Skip to main content
SpringerLink
Log in

Tryptanthrin prevents oxidative stress-mediated apoptosis through AMP-activated protein kinase-dependent p38 mitogen-activated protein kinase activation

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) has been reported to have a variety of pharmacological activities. Present study investigated the cytoprotective effects of tryptanthrin on arachidonic acid (AA) + iron-mediated oxidative stress and the molecular mechanisms responsible. In HepG2 cells, pretreatment with tryptanthrin inhibited the cytotoxic effect of AA + iron in a concentration-dependent manner. In addition, tryptanthrin prevented the changes in the levels of apoptosis-related proteins, and attenuated reactive oxygen species production, glutathione depletion, and mitochondrial membrane impairment induced by AA + iron. Mechanistic investigations showed that tryptanthrin increased the phosphorylations of AMP-activated protein kinase (AMPK) and of p38 mitogen-activated protein kinase (p38). Furthermore, inhibition of AMPK or p38 reduced the ability of tryptanthrin to prevent AA + iron-induced cell death and mitochondrial dysfunction. Transfection experiments using AMPK mutants indicated that p38 phosphorylation by tryptanthrin was dependent on AMPK activation. In a phenylhydrazine-induced acute liver injury model, tryptanthrin decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin in mice. Additionally, tryptanthrin reduced numbers of degenerating hepatocytes, infiltrating inflammatory cells, 4-hydroxynonenal-, and nitrotyrosine-positive cells in hepatic tissues. Thus, these results suggest tryptanthrin has therapeutic potential to protect cells from oxidative injury via AMPK-dependent p38 activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Balboa MA, Balsinde J (2006) Oxidative stress and arachidonic acid mobilization. Biochim Biophys Acta 1761:385–391

    Article  CAS  PubMed  Google Scholar 

  • Batts KP (2007) Iron overload syndromes and the liver. Mod Pathol 20:S31–39

    Article  PubMed  Google Scholar 

  • Caro AA, Cederbaum AI (2001) Synergistic toxicity of iron and arachidonic acid in HepG2 cells overexpressing CYP2E1. Mol Pharmacol 60:742–752

    CAS  PubMed  Google Scholar 

  • Chang HN, Huang ST, Yeh YC, Wang HS, Wang TH, Wu YH, Pang JH (2015) Indigo naturalis and its component tryptanthrin exert anti-angiogenic effect by arresting cell cycle and inhibiting Akt and FAK signaling in human vascular endothelial cells. J Ethnopharmacol 174:474–481

    Article  CAS  PubMed  Google Scholar 

  • Cichoż-Lach H, Michalak A (2014) Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 20:8082–8091

    Article  PubMed  PubMed Central  Google Scholar 

  • Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C (2008) Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res 103:983–991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii Y, Sakurai J (1989) Contraction of the rat isolated aorta caused by Clostridium perfringens alpha toxin (phospholipase C): evidence for the involvement of arachidonic acid metabolism. Br J Pharmacol 97:119–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ha do T, Oh J, Khoi NM, Dao TT, Dung le V, Do TN, Lee SM, Jang TS, Jeong GS, Na M (2013) In vitro and in vivo hepatoprotective effect of ganodermanontriol against t-BHP-induced oxidative stress. J Ethnopharmacol 150:875–885

  • Han NR, Moon PD, Kim HM, Jeong HJ (2014) Tryptanthrin ameliorates atopic dermatitis through down-regulation of TSLP. Arch Biochem Biophys 542:14–20

    Article  CAS  PubMed  Google Scholar 

  • Honda G, Tabata M (1979) Isolation of antifungal principle tryptanthrin, from Strobilanthes cusia O. Kuntze. Planta Med 36:85–90

    Article  CAS  PubMed  Google Scholar 

  • Honda G, Tosirisuk V, Tabata M (1980) Isolation of an antidermatophytic, tryptanthrin, from indigo plants, Polygonum tinctorium and Isatis tinctoria. Planta Med 38:275–276

    Article  CAS  PubMed  Google Scholar 

  • Ishihara T, Kohno K, Ushio S, Iwaki K, Ikeda M, Kurimoto M (2000) Tryptanthrin inhibits nitric oxide and prostaglandin E(2) synthesis by murine macrophages. Eur J Pharmacol 407:197–204

