中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 39 Issue 11
Nov.  2023
Turn off MathJax
Article Contents

Effect and mechanism of safranal in a mouse model of sepsis-related liver injury induced by lipopolysaccharide

DOI: 10.3969/j.issn.1001-5256.2023.11.019
Research funding:

‍National Natural Science Foundation of China (82170587)

More Information
  • Corresponding author: FU Wenguang, fuwg@swmu.edu.cn (ORCID: 0000-0003-3672-9728)
  • Received Date: 2023-02-19
  • Accepted Date: 2023-03-18
  • Published Date: 2023-11-28
  •   Objective  To investigate the protective effect of safranal against sepsis-related liver injury (SRLI) induced by lipopolysaccharide (LPS) in mice and its mechanism.  Methods  A total of 32 experimental male C57BL/6 mice were divided into control group, single drug group, model group, and treatment group using the simple random method, with 8 mice in each group. The mice in the single drug group and the treatment group were intraperitoneally injected with safranal (60 mg/kg) for 7 days of pretreatment, and the mice in the model group and the treatment group were intraperitoneally injected with LPS (10 mg/kg) to induce acute liver injury. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured; HE staining was used to observe liver tissue sections; immunohistochemistry was used to analyze the expression of the downstream protein heme oxygenase-1 (HO-1) in the signal pathway; TUNEL was used to analyze the apoptosis of hepatocytes; Western blot was used to measure the expression of total proteins (nuclear factor erythroid 2-related factor 2 [Nrf-2] and HO-1) in liver tissue. The human liver cell line L02 was pretreated with safranal (100 μmol/L), followed by induction of acute hepatocellular injury with LPS (100 ng/mL), and DCFH-DA fluorescent labeling was used to detect reactive oxygen species (ROS).  Results  After safranal pretreatment, the treatment group had significantly lower levels of ALT and AST than the model group (both P<0.001), with a relatively intact pseudolobular structure and a smaller necrotic area in the liver. Compared with the model group, the treatment group had significant increases in the expression levels of Nrf2 and HO-1 in liver tissue after safranal+LPS treatment (both P<0.001), and immunohistochemistry showed that safranal pretreatment increased the number of HO-1-positive cells. In the cell model of LPS-induced acute liver injury, the treatment group had a significant reduction in the production of ROS compared with the model group.  Conclusion  Safranal can exert a protective effect against SRLI induced by LPS in mice through the Nrf2/HO-1 pathway.

     

  • loading
  • [1]
    LI Q, TAN Y, CHEN SN, et al. Irisin alleviates LPS-induced liver injury and inflammation through inhibition of NLRP3 inflammasome and NF-κB signaling[J]. J Recept Signal Transduct Res, 2021, 41( 3): 294- 303. DOI: 10.1080/10799893.2020.1808675.
    [2]
    ZHANG J, LI XY, CHEN JP, et al. Advances in microRNA and pathogenesis of sepsis[J]. Trauma Crit Care Med, 2021, 9( 4): 315- 318. DOI: 10.16048/j.issn.2095-5561.2021.04.20.

    张杰, 李小悦, 陈建平, 等. 微小RNA与脓毒症发病机制研究进展[J]. 创伤与急危重病医学, 2021, 9( 4): 315- 318. DOI: 10.16048/j.issn.2095-5561.2021.04.20.
    [3]
    CARPINO G, DEL BEN M, PASTORI D, et al. Increased liver localization of lipopolysaccharides in human and experimental NAFLD[J]. Hepatology, 2020, 72( 2): 470- 485. DOI: 10.1002/hep.31056.
    [4]
    JING ZT, LIU W, XUE CR, et al. AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 316( 3): G387- G396. DOI: 10.1152/ajpgi.00350.2018.
    [5]
    YAN CY, OUYANG SH, WANG X, et al. Celastrol ameliorates Propionibacterium acnes/LPS-induced liver damage and MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3[J]. Phytomedicine, 2021, 80: 153398. DOI: 10.1016/j.phymed.2020.153398.
    [6]
    CIESIELSKA A, MATYJEK M, KWIATKOWSKA K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling[J]. Cell Mol Life Sci, 2021, 78( 4): 1233- 1261. DOI: 10.1007/s00018-020-03656-y.
    [7]
    ISHIDA K, KAJI K, SATO S, et al. Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway[J]. J Nutr Biochem, 2021, 89: 108573. DOI: 10.1016/j.jnutbio.2020.108573.
    [8]
    LIAO Y, HE YH, LUO YW. Role of oxidative stress in acute liver injury[J]. J Clin Hepatol, 2022, 38( 10): 2402- 2407. DOI: 10.3969/j.issn.1001-5256.2022.10.039.

