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Cited by 31Drug-Induced Hepatotoxicity and ProtectionMedicinal Plants and NeuroprotectionPlant Toxicity and Pharmacological Properties

Hepatoprotective effect of Centella asiatica 50% ethanol extract against acetaminophen-induced acute liver injury in BALB/c mice

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Park, Dae Won, Jeon, Hyelin, Kwon, Jeong Eun, Lee, Young Geun, So, Rina, Choe, Tae Hwan, Jeong, Yong Joon, Kang, Se Chan·2021·Toxicological Research
DOI 10.1007/s43188-020-00063-0PMC PMC8007681
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Abstract

N-acetyl-p-aminophenol (acetaminophen, APAP) is a well-known component of analgesic and antipyretic monotherapy products. However, exceeding the recommended dose can lead to serious injury to the liver. We conducted this study to determine the potential of Centella asiatica as a natural substance to protect against APAP-induced liver injury. When acute hepatotoxicity was induced in mice by APAP overdose, their liver weight decreased significantly (p < 0.05). However, mice treated with C. asiatica 50% ethanol extract (CA-HE50, 200 mg/kg) for a week before induction of hepatotoxicity by APAP had similar liver weights to those of mice in which hepatotoxicity was not induced. In particular, levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, which are biomarkers of liver injury, were significantly increased by APAP and dose-dependently decreased by CA-HE50 (p < 0.05). Glutathione and malondialdehyde, indicators of oxidative stress, were significantly changed by APAP and CA-HE50 (p < 0.05). In addition, hepatic necrosis and expression of genes encoding pro-inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, and IL-4) induced by APAP were inhibited by CA-HE50, and these results were dose-dependent. Through our in vivo studies, we found that CA-HE50 can help prevent APAP-induced hepatic tissue injury in BALB/c mice. Furthermore, CA-HE50 was effective at protecting RAW 264.7 cells from lipopolysaccharide-induced cytotoxicity and inhibiting the release of nitric oxide from these cells; in particular, asiaticoside was found to be a key component of CA-HE50 responsible for these effects. Therefore, we suggest that CA-HE50 has potential applications in functional health foods and drugs.

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  • Antioxidant and anti-inflammatory actions of CA-HE50 were due to asiaticoside content present in the extract.

    “The antioxidant and anti‐inflammatory actions were identified to be due to the asiaticoside content present in the extract.”

    From Therapeutic Properties and Pharmacological Activities of Asiaticoside and Madecassoside: A Review (2023) · cites this paper as [107]

    The Cell protective efficacy of triterpenoid saponins section identifies asiaticoside as an active component and attributes CA-HE50’s cell-protective effect to it; the Abstract also links it to reduced nitric oxide release. But the CA-HE50 inhibits lipid peroxidation in the liver section attributes the extract’s antioxidant results to numerous phytochemicals, not specifically to asiaticoside. The claim overstates asiaticoside’s role as the identified cause of both actions. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Asiaticoside is an effective phytochemical in protecting against APAP-induced liver injury.

    “Hence, asiaticoside is an effective phytochemical in protecting against APAP‐induced liver injury.”

    From Therapeutic Properties and Pharmacological Activities of Asiaticoside and Madecassoside: A Review (2023) · cites this paper as [107]

    The Discussion describes asiaticoside (AS) as a strong potential candidate for protection against APAP-induced liver injury. But the paper tested AS in cells, while its mouse results concern the whole Centella asiatica extract; it does not establish AS itself as effective against APAP-induced liver injury in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • GSH depletion, MDA overproduction and overexpressed inflammatory markers caused by APAP are reversed by CA-HE50 treatment.

    “The observed GSH depletion, MDA overproduction and overexpressed inflammatory markers caused by APAP have been seen to be reversed by CA‐HE50 treatment.”

    From Therapeutic Properties and Pharmacological Activities of Asiaticoside and Madecassoside: A Review (2023) · cites this paper as [107]

  • Excessive APAP results in oxidative stress in liver tissues due to increase in MDA content and reduction in GSH levels, as well as inflammatory cell infiltration and overexpression of pro-inflammatory cytokines (TNF-α and IL-1β), ultimately leading to hepatotoxicity.

    “excessive APAP results in oxidative stress in liver tissues due to increase in MDA content and reduction in GSH levels, as well as inflammatory cell infiltration and overexpression of pro‐inflammatory cytokines (such as TNF‐α and IL‐1β), ultimately leading to hepatoxicity.”

