Hepatoprotective effects of Curcuma xanthorrhiza Roxb. extract via free radical scavenger, inhibiting apoptosis and inflammation mechanisms in acetaminophen-induced liver injury

Document Type : Original Article

Authors

1 Faculty of Medicine, Universitas Prima Indonesia, Medan 20118, North Sumatera, Indonesia

2 Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung 40163, Indonesia

3 Faculty of Pharmacy, Jenderal Achmad Yani University, Cimahi 40531, Indonesia

4 Faculty of Medicine, Maranatha Christian University, Bandung 40164, West Java, Indonesia

10.22038/ijbms.2025.82500.17833

Abstract

Objective(s): Acetaminophen (APAP)-mediated liver injury poses a significant public health concern. Curcuma xanthorrhiza extract (CXE) has been traditionally used for its hepatoprotective properties. This research aimed to assess the hepatoprotective effects of CXE in APAP-mediated hepatotoxicity by investigating the modulatory effects of CXE on key biomarkers, including Interleukin (IL), namely, (IL-6), IL-10, IL-1β, Nitric Oxide (NO), Lactate Dehydrogenase (LDH), and the genes expression related to apoptosis-like Caspase-3 (Casp-3), Casp-9, and genes related to liver metabolic c-Jun N-terminal Kinase (JNK), in APAP-mediated HepG2 cells.
Materials and Methods: APAP-induced HepG2 cells were treated with different concentrations of CXE. IL-6, IL-10, IL were measured using an Enzyme-linked Immunosorbent Assay (ELISA) and NO, LDH were measured using colorimetric assay. Gene expression was analyzed using quantitative Real-Time Reverse Transcription (qRT-PCR).
Results: CXE significantly reduced IL-1β and IL-6 levels, enhanced IL-10 production, and attenuated NO levels in APAP-mediated hepatotoxicity. CXE also suppressed the expression of Casp-9, Casp-3, JNK, and LDH levels. The study presented a concentration-dependent response, with 125 μg/ml CXE exhibiting the most pronounced effects. CXE effectively modulated immune responses, decreased oxidative stress, and inhibited apoptotic and inflammatory pathways in APAP-mediated hepatotoxic cells.
Conclusion: These studies highlight the CXE potential as a therapeutic candidate for liver disorders, particularly in drug-mediated liver injury.

