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Amelioration of hepatic function, oxidative stress, and histopathologic damages by Cassia fistula L. fraction in thioacetamide-induced liver toxicity

  • Sandeep Kaur
  • Dipakshi Sharma
  • Amrit Pal Singh
  • Satwinderjeet KaurEmail author
Research Article
  • 58 Downloads

Abstract

Cassia fistula L. (Caesalpinioideae) is a highly admirable medicinal plant and is traditionally recommended for the treatment of rheumatism, liver disorders, jaundice, and other inflammatory diseases. This study was designed to investigate the hepatoprotective properties of ethyl acetate fraction from C. fistula leaves in an animal model. Treatment with thioacetamide significantly elevated the level of serum glutamic-oxaloacetic transaminase (1.75-fold), alkaline phosphatase (4.07-fold), and total bilirubin (2.29-fold) as compared to the control. It was found that pretreatment of fraction followed by consecutive 2 days thioacetamide reduced the conversion of thioacetamide carcinogen to its reactive metabolites by phase I enzymes and increased the level of detoxification phase II along with antioxidative enzymes. The histopathological studies revealed the hepatoprotective nature of the fraction in restoring the normal architecture of thioacetamide-intoxicated damaged liver. The fraction showed downregulation in the expression level of p-PI3K, p-Akt, and p-mTOR pointing towards its chemopreventive potential. The HPLC analysis of the fraction had shown the dominance of three phenolic compounds namely, catechin, epicatechin, and chlorogenic acid. The above studies comprising histopathological, immunohistochemical, and hepatic enzymes are strong indicative of the potential protective ability of ethyl acetate fraction phytoconstituents against thioacetamide-induced toxicity.

Graphical abstract

Keywords

Cassia fistula Thioacetamide Hepatoprotection p-PI3K p-Akt p-mTOR 

Abbreviation

ROS

reactive oxygen species

RNS

reactive nitrogen species

HPLC

high-performance liquid chromatography

MDA

malondialdehyde

CYP

cytochrome P450

TAA

thioacetamide

p-PI3

phosphorylated-phosphatidylinositol-3-kinase

p-Akt

phosphorylated-Akt

p-mTOR

phosphorylated-mammalian target of rapamycin

GSSG

oxidized glutathione

GSH

reduced glutathione

bw

bodyweight

i.p

intraperitoneal

CPCSEA

Committee for the Purpose of Control and Supervision of Experiments on Animals

ANOVA

analysis of variance

MLR

multiple linear regression

Notes

Acknowledgments

We would like to acknowledge Dr. (Prof.) Mridu Manjari, Department of Pathology (Sri Guru Ramdas Cancer hospital and University of Health Sciences, Amritsar) for performing histopathological studies and for immunohistochemical studies; Centre for Emerging Life Science for HPLC analysis and Mr. Manjinder Singh (Department of Pharmaceutical Sciences) for animal handling, Guru Nanak Dev University, Amritsar.

Author's Contribution

Provided guidance, drafted the manuscript and revising it critically, and finalized it with her personal inputs: S.J.K. and A.P.S. Performed the experiments and reviewed the literature: S.K., A.P.S, and D.S. Statistical analysis of the results, interpretation of data: S.K., A.P.S, and D.S. Designed the table, figures, and images: S.K and S.J.K.

Funding

This study receives financial assistance provided by the Indian Council of Medical Research (ICMR) [59/36/2011/BMS/TRM] and the Fund for Improvement of S & T Infrastructure (FIST) programme of Department of Science and Technology (DST) [SR/S9/Z-23/2010/20(C)], New Delhi, India.

Compliance with ethical standards

Ethical approval and consent to participate

This study was approved by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSE), Government of India (226/CPCSEA/2014/06). All animals were humane care according to the criteria outlined in the guidelines of the Institutional Animal Ethics Committee (IAEC) and written informed consent was obtained.

Competing interests

The authors declare that they have no competing interests.

