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The protective efficacy of soursop fruit extract against hepatic injury associated with acetaminophen exposure is mediated through antioxidant, anti-inflammatory, and anti-apoptotic activities

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Abstract

In the current report, we examined the potential beneficial role of soursop fruit extract (SSFE) on liver injury induced by a single paracetamol (APAP) overdose (2000 mg/kg). Thirty-five Wistar albino rats were randomly divided into five groups as follows: control, SSFE, APAP, SSFE+APAP, and silymarin (SIL)+APAP. APAP intoxication was found to elevate alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels. Moreover, it increased the levels of malondialdehyde, nitrites, and nitrates and depleted glutathione, superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. APAP intoxication inactivated the nuclear factor erythroid 2-related factor 2 (Nrf2) defense pathway and upregulated the expression of heme oxygenase-1 (HO-1). APAP administration enhanced the activation of nuclear factor-kappa B (NF-κB), the elevation of tumor necrosis factor-alpha and interleukin 1-beta levels, and the upregulation of inducible nitric oxide synthase mRNA expression. In addition, APAP activated the overexpression of Bax protein, increased release of cytochrome c, and the downregulation of Bcl-2 protein. Finally, APAP-induced overexpression of transforming growth factor-beta (TGF-β) further suggested enhanced liver damage. On the other hand, SSFE pretreatment attenuated these biochemical, molecular, and histopathological alterations in the liver, which might be partially due to the regulation of hepatic Nrf2/HO-1 and downregulation of NF-κB and TGF-β.

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Abbreviations

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

APAP:

Paracetamol

AST:

Aspartate aminotransferase

CAT:

Catalase

GSH:

Glutathione

GSH-Px:

Glutathione peroxidase

GSH-R:

Glutathione reductase

HO-1:

Heme oxygenase-1

IL-1β:

Interleukin-1 beta

iNOS:

Inducible nitric oxide synthase

MDA:

Malondialdehyde

NAPQI:

N-acetyl-P-benzoquinone imine

NO:

Nitric oxide

Nrf2:

Nuclear factor erythroid 2–related factor 2

SIL:

Silymarin

SOD:

Superoxide dismutase

SSFE:

Soursop fruit extract

TGF-β:

tumor growth factor-beta

TNF-α:

tumor necrosis factor-alpha

References

  • Adewole SO, Ojewole JA (2008) Protective effects of Annona muricata Linn. (Annonaceae) leaf aqueous extract on serum lipid profiles and oxidative stress in hepatocytes of streptozotocin-treated diabetic rats. Afr J Tradit Complement Altern Med 6:30–41

    Google Scholar 

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    CAS  Google Scholar 

  • Almeer RS, Abdel Moneim AE (2018) Evaluation of the protective effect of olive leaf extract on cisplatin-induced testicular damage in rats. Oxidative Med Cell Longev 2018:11

    Google Scholar 

  • Al-Olayan EM, El-Khadragy MF, Aref AM, Othman MS, Kassab RB, Abdel Moneim AE (2014) The potential protective effect of Physalis peruviana L. against carbon tetrachloride-induced hepatotoxicity in rats is mediated by suppression of oxidative stress and downregulation of MMP-9 expression. Oxidative Med Cell Longev 2014:381413

    Google Scholar 

  • Araujo JA, Zhang M, Yin F (2012) Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol 3:119

    Google Scholar 

  • Arthur F, Woode E, Larbie C (2012) Bilirubin lowering potential of Annona muricata (Linn.) in temporary jaundiced rats. Am J Pharmacol Toxicol 7(2):33–40

    Google Scholar 

  • Bian X, Wang S, Liu J, Zhao Y, Li H, Zhang L, Li P (2018) Hepatoprotective effect of chiisanoside against acetaminophen-induced acute liver injury in mice. Nat Prod Res:1–4. https://doi.org/10.1080/14786419.2018.1460841

  • Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI (2015) Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol 63:503–514

    CAS  Google Scholar 

  • Chiu H, Brittingham JA, Laskin DL (2002) Differential induction of heme oxygenase-1 in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in the rat: effects of hemin and biliverdin. Toxicol Appl Pharmacol 181:106–115

