Abstract
Geraniol (GOH) is a natural essential oil that possesses antioxidant, anti-inflammatory, and antiapoptotic properties by various signaling pathways. Liver ischemia-reperfusion injury (IRI) is a serious event that triggers liver dysfunction or even failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor, maintains cellular defense mechanism through antioxidant and anti-inflammatory properties. To detect GOH effect against liver IRI through the activation of the Nrf2/HO-1 antioxidant pathway, five groups of rats were randomized to normal, sham, IR, GOH, and GOH/IR. Blood samples and liver tissues were collected to measure various biochemical parameters related to liver function, and oxidative stress as well as inflammatory and apoptotic indicators besides liver tissue histopathology was evaluated by light microscopy. GOH induces activation of Nrf2 along with the upregulation of HO-1 expression. Also, the antioxidant activity of GOH was shown by the elevation of total antioxidant capacity and GSH levels, together with normalizing malondialdehyde. Regarding the anti-inflammatory effect of GOH, it suppresses the levels of TNF-α, iNOS, and COX-2. Additionally, the antiapoptotic effect of GOH, Bax, and caspase-3, 9 were reduced in liver tissue. GOH is a promising hepatoprotective agent in liver IRI through the activation of Nrf2/HO-1 antioxidant pathway.
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02 June 2023
A Correction to this paper has been published: https://doi.org/10.1007/s00210-023-02549-8
Abbreviations
- IRI:
-
Ischemia-reperfusion injury
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- GOH:
-
Geraniol
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- TAC:
-
Total antioxidant capacity
- MDA:
-
Malondialdehyde
- GSH:
-
Reduced glutathione
- TNF-α:
-
Tumor necrosis factor-alpha
- iNOS:
-
Inducible nitric oxide synthase
- COX-2:
-
Cyclooxygenase-2
- HO-1:
-
Hemeoxygenase-1
References
Abdel-Gaber SA, Ibrahim MA, Amin EF, Ibrahim SA, Mohammed RK, Abdelrahman AM (2015) Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia–reperfusion-induced hepatic injury in rats. Life Sci 134:42–48. https://doi.org/10.1016/j.lfs.2015.04.025
Andrade BFMT, Braga CP, Dos Santos KC et al (2014) Effect of inhaling Cymbopogon martinii essential oil and geraniol on serum biochemistry parameters and oxidative stress in rats. Biochem Res Int 2014:493183–493187. https://doi.org/10.1155/2014/493183
Araujo JA, Zhang M, Yin F (2012) Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol 3:119. https://doi.org/10.3389/fphar.2012.00119
Arunachalam K, Ramar M, Ramanathan S, Govindaraju A, Shunmugiah KP, Kandasamy R, Arumugam VR (2018) In vivo protective effect of geraniol on colonization of Staphylococcus epidermidis in rat jugular vein catheter model. Pathog Dis 76. https://doi.org/10.1093/femspd/fty055
Bai J, Meng Z (2005) Expression of apoptosis-related genes in livers from rats exposed to sulfur dioxide. Toxicology 216:253–260. https://doi.org/10.1016/j.tox.2005.08.016
Bancroft JD, Gamble M (2002) Theory and practice of histological techniques. Churchill Livingstone
Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta - Mol Cell Res 1865:721–733. https://doi.org/10.1016/j.bbamcr.2018.02.010
Canbek M, Uyanoglu M, Canbek S et al (2017) The effect of geraniol on liver regeneration after hepatectomy in rats. In Vivo 31:209–213. https://doi.org/10.21873/invivo.11047
