID: 25611086]
[18]
Jiang, Y.; Li, D.; Ma, X.; Jiang, F.; He, Q.; Qiu, S.; Li, Y.; Wang, G. Selaginella helvetica ionic liquid-ultrasound-based extraction of biflavonoids from and investigation of their antioxidant activity. Molecules, 2018, 23(12), 3284.
[http://dx.doi.org/10.3390/molecules23123284] [PMID: 30544984]
[19]
Lou, J.S.; Bi, W.C.; Chan, G.K.L.; Jin, Y.; Wong, C.W.; Zhou, Z.Y.; Wang, H.Y.; Yao, P.; Dong, T.T.X.; Tsim, K.W.K. Ginkgetin induces autophagic cell death through p62/SQSTM1-mediated autolysosome formation and redox setting in non-small cell lung cancer. Oncotarget, 2017, 8(54), 93131-93148.
[http://dx.doi.org/10.18632/oncotarget.21862] [PMID: 29190983]
[20]
Lian, N.; Tong, J.; Li, W.; Wu, J.; Li, Y. Ginkgetin ameliorates experimental atherosclerosis in rats. Biomed. Pharmacother., 2018, 102, 510-516.
[http://dx.doi.org/10.1016/j.biopha.2018.03.107] [PMID: 29579712]
[21]
Liu, P.K.; Weng, Z.M.; Ge, G.B.; Li, H.L.; Ding, L.L.; Dai, Z.R.; Hou, X.D.; Leng, Y.H.; Yu, Y.; Hou, J. Biflavones from Ginkgo biloba as novel pancreatic lipase inhibitors: Inhibition potentials and mechanism. Int. J. Biol. Macromol., 2018, 118(Pt B), 2216-2223.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.07.085] [PMID: 30009906]
[22]
You, X.Y.; Xue, Q.; Fang, Y.; Liu, Q.; Zhang, C.F.; Zhao, C.; Zhang, M.; Xu, X.H. Preventive effects of Ecliptae herba extract and its component, ecliptasaponin A, on bleomycin-induced pulmonary fibrosis in mice. J. Ethnopharmacol., 2015, 175, 172-180.
[http://dx.doi.org/10.1016/j.jep.2015.08.034] [PMID: 26385580]
[23]
Szapiel, S.V.; Elson, N.A.; Fulmer, J.D.; Hunninghake, G.W.; Crystal, R.G. Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am. Rev. Respir. Dis., 1979, 120(4), 893-899.
[http://dx.doi.org/10.1164/arrd.1979.120.4.893] [PMID: 92208]
[24]
Tao, L.; Yang, J.; Cao, F.; Xie, H.; Zhang, M.; Gong, Y.; Zhang, C. Mogroside IIIE, a novel anti-fibrotic compound, reduces pulmonary fibrosis through Toll like receptor 4 pathways. J. Pharmacol. Exp. Ther., 2017, 361(2), 268-279.
[http://dx.doi.org/10.1124/jpet.116.239137] [PMID: 28280123]
[25]
Caja, L.; Dituri, F.; Mancarella, S.; Caballero-Diaz, D.; Moustakas, A.; Giannelli, G.; Fabregat, I. TGF-β and the tissue microenvironment: relevance in fibrosis and cancer. Int. J. Mol. Sci., 2018, 19(5), E1294.
[http://dx.doi.org/10.3390/ijms19051294] [PMID: 29701666]
[26]
Chen, L.; Li, S.; Li, W. LOX/LOXL in pulmonary fibrosis: potential therapeutic targets. J. Drug Target., 2019, 27(7), 790-796.
[http://dx.doi.org/10.1080/1061186X.2018.1550649] [PMID: 30457362]
[27]
Sato, N.; Takasaka, N.; Yoshida, M.; Tsubouchi, K.; Minagawa, S.; Araya, J.; Saito, N.; Fujita, Y.; Kurita, Y.; Kobayashi, K.; Ito, S.; Hara, H.; Kadota, T.; Yanagisawa, H.; Hashimoto, M.; Utsumi, H.; Wakui, H.; Kojima, J.; Numata, T.; Kaneko, Y.; Odaka, M.; Morikawa, T.; Nakayama, K.; Kohrogi, H.; Kuwano, K. Metformin attenuates lung fibrosis development via NOX4 suppression. Respir. Res., 2016, 17(1), 107.
[http://dx.doi.org/10.1186/s12931-016-0420-x] [PMID: 27576730]
[28]
Dong, J.; Ma, Q. Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-β1 activation and myofibroblast differentiation. Part. Fibre Toxicol., 2017, 14(1), 18.
[http://dx.doi.org/10.1186/s12989-017-0198-0] [PMID: 28595626]
[29]
Zhao, Y.; Shi, X.; Ding, C.; Feng, D.; Li, Y.; Hu, Y.; Wang, L.; Gao, D.; Tian, X.; Yao, J. Carnosic acid prevents COL1A2 transcription through the reduction of Smad3 acetylation via the AMPKα1/SIRT1 pathway. Toxicol. Appl. Pharmacol., 2018, 339, 172-180.