    CAS  Google Scholar 

  • Chung RT, Stravitz RT, Fontana RJ, Schiodt FV, Mehal WZ, Reddy KR, Lee WM (2012) Pathogenesis of liver injury in acute liver failure. Gastroenterology 143:e1–e7

    CAS  Google Scholar 

  • Das J, Ghosh J, Manna P, Sil PC (2010) Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic Res 44:340–355

    CAS  Google Scholar 

  • De Vega L, Fernandez RP, Mateo MC, Bustamante JB, Herrero AM, Munguira EB (2002) Glutathione determination and a study of the activity of glutathione-peroxidase, glutathione-transferase, and glutathione-reductase in renal transplants. Ren Fail 24:421–432

    Google Scholar 

  • Dkhil M, Abdel Moneim A, Hafez T, Mubaraki M, Mohamed W, Thagfan F, Al-Quraishy S (2019) Myristica fragrans kernels prevent paracetamol-induced hepatotoxicity by inducing anti-apoptotic genes and Nrf2/HO-1 pathway. Int J Mol Sci 20(4):993

    CAS  Google Scholar 

  • Dokumacioglu E, Iskender H, Aktas MS, Hanedan B, Dokumacioglu A, Sen TM, Musmul A (2017) The effect of sulforaphane on oxidative stress and inflammation in rats with toxic hepatitis induced by acetaminophene. Bratisl Lek Listy 118:453–459

    CAS  Google Scholar 

  • Du K, Williams CD, McGill MR, Xie Y, Farhood A, Vinken M, Jaeschke H (2013) The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation. Toxicol Appl Pharmacol 273:484–491

    CAS  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82(1):70–77

  • Fabregat I, Moreno-Caceres J, Sanchez A, Dooley S, Dewidar B, Giannelli G, Ten Dijke P (2016) TGF-beta signalling and liver disease. FEBS J 283:2219–2232

    CAS  Google Scholar 

  • Fisher AEO, Maxwell SC, Naughton DP (2003) Catalase and superoxide dismutase mimics for the treatment of inflammatory diseases. Inorg Chem Commun 6:1205–1208

    CAS  Google Scholar 

  • Florence NT, Benoit MZ, Jonas K, Alexandra T, Desire DD, Pierre K, Theophile D (2014) Antidiabetic and antioxidant effects of Annona muricata (Annonaceae), aqueous extract on streptozotocin-induced diabetic rats. J Ethnopharmacol 151:784–790

    Google Scholar 

  • Giannini EG, Testa R, Savarino V (2005) Liver enzyme alteration: a guide for clinicians. CMAJ 172:367–379

    Google Scholar 

  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138

    CAS  Google Scholar 

  • Guan YS, He Q (2015) Plants consumption and liver health. Evid Based Complement Alternat Med 2015:824185

    Google Scholar 

  • Guo LM, Liu JY, Xu DZ, Li BS, Han H, Wang LH, Zhang WY, Lu LH, Guo X, Sun FX, Zhang HY, Liu XD, Zhang JP, Yao Y, He ZP, Wang MM (2003) Application of molecular adsorbents recirculating system to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int 23(Suppl 3):16–20

    CAS  Google Scholar 

  • Hamid RA, Foong CP, Ahmad Z, Hussain MK (2012) Antinociceptive and anti-ulcerogenic activities of the ethanolic extract of Annona muricata leaf. Rev Bras 22:630–641

    Google Scholar 

  • Hinson JA, Roberts DW, James LP (2010) Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 196:369–405

  • Horng CT, Liu ZH, Huang YT, Lee HJ, Wang CJ (2017) Extract from Mulberry (Morus australis) leaf decelerate acetaminophen induced hepatic inflammation involving downregulation of myeloid differentiation factor 88 (MyD88) signals. J Food Drug Anal 25:862–871

    CAS  Google Scholar 

  • Hu B, Colletti LM (2010) CXC receptor-2 knockout genotype increases X-linked inhibitor of apoptosis protein and protects mice from acetaminophen hepatotoxicity. Hepatology 52:691–702