Cao L, Quan X-B, Zeng W-J, et al (2016) Mechanism of hepatocyte apoptosis. J Cell Death 9:JCD.S39824. https://doi.org/10.4137/JCD.S39824
Cardozo MT, de Conti A, Ong TP, Scolastici C, Purgatto E, Horst MA, Bassoli BK, Moreno FS (2011) Chemopreventive effects of β-ionone and geraniol during rat hepatocarcinogenesis promotion: distinct actions on cell proliferation, apoptosis, HMGCoA reductase, and RhoA. J Nutr Biochem 22:130–135. https://doi.org/10.1016/j.jnutbio.2009.12.007
Ceyhan E, Canbek M (2017) Determining the effects of geraniol on liver regeneration via the nuclear factor kB pathway after partial hepatectomy. Altern Ther Health Med 23:38–45
Chen W, Viljoen AM (2010) Geraniol—a review of a commercially important fragrance material. South African J Bot 76:643–651. https://doi.org/10.1016/J.SAJB.2010.05.008
Chen J, Fan X, Zhou L et al (2015) Treatment with geraniol ameliorates methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in rats. Hepatology. https://doi.org/10.1111/jgh.13272
Chen J, Fan X, Zhou L, Gao X (2016) Treatment with geraniol ameliorates methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol 31:1357–1365. https://doi.org/10.1111/jgh.13272
Clavien PA, Harvey PR, Strasberg SM (1992) Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies Transplantation 53:957–978
de Oliveira THC, Marques PE, Proost P, Teixeira MMM (2018) Neutrophils: a cornerstone of liver ischemia and reperfusion injury. Lab Investig 98:51–62. https://doi.org/10.1038/labinvest.2017.90
Fayez AM, Zakaria S, Moustafa D (2018) Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. Biomed Pharmacother 105: https://doi.org/10.1016/j.biopha.2018.05.145
Franklin CC, Backos DS, Mohar I, White CC, Forman HJ, Kavanagh TJ (2009) Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol Asp Med 30:86–98. https://doi.org/10.1016/j.mam.2008.08.009
Gong X, Zhang L, Jiang R, Ye M, Yin X, Wan J (2013) Anti-inflammatory effects of mangiferin on sepsis-induced lung injury in mice via up-regulation of heme oxygenase-1. J Nutr Biochem 24:1173–1181. https://doi.org/10.1016/j.jnutbio.2012.09.003
Guan L-Y, Fu P-Y, Li P-D, Li ZN, Liu HY, Xin MG, Li W (2014) Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide. World J Gastrointest Surg 6:122–128. https://doi.org/10.4240/wjgs.v6.i7.122
Guicciardi ME, Malhi H, Mott JL, Gores GJ (2013) Apoptosis and necrosis in the liver. In: Comprehensive physiology. John Wiley & Sons, Inc., Hoboken, NJ, USA, pp 977–1010
Hasan SK, Sultana S (2015) Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats. Toxicol Mech Methods 25:559–573. https://doi.org/10.3109/15376516.2015.1070225
Hennig P, Garstkiewicz M, Grossi S, di Filippo M, French L, Beer HD (2018) The crosstalk between Nrf2 and inflammasomes. Int J Mol Sci 19:562. https://doi.org/10.3390/ijms19020562
Huang Y, Rabb H, Womer KL (2007) Ischemia–reperfusion and immediate T cell responses. Cell Immunol 248:4–11. https://doi.org/10.1016/j.cellimm.2007.03.009
Huang Y, Yang X-L, Ni Y-H, Xu Z-M (2018) Geraniol suppresses proinflammatory mediators in phorbol 12-myristate 13-acetate with A23187-induced HMC-1 cells. Drug Des Devel Ther Volume 12:2897–2903. https://doi.org/10.2147/DDDT.S145702