    廖月, 何毅怀, 罗亚文. 氧化应激在急性肝损伤中的作用[J]. 临床肝胆病杂志, 2022, 38( 10): 2402- 2407. DOI: 10.3969/j.issn.1001-5256.2022.10.039.
    [9]
    YANG WC, WANG YX, ZHANG CG, et al. Maresin1 protect against ferroptosis-induced liver injury through ROS inhibition and Nrf2/HO-1/GPX4 activation[J]. Front Pharmacol, 2022, 13: 865689. DOI: 10.3389/fphar.2022.865689.
    [10]
    ZHANG HB, YUAN B, HUANG HF, et al. Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation[J]. Braz J Med Biol Res, 2018, 51( 10): e7439. DOI: 10.1590/1414-431x20187439.
    [11]
    FOROUZANFAR F, ASADPOUR E, HOSSEINZADEH H, et al. Safranal protects against ischemia-induced PC12 cell injury through inhibiting oxidative stress and apoptosis[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394( 4): 707- 716. DOI: 10.1007/s00210-020-01999-8.
    [12]
    HOSSEINI A, RAZAVI BM, HOSSEINZADEH H. Pharmacokinetic properties of saffron and its active components[J]. Eur J Drug Metab Pharmacokinet, 2018, 43( 4): 383- 390. DOI: 10.1007/s13318-017-0449-3.
    [13]
    NANDA SJ, MADAN K. The role of Safranal and saffron stigma extracts in oxidative stress, diseases and photoaging: A systematic review[J]. Heliyon, 2021, 7( 2): e06117. DOI: 10.1016/j.heliyon.2021.e06117.
    [14]
    LOO DT. TUNEL assay: An overview of techniques[M]// In Situ Detection of DNA Damage. New Jersey: Humana Press, 2003: 21- 30. DOI: 10.1385/1-59259-179-5: 21.
    [15]
    LI QH, ZHAO QW. Effect of continuous blood purification on inflammatory factors and vascular endothelial permeability in sepsis patients with acute respiratory distress syndrome[J]. Trauma Crit Care Med, 2021, 9( 4): 304- 306. DOI: 10.16048/j.issn.2095-5561.2021.04.16.

    李秋红, 赵千文. 连续性血液净化对脓毒症并发急性呼吸窘迫综合征患者炎症因子及血管内皮通透性影响[J]. 创伤与急危重病医学, 2021, 9( 4): 304- 306. DOI: 10.16048/j.issn.2095-5561.2021.04.16.
    [16]
    ZUO HZ, TIAN LJ, YANG XF, et al. Study on Logistic regression analysis of risk factors for secondary acute kidney injury in patients with sepsis[J]. J Changchun Univ Chin Med, 2023, 39( 8): 915- 920. DOI: 10.13463/j.cnki.cczyy.2023.08.021.

    左海忠, 田六九, 杨晓帆, 等. 脓毒症患者继发急性肾损伤危险因素Logistic 回归方程研究[J]. 长春中医药大学学报, 2023, 39( 8): 915- 920. DOI: 10.13463/j.cnki.cczyy.2023.08.021.
    [17]
    LELUBRE C, VINCENT JL. Mechanisms and treatment of organ failure in sepsis[J]. Nat Rev Nephrol, 2018, 14( 7): 417- 427. DOI: 10.1038/s41581-018-0005-7.
    [18]
    WU Y, REN JA. Role of oxidative stress in liver injury caused by sepsis[J]. Chin J Pact Surg, 2014, 34( 2): 187- 189.