    CAS  Google Scholar 

  • Jaeschke H, Knight TR, Bajt ML (2003) The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett 144:279–288

    CAS  Google Scholar 

  • Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9:515–540

    CAS  Google Scholar 

  • Kaya H, Polat B, Albayrak A, Mercantepe T, Buyuk B (2018) Protective effect of an L-type calcium channel blocker, amlodipine, on paracetamol-induced hepatotoxicity in rats. Hum Exp Toxicol 37(11):1169–1179

  • Kim GT, Tran NK, Choi EH, Song YJ, Song JH, Shim SM, Park TS (2016) Immunomodulatory efficacy of standardized Annona muricata (Graviola) leaf extract via activation of mitogen-activated protein kinase pathways in RAW 264.7 macrophages. Evid Based Complement Alternat Med 2016:2905127

    Google Scholar 

  • Kumari A, Kakkar P (2012) Lupeol prevents acetaminophen-induced in vivo hepatotoxicity by altering the Bax/Bcl-2 and oxidative stress-mediated mitochondrial signaling cascade. Life Sci 90:561–570

    CAS  Google Scholar 

  • Laksmitawati DR, Prasanti AP, Larasinta N, Syauta GA, Hilda R, Ramadaniati HU, Widyastuti A, Karami N, Afni M, Rihibiha DD, Kusuma HSW, Widowati W (2016) Anti-inflammatory potential of gandarusa (Gendarussa vulgaris Nees) and soursoup (Annona muricata L) extracts in LPS stimulated-macrophage cell (RAW264.7). J Nat Remed 16:73–81

    Google Scholar 

  • Lee WM, Seremba E (2009) Drug-induced liver disease. In: Yamada T (ed) Textbook of gastroenterology. Blackwell Publishing, Oxford, pp 2167–2184

    Google Scholar 

  • Li G, Chen JB, Wang C, Xu Z, Nie H, Qin XY, Chen XM, Gong Q (2013) Curcumin protects against acetaminophen-induced apoptosis in hepatic injury. World J Gastroenterol 19:7440–7446

    Google Scholar 

  • Li L, Huang W, Wang S, Sun K, Zhang W, Ding Y, Zhang L, Tumen B, Ji L, Liu C (2018) Astragaloside IV attenuates acetaminophen-induced liver injuries in mice by activating the Nrf2 signaling pathway. Molecules 23. https://doi.org/10.3390/molecules23082032

  • Lin G, Luo D, Liu J, Wu X, Chen J, Huang Q, Su L, Zeng L, Wang H, Su Z (2018) Hepatoprotective effect of polysaccharides isolated from Dendrobium officinale against acetaminophen-induced liver injury in mice via regulation of the Nrf2-Keap1 signaling pathway. Oxidative Med Cell Longev 2018:6962439

    Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  • Moghadamtousi SZ, Kadir HA, Paydar M, Rouhollahi E, Karimian H (2014a) Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-kappaB. BMC Complement Altern Med 14:299

    Google Scholar 

  • Moghadamtousi SZ, Rouhollahi E, Karimian H, Fadaeinasab M, Abdulla MA, Kadir HA (2014b) Gastroprotective activity of Annona muricata leaves against ethanol-induced gastric injury in rats via Hsp70/Bax involvement. Drug Des Devel Ther 8:2099–2110

    CAS  Google Scholar 

  • Moghadamtousi SZ, Fadaeinasab M, Nikzad S, Mohan G, Ali HM, Kadir HA (2015a) Annona muricata (Annonaceae): a review of its traditional uses, isolated acetogenins and biological activities. Int J Mol Sci 16:15625–15658

    CAS  Google Scholar 

  • Moghadamtousi SZ, Rouhollahi E, Hajrezaie M, Karimian H, Abdulla MA, Kadir HA (2015b) Annona muricata leaves accelerate wound healing in rats via involvement of Hsp70 and antioxidant defence. Int J Surg 18:110–117

    Google Scholar 

  • Ning C, Gao X, Wang C, Kong Y, Liu Z, Sun H, Sun P, Huo X, Ma X, Meng Q, Liu K (2018) Ginsenoside Rg1 protects against acetaminophen-induced liver injury via activating Nrf2 signaling pathway in vivo and in vitro. Regul Toxicol Pharmacol 98:58–68