    From Therapeutic Properties and Pharmacological Activities of Asiaticoside and Madecassoside: A Review (2023) · cites this paper as [107]

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Research works printed but not linked: 31

  1. Jaeschke H, Xie Y, McGill MR (2014) APAP-induced liver injury: from animal models to humans. J Clin Transl Hepatol 2:153-161. https ://doi.org/10.14218 /JCTH.2014.00014 · DOI
  2. Woolbright BL, Jaeschke H (2017) Role of the inflammasome in APAP-induced liver injury and acute liver failure. J Hepatol 66:836-848. https ://doi.org/10.1016/j.jhep.2016.11.017 · DOI
  3. Herndon CM, Dankenbring DM (2014) Patient perception and knowledge of APAP in a large family medicine service. J Pain Palliat Care Pharmacother 28:109-116. https ://doi. org/10.3109/15360 288.2014.90899 3 · DOI
  4. Clark R, Fisher JE, Sketris IS, Johnston GM (2012) Population prevalence of high dose paracetamol in dispensed paracetamol/ opioid prescription combinations: an observational study. BMC Clin Pharmacol 12:11. https ://doi.org/10.1186/1472-6904-12-11 · DOI
  5. Lancaster EM, Hiatt JR, Zarrinpar A (2014) APAP hepatotox- icity: an updated review. Arch Toxicol 89:193-199. https ://doi. org/10.1007/s0020 4-014-1432-2 · DOI
  6. Kane AE, Mitchell SJ, Mach J (2016) APAP hepatotoxicity in mice: effect of age, frailty and exposure type. Exp Gerontol 73:95-106. https ://doi.org/10.1016/j.exger .2015.11.013 · DOI
  7. Murray KF, Hadzic N, Wirth S, Bassett M, Kelly D (2008) Drug- related hepatotoxicity and acute liver failure. J Pediatr Gastroen- terol Nutr 47:395-405. https ://doi.org/10.1097/MPG.0b013 e3181 70946 4 · DOI
  8. Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from APAP hepatotoxicity. Drug Metab Rev 44:88-106. https ://doi.org/10.3109/03602 532.2011.60268 8 · DOI
  9. Nourjah P, Ahmad SR, Karwoski C, Willy M (2006) Estimates of APAP (Paracetomal)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf 15:398-405. https ://doi. org/10.1002/pds.1191 · DOI
  10. Miller LL, Bly CG, Watson ML, Bale WF (1951) The dominant role of the liver in plasma protein synthesis, a direct study of the isolated perfused rat liver with the aid of lysine-ϵ-C14. J Exp Med 94:431-453. https ://doi.org/10.1084/jem.94.5.431 · DOI
  11. Shaabana HAE, El-Ghoraba AH, Shibamotob T (2012) Bioactivity of essential oils and their volatile aroma com- ponents: review. J Essent Oil Res 24:203-212. https ://doi. org/10.1080/10412 905.2012.65952 8 · DOI
  12. Jamil SS, Nizami Q, Salam M (2007) Centella asiatica (Linn.) urban o' a review. Nat Pro Radiance 6:158-170. https ://doi. org/10.1084/jem.94.5.431 · DOI
  13. Zahara K, Bibi Y, Tabassum S (2014) Clinical and therapeutic benefits of Centella asiatica. Pure Appl Biol 3:152-159. https ://doi.org/10.19045 /bspab .2014.34004 · DOI
  14. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying APAP-induced hepatotoxicity in humans and mice involves mitochondrial dam- age and nuclear DNA fragmentation. J Clin Invest 122:1574- 1583. https ://doi.org/10.1172/JCI59 755 · DOI
  15. Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, For- ster J, Jaeschke H (2014) Mechanisms of APAP-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol 279:266-274. https ://doi.org/10.1016/j.taap.2014.05.010 · DOI
  16. Kato GJ, McGowan V, Machado RF, Little JA, Taylor J, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT (2006) Lactate dehydrogenase as a biomarker of hemoly- sis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 107:2279-2285. https ://doi.org/10.1182/blood -2005-06-2373 · DOI · Paper page
  17. Tomasi TB Jr, Tisdale WA (1964) Serum gamma-globulins in acute and chronic liver diseases. Nature 201:834-835. https :// doi.org/10.1038/20183 4a0 · DOI
  18. Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The role of oxidative stress and antioxidants in liver dis- eases. Int J Mol Sci 16:26087-260124. https ://doi.org/10.3390/ ijms1 61125 942 · DOI
  19. Liu WX, Jia FL, He YY, Zhang BX (2012) Protective effects of 5-methoxypsoralen against APAP induced hepatotoxic- ity in mice. World J Gastroenterol 18:2197-2202. https ://doi. org/10.3748/wjg.v18.i18.2197 · DOI