[http://dx.doi.org/10.1016/j.taap.2017.12.010] [PMID: 29253500]
[30]
Rangarajan, S.; Bone, N.B.; Zmijewska, A.A.; Jiang, S.; Park, D.W.; Bernard, K.; Locy, M.L.; Ravi, S.; Deshane, J.; Mannon, R.B.; Abraham, E.; Darley-Usmar, V.; Thannickal, V.J.; Zmijewski, J.W. Metformin reverses established lung fibrosis in a bleomycin model. Nat. Med., 2018, 24(8), 1121-1127.
[http://dx.doi.org/10.1038/s41591-018-0087-6] [PMID: 29967351]
[31]
Sun, J.; Chen, X.; Liu, T.; Jiang, X.; Wu, Y.; Yang, S.; Hua, W.; Li, Z.; Huang, H.; Ruan, X.; Du, X. Berberine protects against palmitate-induced apoptosis in tubular epithelial cells by promoting fatty acid oxidation. Med. Sci. Monit., 2018, 24, 1484-1492.
[http://dx.doi.org/10.12659/MSM.908927] [PMID: 29528039]
[32]
Wu, Y.L.; Zhang, Y.J.; Yao, Y.L.; Li, Z.M.; Han, X.; Lian, L.H.; Zhao, Y.Q.; Nan, J.X. Cucurbitacin E ameliorates hepatic fibrosis in vivo and in vitro through activation of AMPK and blocking mTOR-dependent signaling pathway. Toxicol. Lett., 2016, 258, 147-158.
[http://dx.doi.org/10.1016/j.toxlet.2016.06.2102] [PMID: 27363783]
[33]
Hwang, J.T.; Kwon, D.Y.; Yoon, S.H. AMP-activated protein kinase: A potential target for the diseases prevention by natural occurring polyphenols. Nat. Biotechnol., 2009, 26(1-2), 17-22.
[http://dx.doi.org/10.1016/j.nbt.2009.03.005] [PMID: 19818314]
[34]
Beek, T.V.A.; Scheeren, H.A.; Rantio, T.; Melger, W.C.; Lelyveld, G.P. Determination of gingkolides and bilobalide in Gingko biloba leaves and phytopharmaceuticals. J. Chromatogr. A, 1991, 543(2), 375-387.
[http://dx.doi.org/10.1016/S0021-9673(01)95789-9]
[35]
Liu, Q.; Chen, L.; Yin, W.; Nie, Y.; Zeng, P.; Yang, X. Anti-tumor effect of ginkgetin on human hepatocellular carcinoma cell lines by inducing cell cycle arrest and promoting cell apoptosis. Cell Cycle, 2022, 21(1), 74-85.
[http://dx.doi.org/10.1080/15384101.2021.1995684] [PMID: 34878966]
[36]
Deng, Z.; Fear, M.W.; Suk Choi, Y.; Wood, F.M.; Allahham, A.; Mutsaers, S.E.; Prêle, C.M. The extracellular matrix and mechanotransduction in pulmonary fibrosis. Int. J. Biochem. Cell Biol., 2020, 126, 105802.
[http://dx.doi.org/10.1016/j.biocel.2020.105802] [PMID: 32668329]
[37]
Li, L.; Cai, L.; Zheng, L.; Hu, Y.; Yuan, W.; Guo, Z.; Li, W. Gefitinib inhibits bleomycin-induced pulmonary fibrosis via alleviating the oxidative damage in mice. Oxid. Med. Cell. Longev., 2018, 2018, 8249693.
[http://dx.doi.org/10.1155/2018/8249693] [PMID: 29849916]
[38]
Papadimitriou, A.; Peixoto, E.B.; Silva, K.C.; Lopes de Faria, J.M.; Lopes de Faria, J.B. Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFβ-1 signaling. J. Nutr. Biochem., 2014, 25(7), 773-784.
[http://dx.doi.org/10.1016/j.jnutbio.2014.03.010] [PMID: 24768660]
[39]
Zhou, C.; Lyu, L.H.; Miao, H.K.; Bahr, T.; Zhang, Q.Y.; Liang, T.; Zhou, H.B.; Chen, G.R.; Bai, Y. Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK-mediated energy metabolism. Mol. Carcinog., 2020, 59(5), 545-556.
[http://dx.doi.org/10.1002/mc.23178] [PMID: 32149414]
[40]
Chai, D.; Zhang, L.; Xi, S.; Cheng, Y.; Jiang, H.; Hu, R. Nrf2 activation induced by sirt1 ameliorates acute lung injury after intestinal ischemia/reperfusion through NOX4-mediated gene regulation. Cell. Physiol. Biochem., 2018, 46(2), 781-792.
[http://dx.doi.org/10.1159/000488736] [PMID: 29621765]
[41]
Manna, P.; Jain, S.K. L-cysteine and hydrogen sulfide increase PIP3 and AMPK/PPARγ expression and decrease ROS and vascular inflammation markers in high glucose treated human U937 monocytes. J. Cell. Biochem., 2013, 114(10), 2334-2345.
[http://dx.doi.org/10.1002/jcb.24578] [PMID: 23733596]