Hepatoprotective activity of Averrhoa bilimbi L. fruit extract on carbon tetrachloride-induced acute liver faiure in Wistar rats

Main Article Content

Rachellicya Ristioni Sihaloho
Chodijah Chodijah
Titiek Sumarawati
Joko Wahyu Wibowo
Siti Thomas Zulaikhah
Agung Putra
Nurul Hidayah
Shabrina Syifa Ghaissani
Mohammad Ariq Nazar


Acute liver failure (ALF) is a state of rapid and progressive deterioration of liver function. Continuous exposure to chemicals and viruses can increase reactive oxygen species (ROS) which leads to prolonged inflammation due to the production of tumor necrosis factor-alpha (TNF-á) thus inhibiting the production of platelet-derived growth factor (PDGF). The objective of this study was to evaluate the effect of administration of Averrhoa bilimbi L. fruit extract on PDGF levels and TNF-á levels in carbon tetrachloride (CCl4)-induced ALF rats.

This study used a post-test-only control group design involving 20 Wistar rats. They were randomized into 4 groups, namely sham, control, T1, and T2. Group T1 was exposed to CCl4 with the administration of A. bilimbi fruit extract at a dose of 500mg/kgBW, while, group T2 was exposed to CCl4 and given A. bilimbi fruit extract of 750 mg/kgBW. On the 15th day, the serum was analyzed to determine the levels of PDGF and TNF-á using ELISA.

The highest mean PDGF level in the control group was 146.60±15.36 pg/mL, while the highest mean TNF-á level in group T1 was 40.11±4.44 pg/mL. The One-way ANOVA test showed that there were significant differences in TNF-á (p=0.002) and PDGF (p=0.000) levels between the study groups.

The administration of A.bilimbi L. fruit extract affected PDGF and TNF-á levels in CCl4-induced ALF rats. The present study revealed that A. bilimbi fruits have significant hepatoprotective activity in experimental Wistar rats.

Article Details

How to Cite
Sihaloho , R. R. ., Chodijah, C., Sumarawati, T. ., Wibowo, J. W. ., Zulaikhah, S. T., Putra, A., Hidayah, N., Ghaissani, S. S., & Nazar, M. A. . (2023). Hepatoprotective activity of Averrhoa bilimbi L. fruit extract on carbon tetrachloride-induced acute liver faiure in Wistar rats. Universa Medicina, 42(1), 61–69. https://doi.org/10.18051/UnivMed.2023.v42.61-69
Original Articles


Interleukin-10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis. Hepatol Res 2018;48:E194–202. doi: 10.1111/hepr.12969.

Putra A, Antari AD, Kustiyah AR, et al. Mesenchymal stem cells accelerate liver regeneration in acute liver failure animal model. Biomed Res Ther 2018;5:2802–10. https://doi.org/10.15419/bmrat.v5i11.496.

Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent redox signaling in TGF-â-mediated fibrotic responses. Redox Biol 2014;2: 267–72. http://dx.doi.org/10.1016/j.redox.2014.01. 012.

Yoshida K, Murata M, Yamaguchi T, Matsuzaki K. TGF-â/Smad signaling during hepatic fibro-carcinogenesis (Review). Int J Oncol 2014;45: 1363–71. doi: 10.3892/ijo.2014.2552.

Fathy M, Okabe M, Eldien HMS, Yoshida T. AT-MSCs antifibrotic activity is improved by eugenol through modulation of TGF-â/Smad signaling pathway in rats. Molecules 2020;25:1–17. doi: 10.3390/molecules25020348.

Choi JS, Jeong IS, Han JH, Cheon SH, Kim SW. IL-10-secreting human MSCs generated by TALEN gene editing ameliorate liver fibrosis through enhanced anti-fibrotic activity. Biomater Sci 2019;7:1078–87.

Konala VBR, Bhonde R, Pal R. Secretome studies of mesenchymal stromal cells (MSCs) isolated from three tissue sources reveal subtle differences in potency. In Vitro Cell Dev Biol Anim 2020;56: 689-700. doi: 10.1007/s11626-020-00501-1.

Roehlen N, Crouchet E, Baumert TF. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells 2020;9:875. doi: 10.3390/cells9040875.

Böttcher K, Pinzani M. Pathophysiology of liver fibrosis and the methodological barriers to the development of anti-fibrogenic agents. Adv Drug Deliv Rev 2017;121:3–8.

Koyama Y, Xu J, Liu X, Brenner DA. New developments on the treatment of liver fibrosis. Dig Dis 2016;34:589–96. doi: 10.1159/000445269.

Elpek GO. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update. World J Gastroenterol 2014;20: 7260-76. DOI: http://dx.doi.org/10.3748/wjg.v20.i23.7260.

Suluvoy JK, Sakthivel KM, Guruvayoorappan GC, Berlin Grace VM. Protective effect of Averrhoa bilimbi L. fruit extract on ulcerative colitis in wistar rats via regulation of inflammatory mediators and cytokines. Biomed Pharmacother 2017;91:1113–21. doi: 10.1016/j.biopha.2017. 05.057.

Labibi MH, Suyatmi, Afifah ZN. Bilimbi fruit (Averrhoa bilimbi Linn.) extract protects liver from damage induced by reheated palm oil on mice (Mus musculus). Nexus Biomedika 2016;5.

Setyawan HY, Sukardi S, Nareswari BF. The phytochemical potential of Averrhoa bilimbi – a review. IOP Conf Ser Earth Environ Sci 2021;733: 012091.