References

  1. Abdeen A, Abdelkader A, Abdo M, Wareth G, Aboubakr M, Aleya L, Abdel-Daim MM (2019) Protective effect of cinnamon against acetaminophen-mediated cellular damage and apoptosis in renal tissue. Environ Sci Pollut Res 26:240–249CrossRefGoogle Scholar
  2. Abdel-Daim MM, Abdellatief SA (2018) Attenuating effects of caffeic acid phenethyl ester and betaine on abamectin-induced hepatotoxicity and nephrotoxicity. Environ Sci Pollut Res 25:15909–15917CrossRefGoogle Scholar
  3. Abdel-Daim MM, Abushouk AI, Reggi R, Yarla NS, Palmery M, Peluso I (2018a) Association of antioxidant nutraceuticals and acetaminophen (paracetamol): friend or foe? J Food Drug Anal 26:S78–S87CrossRefGoogle Scholar
  4. Abdel-Daim MM, Sooud KA-EL, Aleya L, Bungǎu SG, Najda A, Saluja R (2018b) Alleviation of Drugs and Chemicals Toxicity: Biomedical Value of Antioxidants. Oxidative Med Cell Longev:1–2.  https://doi.org/10.1155/2018/6276438
  5. Abdel-Daim MM, Zakhary N, Aleya L, Bungǎu SG, Bohara RA, Siddiqi NJ (2018c) Aging, Metabolic, and Degenerative Disorders: Biomedical Value of Antioxidants. Oxidative Med Cell Longev:1–2.  https://doi.org/10.1155/2018/2098123
  6. Abdel-Daim MM, Dessouki AA, Abdel-Rahman HG, Eltaysh R, Alkahtani S (2019) Hepatorenal protective effects of taurine and N-acetylcysteine against fipronil-induced injuries: the antioxidant status and apoptotic markers expression in rats. Sci Total Environ 650:2063–2073CrossRefGoogle Scholar
  7. Aebi H (1984) Catalase in vitro. In: Colowick, Kaplan SP (eds) Methods in enzymology, vol 105. Academic Press, New York, pp 121–126Google Scholar
  8. Allocati N, Masulli M, Di Ilio C, Federici L (2018) Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis 7(1):8.  https://doi.org/10.1038/s41389-017-0025-3 CrossRefGoogle Scholar
  9. Al-Sayed E, Abdel-Daim MM, Kilany OE, Karonen M, Sinkkonen J (2015) Protective role of polyphenols from Bauhinia hookeri against carbon tetrachloride-induced hepato- and nephrotoxicity in mice. Ren Fail 37(7):1198–1207CrossRefGoogle Scholar
  10. Al-Sayed E, Abdel-Daim MM, Khattab MA (2018) Hepatoprotective activity of praecoxin A isolated from Melaleuca ericifolia against carbon tetrachloride-induced hepatotoxicity in mice. Impact on oxidative stress, inflammation, and apoptosis. Phytother Res:1–10.  https://doi.org/10.1002/ptr.6242
  11. Anderson ME (1985) Determination of glutathione and glutathione disulfide in biological samples. In: Meister A (ed) Methods in enzymology, vol 113. Academic Press, NewYork, pp 548–551Google Scholar
  12. Arora N, Bansal MP, Koul A (2013) Modulatory effects of Azadirachta indica leaf extract on cutaneous and hepatic biochemical status during promotion phase of DMBA/TPA-induced skin tumorigenesis in mice. Indian J Biochem Biophys 50(2):105–113Google Scholar
  13. Baali N, Belloum Z, Baali S, Chabi B, Pessemesse L, Fouret G, Ameddah S, Benayache F, Benayache S, Feillet-Coudray C, Cabello G, Wrutniak-Cabello C (2016) Protective activity of total polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in acetaminophen-induced hepatotoxicity in rats. Nutrients 8(4):193.  https://doi.org/10.3390/nu8040193 CrossRefGoogle Scholar
  14. Bardi DA, Halabi MF, Hassandarvish P, Rouhollahi E, Paydar M, Moghadamtousi SZ, Al-Wajeeh NS, Ablat A, Abdullah NA, Abdulla MA (2014) Andrographis paniculata leaf extract prevents thioacetamide-induced liver cirrhosis in rats. PLoS One 9(10):e109424CrossRefGoogle Scholar
  15. Bashandy SAE, Ebaid H, Abdelmottaleb Moussa SA, Alhazza IM, Hassan I, Alaamer A, Tamimi J (2018) Potential effects of the combination of nicotinamide, vitamin B2 and vitamin C on oxidative-mediated hepatotoxicity induced by thioacetamide. Lipids Health Dis 17:29CrossRefGoogle Scholar
