Abstract
Systemic or hepatic inflammation is caused by intraperitoneal application of lipopolysaccharide (LPS). In this study, we investigated anti-inflammatory and antioxidant properties of combination of ginsenoside-Rg2 (G-Rg2) and -Rh1 (G-Rh1) on liver function under LPS challenging. We first confirmed that G-Rg2 and -Rh1 at 100 μg/ml did not show cytotoxicity in HepG2 cells. G-Rg2 and -Rh1 treatment significantly inhibited activation of STAT3 and TAK1, and inflammatory factors including iNOS, TNF-α, and IL-1β in peritoneal macrophages. In HepG2 cells, G-Rg2 and -Rh1 treatment inhibited activation of STAT3 and TAK1/c-Jun N-terminal kinase, and down-regulated nuclear translocation of NF-κB transcription factor. In addition, LPS-induced mitochondrial dysfunction was restored by treatment with G-Rg2 and -Rh1. Interestingly, pretreatment with G-Rg2 and -Rh1 effectively inhibited mitochondrial damage-mediated ROS production induced by LPS stimulation, and alterations of Nrf2 nuclear translocation and ARE promotor activity were involved in G-Rg2 and -Rh1 effects on balancing ROS levels. In liver tissues of LPS-treated mice, G-Rg2 and -Rh1 treatment protected liver damages and increased Nrf2 expression while reducing CD45 expression. Taken together, G-Rg2 and -Rh1 exerts a protective effect on liver function by increasing antioxidant through Nrf2 and anti-inflammatory activities through STAT3/TAK1 and NF-κB signaling pathways in liver cells and macrophages.
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References
Ahmed SM, Luo L, Namani A, Wang XJ, Tang X (2017) Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis 1863:585–597. https://doi.org/10.1016/j.bbadis.2016.11.005
Baatar D, Siddiqi MZ, Im WT, Ul Khaliq N, Hwang SG (2018) Anti-inflammatory effect of ginsenoside Rh2-Mix on lipopolysaccharide-stimulated RAW 264.7 murine macrophage cells. J Med Food 21:951–960. https://doi.org/10.1089/jmf.2018.4180
Bak MJ, Jun M, Jeong WS (2012) Antioxidant and hepatoprotective effects of the red ginseng essential oil in H(2)O(2)-treated hepG2 cells and CCl(4)-treated mice. Int J Mol Sci 13:2314–2330. https://doi.org/10.3390/ijms13022314
Cecconi M, Evans L, Levy M, Rhodes A (2018) Sepsis and septic shock. Lancet 392:75–87. https://doi.org/10.1016/S0140-6736(18)30696-2
Hai Y, Wang X, Song P, Li JY, Zhao LH, Xie F, Tan XM, Xie QJ, Yu L, Li Y, Wu ZR, Li HY (2019) Realgar transforming solution-induced differentiation of NB4 cell by the degradation of PML/RARalpha partially through the ubiquitin-proteasome pathway. Arch Pharm Res 42:684–694. https://doi.org/10.1007/s12272-019-01170-9
Hassanein T, Frederick T (2004) Mitochondrial dysfunction in liver disease and organ transplantation. Mitochondrion 4:609–620. https://doi.org/10.1016/j.mito.2004.07.015
Huynh DTN, Baek N, Sim S, Myung CS, Heo KS (2020a) Minor ginsenoside Rg2 and Rh1 attenuates LPS- via downregulating induced acute liver and kidney damages activation of TLR4-STAT1 and inflammatory cytokine production in macrophages. Int J Mol Sci 21:6656. https://doi.org/10.3390/ijms21186656
Huynh DTN, Jin Y, Myung CS, Heo KS (2020b) Inhibition of p90RSK is critical to abolish Angiotensin II-induced rat aortic smooth muscle cell proliferation and migration. Biochem Biophys Res Commun 523:267–273. https://doi.org/10.1016/j.bbrc.2019.12.053
Irie T, Muta T, Takeshige K (2000) TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-kappaB in lipopolysaccharide-stimulated macrophages. FEBS Lett 467:160–164. https://doi.org/10.1016/s0014-5793(00)01146-7
Jaeschke H (2000) Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol 15:718–724. https://doi.org/10.1046/j.1440-1746.2000.02207.x
Jiang Z, Meng Y, Bo L, Wang C, Bian J, Deng X (2018) Sophocarpine attenuates LPS-induced liver injury and improves survival of mice through suppressing oxidative stress, inflammation, and apoptosis. Mediat Inflamm 2018:5871431. https://doi.org/10.1155/2018/5871431
Jin Y, Huynh DTN, Nguyen TLL, Jeon H, Heo KS (2020) Therapeutic effects of ginsenosides on breast cancer growth and metastasis. Arch Pharm Res 43:773–787. https://doi.org/10.1007/s12272-020-01265-8
Kim DH (2018) Gut microbiota-mediated pharmacokinetics of ginseng saponins. J Ginseng Res 42:255–263. https://doi.org/10.1016/j.jgr.2017.04.011
Lee J, Park JS, Roh YS (2019) Molecular insights into the role of mitochondria in non-alcoholic fatty liver disease. Arch Pharm Res 42:935–946. https://doi.org/10.1007/s12272-019-01178-1