Keywords

Main Subjects

References

1. Beier JI, Arteel GE. Environmental exposure as a risk-modifying factor in liver diseases: Knowns and unknowns. Acta Pharm Sin B 2021; 11: 3768-3778. 
2. Ayoub SS. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature 2021; 8: 351-371. 
3. Jaeschke H, Akakpo JY, Umbaugh DS, Ramachandran A. Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure. Toxicol Sci 2020; 174: 159-167. 
4. Lv L, Xu C, Mo X, Sun HY, Bi H. Green tea polyphenols protect against acetaminophen-induced liver injury by regulating the drug metabolizing enzymes and transporters. Evid Based Complement Alternat Med 2020; 2020: 2696432-2696449. 
5. Chiew AL, Isbister GK, Stathakis P, Isoardi KZ, Page C, Ress K, et al. Acetaminophen metabolites on presentation following an acute acetaminophen overdose (ATOM‐7). Clin Pharmacol Ther 2023; 113: 1304-1314. 
6. McGill MR, Hinson JA. The development and hepatotoxicity of acetaminophen: Reviewing over a century of progress. Drug Metab Rev 2020; 52: 472-500. 
7. Jeong TB, Kim JH, Kim SH, Lee S, Son SW, Lim Y, et al. Comparison of toxic responses to acetaminophen challenge in icr mice originating from different sources. Lab Anim Res 2019; 35: 1-7. 
8. Shi S, Wang L, Van der Laan LJ, Pan Q, Verstegen MM. Mitochondrial dysfunction and oxidative stress in liver transplantation and underlying diseases: new insights and therapeutics. Transplantation 2021; 105: 2362-2373. 
9. Niederreiter L, Tilg H. Cytokines and fatty liver diseases. Liver Res 2018; 2: 14-20. 
10. Win S, Than TA, Zhang J, Oo C, Min RWM, Kaplowitz N. New insights into the role and mechanism of c‐Jun‐N‐terminal kinase signaling in the pathobiology of liver diseases. Hepatology 2018; 67: 2013-2024. 
11. Huang K, Mukherjee S, DesMarais V, Albanese JM, Rafti E, Draghi IIA, et al. Targeting the PXR–TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis. Pediatr Res 2018; 83: 1031-1040. 
12. Shojaie L, Iorga A, Dara L. Cell death in liver diseases: A review. Int J Mol Sci 2020; 21: 9682-9729. 
13. Effenberger M, Grander C, Grabherr F, Griesmacher A, Ploner T, Hartig F, et al. Systemic inflammation as fuel for acute liver injury in COVID-19. Dig Liver Dis 2021; 53: 158-165. 
14. El Shaffei I, Abdel-Latif GA, Farag DB, Schaalan M, Salama RM. Ameliorative effect of betanin on experimental cisplatin-induced liver injury; the novel impact of miRNA-34a on the SIRT1/PGC-1α signaling pathway. J Biochem Mol Toxicol 2021; 35: 1-14. 
15. Latief U, Ahmad R. Herbal remedies for liver fibrosis: A review on the mode of action of fifty herbs. J Tradit Complement Med 2018; 8: 352-360. 
16. Li X, Sun R, Liu R. Natural products in licorice for the therapy of liver diseases: progress and future opportunities. Pharmacol Res 2019; 144: 210-226. 
17. Pramono S, Arifah FH, Pribadi FH, Nugroho AE. Hepatoprotective activity of Curcuma xanthorrhiza roxb. paracetamol-induced liver damage in rats and correlation with their chemical compounds. TJPS 2018; 42: 188-195. 
18. Devaraj S, Ismail S, Ramanathan S, Yam MF. Investigation of antioxidant and hepatoprotective activity of standardized Curcuma xanthorrhiza rhizome in carbon tetrachloride-induced hepatic damaged rats. Sci World J 2014: 2014: 353128-353136. 
19. Sahoo A, Jena S, Ray A, Dash KT, Nayak S, Panda PC. Chemical constituent analysis and antioxidant activity of leaf essential oil of Curcuma xanthorrhiza. J Essent Oil-Bear Plants 2021; 24: 736-744. 
20. Laksmitawati DR, Pratami DK, Widowati W, Kusuma HSW, Wijayanti CR, Wahyuni CD, et al. Antioxidant Properties of Curcuma longa L. and Curcuma xanthorrhiza Rhizomes. In Proceedings of the 1st International Conference on Emerging Issues in Technology, Engineering and Science (ICE-TES 2021), 2022. p.104-111. 
21. Widowati W, Darsono L, Lucianus J, Setiabudi E, Obeng SS, Stefani S, et al. Butterfly pea flower (Clitoria ternatea L.) extract displayed antidiabetic effect through antioxidant, anti-inflammatory, lower hepatic GSK-3β, and pancreatic glycogen on Diabetes Mellitus and dyslipidemia rat. J King Saud Univ Sci 2023; 35: 102579-102589. 
22. Ginting CN, Lister INE, Girsang E, Widowati W, Yusepany DT, Azizah AM, et al. Hepatotoxicity prevention in acetaminophen-induced HepG2 cells by red betel (Piper crocatum Ruiz and Pav) extract from indonesia via antioxidant, anti-inflammatory, and anti-necrotic. Heliyon 2021; 7: e05620-5627.  
23. Widowati W, Jasaputra DK, Gunawan KY, Kusuma HSW, Arumwardana S, Wahyuni CD, et al. Turmeric extract potential inhibit inflammatory marker in lps-stimulated marcophage cells. Int J Appl Pharm 2021; 13: 7-11. 
24. Lister INE, Ginting CN, Girsang E, Nataya ED, Azizah AM, Widowati W. Hepatoprotective properties of red betel (Piper crocatum Ruiz and Pav) leaves extract towards H2O2-induced HepG2 cells via anti-inflammatory, antinecrotic, antioxidant potency. Saudi Pharm J 2020; 28: 1182-1189. 