  16. Bhalerao SA, Kelkar TS (2012) Traditional medicinal uses, phytochemical profile and pharmacological activities of Cassia fistula Linn. Int Res J Biol 1(5):79–84Google Scholar
  17. Carlberg I, Mannervik B (1975) Glutathione reductase. In: Meister A (ed) Methods in enzymology, vol 113. Academic Press, New York, pp 484–490Google Scholar
  18. Chhabra G, Singh CK, Ndiaye MA, Fedorowicz S, Molot A, Ahmad N (2018) Prostate cancer chemoprevention by natural agents: clinical evidence and potential implications. Cancer Lett 422:9–18CrossRefGoogle Scholar
  19. Choi SJ, Kim M, Kim SH, Jeon JK (2003) Microplate assay measurement of cytochrome P450-carbon monoxide complexes. J Biochem Mol Biol 36(3):332–335Google Scholar
  20. Devasagayam TPA, Boloor KK, Ramasarma T (2003) Methods for estimating lipid peroxidation: ananalysis of merits and demerits. Indian J Biochem Biophys 40:300–308Google Scholar
  21. Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13(2):140–156CrossRefGoogle Scholar
  22. Gan FF, Ling H, Ang XA (2013) Novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways. Toxicol Appl Pharmacol 272:852–862CrossRefGoogle Scholar
  23. Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferase—the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139Google Scholar
  24. Hajovsky H, Hu G, Koen Y, Sarma D, Cui W, Moore DS, Staudinger JL, Hanzlik RP (2012) Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem Res Toxicol 25:1955–1963CrossRefGoogle Scholar
  25. Hamada S, Ohyama W, Takashima R, Shimada K, Matsumoto K, Kawakami S, Uno F, Sui H, Shimada Y, Imamura T, Matsumura S, Sanada H, Inoue K, Muto S, Ogawa I, Hayashi A, Takayanagi T, Ogiwara Y, Maeda A, Okada E, Terashima Y, Takasawa H, Narumi K, Wako Y, Kawasako K, Sano M, Ohashi N, Morita T, Kojima H, Honma M, Hayashi M (2015) Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the collaborative study group for the micronucleus test (CSGMT)/the Japanese Environmental Mutagen Society (JEMS) – Mammalian Mutagenicity Study Group (MMS). Mutat Res 780–781:2–17CrossRefGoogle Scholar
  26. Jiang ZY, Hunt JV, Wolff SP (1992) Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxides in low density lipoprotein. Anal Biochem 202:384–389CrossRefGoogle Scholar
  27. Kalantari H, Jalali M, Jalali A, Mahdavinia M, Salimi A, Juhasz B, Tosaki A, Gesztelyi R (2011) Protective effect of Cassia fistula fruit extract against bromobenzene-induced liver injury in mice. Hum Exp Toxicol 30(8):1039–1044CrossRefGoogle Scholar
  28. Kaur V, Kumar M, Kaur P, Kaur S, Singh AP, Kaur SJ (2017) Hepatoprotective activity of Butea monosperma bark against thioacetamide-induced liver injury in rats. Biomed Pharmacother 89:332–341CrossRefGoogle Scholar
  29. Koppula S, Yum M-J, Kim J-S, Shin G-M, Chae Y-J, Yoon T, Chun C-S, Lee J-D, Song MD (2017) Anti-fibrotic effects of Orostachys japonicus A. Berger (Crassulaceae) on hepatic stellate cells and thioacetamide-induced fibrosis in rats. Nutr Res Pract 11(6):470–478CrossRefGoogle Scholar
  30. Kristin R, Landis-Piwowar Iyer NR (2014) Cancer chemoprevention: Current State of the Art. Can Growth Metast 7:19–25Google Scholar
  31. Lampe WJ, King BI, Li S, Grate TM, Barale VK, Chen C, Fenz Z, Potter DJ (2000) Brassica vegetables increase and apiaceous vegetables decrease cytochrome P4501A2 activity in humans: changes in caffeine metabolite. Ratios in response to controlled vegetable diets. Carcinogenesis 21:1157–1162CrossRefGoogle Scholar
  32. Li S, Hong M, Tan HY, Wang N, Feng YB (2016) Insights into the role and interdependence of oxidative stress and inflammation in liver diseases. Oxidative Med Cell Longev 2016:1–21.  https://doi.org/10.1155/2016/4234061
