Role of Natural Marine Products in the Treatment of Hepatic Stellate Cell- Related Liver Fibrosis

Ching-Hung Chen¹, Chang-Hsun Ho¹ and Chan-Yen Kuo^2*

¹Department of Anesthesiology, Show Chwan Memorial Hospital, Changhua, Taiwan

²Graduate Institute of Systems Biology and Bioinformatics, National Central University, Chung-li, Taiwan

*Corresponding Author:

Chan-Yen Kuo
Graduate Institute of Systems Biology and Bioinformatics
National Central University, Chung-li, Taiwan
Tel: +886-3-4227151
Fax: +886-3-4226062
E-mail: cykuo@thu.edu.tw

Received date: November 25, 2016; Accepted date: November 26, 2016; Published date: November 30, 2016

Citation: Chen CH, Ho CH, Kuo CY (2016) Role of Natural Marine Products in the Treatment of Hepatic Stellate Cell-Related Liver Fibrosis. J Tradi Med Clin Natur 5:e125.

Copyright: © 2016 Chen CH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Traditional Medicine & Clinical Naturopathy

Introduction

Activation of Hepatic Stellate Cells (HSCs) is a key event in the development of liver fibrosis. Anti-fibrosis occurs by two pathways— reversion of the stellate cells to a quiescent state or clearance of the cells by apoptosis. Natural marine products have been reported to inhibit tumor growth and inflammation. However, their effect on liver fibrosis is uncertain. In this review, we discuss the role of natural marine products in the treatment of liver fibrosis. We propose that these products can act as novel therapeutic agents for treating hepatic stellate cell-related liver fibrosis.

Liver fibrosis and HSC activation

Liver fibrosis is a disease that is characterized by severe morbidity and significant mortality [1-3]. Activated Hepatic Stellate Cells (HSCs) are critical for liver fibrosis [4]. During liver fibrosis, activated HSCs induce proliferation, inhibit apoptosis, accumulate Excessive Extracellular Matrix (ECM), and produce pro-inflammatory proteins [5,6]. Therefore, HSCs are an attractive target for anti-fibrotic therapy [7,8]. The anti-fibrotic strategies include decreasing the number of activated HSCs via inhibition of proliferation or induction of apoptosis and inhibiting the excessive deposition of ECM [9]. Thus, suppression of HSC growth and/or induction of HSC apoptosis by natural products are considered as effective options to ameliorate liver fibrosis.

Natural marine products for treatment of liver fibrosis

Natural marine products have a wide variety of biomedical effects such as anti-tumor, anti-bacterial, anti-fungal, anti-viral, anti-helminthic, anti-protozoan, and anti-allergic effects [10-13]. Several compounds have been isolated from these products, which are important sources of drug discovery [10,14]. However, the pharmacological effects of natural marine products and their underlying mechanisms in the development of HSC-related liver fibrosis are still unclear. Therefore, investigation of HSC activation-dependent liver fibrosis is necessary to understand the importance of inducing apoptosis of HSCs towards treatment of this disease [6,15-18].

Reactive Oxygen Species (ROS) and HSC activation

It is well documented that ROS is a critical mediator of liver fibrogenesis in vitro and in vivo [19-22]. Overproduction of ROS causes apoptosis in isolated primary activated HSCs from human and rat [23]. Furthermore, Glutathione (GSH) is a major intracellular antioxidant that plays a significant role in the regulation of cell viability in HSCs [24]. GSH exerts an anti-apoptotic effect by controlling ROS-induced cell death [25]. GSH depletion increases the sensitivity of HSCs to oxidative stress-induced cell death [25,26].

Signaling pathways in liver fibrosis

Mitogen-Activated Protein Kinases (MAPKs) such as ERK, JNK, p38 kinase, and MAP kinase-1, are important mediators of diverse physiological processes and are critical for induction of oxidative stress response [27-29]. In addition, it is well-known that the MAPK signaling pathway is involved in cell growth and activation in HSCs [30,31]. However, Yu et al. found that continuous generation of H₂O₂ caused inhibition of growth of human gingival fibroblasts, which is independent of MAPK activation [32]. The role of the MAPK pathway in the oxidative stress-induced apoptosis of HSCs is unclear. Mao et al. suggested that shikonin-induced Chronic Myelogenous Leukemia (CML) cells undergo apoptosis via the ROS/JNK pathway. In contrast, it has been reported that panaxydol induces apoptosis via the ROS/JNK pathway [33].

Conclusion

Activated HSCs play important roles in the pathogenesis of liver fibrosis [34]. Growing evidence suggest that induction of HSC apoptosis and inhibition of HSC growth can be effective strategies for treatment and/or prevention of liver fibrosis [6,16-18,35,36]. Furthermore, drug development from natural marine products may serve as additional therapeutic approaches for inhibition of hepatic fibrogenesis via HSC apoptosis.

Acknowledgement

This study was supported by grants RD105506 to RD105056 from Show Chwan Memorial Hospital, Changhua, Taiwan.

