Download PDF
Drug Res (Stuttg) 2022; 72(05): 245-254
DOI: 10.1055/a-1792-2678
Original Article

Therapeutic Potential of Isorhamnetin following Acetaminophen-Induced Hepatotoxicity through Targeting NLRP3/NF-κB/Nrf2

Ali-Mohammad Rousta
1   School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Seyed-Mohamad-Sadegh Mirahmadi
1   School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Alireza Shahmohammadi
1   School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Zhila Mehrabi
2   Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Soudabeh Fallah
3   Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Tourandokht Baluchnejadmojarad
2   Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
,
Mehrdad Roghani
4   Neurophysiology Research Center, Shahed University, Tehran, Iran
› Author Affiliations Funding This research project was financially supported in 2020 by National Institute for Medical Research Development (NIMAD) of Iran (grant number 987766).
› Further Information
Also available at
    Permissions and Reprints

Abstract

Acetaminophen (APAP)-induced acute liver injury (ALI) is the principal cause of acute liver failure (ALF) in some countries including the United States and with few available treatments. Isorhamnetin is a bioflavonoid that is found in medicinal plants like Hippophae rhamnoides L. and Ginkgo biloba L. with promising potential to regulate inflammatory responses. In this study, we evaluated the possible effect of isorhamnetin in prevention of APAP-induced ALI and analyzed further the involvement of oxidative stress and inflammation-associated factors. Male C57BL/6 mice were given isorhamnetin (25 or 100 mg/kg b.w., p.o.) three times at 48, 24, and 1 h before APAP administration (300 mg/kg b.w., i.p.). Functional indicators of liver injury were measured as well as analysis of oxidative stress- and inflammation-associated indices and liver histopathology was also conducted. Isorhamnetin at the higher dose of 100 mg/kg significantly lowered serum levels of ALT, ALP, and AST in addition to reduction of ROS, TBARS, IL-6, TNFα, NF-kB, NLRP3, caspase 1, and MPO and significantly prevented reduction of GSH, SOD activity, sirtuin 1, and Nrf2. Additionally, isorhamnetin alleviated pathological changes of the liver tissue and suitably reversed NF-kB and Nrf2 immunoreactivity. These findings show protective effect of isorhamnetin against acetaminophen-induced liver injury through reducing oxidative stress, inflammation, and pyroptosis which is attributed to its regulation of NF-kB, Nrf2, NLRP3, and sirtuin 1.