Xianyuan L, Wei Z, Yaqian D, et al. Anti-renal fibrosis effect of asperulosidic acid via TGF-â1/smad2/smad3 and NF-êB signaling pathways in a rat model of unilateral ureteral obstruction. Phytomedicine 2019;53:274–85. https://doi.org/10.1016/j.phymed.2018.09.009.

Zhou X, Du HH, Ni L, et al. Nicotinamide mononucleotide combined with Lactobacillus fermentum TKSN041 reduces the photoaging damage in murine skin by activating AMPK signaling pathway. Front Pharmacol 2021;12: 643089. doi: 10.3389/fphar.2021.643089.

Xu Y, Tang X, Yang M, et al. Interleukin 10 gene-modified bone marrow-derived dendritic cells attenuate liver fibrosis in mice by inducing regulatory T cells and inhibiting the TGF-â/Smad signaling pathway. Mediators Inflamm 2019;2019: 4652596. doi: 10.1155/2019/4652596.

Sungkar T, Putra A, Lindarto D, Sembiring RJ. Intravenous umbilical cord-derived mesenchymal stem cells transplantation regulates hyaluronic acid and interleukin-10 secretion producing low-grade liver fibrosis in experimental rat. Med Arch 2020 ;74:177-82. doi: 10.5455/medarh.2020.74.177-182.

Lee YR, Noh EM, Han JH, et al. Brazilin inhibits UVB-induced MMP-1/3 expressions and secretions by suppressing the NF-êB pathway in human dermal fibroblasts. Eur J Pharmacol 2012; 674:80–6. DOI: 10.1016/j.ejphar.2011.10.016.

Giannone FA, Baldassarre M, Domenicali M, et al. Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis. Lab Invest 2012;92:384-95. doi: 10.1038/labinvest.

El Agha E, Kramann R, Schneider RK, et al. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 2017;21:166–77. doi: 10.1016/j.stem.2017. 07.011.

Roskoski R Jr. The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders. Pharmacol Res 2018;129:65–83. doi: 10.1016/j.phrs.2018.01.021.

Sungkar T, Putra A, Lindarto D, Sembiring RJ. The effect of mesenchymal stem cells for the reduction of liver fibrosis through platelet derived growth factorâ regulation in rats. Biochem Cell Arch 2019;19:4749–53.

Suluvoy JK, Berlin Grace VM. Phytochemical profile and free radical nitric oxide (NO) scavenging activity of Averrhoa bilimbi L. fruit extract. 3 Biotech 2017;7:85. doi: 10.1007/s13205-017-0678-9.

Turkoglu M, Pekmezci E, Kilic S. Green tea extract exerts anabolic effects on extracellular matrix of the skin. Indian J Pharm Sci 2020;82:368–73. DOI: 10.36468/pharmaceutical-sciences.658.

Alhassan A, Ahmed Q. Averrhoa bilimbi Linn.: a review of its ethnomedicinal uses, phytochemistry, and pharmacology. J Pharm Bioallied Sci 2016;8:265-71. doi: 10.4103/0975-7406.199342.

Thamizh Selvam N, Santhi PS, Sanjayakumar YR, Venugopalan TN, Vasanthakumar KG, Swamy GK. Hepatoprotective activity of Averrhoa bilimbi fruit in acetaminophen induced hepatotoxicity in wistar albino rats. J Chem Pharm Res 2015;7:535–40.

Singh DR, Singh S, Salim KM, Srivastava RC. Estimation of phytochemicals and antioxidant activity of underutilized fruits of Andaman Islands (India). Int J Food Sci Nutr 2012;66:446–52. doi: 10.3109/09637486.2011.634788.

Yang F, Luo L, Zhu ZD, et al. Chlorogenic acid inhibits liver fibrosis by blocking the miR-21-regulated TGF-â1/Smad7 signaling pathway in vitro and in vivo. Front Pharmacol 2017;8:1–13. doi: 10.3389/fphar.2017.00929.

Sa’dyah NAC, Putra A, Dirja BT, Hidayah N, Azzahara SY, RCS Irawan. Suppression of transforming growth factor-â by mesenchymal stem-cells accelerates liver regeneration in liver fibrosis animal model. Univ Med 2021;40:29–35. doi: 10.18051/UnivMed.2021.v40.29.

Hu C, Zhao L, Duan J, Li L. Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis. J Cell Mol Med 2019;23:1657–70. doi: 10.1111/jcmm. 14115.

Kim R, Song BW, Kim M, et al. Regulation of alternative macrophage activation by MSCs derived hypoxic conditioned medium, via the TGF-a1/Smad3 pathway. BMB Rep 2020;53:600. doi: 10.5483/BMBRep.2020.53.11.177.

Auffenberg GB, Helfand BT, Mcvary KT. Normal erectile physiology. In: McVary KT, Kohler TS, editors. 2nd ed. Contemporary treatment of erectile dysfunction: a clinical guide. New York: Springer Publishing; 2016. DOI: 10.1007/978-3-319-31587-4_2.

Costa-Beber LC, Hirsch GE, Heck TG, Ludwig MS. Chaperone duality: the role of extracellular and intracellular HSP70 as a biomarker of endothelial dysfunction in the development of atherosclerosis. Arch Physiol Biochem 2022;128: 1016-23. doi: 10.1080/13813455.2020. 1745850.

Sungkar T, Putra A, Lindarto D, Sembiring RJ. Anti-fibrotic effect of intravenous umbilical cord-derived mesenchymal stem cells (UC-MSCs) injection in experimental rats induced liver fibrosis. Med Glas (Zenica) 2021;18:62-9. doi: 10.17392/1211-21.