  20. Milton PS, Muthumani M, Shagirtha K (2013) Quercetin poten- tially attenuates cadmium induced oxidative stress mediated car- diotoxicity and dyslipidemia in rats. Eur Rev Med Pharmacol Sci 17:582-595. https ://doi.org/10.1007/s1201 2-013-9227-x · DOI
  21. Shukla A, Rasik AM, Dhawan BN (1999) Asiaticoside-induced elevation of antioxidant levels in healing wounds. Phytother Res 13:50-54. https ://doi.org/10.1002/(SICI)1099-1573(19990 2)13:1<50::AID-PTR36 8>3.0.CO;2-V 26. Shao W, Cao X, Shen L, Zhang F, Yu B (2017) A convergent synthesis of the triterpene saponin asiaticoside. Asian J Org Chem 6:1270-1276. https ://doi.org/10.1002/ajoc.20170 0153 · DOI
  22. Park DW, Jeon H, So R, Kang SC (2020) Centella asiatica extract prevents visual impairment by promoting the production of rhodopsin in the retina. Nutr Res Pract 14:203-217. https :// doi.org/10.4162/nrp.2020.14.3.203 · DOI
  23. Nourjah P, Ahmad SR, Pharm CK, Willy M (2006) Estimates of acetaminophen (paracetomal)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf 15:398-405. https ://doi. org/10.1002/pds.1191 · DOI
  24. Rubin JB, Hameed B, Gottfried M, Lee WM, Sarkar M (2018) Acute liver failure study group. Acetaminophen-induced acute liver failure is more common and more severe in women. Clin Gastroenterol Hepatol 16:936-946. https ://doi.org/10.1016/j. cgh.2017.11.042 · DOI
  25. McNulty R, Lim JME, Chandru P, Gunja N (2018) Fewer adverse effects with a modified two-bag acetylcysteine protocol in par- acetamol overdose. Clin Toxicol (Phila) 56:618-621. https ://doi. org/10.1080/15563 650.2017.14088 12 · DOI
  26. Uchida NS, Silva-Filho SE, Aguiar RP, Wiirzler LAM, Cardia GFE, Cavalcante HAO, Silva-Comar FMS, Becker TCA, Silva EL, Bersani-Amado CA, Cuman RKN (2017) Protective effect of cymbopogon citratus essential oil in experimental model of acetaminophen-induced liver injury. Am J Chin Med 45:515-532. https ://doi.org/10.1142/S0192 415X1 75003 18 · DOI
  27. Yan M, Huo Y, Yin S, Hu H (2018) Mechanisms of acetami- nophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 17:274-283. https ://doi.org/10.1016/j. redox .2018.04.019 · DOI
  28. Du K, Ramachandran A, Jaeschke H (2016) Oxidative stress dur- ing acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol 10:148-156. https :// doi.org/10.1016/j.redox .2016.10.001 · DOI
  29. Liang H, Feng Y, Cui R, Qiu M, Zhang J, Liu C (2018) Simvasta- tin protects against acetaminophen-induced liver injury in mice. Biomed Pharmacother 98:916-924. https ://doi.org/10.1016/j. bioph a.2017.12.076 · DOI
  30. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Mono- cyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313-326. https ://doi.org/10.1089/jir.2008.0027 · DOI · Paper page
  31. Wang L, Li X, Chen C (2018) Inhibition of acetaminophen- induced hepatotoxicity in mice by exogenous thymosinβ4 treat- ment. Int Immunopharmacol 61:20-28. https ://doi.org/10.1016/j. intim p.2018.05.011 · DOI

Cited by

Sorted by citations

Authors
Park, D. W., Jeon, H., Kwon, J. E., Lee, Y. G., So, R., Choe, T. H., Jeong, Y. J., & Kang, S. C.
Affiliations
Kyung Hee University (KR)
Corresponding author
Kang, Se Chan
ORCID
Venue
Toxicological Research
Publisher
Springer Science and Business Media LLC
Published
2020-09-07
Volume
37
Issue
2
Pages
261-275
ISSN
  • 1976-8257 (ISSN-L)
  • 2234-2753
DOI
10.1007/s43188-020-00063-0
PMC
PMC8007681
OpenAlex
W3084899422
Cited by
31
References
3
Citations by year
2026: 5 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 3 · 2021: 1
FWCI
2.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Toxicological Research (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (117050-3)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant Toxicity and Pharmacological Properties
Keywords
Centella asiatica, hepatoprotection, acetaminophen hepatotoxicity, asiaticoside, oxidative stress, inflammatory cytokines, TNF-α, IL-1β, IL-4, glutathione, malondialdehyde, RAW 264.7 macrophages, nitric oxide, liver injury biomarkers, functional food ingredients

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