Full Text:   <1337>

Summary:  <433>

Suppl. Mater.: 

CLC number: 

On-line Access: 2024-08-27

Received: 2023-10-17

Revision Accepted: 2024-05-08

Crosschecked: 2023-07-17

Cited: 0

Clicked: 1670

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Jingquan DONG

https://orcid.org/0000-0001-9696-9681

Mian FU

https://orcid.org/0009-0006-6733-0970

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.7 P.617-631

http://doi.org/10.1631/jzus.B2200612


Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways


Author(s):  Xiao ZHANG, Zhicheng DONG, Hui FAN, Qiankun YANG, Guili YU, Enzhuang PAN, Nana HE, Xueqing LI, Panpan ZHAO, Mian FU, Jingquan DONG

Affiliation(s):  Jiangsu Key Laboratory of Marine Bioresources and Environment / Co-Innovation Center of Jiangsu Marine Bio-Industry Technology / Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University,Lianyungang222005,China; more

Corresponding email(s):   fumian@mail.nankai.edu.cn, 2018000029@jou.edu.cn

Key Words:  Scutellarin, Oxidative stress, Alcoholic liver disease, Inflammation


Xiao ZHANG, Zhicheng DONG, Hui FAN, Qiankun YANG, Guili YU, Enzhuang PAN, Nana HE, Xueqing LI, Panpan ZHAO, Mian FU, Jingquan DONG. Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways[J]. Journal of Zhejiang University Science B, 2023, 24(7): 617-631.

@article{title="Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways",
author="Xiao ZHANG, Zhicheng DONG, Hui FAN, Qiankun YANG, Guili YU, Enzhuang PAN, Nana HE, Xueqing LI, Panpan ZHAO, Mian FU, Jingquan DONG",
journal="Journal of Zhejiang University Science B",
volume="24",
number="7",
pages="617-631",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200612"
}

%0 Journal Article
%T Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways
%A Xiao ZHANG
%A Zhicheng DONG
%A Hui FAN
%A Qiankun YANG
%A Guili YU
%A Enzhuang PAN
%A Nana HE
%A Xueqing LI
%A Panpan ZHAO
%A Mian FU
%A Jingquan DONG
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 7
%P 617-631
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200612

TY - JOUR
T1 - Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways
A1 - Xiao ZHANG
A1 - Zhicheng DONG
A1 - Hui FAN
A1 - Qiankun YANG
A1 - Guili YU
A1 - Enzhuang PAN
A1 - Nana HE
A1 - Xueqing LI
A1 - Panpan ZHAO
A1 - Mian FU
A1 - Jingquan DONG
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 7
SP - 617
EP - 631
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200612


Abstract: 
alcoholic liver disease (ALD) is the most frequent liver disease worldwide, resulting in severe harm to personal health and posing a serious burden to public health. Based on the reported antioxidant and anti-inflammatory capacities of scutellarin (SCU), this study investigated its protective role in male BALB/c mice with acute alcoholic liver injury after oral administration (10, 25, and 50 mg/kg). The results indicated that SCU could lessen serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and improve the histopathological changes in acute alcoholic liver; it reduced alcohol-induced malondialdehyde (MDA) content and increased glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity. Furthermore, SCU decreased tumor necrosis factor-‍α (TNF-‍α), interleukin-6 (IL-6), andIL-‍1β messenger RNA (mRNA) expression levels, weakened inducible nitric oxide synthase (iNOS) activity, and inhibited nucleotide-binding oligomerization domain (NOD)‍-like receptor protein 3 (NLRP3) inflammasome activation. Mechanistically, SCU suppressed cytochrome P450 family 2 subfamily E member 1 (CYP2E1) upregulation triggered by alcohol, increased the expression of oxidative stress-related nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, and suppressed the inflammation-related degradation of inhibitor of nuclear factor-‍κB (NF-‍κB)‍-‍α (IκBα) as well as activation of NF‍-‍κB by mediating the protein kinase B (AKT) and p38 mitogen-activated protein kinase (MAPK) pathways. These findings demonstrate that SCU protects against acute alcoholic liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and suppressing inflammation by regulating the AKT, p38 MAPK/NF-κB pathways.