    CAS  Google Scholar 

  • Quilez AM, Montserrat-de la Paz S, De la Puerta R, Fernández-Arche MA, García-Giménez MD (2015) Validation of ethnopharmacological use as anti-inflammatory of a decoction from Annona Muricata leaves. Afr J Tradit Complement Altern Med 12:14–20

    CAS  Google Scholar 

  • Rajasekaran A, Periyasamy M (2012) Hepatoprotective effect of ethanolic extract of Trichosanthes lobata on paracetamol-induced liver toxicity in rats. Chin Med 7:12

    Google Scholar 

  • Reisman SA, Csanaky IL, Aleksunes LM, Klaassen CD (2009) Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice. Toxicol Sci 109:31–40

    CAS  Google Scholar 

  • Siddiqui RA, Simjee SU, Kabir N, Ateeq M, Shah MR, Hussain SS (2018) N-(2-hydroxyphenyl)acetamide and its gold nanoparticle conjugation prevent glycerol-induced acute kidney injury by attenuating inflammation and oxidative injury in mice. Mol Cell Biochem 450(1–2):43–52

    Google Scholar 

  • Waters E, Wang JH, Redmond HP, Wu QD, Kay E, Bouchier-Hayes D (2001) Role of taurine in preventing acetaminophen-induced hepatic injury in the rat. Am J Physiol Gastrointest Liver Physiol 280:G1274–G1279

    CAS  Google Scholar 

  • Wu H, Zhang G, Huang L, Pang H, Zhang N, Chen Y, Wang G (2017) Hepatoprotective effect of polyphenol-enriched fraction from Folium Microcos on oxidative stress and apoptosis in acetaminophen-induced liver injury in mice. Oxidative Med Cell Longev 2017:3631565

    Google Scholar 

  • Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N (2016) Acetaminophen-induced hepatotoxicity: a comprehensive update. J Clin Transl Hepatol 4:131–142

    Google Scholar 

  • Zamudio-Cuevas Y, Diaz-Sobac R, Vazquez-Luna A, Landa-Solis C, Cruz-Ramos M, Santamaria-Olmedo M, Martinez-Flores K, Fuentes-Gomez AJ, Lopez-Reyes A (2014) The antioxidant activity of soursop decreases the expression of a member of the NADPH oxidase family. Food Funct 5:303–309

    CAS  Google Scholar 

  • Zuckerbraun BS, Billiar TR (2003) Heme oxygenase-1: a cellular Hercules. Hepatology 37:742–744

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Human Anatomy, College of Medicine, Taif University, Taif, Saudi Arabia

    Ashraf Y. Al-Brakati

  2. Chemistry Department, Faculty of Science, Helwan University, Cairo, 11795, Egypt

    Manar S. Fouda

  3. Obestetrics and Gynecology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt

    Ahmed M. Tharwat

  4. Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam

    Ehab Kotb Elmahallawy

  5. Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam

    Ehab Kotb Elmahallawy

  6. Zoology and Entomology Department, Faculty of Science, Helwan University, Cairo, 11795, Egypt

    Rami B. Kassab & Ahmed E. Abdel Moneim

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  1. Ashraf Y. Al-Brakati
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  2. Manar S. Fouda
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  3. Ahmed M. Tharwat
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  4. Ehab Kotb Elmahallawy
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  6. Ahmed E. Abdel Moneim
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Correspondence to Ehab Kotb Elmahallawy.

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All experiments were conducted according to the ethical standards approved by the Committee on Research Ethics for Laboratory Animal Care at the Department of Zoology, Faculty of Science, Helwan University (approval no, HU2017/Z/03).

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Al-Brakati, A.Y., Fouda, M.S., Tharwat, A.M. et al. The protective efficacy of soursop fruit extract against hepatic injury associated with acetaminophen exposure is mediated through antioxidant, anti-inflammatory, and anti-apoptotic activities. Environ Sci Pollut Res 26, 13539–13550 (2019). https://doi.org/10.1007/s11356-019-04935-3

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