Key words

Isorhamnetin - Acetaminophen - Acute liver injury - Hepatoprotective


Publication History

Received: 23 December 2021

Accepted: 07 March 2022

Article published online:
31 March 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Stravitz RT, Lee WM. Acute liver failure. The Lancet 2019; 394: 869-881
    CrossrefPubMedSearch in Google Scholar
  • 2 Yoon E, Babar A, Choudhary M. et al. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. Journal of clinical and translational hepatology 2016; 4: 131-142
    PubMedSearch in Google Scholar
  • 3 James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metabolism and Disposition: The Biological Fate of Chemicals 2003; 31: 1499-1506
    CrossrefPubMedSearch in Google Scholar
  • 4 Yan M, Huo Y, Yin S. et al. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 2018; 17: 274-283
    CrossrefPubMedSearch in Google Scholar
  • 5 Yang R, Song C, Chen J. et al. Limonin ameliorates acetaminophen-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1. Phytomedicine 2020; 69: 153211
    CrossrefPubMedSearch in Google Scholar
  • 6 Olivo R, Guarrera JV, Pyrsopoulos NT. Liver Transplantation for Acute Liver Failure. Clin Liver Dis 2018; 22: 409-417
    CrossrefPubMedSearch in Google Scholar
  • 7 Jin Y, Wang H, Yi K. et al. Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure. Nanomicro Lett 2020; 13: 25
    PubMedSearch in Google Scholar
  • 8 Li Z, Feng H, Han L. et al. Chicoric acid ameliorate inflammation and oxidative stress in Lipopolysaccharide and d-galactosamine induced acute liver injury. J Cell Mol Med. 2020
    PubMedSearch in Google Scholar
  • 9 Kawser Hossain M, Abdal Dayem A, Han J. et al. Molecular Mechanisms of the Anti-Obesity and Anti-Diabetic Properties of Flavonoids. International Journal of Molecular Sciences 2016; 17: 569-569
    CrossrefPubMedSearch in Google Scholar
  • 10 Gong G, Guan YY, Zhang ZL. et al. Isorhamnetin: A review of pharmacological effects. Biomedicine and Pharmacotherapy 2020; 128: 110301
    CrossrefPubMedSearch in Google Scholar
  • 11 Yang JH, Kim SC, Kim KM. et al. Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress. European Journal of Pharmacology 2016; 783: 92-102
    CrossrefPubMedSearch in Google Scholar
  • 12 Dong GZ, Lee JH, Ki SH. et al. AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction. European Journal of Pharmacology 2014; 740: 634-640
    CrossrefPubMedSearch in Google Scholar
  • 13 Ren X, Han L, Li Y. et al. Isorhamnetin attenuates TNF-α-induced inflammation, proliferation, and migration in human bronchial epithelial cells via MAPK and NF-κB pathways. Anat Rec (Hoboken) 2021; 304: 901-913
    CrossrefPubMedSearch in Google Scholar
  • 14 Ganbold M, Owada Y, Ozawa Y. et al. Isorhamnetin Alleviates Steatosis and Fibrosis in Mice with Nonalcoholic Steatohepatitis. Scientific Reports 2019; 9: 16210
    CrossrefPubMedSearch in Google Scholar
  • 15 Qi F, Sun JH, Yan JQ. et al. Anti-inflammatory effects of isorhamnetin on LPS-stimulated human gingival fibroblasts by activating Nrf2 signaling pathway. Microbial Pathogenesis 2018; 120: 37-41
    CrossrefPubMedSearch in Google Scholar
  • 16 Wimborne HJ, Hu J, Takemoto K. et al. Aldehyde dehydrogenase-2 activation decreases acetaminophen hepatotoxicity by prevention of mitochondrial depolarization. Toxicol Appl Pharmacol 2020; 396: 114982
    CrossrefPubMedSearch in Google Scholar
  • 17 Gao L, Yao R, Liu Y. et al. Isorhamnetin protects against cardiac hypertrophy through blocking PI3K-AKT pathway. Mol Cell Biochem 2017; 429: 167-177
    CrossrefPubMedSearch in Google Scholar
  • 18 Mondal M, Hossain MM, Hasan MR. et al. Hepatoprotective and Antioxidant Capacity of Mallotus repandus Ethyl Acetate Stem Extract against d-Galactosamine-Induced Hepatotoxicity in Rats. ACS Omega 2020; 5: 6523-6531
    CrossrefPubMedSearch in Google Scholar
  • 19 Mohamadi-Zarch SM, Baluchnejadmojarad T, Nourabadi D. et al. Protective effect of diosgenin on LPS/D-Gal-induced acute liver failure in C57BL/6 mice. Microb Pathog 2020; 146: 104243
    CrossrefPubMedSearch in Google Scholar
  • 20 Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Analytical Biochemistry 1968; 25: 192-205
    CrossrefPubMedSearch in Google Scholar
  • 21 Nandi A, Chatterjee IB. Assay of superoxide dismutase activity in animal tissues. Journal of Biosciences 1988; 13: 305-315
    CrossrefPubMedSearch in Google Scholar
  • 22 Aebi H. [13] Catalase in vitro. Methods in Enzymology. 105. Academic Press; 1984. p 121-126
    Search in Google Scholar
  • 23 Pulli B, Ali M, Forghani R. et al. Measuring myeloperoxidase activity in biological samples. PloS One 2013; 8: e67976
    CrossrefPubMedSearch in Google Scholar
  • 24 Khosravi Z, Sedaghat R, Baluchnejadmojarad T. et al. Diosgenin ameliorates testicular damage in streptozotocin-diabetic rats through attenuation of apoptosis, oxidative stress, and inflammation. International Immunopharmacology 2019; 70: 37-46