灯盏花乙素通过调节Nrf2/HO-1通路抑制氧化应激以及通过调节AKT、p38 MAPK/NF-κB通路抑制炎症反应预防急性酒精性肝损伤

张潇1,董志成2,樊慧1,杨乾坤1,余桂丽1,潘恩壮1,何娜娜1,李雪晴1,赵盼盼1,付免1,董井泉1
1江苏海洋大学药学院江苏省海洋生物资源与环境重点实验室/江苏省海洋生物产业技术协同创新中心/江苏省海洋药物化合物筛选重点实验室,中国连云港,222005
2连云港市第二人民医院肿瘤科,中国连云港,222000
3连云港市第一人民医院神经科学研究所,中国连云港,222000
摘要:肝病(ALD)是世界上最常见的肝脏疾病,严重危害个人健康,对公共卫生造成严重负担。基于灯盏花乙素(SCU)抗氧化和抗炎能力的报道,本研究探究了SCU(10、25和50 mg/kg,口服给药)对急性酒精性肝损伤BALB/c小鼠的保护作用。结果表明:SCU可降低血清谷丙转氨酶(ALT)和天冬氨酸转氨酶(AST)水平,改善急性酒精性肝组织病理改变;降低酒精诱导的丙二醛(MDA)含量,提高谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)和超氧化物歧化酶(SOD)活性。此外,SCU会降低肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)和IL-1β的mRNA表达水平,削弱诱导型一氧化氮合酶(iNOS)活性和抑制NOD样受体蛋白3(NLRP3)炎症小体激活。从机制方面而言,SCU可抑制酒精诱导的CYP450代谢酶家族中的CYP2E1上调,增加氧化应激相关的核因子E2相关因子2(Nrf2)和血红素加氧酶-1(HO-1)通路的表达,通过介导蛋白激酶B(AKT)和p38 MAPK通路抑制炎症相关核因子-κB抑制蛋白α因子(IκBα)的降解以及核因子-κB因子(NF-κB)的激活。这些结果表明,SCU通过调控Nrf2/HO-1通路抑制氧化应激,通过调控AKT、p38 MAPK/NF-κB通路抑制炎症反应,从而保护急性酒精性肝损伤。

关键词:灯盏花乙素;氧化应激;酒精性肝病;炎症

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AnYN,ZhangHF,WangC,et al.,2019.Activation of ROS/MAPKs/NF-κB/NLRP3 and inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis.FASEB J,33(11):12515-12527.

[2]BatailleAM,ManautouJE,2012.Nrf2: a potential target for new therapeutics in liver disease.Clin Pharmacol Ther,92(3):340-348.

[3]BianHT,WangGH,HuangJJ,et al.,2020.Scutellarin protects against lipopolysaccharide-induced behavioral deficits by inhibiting neuroinflammation and microglia activation in rats.Int Immunopharmacol,88:106943.

[4]CeniE,MelloT,GalliA,2014.Pathogenesis of alcoholic liver disease: role of oxidative metabolism.World J Gastroenterol,20(47):17756-17772.

[5]ChenMF,GongF,ZhangYY,et al.,2019.Preventive effect of YGDEY from tilapia fish skin gelatin hydrolysates against alcohol-induced damage in HepG2 cells through ROS-mediated signaling pathways.Nutrients,11(2):392.

[6]ChenYR,QueRY,LinLB,et al.,2020.Inhibition of oxidative stress and NLRP3 inflammasome by Saikosaponin-d alleviates acute liver injury in carbon tetrachloride-induced hepatitis in mice.Int J Immunopathol Pharmarol,34:2058738420950593.

[7]ChenYY,ZhangCL,ZhaoXL,et al.,2014.Inhibition of cytochrome P4502E1 by chlormethiazole attenuated acute ethanol-induced fatty liver.Chem Biol Interact,222:18-26.

