Alpha-pinene Ameliorates Liver Fibrosis by Suppressing Oxidative Stress, Inflammation, and the TGF-β/Smad3 Signaling Pathway

Overview

Journal Iran J Basic Med Sci

Publisher Mashhad University of Medical Sciences

Specialty General Medicine

Date 2025 Feb 19

PMID 39968080

Authors

Fatemeh Noroozi

Masoumeh Asle-Rousta

Rahim Amini

Zeinab Sahraeian

Affiliations

Soon will be listed here.

Abstract

Objectives: A monoterpene alpha-pinene possesses anti-oxidant, anti-inflammatory, and anti-apoptotic properties. Here, we investigated the effect of alpha-pinene on molecular, biochemical, and histological changes induced by carbon tetrachloride (CCl) in the liver of male Wistar rats.

Materials And Methods: Animals were divided into four groups: Control, Pinene, CCl, and CCl.Pinene. Pinene and CCl.Pinene groups were given alpha-pinene (50 mg/kg/day) through intraperitoneal (IP) injections for six consecutive weeks. CCl and CCl.Pinene groups received IP injections of CCl (2 ml/kg twice weekly for six consecutive weeks).

Results: The results revealed that alpha-pinene inhibited enhancing liver enzyme AST (<0.001), ALT (<0.001), ALP (<0.01), and GGT (<0.001) activity in CCl.Pinene rats. It reduced malondialdehyde (<0.05) and nitric oxide (<0.05) levels and increased the catalase enzyme activity (<0.05) and glutathione levels (<0.01) in the liver. Likewise, alpha-pinene suppressed proinflammatory and profibrotic gene expression and prevented significant histological damage and collagen deposition in the liver of these animals. Also, alpha-pinene reduced the expression of TLR4 (<0.01), NF-κB (<0.05), PI3K (<0.05), Akt (<0.05), mTOR (<0.01), TGF-β1 (<0.01), and Smad3 (<0.01) in the liver of rats receiving CCl.

Conclusion: We concluded that alpha-pinene reduced CCl-induced liver fibrosis by lowering oxidative stress, suppressing liver inflammation, and inhibiting TLR4/NF-κB, TGF-β/Smad3, and PI3K/Akt/mTOR signaling pathways. Consequently, alpha-pinene may have potential therapeutic value in treating liver diseases.

References

Allenspach M, Steuer C . α-Pinene: A never-ending story. Phytochemistry. 2021; 190:112857. DOI: 10.1016/j.phytochem.2021.112857. View

Ben Hsouna A, Dhibi S, Dhifi W, Mnif W, Ben Nasr H, Hfaiedh N . Chemical composition and hepatoprotective effect of essential oil from L. flowers against CCL-induced acute hepatotoxicity in rats. RSC Adv. 2022; 9(7):3777-3787. PMC: 9060237. DOI: 10.1039/c8ra08204a. View

Satou T, Kasuya H, Maeda K, Koike K . Daily inhalation of α-pinene in mice: effects on behavior and organ accumulation. Phytother Res. 2014; 28(9):1284-7. DOI: 10.1002/ptr.5105. View

Shan L, Ding Y, Fu Y, Zhou L, Dong X, Chen S . mTOR Overactivation in Mesenchymal cells Aggravates CCl- Induced liver Fibrosis. Sci Rep. 2016; 6:36037. PMC: 5098141. DOI: 10.1038/srep36037. View

Antar S, Ashour N, Marawan M, Al-Karmalawy A . Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation. Int J Mol Sci. 2023; 24(4). PMC: 9963026. DOI: 10.3390/ijms24044004. View

Magaye R, Savira F, Hua Y, Xiong X, Huang L, Reid C . Attenuating PI3K/Akt- mTOR pathway reduces dihydrosphingosine 1 phosphate mediated collagen synthesis and hypertrophy in primary cardiac cells. Int J Biochem Cell Biol. 2021; 134:105952. DOI: 10.1016/j.biocel.2021.105952. View