    CrossrefPubMedSearch in Google Scholar
  • 25 Lyu Z, Ji X, Chen G. et al. Atractylodin ameliorates lipopolysaccharide and d-galactosamine-induced acute liver failure via the suppression of inflammation and oxidative stress. Int Immunopharmacol 2019; 72: 348-357
    CrossrefPubMedSearch in Google Scholar
  • 26 Ali SA, Sharief NH, Mohamed YS. Hepatoprotective Activity of Some Medicinal Plants in Sudan. Evidence-Based Complementary and Alternative Medicine 2019; 2019: 2196315
    PubMedSearch in Google Scholar
  • 27 Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ: Canadian Medical Association journal=journal de l'Association medicale canadienne 2005; 172: 367-379
    CrossrefPubMedSearch in Google Scholar
  • 28 Xiong W, Yuan Z, Wang T. et al. Quercitrin Attenuates Acetaminophen-Induced Acute Liver Injury by Maintaining Mitochondrial Complex I Activity. Frontiers in Pharmacology 2021; 12: 586010
    CrossrefPubMedSearch in Google Scholar
  • 29 Araujo J, Zhang M, Yin F. Heme Oxygenase-1, Oxidation, Inflammation, and Atherosclerosis. Frontiers in Pharmacology 2012; 3: 119
    CrossrefPubMedSearch in Google Scholar
  • 30 Albrahim T, Alonazi MA. Lycopene corrects metabolic syndrome and liver injury induced by high fat diet in obese rats through antioxidant, anti-inflammatory, antifibrotic pathways. Biomedicine and Pharmacotherapy 2021; 141: 111831
    CrossrefPubMedSearch in Google Scholar
  • 31 Mulita F, Karpetas G, Liolis E. et al. Comparison of analgesic efficacy of acetaminophen monotherapy versus acetaminophen combinations with either pethidine or parecoxib in patients undergoing laparoscopic cholecystectomy: a randomized prospective study. Med Glas (Zenica) 2021; 18: 27-32
    PubMedSearch in Google Scholar
  • 32 Akakpo JY, Ramachandran A, Orhan H. et al. 4-methylpyrazole protects against acetaminophen-induced acute kidney injury. Toxicol Appl Pharmacol 2020; 409: 115317
    CrossrefPubMedSearch in Google Scholar
  • 33 Islam MT, Quispe C, Islam MA. et al. Effects of nerol on paracetamol-induced liver damage in Wistar albino rats. Biomed Pharmacother 2021; 140: 111732
    CrossrefPubMedSearch in Google Scholar
  • 34 Hanawa N, Shinohara M, Saberi B. et al. Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 2008; 283: 13565-13577
    CrossrefPubMedSearch in Google Scholar
  • 35 Nakagawa H, Maeda S, Hikiba Y. et al. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology 2008; 135: 1311-1321
    CrossrefPubMedSearch in Google Scholar
  • 36 Ozer J, Ratner M, Shaw M. et al. The current state of serum biomarkers of hepatotoxicity. Toxicology 2008; 245: 194-205
    CrossrefPubMedSearch in Google Scholar
  • 37 Huang R, Pan H, Zhou M. et al. Potential liver damage due to co-exposure to As, Cd, and Pb in mining areas: Association analysis and research trends from a Chinese perspective. Environ Res 2021; 201: 111598
    CrossrefPubMedSearch in Google Scholar
  • 38 Igarashi K, Mikami T, Takahashi Y. et al. Comparison of the preventive activity of isorhamnetin glycosides from atsumi-kabu (red turnip, Brassica, campestris L.) leaves on carbon tetrachloride-induced liver injury in mice. Bioscience, Biotechnology, and Biochemistry 2008; 72: 856-860
    CrossrefPubMedSearch in Google Scholar
  • 39 Chauhan AK, Kim J, Lee Y. et al. Isorhamnetin Has Potential for the Treatment of Escherichia coli-Induced Sepsis. Molecules 2019; 24: 3984
    CrossrefPubMedSearch in Google Scholar
  • 40 Jaeschke H, Williams CD, McGill MR. et al. Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products. Food and Chemical Toxicology 2013; 55: 279-289
    CrossrefPubMedSearch in Google Scholar
  • 41 Shan Z, Ju C. Hepatic Macrophages in Liver Injury. Frontiers in Immunology 2020; 11: 322-322
    CrossrefPubMedSearch in Google Scholar
  • 42 Chen F, Hu M, Shen Y. et al. Isorhamnetin promotes functional recovery in rats with spinal cord injury by abating oxidative stress and modulating M2 macrophages/microglia polarization. European Journal of Pharmacology 2021; 895: 173878
    CrossrefPubMedSearch in Google Scholar
  • 43 Liu G, Jiang C, Li D. et al. Isorhamnetin alleviates esophageal mucosal injury in a chronic model of reflux esophagitis. European Journal of Pharmacology 2019; 864: 172720
    CrossrefPubMedSearch in Google Scholar
  • 44 Lv H, Qi Z, Wang S. et al. Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure. Front Immunol 2017; 8: 785
    CrossrefPubMedSearch in Google Scholar
  • 45 Pan CW, Pan ZZ, Hu JJ. et al. Mangiferin alleviates lipopolysaccharide and D-galactosamine-induced acute liver injury by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation. Eur J Pharmacol 2016; 770: 85-91
    CrossrefPubMedSearch in Google Scholar