    吴吟, 任建安. 氧化应激在脓毒症导致的肝损伤中的作用[J]. 中国实用外科杂志, 2014, 34( 2): 187- 189.
    [19]
    CERDÁ-BERNAD D, VALERO-CASES E, PASTOR JJ, et al. Saffron bioactives crocin, crocetin and safranal: Effect on oxidative stress and mechanisms of action[J]. Crit Rev Food Sci Nutr, 2022, 62( 12): 3232- 3249. DOI: 10.1080/10408398.2020.1864279.
    [20]
    ABDALLA Y, ABDALLA A, HAMZA AA, et al. Safranal prevents liver cancer through inhibiting oxidative stress and alleviating inflammation[J]. Front Pharmacol, 2022, 12: 777500. DOI: 10.3389/fphar.2021.777500.
    [21]
    GUPTA M, WANI A, AHSAN AU, et al. Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization[J]. Toxicol Appl Pharmacol, 2021, 423: 115582. DOI: 10.1016/j.taap.2021.115582.
    [22]
    ABDALLA A, MURALI C, AMIN A. Safranal inhibits angiogenesis via targeting HIF-1α/VEGF machinery: in vitro and Ex vivo insights[J]. Front Oncol, 2022, 11: 789172. DOI: 10.3389/fonc.2021.789172.
    [23]
    XIAO Q, SUN YY, LU ZJ, et al. Protective effects of safranal on diabetic retinopathy in human microvascular endothelial cells and related pathways analyzed with transcriptome sequencing[J]. Front Endocrinol, 2022, 13: 945446. DOI: 10.3389/fendo.2022.945446.
    [24]
    ÖN ALAYUNT, AKSOY L, KARAFAKIOĞLU YS, et al. Assessment of anti-inflammatory and antioxidant properties of safranal on CCl4-induced oxidative stress and inflammation in rats[J]. An Acad Bras Cienc, 2019, 91( 2): e20181235. DOI: 10.1590/0001-3765201920181235.
    [25]
    SABIR U, IRFAN HM, ALAMGEER, et al. Reduction of hepatic steatosis, oxidative stress, inflammation, ballooning and insulin resistance after therapy with safranal in NAFLD animal model: A new approach[J]. J Inflamm Res, 2022, 15: 1293- 1316. DOI: 10.2147/JIR.S354878.
    [26]
    CAO LJ, GONG H, YAN M, et al. Research progress on Nrf2-ARE signaling pathway involved in liver disease pathological mechanism[J]. Chin Pharmacol Bull, 2015, 31( 8): 1057- 1061. DOI: 10.3969/j.issn.1001-1978.2015.08.006.

    曹玲娟, 龚慧, 颜苗, 等. Nrf2-ARE信号通路参与肝脏疾病病理机制研究进展[J]. 中国药理学通报, 2015, 31( 8): 1057- 1061. DOI: 10.3969/j.issn.1001-1978.2015.08.006.
    [27]
    LU XL, JIANG YY, CAO Q. The role of oxidative stress and nuclear factor erythroid 2-related factor 2 in nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2020, 36( 4): 924- 927. DOI: 10.3969/j.issn.1001-5256.2020.04.048.

    陆孝良, 蒋元烨, 曹勤. 氧化应激与核因子E2相关因子2在非酒精性脂肪性肝病中的作用[J]. 临床肝胆病杂志, 2020, 36( 4): 924- 927. DOI: 10.3969/j.issn.1001-5256.2020.04.048.
    [28]
    WANG TT, CHEN CY, YANG L, et al. Role of Nrf2/HO-1 signal axis in the mechanisms for oxidative stress-relevant diseases[J]. J Cent South Univ Med Sci, 2019, 44( 1): 74- 80. DOI: 10.11817/j.issn.1672-7347.2019.01.012.

    王甜甜, 陈淳媛, 杨雷, 等. Nrf2/HO-1信号轴在氧化应激性疾病中的机制[J]. 中南大学学报(医学版), 2019, 44( 1): 74- 80. DOI: 10.11817/j.issn.1672-7347.2019.01.012.
    [29]
    LERTNIMITPHUN P, ZHANG WH, FU WW, et al. Safranal alleviated OVA-induced asthma model and inhibits mast cell activation[J]. Front Immunol, 2021, 12: 585595. DOI: 10.3389/fimmu.2021.585595.
    [30]
    WANG HF, ZHENG B, CHE KM, et al. Protective effects of safranal on hypoxia/reoxygenation-induced injury in H9c2 cardiac myoblasts via the PI3K/AKT/GSK3β signaling pathway[J]. Exp Ther Med, 2021, 22( 6): 1400. DOI: 10.3892/etm.2021.10836.
    [31]
    XUE YR, JIN WY, XUE YC, et al. Safranal, an active constituent of saffron, ameliorates myocardial ischemia via reduction of oxidative stress and regulation of Ca2+ homeostasis[J]. J Pharmacol Sci, 2020, 143( 3): 156- 164. DOI: 10.1016/j.jphs.2020.03.005.
    [32]
    ZHANG YB, ZHAO Y, GUO JY, et al. Anticancer activity of safranal against colon carcinoma is due to induction of apoptosis and G2/M cell cycle arrest mediated by suppression of mTOR/PI3K/Akt pathway[J]. J BUON, 2021, 26( 1): 297.
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(6)

    Article Metrics

    Article views (95) PDF downloads(22) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return