25. Novilla A, Djamhuri DS, Nurhayati B, Rihibiha DD, Afifah E, Widowati W. Anti-inflammatory properties of oolong tea (Camellia sinensis) ethanol extract and epigallocatechin gallate in LPS-induced RAW 264.7 cells. Asian Pac J Trop Biomed 2017; 7: 1005-1009. 
26. Girsang E, Lister INE, Ginting CN, Nasution SL, Suhartina S, Munshy UZ, et al. Antioxidant and anti-inflammatory activity of Salacca zalacca (Gaertn.) voss peel ethanolic extract on lead induced fibroblast cells. Science and Technology Publication 2020; 68-73. 
27. Widowati W, Prahastuti S, Hidayat M, Hasianna ST, Wahyudianingsih R, Eltania TF, et al. Detam 1 black soybean against cisplatin-induced acute ren failure on rat model via antioxidant, antiinflammatory and antiapoptosis potential. J Tradit Complement 2022; 12: 426-435. 
28. Hassanzadeh K, Vahabzadeh Z, Bucarello L, Dragotto J, Corbo M, Maccarone R, et al. Protective effect of curcuma extract in an ex vivo model of retinal degeneration via antioxidant activity and targeting the SUMOylation. Oxid Med Cell Longev 2022; 2022: 8923615-8923630. 
29. Lister INE, Ginting CN, Girsang E, Amansyah A, Chiuman L, Yanti NLWE, et al. Hepatoprotective effect of eugenol on acetaminophen-induced hepatotoxicity in HepG2 cells. J Phys Conf Ser 2019; 1374: 012009-012017. 
30. Girsang E, Ginting CN, Lister INE, Gunawan K, Widowati W. Anti-inflammatory and antiaging properties of chlorogenic acid on UV-induced fibroblast cell. PeerJ 2021; 9: e11419-11434. 
31. Rahmat E, Lee J, Kang Y. Javanese turmeric (Curcuma xanthorrhiza Roxb.): Ethnobotany, phytochemistry, biotechnology, and pharmacological activities.  Based Complement Alternat Med 2021 Jun 11:2021:9960813. 
32. Masfufatun M, Sari M, Jamilah A. The antioxidant and hepatoprotective potential of temulawak (Curcuma xanthorrhiza Roxb) ethanol extract in paracetamol-induced rats. ICoSTE 2020.p.1-9.  
33. Hasan AEZ, Falah S, Handharyani E, Dwicesaria MA. Transaminase enzyme activity and histopathology evaluation of rat’s liver induced by DMBA with temulawak extract (Curcuma xanthorrhiza). J Adv Sci Eng Inf Techno 2023; 13: 267. 
34. Ardiyanto D, Zulkarnain Z, Astana PRW, Triyono A, Novianto F, Fitriani U, et al. Efficacy of hepatoprotector jamu formula (combination of Curcuma longa, Curcuma xanthorrhiza, and Taraxacum officinale) compared to Fructus schizandrae extract in mild liver injury: A randomized controlled trial. IOP Conf Ser Earth Environ Sci 2021; 913: 012089-012099. 
35. Lashgari NA, Khayatan D, Roudsari NM, Momtaz S, Dehpour AR, Abdolghaffari AH. Therapeutic approaches for cholestatic liver diseases: The role of nitric oxide pathway. Naunyn Schmiedebergs Arch Pharmacol 2023; 397: 1433-1454. 
36. Klein R, Nagy O, Tóthová C, Chovanová F. Clinical and diagnostic significance of lactate dehydrogenase and its isoenzymes in animals. Vet Med Int 2020; 2020: 5346483-5346494. 
37. Majeed HJ, Ismail PA, Hassan LM. Evaluation of serum nitric oxide levels and some biochemical parameters in patients with liver cirrhosis. Am J Biomed Sci Res 2020; 8: 18-22. 
38. Puteri AIS, Sandhika W, Hasanatuludhhiyah N. Effect of Javanese turmeric (Curcuma xanthorrhiza) extract on hepatitis model of alcohol-induced mice. J Kedokteran Brawijaya 2020; 31: 39-42. 
39. Kritas SK, Ronconi G, Conti P, Pandolfi F. Interrelationship between inflammatory cytokines (IL-1, IL-6, IL-33, IL-37) and acquired immunity. J Biol Regul Homeost Agents 2019; 33: 1321-1326.
40. Tran HB, Chen SC, Chaung HC, Cheng TC. Molecular cloning of IL-6, IL-10, IL-11, IFN-ɤ and modulation of pro-and anti-inflammatory cytokines in cobia (Rachycentron canadum) after Photobacterium damselae subsp. Piscicida infection. Comp Biochem Physiol B Biochem Mol Biol 2019; 230: 10-18. 
41. Megha KB, Joseph X, Akhil V, Mohanan PV. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine 2021; 91: 153712-153730. 
42. Ahmed H, Fazal N, Ahmad M R, Ijaz B, Bilal A Z, Ilyas S, et al. S-Allyl-L-cysteine-induced anti-inflammatory and anti-apoptotic effects in chondrocytes is associated with suppression of the mitochondrial inflammation pathway. Biol Clin Sci Res 2022; 2022: 179. 
43. Chen J, Ye C, Wan C, Li G, Peng L, Peng Y, et al. The roles of c-Jun N-terminal kinase (JNK) in infectious diseases. Int J Mol Sci 2021; 22: 9640-9655. 
44. Farzaei MH, Zobeiri M, Parvizi F, El-Senduny FF, Marmouzi I, Coy-Barrera E, et al. Curcumin in liver diseases: A systematic review of the cellular mechanisms of oxidative stress and clinical perspective. Nutrients 2018; 10: 855-883. 
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 8
August 2025
Pages 1100-1106

Files

Share

How to cite

Statistics