[8]DingRB,TianK,CaoYW,et al.,2015.Protective effect ofPanax notoginseng saponins on acute ethanol-induced liver injury is associated with ameliorating hepatic lipid accumulation and reducing ethanol-mediated oxidative stress.J Agric Food Chem,63(9):2413-2422.

[9]FanH,MaXD,LinP,et al.,2017.Scutellarin prevents nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia via PI3K/AKT-dependent activation of nuclear factor (erythroid-derived 2)‍-like 2 (Nrf2) in rats. Med Sci Monit,23:5599-5612.

[10]FanH,TuTT,ZhangX,et al.,2022.Sinomenine attenuates alcohol-induced acute liver injury via inhibiting oxidative stress, inflammation and apoptosis in mice.Food Chem Toxicol,159:112759.

[11]Galicia-MorenoM,Lucano-LanderosS,Monroy-RamirezHC,et al.,2020.Roles of Nrf2 in liver diseases: molecular, pharmacological, and epigenetic aspects.Antioxidants,9(10):980.

[12]GouillonZQ,LucasD,LiJ,et al.,2000.Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole.Proc Soc Exp Biol Med,224(4):302-308.

[13]GuoFF,XiaoM,WangSY,et al.,2020.Downregulation of mitogen-activated protein kinases (MAPKs) in chronic ethanol-induced fatty liver.Toxicol Mech Methods,30(6):407-416.

[14]GuoXL,CuiRB,ZhaoJJ,et al.,2016.Corosolic acid protects hepatocytes against ethanol-induced damage by modulating mitogen-activated protein kinases and activating autophagy.Eur J Pharmacol,791:578-588.

[15]HayesJD,Dinkova-KostovaAT,2014.The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.Trends Biochem Sci,39(4):199-218.

[16]HeY,HaraH,NúñezG,2016.Mechanism and regulation of NLRP3 inflammasome activation.Trends Biochem Sci,41(12):1012-1021.

[17]HoekJB,PastorinoJG,2004.Cellular signaling mechanisms in alcohol-induced liver damage.Semin Liver Dis,24(3):257-272.

[18]HuX,WuXF,ZhaoB,et al.,2019.Scutellarin protects human retinal pigment epithelial cells against hydrogen peroxide (H2O2)-induced oxidative damage.Cell Biosci,9:12.

[19]IranshahyM,IranshahiM,AbtahiSR,et al.,2018.The role of nuclear factor erythroid 2-related factor 2 in hepatoprotective activity of natural products: a review.Food Chem Toxicol,120:261-276.

[20]ItohK,ChibaT,TakahashiS,et al.,1997.An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.Biochem Biophys Res Commun,236(2):313-322.

[21]JiWL,LiangK,AnR,et al.,2019.Baicalin protects against ethanol-induced chronic gastritis in rats by inhibiting Akt/NF-κB pathway.Life Sci,239:117064.

[22]KimMS,OngM,QuXQ,2016.Optimal management for alcoholic liver disease: conventional medications, natural therapy or combination?World J Gastroenterol,22(1):8-23.

[23]KirpichIA,MillerME,CaveMC,et al.,2016.Alcoholic liver disease: update on the role of dietary fat.Biomolecules,6(1):1.

[24]KongLZ,ChandimaliN,HanYH,et al.,2019.Pathogenesis, early diagnosis, and therapeutic management of alcoholic liver disease.Int J Mol Sci,20(11):2712.

[25]KubesP,MehalWZ,2012.Sterile inflammation in the liver.Gastroenterology,143(5):1158-1172.

[26]LeungTM,NietoN,2013.CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease.J Hepatol,58(2):395-398.

[27]LiB,NasserMI,MasoodM,et al.,2020.Efficiency of traditional Chinese medicine targeting the Nrf2/HO-1 signaling pathway.Biomed Pharmacother,126:110074.