    Article  CAS  PubMed  Google Scholar 

  • Iwaki K, Ohashi E, Arai N, Kohno K, Ushio S, Taniguchi M, Fukuda S (2011) Tryptanthrin inhibits Th2 development, and IgE-mediated degranulation and IL-4 production by rat basophilic leukemia RBL-2H3 cells. J Ethnopharmacol 134:450–459

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Chen C, Li Z, Guo W, Gegner JA, Lin S, Han J (1996) Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem 271:17920–17926

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, Di Padova F, Ulevitch RJ, Han J (1997) Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem 272:30122–30128

    Article  CAS  PubMed  Google Scholar 

  • Jin JP, Jang JS (2013) Herbal Dictionary, 1st edn. Beobin publisher, Seoul (Korea), pp 550

  • Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25

    Article  CAS  PubMed  Google Scholar 

  • Kim YW, Lee SM, Shin SM, Hwang SJ, Brooks JS, Kang HE, Lee MG, Kim SC, Kim SG (2009) Efficacy of sauchinone as a novel AMPK-activating lignan for preventing iron-induced oxidative stress and liver injury. Free Radic Biol Med 47:1082–1092

    Article  CAS  PubMed  Google Scholar 

  • Kim N, Kim HM, Lee ES, Lee JO, Lee HJ, Lee SK, Moon JW, Kim JH, Kim JK, Kim SJ, Park SH, Chung CH, Kim HS (2015) Dibenzoylmethane exerts metabolic activity through regulation of AMP-activated protein kinase (AMPK)-mediated glucose uptake and adipogenesis pathways. PLoS ONE 10:e0120104

    Article  PubMed  PubMed Central  Google Scholar 

  • Kimoto T, Hino K, Koya-Miyata S, Yamamoto Y, Takeuchi M, Nishizaki Y, Micallef MJ, Ushio S, Iwaki K, Ikeda M, Kurimoto M (2001) Cell differentiation and apoptosis of monocytic and promyelocytic leukemia cells (U-937 and HL-60) by tryptanthrin, an active ingredient of Polygonum tinctorium Lour. Pathol Int 51:315–325

    Article  CAS  PubMed  Google Scholar 

  • Ko HL, Jegal KH, Song SY, Kim NE, Kang J, Byun SH, Kim YW, Cho IJ, Kim SC (2015) Water extract of Rosa laevigata Michx. protects hepatocytes from arachidonic acid and iron-mediated oxidative stress. Kor J Herbol 30:7–15

    Article  Google Scholar 

  • Ko HL, Jung EH, Jung DH, Kim JK, Ku SK, Kim YW, Kim SC, Zhao R, Lee CW, Cho IJ (2016) Paeonia japonica root extract protects hepatocytes against oxidative stress through inhibition of AMPK-mediated GSK3β. J Funct Foods 20:303–316

    Article  CAS  Google Scholar 

  • Lage R, Diéguez C, Vidal-Puig A, López M (2008) AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 14:539–549

    Article  CAS  PubMed  Google Scholar 

  • Lee WH, Wu HH, Huang WJ, Li YN, Lin RJ, Lin SY, Liang YC (2015) N-hydroxycinnamide derivatives of osthole ameliorate hyperglycemia through activation of AMPK and p38 MAPK. Molecules 20:4516–4529

    Article  CAS  PubMed  Google Scholar 

  • Lin YK, Chen HW, Leu YL, Yang YL, Fang Y, Su Pang JH, Hwang TL (2013) Indigo naturalis upregulates claudin-1 expression in human keratinocytes and psoriatic lesions. J Ethnopharmacol 145:614–620

    Article  PubMed  Google Scholar 

  • Moirand R, Mendler MH, Guillygomarc’h A, Brissot P, Deugnier Y (2000) Nonalcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload? J Hepatol 33:1024–1026

  • Moon SY, Lee JH, Choi HY, Cho IJ, Kim SC, Kim YW (2014) Tryptanthrin protects hepatocytes against oxidative stress via activation of the extracellular signal-regulated kinase/NF-E2-related factor 2 pathway. Biol Pharm Bull 37:1633–1640