Jaeschke H, Farhood A (1991) Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Phys 260:G355–G362. https://doi.org/10.1152/ajpgi.1991.260.3.G355
Jaeschke H, Woolbright BL (2012) Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando) 26:103–114. https://doi.org/10.1016/j.trre.2011.10.006
Jaeschke H, Farhood A, Smith CW (1990) Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo. FASEB J 4:3355–3359
Jayachandran M, Chandrasekaran B, Namasivayam N (2015a) Geraniol attenuates oxidative stress by Nrf2 activation in diet-induced experimental atherosclerosis. J Basic Clin Physiol Pharmacol 26:335–346. https://doi.org/10.1515/jbcpp-2014-0057
Jayachandran M, Chandrasekaran B, Namasivayam N (2015b) Effect of geraniol, a plant derived monoterpene on lipids and lipid metabolizing enzymes in experimental hyperlipidemic hamsters. Mol Cell Biochem 398:39–53. https://doi.org/10.1007/s11010-014-2203-3
Jollow D, Mitchell JR, Zampaglione N, Gillette JR (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169. https://doi.org/10.1159/000136485
Kandeil MA, Mahmoud MO, Abdel-Razik A-RH, Gomaa SB (2019) Thymoquinone and geraniol alleviate cisplatin-induced neurotoxicity in rats through downregulating the p38 MAPK/STAT-1 pathway and oxidative stress. Life Sci 228:145–151. https://doi.org/10.1016/j.lfs.2019.04.065
Kaspar JW, Niture SK, Jaiswal AK (2009) Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 47:1304–1309. https://doi.org/10.1016/j.freeradbiomed.2009.07.035
Ke B, Shen X-D, Zhang Y, Ji H, Gao F, Yue S, Kamo N, Zhai Y, Yamamoto M, Busuttil RW, Kupiec-Weglinski JW (2013) KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. J Hepatol 59:1200–1207. https://doi.org/10.1016/j.jhep.2013.07.016
Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116. https://doi.org/10.1146/annurev.pharmtox.46.120604.141046
Khan AQ, Khan R, Qamar W, Lateef A, Rehman MU, Tahir M, Ali F, Hamiza OO, Hasan SK, Sultana S (2013) Geraniol attenuates 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in mouse skin: possible role of p38 MAP kinase and NF-κB. Exp Mol Pathol 94:419–429. https://doi.org/10.1016/j.yexmp.2013.01.006
Kim S-H, Bae HC, Park E-J, Lee CR, Kim BJ, Lee S, Park HH, Kim SJ, So I, Kim TW, Jeon JH (2011) Geraniol inhibits prostate cancer growth by targeting cell cycle and apoptosis pathways. Biochem Biophys Res Commun 407:129–134. https://doi.org/10.1016/j.bbrc.2011.02.124
Kudoh K, Uchinami H, Yoshioka M, Seki E, Yamamoto Y (2014) Nrf2 activation protects the liver from ischemia/reperfusion injury in mice. Ann Surg 260:118–127. https://doi.org/10.1097/SLA.0000000000000287
Lee C, Park GH, Kim C-Y, Jang J-H (2011) [6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. Food Chem Toxicol 49:1261–1269. https://doi.org/10.1016/j.fct.2011.03.005
Liu S-X, Zhang Y, Wang Y-F, Li XC, Xiang MX, Bian C, Chen P (2012) Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A conferring protection from anoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes. Int J Cardiol 160:95–101. https://doi.org/10.1016/j.ijcard.2011.03.033
Liu Z, Lai C-H, Zhang X, Luo J, Huang X, Qi X, Wang W, Zhong Z, Xiaoli F, Li L, Xiong Y, Senninger N, Wang Y, Ye Q, Ye S (2019) Simvastatin ameliorates total liver ischemia/reperfusion injury via KLF2-mediated mechanism in rats. Clin Res Hepatol Gastroenterol 43:171–178. https://doi.org/10.1016/j.clinre.2018.08.014
Luo J-F, Shen X-Y, Lio CK, Dai Y, Cheng CS, Liu JX, Yao YD, Yu Y, Xie Y, Luo P, Yao XS, Liu ZQ, Zhou H (2018) Activation of Nrf2/HO-1 pathway by Nardochinoid C inhibits inflammation and oxidative stress in lipopolysaccharide-stimulated macrophages. Front Pharmacol 9:911. https://doi.org/10.3389/fphar.2018.00911
Madankumar A, Tamilarasi S, Premkumar T, Gopikrishnan M, Nagabhishek N, Devaki T (2017) Geraniol attenuates 4NQO-induced tongue carcinogenesis through downregulating the activation of NF-κB in rats. Mol Cell Biochem 434:7–15. https://doi.org/10.1007/s11010-017-3030-0
Meng X, Hu L, Li W (2019) Baicalin ameliorates lipopolysaccharide-induced acute lung injury in mice by suppressing oxidative stress and inflammation via the activation of the Nrf2-mediated HO-1 signaling pathway. Naunyn Schmiedeberg's Arch Pharmacol 392:1421–1433. https://doi.org/10.1007/s00210-019-01680-9
Motiño O, Francés DE, Casanova N, Fuertes-Agudo M, Cucarella C, Flores JM, Vallejo-Cremades MT, Olmedilla L, Pérez Peña J, Bañares R, Boscá L, Casado M, Martín-Sanz P (2018) Protective role of hepatocyte cyclooxygenase-2 expression against liver ischemia-reperfusion injury in mice. Hepatology. 70:650–665. https://doi.org/10.1002/hep.30241
Moustafa D, Rabie M, Attia AS, Saleh S (2012) Does sirolimus attenuate the damage induced by partial warm ischemia/reperfusion injury in rat livers? Egypt J Basic Clin Pharmacol 2:. https://doi.org/10.11131/2012/101334
Nakamura K, Zhang M, Kageyama S, Ke B, Fujii T, Sosa RA, Reed EF, Datta N, Zarrinpar A, Busuttil RW, Araujo JA, Kupiec-Weglinski JW (2017) Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol 67:1232–1242. https://doi.org/10.1016/j.jhep.2017.08.010
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Ozkaya A, Sahin Z, Gorgulu A, Yuce A, Celik S (2017) Geraniol attenuates hydrogen peroxide-induced liver fatty acid alterations in male rats. J Intercult Ethnopharmacol 6:29–35. https://doi.org/10.5455/jice.20160928012410
Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424. https://doi.org/10.1152/physrev.00029.2006
Pan H, He M, Liu R, Brecha NC, Yu ACH, Pu M (2014) Sulforaphane protects rodent retinas against ischemia-reperfusion injury through the activation of the Nrf2/HO-1 antioxidant pathway. PLoS One 9:e114186. https://doi.org/10.1371/journal.pone.0114186
Panuganti SD, Khan FD, Svensson CK (2006) Enhanced xenobiotic-induced hepatotoxicity and Kupffer cell activation by restraint-induced stress. J Pharmacol Exp Ther 318:26–34. https://doi.org/10.1124/jpet.106.100933
Rojo de la Vega M, Chapman E, Zhang DD (2018) NRF2 and the hallmarks of cancer. Cancer Cell 34:21–43. https://doi.org/10.1016/j.ccell.2018.03.022
Serracino-Inglott F, Habib NA, Mathie RT (2001) Hepatic ischemia-reperfusion injury. Am J Surg 181:160–166. https://doi.org/10.1016/s0002-9610(00)00573-0
Shah ZA, Li R-C, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S, Doré S (2007) Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury. Neuroscience 147:53–59. https://doi.org/10.1016/j.neuroscience.2007.02.066
Sharawy MH, Abdelrahman RS, El-Kashef DH (2018) Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner. Life Sci 208:79–86. https://doi.org/10.1016/j.lfs.2018.07.019
Shen M, Lu J, Dai W, Wang F, Xu L, Chen K, He L, Cheng P, Zhang Y, Wang C, Wu D, Yang J, Zhu R, Zhang H, Zhou Y, Guo C (2013) Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy. Mediat Inflamm 2013:461536–461512. https://doi.org/10.1155/2013/461536
Shuh M, Bohorquez H, Loss GE, Cohen AJ (2013) Tumor necrosis factor-α: life and death of hepatocytes during liver ischemia/reperfusion injury. Ochsner J 13:119–130
Singh BK, Tripathi M, Chaudhari BP, Pandey PK, Kakkar P (2012) Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. PLoS One 7:e34200. https://doi.org/10.1371/journal.pone.0034200
Stocker R, Yamamoto Y, McDonagh A, et al (1987) Bilirubin is an antioxidant of possible physiological importance. Science (80- ) 235:1043–1046. https://doi.org/10.1126/science.3029864
Vomund S, Schäfer A, Parnham MJ, Brüne B, von Knethen A (2017) Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci 18:2772. https://doi.org/10.3390/ijms18122772
Wang W, Wu L, Li J, Ji J, Chen K, Yu Q, Li S, Feng J, Liu T, Zhang J, Chen J, Zhou Y, Mao Y, Wang F, Dai W, Fan X, Guo C, Wu J (2019) Alleviation of hepatic ischemia reperfusion injury by oleanolic acid pretreating via reducing HMGB1 release and inhibiting apoptosis and autophagy. Mediat Inflamm 2019:1–10. https://doi.org/10.1155/2019/3240713
Wittig C, Scheuer C, Parakenings J, Menger MD, Laschke MW (2015) Geraniol suppresses angiogenesis by downregulating vascular endothelial growth factor (VEGF)/VEGFR-2 signaling. PLoS One 10:e0131946. https://doi.org/10.1371/journal.pone.0131946
Wu L, Zhang Q, Dai W, Li S, Feng J, Li J, Liu T, Xu S, Wang W, Lu X, Yu Q, Chen K, Xia Y, Lu J, Zhou Y, Fan X, Guo C (2017) Quercetin pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy by inhibiting ERK/NF-κB pathway. Gastroenterol Res Pract 2017:9724217–9724215. https://doi.org/10.1155/2017/9724217
Xu D, Chen L, Chen X, Wen Y, Yu C, Yao J, Wu H, Wang X, Xia Q, Kong X (2017) The triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy. Cell Death Dis 8:e2983. https://doi.org/10.1038/cddis.2017.386
Yilmaz S, Ates E, Tokyol C, Pehlivan T, Erkasap S, Koken T (2004) The protective effect of erythropoietin on ischaemia/reperfusion injury of liver. HPB 6:169–173. https://doi.org/10.1080/13651820410026077
Zhang N, Han L, Xue Y, Deng Q, Wu Z, Peng H, Zhang Y, Xuan L, Pan G, Fu Q (2019) The protective effect of magnesium lithospermate B on hepatic ischemia/reperfusion via inhibiting the Jak2/Stat3 signaling pathway. Front Pharmacol 10:1–13. https://doi.org/10.3389/fphar.2019.00620
Zhou R, Deng J, Zhang M, Zhou HD, Wang YJ (2011) Association between bone mineral density and the risk of Alzheimer’s disease. J Alzheimers Dis 24:101–108. https://doi.org/10.3233/JAD-2010-101467
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Soad Z. El-Emam, Dina M. Abo El-Ella, and Ayman A. Soubh designed the experiments. Dina M. Abo El-Ella, Asmaa K. Al-Mokaddem, and Soad Z. El-Emam performed the experiments. Dina M. Abo El-Ella wrote the paper. Soad Z. El-Emam revised and finalized the manuscript
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El-Emam, S.Z., Soubh, A.A., Al-Mokaddem, A.K. et al. Geraniol activates Nrf-2/HO-1 signaling pathway mediating protection against oxidative stress-induced apoptosis in hepatic ischemia-reperfusion injury. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1849–1858 (2020). https://doi.org/10.1007/s00210-020-01887-1
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DOI: https://doi.org/10.1007/s00210-020-01887-1