  33. Liu Y, Yin T, Feng Y, Cona MM, Huang G, Liu J, Song S, Jiang Y, Xia Q, Swinnen JV, Bormans G, Himmelreich U, Oyen R, Ni Y (2015) Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research. Quant Imaging Med Surg 5(5):708–729Google Scholar
  34. Mihara K, Sato R (1972) Partial purification of cytochrome b5 reductase from rabit liver microsome with detergent and its properties. J Biochem 71:725–735Google Scholar
  35. Noorhajati H, Tanjung M, Aminah NS, Suwandi JS (2012) Antioxidant Activities of Extracts of Trengguli Stem Bark (Cassia fistula L.). IJBAS 12(4):85–89Google Scholar
  36. Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver micro-somes. J Biol Chem 239(7):2370–2378Google Scholar
  37. Omura T, Takasue S (1970) A new method for simultaneous purification of cytochrome b5 and NADPH-cytochrome c reductase from rat liver micro-somes. J Biochem 67:249–257CrossRefGoogle Scholar
  38. Pallottini V, Martini C, Bassi AM, Romano P, Nanni G, Trentalance A (2006) Rat HMGCoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content. J Hepatol 44(2):368–374CrossRefGoogle Scholar
  39. Petrovska BB (2012) Historical review of medicinal plants’ usage. Pharmacogn Rev 6(11):1–5CrossRefGoogle Scholar
  40. Poli GPM (1997) Oxidative damage and fibrogenesis. Free Radic Biol Med 22:287–305CrossRefGoogle Scholar
  41. Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 64:1–11Google Scholar
  42. Pradeep K, Mohan CV, Gobianand K, Karthikeyan S (2007) Effect of Cassia fistula Linn. leaf extract on diethylnitrosamine induced hepatic injury in rats. Chem Biol Interact 167(1):12–18CrossRefGoogle Scholar
  43. Quintanilha LF, Takami T, Hirose Y, Fujisawa K, Murata Y, Yamamoto N, dos RC, Goldenberg S, Terai S, Sakaida I (2014) Canine mesenchymal stem cells show antioxidant properties against thioacetamide-induced liver injury in vitro and in vivo. Hepatol Res 44:206–217CrossRefGoogle Scholar
  44. Sabir SM, Rocha JBT, Boligon AA, Athayde ML (2017) Hepatoprotective activity and phenolic profile of Zanthoxylum alatum Roxb. fruit extract. Pak J Pharm Sci 30(5):1551–1556Google Scholar
  45. Shu L, Cheung K-L, Khor TO, Chen C, Kong A-N (2010) Phytochemicals: cancer chemoprevention and suppression of tumor onset and metastasis. Cancer Metastasis Rev 29:483–502CrossRefGoogle Scholar
  46. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85.Google Scholar
  47. Watson RR, Preedy V (2012) Bioactive food as dietary interventions for liver and gastrointestinal disease, 1st edn. Academic Press, Elsevier Inc., USAGoogle Scholar
  48. Wu D, Zhai Q, Shi X (2006) Alcohol-induced oxidative stress and cell responses. J Gastroenterol Hepatol 21(3):S26–S29CrossRefGoogle Scholar
  49. Xie Y, Wang G, Wang H, Yao X, Jiang S, Kang A (2012) Cytochrome P450 dysregulations in thioacetamide-induced liver cirrhosis in rats and the counteracting effects of hepatoprotective agents. Drug Metab Dispos 40:796–802CrossRefGoogle Scholar
  50. Yeung AWK, Tzvetkov NT, El-Tawil OS, Bungǎu SG, Abdel-Daim MM, Atanasov AG (2019) Antioxidants: scientific literature landscape analysis. Oxidative Med Cell Longev 2019:1–12.  https://doi.org/10.1155/2019/8278454

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sandeep Kaur
    • 1
  • Dipakshi Sharma
    • 1
  • Amrit Pal Singh
    • 2
  • Satwinderjeet Kaur
    • 1
    Email author
  1. 1.Genetic Toxicology Laboratory, Department of Botanical and Environmental SciencesGuru Nanak Dev UniversityAmritsarIndia
  2. 2.Department of Pharmaceutical SciencesGuru Nanak Dev UniversityAmritsarIndia

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