    Article  CAS  PubMed  Google Scholar 

  • Nader N, Ng SS, Lambrou GI, Pervanidou P, Wang Y, Chrousos GP, Kino T (2010) AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK. Mol Endocrinol 24:1748–1764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishihara M, Miura T, Miki T, Tanno M, Yano T, Naitoh K, Ohori K, Hotta H, Terashima Y, Shimamoto K (2007) Modulation of the mitochondrial permeability transition pore complex in GSK-3β-mediated myocardial protection. J Mol Cell Cardiol 43:564–570

    Article  CAS  PubMed  Google Scholar 

  • Peralta C, Bartrons R, Serafin A, Blázquez C, Guzmán M, Prats N, Xaus C, Cutillas B, Gelpí E, Roselló-Catafau J (2001) Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat. Hepatology 34:1164–1173

    Article  CAS  PubMed  Google Scholar 

  • Pergola C, Jazzar B, Rossi A, Northoff H, Hamburger M, Sautebin L, Werz O (2012) On the inhibition of 5-lipoxygenase product formation by tryptanthrin: mechanistic studies and efficacy in vivo. Br J Pharmacol 165:765–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plitzko I, Mohn T, Sedlacek N, Hamburger M (2009) Composition of indigo naturalis. Planta Med 75:860–863

    Article  CAS  PubMed  Google Scholar 

  • Sakai N, Van Sweringen HL, Quillin RC, Schuster R, Blanchard J, Burns JM, Tevar AD, Edwards MJ, Lentsch AB (2012) Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice. Hepatology 56:1468–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santacatterina F, Sánchez-Cenizo L, Formentini L, Mobasher MA, Casas E, Rueda CB, Martínez-Reyes I, Núñez de Arenas C, García-Bermúdez J, Zapata JM, Sánchez-Aragó M, Satrústegui J, Valverde ÁM, Cuezva JM (2016) Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state. Oncotarget 7:490–508

    Article  PubMed  Google Scholar 

  • Scorrano L, Penzo D, Petronilli V, Pagano F, Bernardi P (2001) Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha apoptotic signaling. J Biol Chem 276:12035–12040

    Article  CAS  PubMed  Google Scholar 

  • Shin SM, Cho IJ, Kim SG (2009) Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol Pharmacol 76:884–895

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Yamamoto M (2015) Molecular basis of the Keap1-Nrf2 system. Free Radic Biol Med 88:93–100

    Article  CAS  PubMed  Google Scholar 

  • Tormos AM, Taléns-Visconti R, Nebreda AR, Sastre J (2013) p38 MAPK: a dual role in hepatocyte proliferation through reactive oxygen species. Free Radic Res 47:905–916

    Article  CAS  PubMed  Google Scholar 

  • Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A, Nussler N (2007) Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol 47:253–261

    Article  CAS  PubMed  Google Scholar 

  • Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB (2006) Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 55:2562–2570

    Article  CAS  PubMed  Google Scholar 

  • Zhang N, Hua Y, Wang C, Sun Y, Wang Z, Liu Z, Liu J (2014) Distribution study of tryptanthrin in rat tissues by HPLC and its relationship with meridian tropism of indigo naturalis in traditional Chinese medicine. Biomed Chromatogr 28:1701–1706

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (No. 2012 R1A5A2A42671316) and by Korea Institute of Oriental Medicine (KIOM) (K16823).

Author information

Authors and Affiliations

  1. College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea

    Eun Hye Jung, Ji Yun Jung, Hae Li Ko, Jae Kwang Kim, Sang Mi Park, Chung A Park, Young Woo Kim, Sae Kwang Ku, Il Je Cho & Sang Chan Kim

  2. HaniBio Co., Ltd, Gyeongsan, Gyeongsangbuk-do, 38540, Republic of Korea

    Dae Hwa Jung

Authors
  1. Eun Hye Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Yun Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hae Li Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jae Kwang Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sang Mi Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dae Hwa Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chung A Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Young Woo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sae Kwang Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Il Je Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sang Chan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Il Je Cho or Sang Chan Kim.

Ethics declarations

Conflict of interest

The authors declare that we have no conflict of interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 991 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, E.H., Jung, J.Y., Ko, H.L. et al. Tryptanthrin prevents oxidative stress-mediated apoptosis through AMP-activated protein kinase-dependent p38 mitogen-activated protein kinase activation. Arch. Pharm. Res. 40, 1071–1086 (2017). https://doi.org/10.1007/s12272-017-0947-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-017-0947-5

Keywords

Search

Navigation