References

1. Bonis PA, Friedman SL, Kaplan MM (2001)Is liver fibrosis reversible? N Engl J Med 344:452-454.
2. Friedman SL (2008) Hepatic fibrosis–overview. Toxicology 254:120-129.
3. Friedman SL(2008) Mechanisms of hepatic fibrogenesis. Gastroenterology 134:1655-1669.
4. Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125-172.
5. Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, et al. (2002) Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem 277:11069-11076.
6. Friedman SL (2010) Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7: 425-436.
7. Fallowfield JA (2011) Therapeutic targets in liver fibrosis. Am J PhysiolGastrointest Liver Physiol 300:G709-G715.
8. Friedman SL (2008) Preface. Hepatic fibrosis: pathogenesis, diagnosis, and emerging therapies. Clin Liver Dis 12:xiii-xiv.
9. Fan HN, Wang HJ, Yang-Dan CR, Ren L, Wang C, et al. (2013) Protective effects of hydrogen sulfide on oxidative stress and fibrosis in hepatic stellate cells. Mol Med Rep7:247-253.
10. .von Schwarzenberg K, Vollmar AM (2013) Targeting apoptosis pathways by natural compounds in cancer: marine compounds as lead structures and chemical tools for cancer therapy. Cancer lett332:295-303.
11. Bhatnagar I, Kim SK (2012) Pharmacologically prospective antibiotic agents and their sources: a marine microbial perspective. Environ ToxicolPharmacol 34:631-643.
12. Bhatnagar I, Kim SK (2010)Immense essence of excellence: marine microbial bioactive compounds. Mar Drugs 8:2673-2701.
13. Fitton JH (2011) Therapies from fucoidan; multifunctional marine polymers. Mar Drugs 9:1731-1760.
14. Molinski TF, Dalisay DS, Lievens SL, Saludes JP (2009) Drug development from marine natural products. Nat Rev Drug Discov 8:69-85.
15. Issa R, Williams E, Trim N, Kendall T, Arthur MJ, et al. (2001) Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut 48:548-557.
16. Ray K (2014) Liver: hepatic stellate cells hold the key to liver fibrosis. Nat Rev GastroenterolHepatol11:74.
17. Puche JE, Saiman Y, Friedman SL (2013) Hepatic stellate cells and liver fibrosis. ComprPhysiol 3:1473-1492.
18. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, et al. (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun,4:2823.
19. Bell LN, Temm CJ, Saxena R, Vuppalanchi R, Schauer P, et al. (2010)Bariatric surgery-induced weight loss reduces hepatic lipid peroxidation levels and affects hepatic cytochrome P-450 protein content. Ann Surg251:1041-1048.
20. Parola M, Robino G (2001) Oxidative stress-related molecules and liver fibrosis. J Hepatol 35:297-306.
21. Poli G, Parola M (1997) Oxidative damage and fibrogenesis. Free Radic Biol Med 22:287-305.
22. Ceni E, Mello T, Galli A (2014) Pathogenesis of alcoholic liver disease: role of oxidative metabolism. WJG 20:17756-17772.
23. Siegmund SV, Qian T, de Minicis S, Harvey-White J, Kunos G, et al. (2007) The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J21:2798-2806.
24. Brunati AM, Pagano MA, Bindoli A, Rigobello MP (2010)Thiol redox systems and protein kinases in hepatic stellate cell regulatory processes. Free Radic Res 44:363-378.
25. Dunning S, Ur Rehman A, Tiebosch MH, Hannivoort RA, Haijer FW, et al. (2013) Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death. Biochim Biophys Acta1832:2027-2034.
26. Dunning S, Hannivoort RA, de Boer JF, Buist-Homan M, Faber KN(2009) Superoxide anions and hydrogen peroxide inhibit proliferation of activated rat stellate cells and induce different modes of cell death. Liver Int 29:922-932.
27. Runchel C, Matsuzawa A, Ichijo H (2011) Mitogen-activated protein kinases in mammalian oxidative stress responses. Antioxid Redox Signal 15:205-218.
28. Zarubin T, Han J (2005) Activation and signaling of the p38 MAP kinase pathway. Cell Res 15:11-18.
29. Chowdhury AA, Chaudhuri J, Biswas N, Manna A, Chatterjee S, et al. (2013) Synergistic apoptosis of CML cells by buthioninesulfoximine and hydroxychavicol correlates with activation of AIF and GSH-ROS-JNK-ERK-iNOS pathway. PloSONE 8:e73672.
30. Huang J, Wu L, Tashiro S, Onodera S, Ikejima T (2008) Reactive oxygen species mediate oridonin-induced HepG2 apoptosis through p53, MAPK, and mitochondrial signaling pathways. J Pharmacol Sci 107:370-379.
31. Szuster-Ciesielska A, Mizerska-Dudka M, Daniluk J, Kandefer-Szerszen M (2013) Butein inhibits ethanol-induced activation of liver stellate cells through TGF-beta, NFkappaB, p38, and JNK signaling pathways and inhibition of oxidative stress. J Gastroenterol 48:222-237.
32. Yu JY, Lee SY, Son YO, Shi X, Park SS, et al. (2012)Continuous presence of H(2)O(2) induces mitochondrial-mediated, MAPK- and caspase-independent growth inhibition and cytotoxicity in human gingival fibroblasts. ToxicolIn Vitro 26:561-570.
33. Kim JY, Yu SJ, Oh HJ, Lee JY, Kim Y, et al. (2011)Panaxydol induces apoptosis through an increased intracellular calcium level, activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species. Apoptosis 16:347-358.
34. Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, et al. (2012) Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143:1073-1083 e1022.
35. Franco R, Cidlowski JA (2012) Glutathione efflux and cell death.Antioxidants &Redox Signaling 17:1694-1713.
36. Kuo LM, Kuo CY, Lin CY, Hung MF, Shen JJ, et al. (2014) Intracellular glutathione depletion by oridonin leads to apoptosis in hepatic stellate cells. Molecules 19: 3327-3344.