  • 46 Deng JS, Jiang WP, Chen CC. et al. Cordyceps cicadae Mycelia Ameliorate Cisplatin-Induced Acute Kidney Injury by Suppressing the TLR4/NF-kappaB/MAPK and Activating the HO-1/Nrf2 and Sirt-1/AMPK Pathways in Mice. Oxid Med Cell Longev 2020; 2020: 7912763
    PubMedSearch in Google Scholar
  • 47 Hu Y, Zhou Q, Liu T. et al. Coixol Suppresses NF-kappaB, MAPK Pathways and NLRP3 Inflammasome Activation in Lipopolysaccharide-Induced RAW 264.7 Cells. Molecules 2020; 25: 894
    CrossrefPubMedSearch in Google Scholar
  • 48 Ahn H, Lee GS. Isorhamnetin and hyperoside derived from water dropwort inhibits inflammasome activation. Phytomedicine 2017; 24: 77-86
    CrossrefPubMedSearch in Google Scholar
  • 49 Zhou F, Mei J, Yuan K. et al. Isorhamnetin attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through modulating reactive oxygen species homeostasis. Journal of Cellular and Molecular Medicine 2019; 23: 4395-4407
    CrossrefPubMedSearch in Google Scholar
  • 50 Miao EA, Rajan JV, Aderem A. Caspase-1-induced pyroptotic cell death. Immunol Rev 2011; 243: 206-214
    CrossrefPubMedSearch in Google Scholar
  • 51 Paridaens A, Raevens S, Colle I. et al. Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication. Liver Int 2017; 37: 748-756
    CrossrefPubMedSearch in Google Scholar
  • 52 Tian W, Zhao J, Choo BK. et al. Camellia japonica diminishes acetaminophen-induced acute liver failure by attenuating oxidative stress in mice. Environmental Science and Pollution Research International. 2021
    PubMedSearch in Google Scholar
  • 53 Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver International 2006; 26: 912-919
    CrossrefPubMedSearch in Google Scholar
  • 54 Zhou X, Yang L, Fan X. et al. Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Galphai/o/ROS/p38 MAPK Signaling Pathway. Cells 2020; 9: 373
    CrossrefPubMedSearch in Google Scholar
  • 55 He M, Horuk R, Moochhala SM. et al. Treatment with BX471, a CC chemokine receptor 1 antagonist, attenuates systemic inflammatory response during sepsis. American Journal of Physiology: Gastrointestinal and Liver Physiology 2007; 292: G1173-G1180
    PubMedSearch in Google Scholar
  • 56 Yang B, Li XP, Ni YF. et al. Protective Effect of Isorhamnetin on Lipopolysaccharide-Induced Acute Lung Injury in Mice. Inflammation 2016; 39: 129-137
    CrossrefPubMedSearch in Google Scholar
  • 57 Kasai S, Shimizu S, Tatara Y. et al. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Biomolecules 2020; 10: 320
    CrossrefPubMedSearch in Google Scholar
  • 58 Habtemariam S. The Nrf2/HO-1 Axis as Targets for Flavanones: Neuroprotection by Pinocembrin, Naringenin, and Eriodictyol. Oxid Med Cell Longev 2019; 2019: 4724920
    CrossrefPubMedSearch in Google Scholar
  • 59 Wei X, Wang H, Sun X. et al. 4-hydroxy-2(3H)-benzoxazolone alleviates acetaminophen-induced hepatic injury by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways. Am J Transl Res 2020; 12: 2169-2180
    PubMedSearch in Google Scholar
  • 60 Wu Y, Fan L, Wang Y. et al. Isorhamnetin Alleviates High Glucose-Aggravated Inflammatory Response and Apoptosis in Oxygen-Glucose Deprivation and Reoxygenation-Induced HT22 Hippocampal Neurons Through Akt/SIRT1/Nrf2/HO-1 Signaling Pathway. Inflammation. 2021
    PubMedSearch in Google Scholar
  • 61 Du K, Ramachandran A, Jaeschke H. Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biol 2016; 10: 148-156
    CrossrefPubMedSearch in Google Scholar
  • 62 Lei XG, Zhu JH, Cheng WH. et al. Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications. Physiological Reviews 2016; 96: 307-364
    CrossrefPubMedSearch in Google Scholar
  • 63 Rousta AM, Mirahmadi SM, Shahmohammadi A. et al. S-allyl cysteine, an active ingredient of garlic, attenuates acute liver dysfunction induced by lipopolysaccharide/d-galactosamine in mouse: Underlying mechanisms. J Biochem Mol Toxicol 2020; e22518
    CrossrefPubMedSearch in Google Scholar
  • 64 Guo H, Sun J, Li D. et al. Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation. Biomedicine and Pharmacotherapy 2019; 112: 108704
    CrossrefPubMedSearch in Google Scholar
  • 65 Jiang W, Zhang X, Hao J. et al. SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells. Scientific Reports 2014; 4: 7456
    CrossrefPubMedSearch in Google Scholar
  • 66 Li Y, Xu W, McBurney MW. et al. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metabolism 2008; 8: 38-48
    CrossrefPubMedSearch in Google Scholar
  • 67 Yang H, Zhang W, Pan H. et al. SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity. PloS One 2012; 7: e46364
    CrossrefPubMedSearch in Google Scholar
  • 68 Zhao TT, Yang TL, Gong L. et al. Isorhamnetin protects against hypoxia/reoxygenation-induced injure by attenuating apoptosis and oxidative stress in H9c2 cardiomyocytes. Gene 2018; 666: 92-99
    CrossrefPubMedSearch in Google Scholar