[28]LiXJ,MuYM,LiTT,et al.,2015.Gynura procumbens reverses acute and chronic ethanol-induced liver steatosis through MAPK/SREBP-1c-dependent and -independent pathways.J Agric Food Chem,63(38):8460-8471.

[29]LiuJY,2014.Ethanol and liver: recent insights into the mechanisms of ethanol-induced fatty liver.World J Gastroenterol,20(40):14672-14685.

[30]LiuSY,TsaiIT,HsuYC,2021.Alcohol-related liver disease: basic mechanisms and clinical perspectives.Int J Mol Sci,22(10):5170.

[31]LiuX,WangYN,WuD,et al.,2019a.Magnolol prevents acute alcoholic liver damage by activating PI3K/Nrf2/PPARγ and inhibiting NLRP3 signaling pathway.Front Pharmacol,10:1459.

[32]LiuX,HouRL,YanJJ,et al.,2019b.Purification and characterization ofInonotus hispidus exopolysaccharide and its protective effect on acute alcoholic liver injury in mice.Int J Biol Macromol,129:41-49.

[33]LiuYG,WangJ,ZhangXR,et al.,2019.Scutellarin exerts hypoglycemic and renal protective effects in db/db mice via the Nrf2/HO-1 signaling pathway.Oxid Med Cell Longev,2019:1354345.

[34]LuYB,WahlLM,2005.Production of matrix metalloproteinase-9 by activated human monocytes involves a phosphatidylinositol-3 kinase/Akt/IKKα/NF-‍κB pathway. J Leukoc Biol,78(1):259-265.

[35]MorganK,FrenchSW,MorganTR,2002.Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage.Hepatology,36(1):122-134.

[36]NiuCW,ShengYC,YangR,et al.,2015.Scutellarin protects against the liver injury induced by diosbulbin B in mice and its mechanism.J Ethnopharmacol,164:301-308.

[37]NowakAJ,ReljaB,2020.The impact of acute or chronic alcohol intake on the NF-κB signaling pathway in alcohol-related liver disease.Int J Mol Sci,21(24):9407.

[38]OrmanES,OdenaG,BatallerR,2013.Alcoholic liver disease: pathogenesis, management, and novel targets for therapy.J Gastroenterol Hepatol,28(S1):77-84.

[39]OtterbeinLE,SoaresMP,YamashitaK,et al.,2003.Heme oxygenase-1: unleashing the protective properties of heme.Trends Immunol,24(8):449-455.

[40]QianLH,LiNG,TangYP,et al.,2011.Synthesis and bio-activity evaluation of scutellarein as a potent agent for the therapy of ischemic cerebrovascular disease.Int J Mol Sci,12(11):8208-8216.

[41]ShimYR,JeongWI,2020.Recent advances of sterile inflammation and inter-organ cross-talk in alcoholic liver disease.Exp Mol Med,52(5):772-780.

[42]SongXL,LiuZH,ZhangJJ,et al.,2018.Anti-inflammatory and hepatoprotective effects of exopolysaccharides isolated fromPleurotus geesteranus on alcohol-induced liver injury.Sci Rep,8:10493.

[43]SpornMB,LibyKT,2012.NRF2 and cancer: the good, the bad and the importance of context.Nat Rev Cancer,12(8):564-571.

[44]SunJ,FuJQ,LiL,et al.,2018.Nrf2 in alcoholic liver disease.Toxicol Appl Pharmacol,357:62-69.

[45]SzaboG,KamathPS,ShahVH,et al.,2019.Alcohol-related liver disease: areas of consensus, unmet needs and opportunities for further study.Hepatology,69(5):2271-2283.

[46]TorresS,SegalésP,García-RuizC,et al.,2022.Mitochondria and the NLRP3 inflammasome in alcoholic and nonalcoholic steatohepatitis.Cells,11(9):1475.

[47]WangJ,CuiL,FengL,et al.,2016.Isoalantolactone inhibits the migration and invasion of human breast cancer MDA-MB-231 cells via suppression of the p38 MAPK/NF-‍κB signaling pathway. Oncol Rep,36(3):1269-1276.