Hu H, Chen D, Wang Y, Feng Y, Cao G, Vaziri N . New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018; 292:76-83. DOI: 10.1016/j.cbi.2018.07.008. View

Draper H, Hadley M . Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990; 186:421-31. DOI: 10.1016/0076-6879(90)86135-i. View

Mohamed M, Younis N, El-Beltagi H, Mohafez O . The Synergistic Hepatoprotective Activity of Rosemary Essential Oil and Curcumin: The Role of the MEK/ERK Pathway. Molecules. 2022; 27(24). PMC: 9781795. DOI: 10.3390/molecules27248910. View

10.

Xiang D, Sun W, Ning B, Zhou T, Li X, Zhong W . The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut. 2017; 67(9):1704-1715. DOI: 10.1136/gutjnl-2016-313392. View

11.

Bae G, Park K, Choi S, Jo I, Choi M, Hong S . Protective effects of alpha-pinene in mice with cerulein-induced acute pancreatitis. Life Sci. 2012; 91(17-18):866-71. DOI: 10.1016/j.lfs.2012.08.035. View

12.

Sanchez-Valle V, Chavez-Tapia N, Uribe M, Mendez-Sanchez N . Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem. 2012; 19(28):4850-60. DOI: 10.2174/092986712803341520. View

13.

Abdelghffar E, Obaid W, Alamoudi M, Mohammedsaleh Z, Annaz H, Abdelfattah M . Thymus fontanesii attenuates CCl-induced oxidative stress and inflammation in mild liver fibrosis. Biomed Pharmacother. 2022; 148:112738. DOI: 10.1016/j.biopha.2022.112738. View

14.

Golob-Schwarzl N, Krassnig S, Toeglhofer A, Park Y, Gogg-Kamerer M, Vierlinger K . New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur J Cancer. 2017; 83:56-70. DOI: 10.1016/j.ejca.2017.06.003. View

15.

Xanthis V, Fitsiou E, Voulgaridou G, Bogadakis A, Chlichlia K, Galanis A . Antioxidant and Cytoprotective Potential of the Essential Oil var and Its Major Components Myrcene and -Pinene. Antioxidants (Basel). 2021; 10(1). PMC: 7830477. DOI: 10.3390/antiox10010127. View

16.

Elbaset M, Salem R, Ayman F, Ayman N, Shaban N, Afifi S . Effect of Empagliflozin on Thioacetamide-Induced Liver Injury in Rats: Role of AMPK/SIRT-1/HIF-1α Pathway in Halting Liver Fibrosis. Antioxidants (Basel). 2022; 11(11). PMC: 9686640. DOI: 10.3390/antiox11112152. View

17.

Hayashi H, Sakai T . Biological Significance of Local TGF-β Activation in Liver Diseases. Front Physiol. 2012; 3:12. PMC: 3277268. DOI: 10.3389/fphys.2012.00012. View

18.

Karthikeyan R, Kanimozhi G, Madahavan N, Agilan B, Ganesan M, Prasad N . Alpha-pinene attenuates UVA-induced photoaging through inhibition of matrix metalloproteinases expression in mouse skin. Life Sci. 2018; 217:110-118. DOI: 10.1016/j.lfs.2018.12.003. View

19.

Wang K, Yang X, Wu Z, Wang H, Li Q, Mei H . Polysaccharide Protected CCl-Induced Liver Fibrosis Through Intestinal Homeostasis and the LPS-TLR4-NF-κB Signaling Pathway. Front Pharmacol. 2020; 11:240. PMC: 7080991. DOI: 10.3389/fphar.2020.00240. View

20.

ZhangDi H, Su S, Wang F, Liang Z, Yan Y, Qin S . Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J Gastroenterol. 2019; 25(33):4835-4849. PMC: 6737310. DOI: 10.3748/wjg.v25.i33.4835. View