Lee SB, Lee WS, Shin JS, Jang DS, Lee KT (2017) Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-alpha, and IL-6 via AP-1, NF-kappaB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int Immunopharmacol 49:21–29. https://doi.org/10.1016/j.intimp.2017.05.021
Li S, Hong M, Tan HY, Wang N, Feng Y (2016) Insights into the role and interdependence of oxidative stress and inflammation in liver diseases. Oxid Med Cell Longev 2016:4234061. https://doi.org/10.1155/2016/4234061
Liu H, Liu M, Jin Z, Yaqoob S, Zheng M, Cai D, Liu J, Guo S (2019) Ginsenoside Rg2 inhibits adipogenesis in 3T3-L1 preadipocytes and suppresses obesity in high-fat-diet-induced obese mice through the AMPK pathway. Food Funct 10:3603–3614. https://doi.org/10.1039/c9fo00027e
Liu X, Yin S, Chen Y, Wu Y, Zheng W, Dong H, Bai Y, Qin Y, Li J, Feng S, Zhao P (2018) LPSinduced proinflammatory cytokine expression in human airway epithelial cells and macrophages via NFkappaB, STAT3 or AP1 activation. Mol Med Rep 17:5484–5491. https://doi.org/10.3892/mmr.2018.8542
Lugrin J, Rosenblatt-Velin N, Parapanov R, Liaudet L (2014) The role of oxidative stress during inflammatory processes. Biol Chem 395:203–230. https://doi.org/10.1515/hsz-2013-0241
Mihaly SR, Ninomiya-Tsuji J, Morioka S (2014) TAK1 control of cell death. Cell Death Differ 21:1667–1676. https://doi.org/10.1038/cdd.2014.123
Nesseler N, Launey Y, Aninat C, Morel F, Malledant Y, Seguin P (2012) Clinical review: the liver in sepsis. Crit Care 16:235. https://doi.org/10.1186/cc11381
Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295. https://doi.org/10.1074/jbc.R900010200
Qi GY, Mi YS, Fan R, Li RN, Wang YW, Li XY, Huang SX, Liu XB (2017) Tea polyphenols ameliorate hydrogen peroxide-and constant darkness-triggered oxidative stress via modulating the Keap1/Nrf2 transcriptional signaling pathway in HepG2 cells and mice liver. RSC Adv 7:32198–32208. https://doi.org/10.1039/c7ra05000c
Quan LH, Min JW, Sathiyamoorthy S, Yang DU, Kim YJ, Yang DC (2012) Biotransformation of ginsenosides Re and Rg1 into ginsenosides Rg2 and Rh1 by recombinant beta-glucosidase. Biotechnol Lett 34:913–917. https://doi.org/10.1007/s10529-012-0849-z
Ren Y, Wang JL, Zhang X, Wang H, Ye Y, Song L, Wang YJ, Tu MJ, Wang WW, Yang L, Jiang B (2017) Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression. Brain Res Bull 134:211–219. https://doi.org/10.1016/j.brainresbull.2017.08.009
Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311–322. https://doi.org/10.1002/(sici)1097-4652(200003)182:3%3c311::Aid-jcp1%3e3.0.Co;2-9
Taguchi K, Kensler TW (2020) Nrf2 in liver toxicology. Arch Pharm Res 43:337–349. https://doi.org/10.1007/s12272-019-01192-3
Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21–27. https://doi.org/10.4049/jimmunol.1401867
Walker SR, Frank DA (2012) Screening approaches to generating STAT inhibitors: allowing the hits to identify the targets. JAKSTAT 1:292–299. https://doi.org/10.4161/jkst.22662
Yang YQ, Yan XT, Wang K, Tian RM, Lu ZY, Wu LL, Xu HT, Wu YS, Liu XS, Mao W, Xu P, Liu B (2018) Triptriolide alleviates lipopolysaccharide-induced liver injury by Nrf2 and NF-kappaB signaling pathways. Front Pharmacol 9:999. https://doi.org/10.3389/fphar.2018.00999
Yuan HD, Kim DY, Quan HY, Kim SJ, Jung MS, Chung SH (2012) Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3beta via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells. Chem Biol Interact 195:35–42. https://doi.org/10.1016/j.cbi.2011.10.006
Zapelini PH, Rezin GT, Cardoso MR, Ritter C, Klamt F, Moreira JC, Streck EL, Dal-Pizzol F (2008) Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 8:211–218. https://doi.org/10.1016/j.mito.2008.03.002
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This research was supported by National Research Foundation of Korea (2019R1C1C100733112).
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Nguyen, T.L.L., Huynh, D.T.N., Jin, Y. et al. Protective effects of ginsenoside-Rg2 and -Rh1 on liver function through inhibiting TAK1 and STAT3-mediated inflammatory activity and Nrf2/ARE-mediated antioxidant signaling pathway. Arch. Pharm. Res. 44, 241–252 (2021). https://doi.org/10.1007/s12272-020-01304-4
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DOI: https://doi.org/10.1007/s12272-020-01304-4