[48]WangJM,ZhangYY,ZhangYS,et al.,2012.Protective effect of lysimachia christinae against acute alcohol-induced liver injury in mice.Biosci Trends,6(2):89-97.

[49]WangLP,MaQ,2018.Clinical benefits and pharmacology of scutellarin: a comprehensive review.Pharmacol Ther,190:105-127.

[50]WangP,GaoC,GuoN,et al.,2018.2'-O-Galloylhyperin isolated fromPyrola incarnata Fisch. attenuates LPS-induced inflammatory response by activation of SIRT1/Nrf2 and inhibition of the NF-‍κB pathways in vitro and vivo. Front Pharmacol,9:679.

[51]WangYY,FanXM,FanB,et al.,2020.Scutellarin reduce the homocysteine level and alleviate liver injury in type 2 diabetes model.Front Pharmacol,11:538407.

[52]WangZG,YaoT,SongZY,2010.Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease.J Lipid Res,51(11):3158-3165.

[53]WuDF,WangXD,ZhouR,et al.,2012.Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy.Free Radic Biol Med,53(6):1346-1357.

[54]XiaoT,CuiYL,JiHY,et al.,2021.Baicalein attenuates acute liver injury by blocking NLRP3 inflammasome.Biochem Biophys Res Commun,534:212-218.

[55]XuL,YuYF,SangR,et al.,2018.Protective effects of taraxasterol against ethanol-induced liver injury by regulating CYP2E1/Nrf2/HO-1 and NF‍-‍κB signaling pathways in mice.Oxid Med Cell Longev,2018:8284107.

[56]XuLJ,ChenRC,ZhangX,et al.,2021.Scutellarin protects against diabetic cardiomyopathy via inhibiting oxidative stress and inflammatory response in mice.Ann Palliat Med,10(3):2481-2493.

[57]YuGL,WangJX,ZhangW,et al.,2021.NLRP3 inflammasome signal pathway involves inVibrio harveyi-induced inflammatory response in murine peritoneal macrophagesin vitro.Acta Biochim Biophys Sin,53(12):1590-1601.

[58]YuWZ,TaoMR,ZhaoYL,et al.,2018.4'-Methoxyresveratrol alleviated AGE-induced inflammation via RAGE-mediated NF‍-κB and NLRP3 inflammasome pathway. Molecules,23(6):1447.

[59]ZengJ,CaiSN,2017.Breviscapine suppresses the growth of non-small cell lung cancer by enhancing microRNA-7 expression.J Biosci,42(1):121-129.

[60]ZengT,ZhangCL,ZhaoN,et al.,2018.Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver.Redox Biol,14:295-304.

[61]ZhangTM,WangK,FanH,et al.,2022.Ameliorative effect of scutellarin on acute alcohol brain injury in mice.J Zhejiang Univ-Sci B (Biomed & Biotechnol),23(3):258-264.

[62]ZhangXX,JiRP,SunHJ,et al.,2018.Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARγ/PGC-1α-Nrf2 pathway.Free Radic Res,52(2):198-211.

[63]ZhangZH,RenZ,ChenS,et al.,2018.ROS generation and JNK activation contribute to 4-methoxy-TEMPO-induced cytotoxicity, autophagy, and DNA damage in HepG2 cells.Arch Toxicol,92(2):717-728.

[64]ZhaoL,MehmoodA,YuanDD,et al.,2021.Protective mechanism of edible food plants against alcoholic liver disease with special mention to polyphenolic compounds.Nutrients,13(5):1612.

[65]ZhaoN,GuoFF,XieKQ,et al.,2018.Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease.Cell Mol Life Sci,75(17):3143-3157.

[66]ZhaoYL,MaX,WangJB,et al.,2016.A system review of anti-fibrogenesis effects of compounds derived from Chinese herbal medicine.Mini-Rev Med Chem,16(2):163-175.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE