The Inhibitory Effect of Geraniol on CCL4-induced Hepatorenal Toxicity in Pregnant Mice Through the PI3K/AKT Signaling Pathway

Overview

Journal Saudi J Med Med Sci

Specialty General Medicine

Date 2024 Feb 16

PMID 38362098

Authors

Sabah Ali Alzahrani

Gamal M Bekhet

Rebai Ben Ammar

Basem M Abdallah

Enas Mohamed Ali

Saeed Y Al-Ramadan

Duaa Althumairy

Peramaiyan Rajendran

Affiliations

Soon will be listed here.

Abstract

Background: Hepatotoxicity caused by CCL is well known. Geraniol (GNL) has high antioxidant effect that can induces liver regeneration. However, the protective effect of GNL effect on CCL-induced hepatorenal toxicity in pregnant mice has not yet been studied.

Objective: To investigate whether GNL could protect against oxidative stress induced by CCL via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which is regulated by phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and has been found to have protective effects on renal and hepatic tissues.

Materials And Methods: Forty-eight female albino mice weighing 25-30 g were randomly allocated to 4 groups: Group I served as a control; Group II received a toxicity-inducing single dose of 15 μL of CCL on the 4 day after mating; Group III received 40 mg/kg GNL + CCL (with GNL from the 1 day of assimilation to delivery); and Group IV received GNL alone from the 1 day of assimilation to the end of the delivery period. GNL was evaluated for its protective effects on hepatotoxicity in CCL-treated pregnant mice. Litter size, weight, survival rate, and resorption were recorded. In addition, H & E staining was done for liver and kidney pathology as well as biochemical markers and oxidative markers malondialdehyde, superoxide dismutase, and catalase were analyzed.

Results: CCL significantly reduced survival rate and increased resorption after exposure. Alanine transaminase and aspartate aminotransferase concentrations in the serum, tissue MDA, blood urea nitrogen, and creatinine were increased after CCL exposure. GNL improved enzyme and antioxidant levels and prevented CCL-induced hepatic injury in mice. Caspase-3 cleavage was decreased by GNL, which increased PI3K, phosphorylated AKT, Nrf2, and B-cell lymphoma 2.

Conclusion: GNL demonstrates a protective effect against CCl4-induced hepatorenal toxicity, mediated through the activation of the PI3K/AKT signaling pathway and the upregulation of Nrf2. These findings highlight the potential therapeutic implications of GNL in mitigating oxidative stress and inflammation in liver and kidney tissues.

References

Kadiiska M, Gladen B, Baird D, Dikalova A, Sohal R, Hatch G . Biomarkers of oxidative stress study: are plasma antioxidants markers of CCl(4) poisoning?. Free Radic Biol Med. 2000; 28(6):838-45. DOI: 10.1016/s0891-5849(00)00198-2. View

Yu M, Wei Z, Xu Z, Pan J, Chen J . Oxidative Damage and Nrf2 Translocation Induced by Toxicities of Deoxynivalenol on the Placental and Embryo on Gestation Day 12.5 d and 18.5 d. Toxins (Basel). 2018; 10(9). PMC: 6162513. DOI: 10.3390/toxins10090370. View

Rotruck J, POPE A, Ganther H, SWANSON A, Hafeman D, Hoekstra W . Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973; 179(4073):588-90. DOI: 10.1126/science.179.4073.588. View

Al-Yahya M, Mothana R, Al-Said M, Al-Dosari M, Al-Musayeib N, Al-Sohaibani M . Attenuation of CCl4-Induced Oxidative Stress and Hepatonephrotoxicity by Saudi Sidr Honey in Rats. Evid Based Complement Alternat Med. 2013; 2013:569037. PMC: 3595690. DOI: 10.1155/2013/569037. View

Burton G, Hempstock J, Jauniaux E . Oxygen, early embryonic metabolism and free radical-mediated embryopathies. Reprod Biomed Online. 2003; 6(1):84-96. DOI: 10.1016/s1472-6483(10)62060-3. View

Rajendran P, Nandakumar N, Rengarajan T, Palaniswami R, Gnanadhas E, Lakshminarasaiah U . Antioxidants and human diseases. Clin Chim Acta. 2014; 436:332-47. DOI: 10.1016/j.cca.2014.06.004. View

Ruvolo P, Deng X, May W . Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia. 2001; 15(4):515-22. DOI: 10.1038/sj.leu.2402090. View

Tantengco O, Silva M, Shahin H, Cosi Bento G, Cursino G, Cayenne S . The role of nuclear factor erythroid 2-related factor 2 (NRF2) in normal and pathological pregnancy: A systematic review. Am J Reprod Immunol. 2021; 86(6):e13496. DOI: 10.1111/aji.13496. View

Chen H, Zhang Y, Zou M, Qi X, Xu S . Bisphenol A aggravates renal apoptosis and necroptosis in selenium-deficient chickens via oxidative stress and PI3K/AKT pathway. J Cell Physiol. 2022; 237(8):3292-3304. DOI: 10.1002/jcp.30781. View

10.

Ammar R, Alamer S, Mohamed M, Althumairy D, Al-Ramadan S, Alfwuaires M . Potential inhibitory effect of geraniol isolated from lemongrass ( Stapf) on tilmicosin-induced oxidative stress in cardiac tissue. Nat Prod Res. 2023; 38(10):1652-1661. DOI: 10.1080/14786419.2023.2215901. View

11.

Beker M, Caglayan B, Caglayan A, Kelestemur T, Yalcin E, Caglayan A . Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival. Sci Rep. 2019; 9(1):19082. PMC: 6910929. DOI: 10.1038/s41598-019-55663-0. View

12.

Rajendran P, Alzahrani A, Ahmed E, Veeraraghavan V . Kirenol Inhibits B[a]P-Induced Oxidative Stress and Apoptosis in Endothelial Cells via Modulation of the Nrf2 Signaling Pathway. Oxid Med Cell Longev. 2021; 2021:5585303. PMC: 8088375. DOI: 10.1155/2021/5585303. View

13.

Kostic T, Popovic D, Perisic Z, Stanojevic D, Dakic S, Saric S . The hepatoprotective effect of aminoguanidine in acute liver injury caused by CCl in rats. Biomed Pharmacother. 2022; 156:113918. DOI: 10.1016/j.biopha.2022.113918. View

14.

Rajendran P, Ammar R, Al-Saeedi F, Mohamed M, ElNaggar M, Al-Ramadan S . Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies. Int J Mol Sci. 2020; 22(1). PMC: 7794799. DOI: 10.3390/ijms22010217. View

15.

Masuda Y . [Learning toxicology from carbon tetrachloride-induced hepatotoxicity]. Yakugaku Zasshi. 2006; 126(10):885-99. DOI: 10.1248/yakushi.126.885. View

16.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

17.

Cheng X, Chapple S, Patel B, Puszyk W, Sugden D, Yin X . Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero. Diabetes. 2013; 62(12):4088-97. PMC: 3837032. DOI: 10.2337/db13-0169. View

18.

Mochizuki M, Shimizu S, Urasoko Y, Umeshita K, Kamata T, Kitazawa T . Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats. J Toxicol Sci. 2009; 34(2):175-81. DOI: 10.2131/jts.34.175. View

19.

Dodson M, Rojo de la Vega M, Cholanians A, Schmidlin C, Chapman E, Zhang D . Modulating NRF2 in Disease: Timing Is Everything. Annu Rev Pharmacol Toxicol. 2018; 59:555-575. PMC: 6538038. DOI: 10.1146/annurev-pharmtox-010818-021856. View

20.

Ammar R, Mohamed M, Alfwuaires M, Alamer S, Bani Ismail M, Veeraraghavan V . Anti-Inflammatory Activity of Geraniol Isolated from Lemon Grass on Ox-LDL-Stimulated Endothelial Cells by Upregulation of Heme Oxygenase-1 via PI3K/Akt and Nrf-2 Signaling Pathways. Nutrients. 2022; 14(22). PMC: 9695721. DOI: 10.3390/nu14224817. View