Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells

BMC Complementary and Alternative Medicine

Zhao-Xiang Bian¹  Siu Wai Tsang¹  Hong-Jie Zhang¹  Lu-Cong Zheng¹  Zesi Lin² 

[1] School of Chinese Medicine, Hong Kong Baptist University, 3/F, SCM Building, 7 Baptist University Road, Kowloon, Hong Kong, SAR, China;School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China

关键词: Pancreatic fibrosis;    Pancreatic stellate cells;    Resveratrol;    Curcumin;    Emodin;    Rhein;   

Others  :  1221534
DOI  :  10.1186/s12906-015-0789-y

 received in 2015-04-08, accepted in 2015-07-21,  发布年份 2015

【 摘 要 】

Background

Pancreatic fibrosis is a prominent histopathological characteristic of chronic pancreatitis and plausibly a dynamic process of transition to the development of pancreatic ductal adenocarcinoma. Conversely, the activation of pancreatic stellate cells (PSCs) has been recently suggested as the key initiating step in pancreatic fibrosis. As natural polyphenols had been largely applied in complementary therapies in the past decade, in this study, we aimed to investigate which groups of phenolic compounds exert promising inhibitory actions on fibrogenesis as there are few effective strategies for the treatment of pancreatic fibrosis to date.

Methods

We examined the anti-fibrotic effects of a variety of herbal constituents using a cellular platform, the LTC-14 cells, which retained essential characteristics and morphologies of primary PSCs, by means of various biochemical assays including cell viability test, real-time polymerase chain reaction and Western blotting analysis.

Results

Among a number of commonly used herbal constituents, we found that the application of rhein, emodin, curcumin and resveratrol significantly suppressed the mRNA and protein levels of several fibrotic mediators namely alpha-smooth muscle actin, type I collagen and fibronectin in LTC-14 cells against transforming growth factor-beta stimulation. Though the values of cytotoxicity varied, the mechanism of the anti-fibrotic action of these four phenolic compounds was principally associated with a decrease in the activation of the nuclear factor-kappaB signaling pathway.

Conclusions

Our findings suggest that the mentioned phenolic compounds may serve as anti-fibrotic agents in PSC-relating disorders and pathologies, particularly pancreatic fibrosis.

【 授权许可】

   
2015 Lin et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

【 参考文献 】

• [1]Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol. 2012; 3:344.
• [2]Masamune A, Watanabe T, Kikuta K, Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol. 2009; 7:S48-54.
• [3]Mews P, Phillips P, Fahmy R, Korsten M, Pirola R, Wilson J, Apte M. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut. 2002; 50:535-41.
• [4]Tsang SW, Zhang H, Lin C, Xiao H, Wong M, Shang H, et al. Rhein, a natural anthraquinone derivative, attenuates the activation of pancreatic stellate cells and ameliorates pancreatic fibrosis in mice with experimental chronic pancreatitis. PLoS One. 2013; doi:. 10. 1371/journal.pone.0082201 webcite
• [5]Jaster R. Molecular regulation of pancreatic stellate cell function. Mol Cancer. 2004; 3:26. BioMed Central Full Text
• [6]Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, Wilson JS, Apte MV. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003; 52:275-82.
• [7]Patel M, Fine DR. Fibrogenesis in the pancreas after acinar cell injury. Scand J Surg. 2005; 94:108-11.
• [8]Witt H. Chronic pancreatitis and cystic fibrosis. Gut. 2003; 52 Suppl 2:ii31-41.
• [9]Fremont L. Biological effects of resveratrol. Life Sci. 2000; 66:663-73.
• [10]Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002; 50:3337-40.
• [11]Kardum N, Konić-Ristić A, Savikin K, Spasić S, Stefanović A, Ivanišević J, Miljković M. Effects of polyphenol-rich chokeberry juice on antioxidant/pro-oxidant status in healthy subjects. J Med Food. 2014; 17:869-74.
• [12]Rizvi SI, Jha R. Strategies for the discovery of anti-aging compounds. Expert Opin Drug Discov. 2011; 6:89-102.
• [13]Sureda A, Tejada S, Bibiloni Mdel M, Tur JA, Pons A. Polyphenols: well beyond the antioxidant capacity: polyphenol supplementation and exercise-induced oxidative stress and inflammation. Curr Pharm Biotechnol. 2014; 15:373-9.
• [14]Chen SS, Corteling R, Stevanato L, Sinden J. Polyphenols inhibit indoleamine 3,5-dioxygenase-1 enzymatic activity--a role of immunomodulation in chemoprevention. Discov Med. 2012; 14:327-33.
• [15]Tsang SW, Bian ZX. Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells. Phytother Res. 2015; 29(3):407-14.
• [16]Sparmann G, Hohenadl C, Tornoe J, Jaster R, Fitzner B, Koczan D, Thiesen HJ, Glass A, Winder D, Liebe S, Emmrich J. Generation and characterization of immortalized rat pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004; 287:G211-9.
• [17]Khan N, Mukhtar H. Tea and health: studies in humans. Curr Pharm Des. 2013; 19:6141-7.
• [18]Li AN, Li S, Zhang YJ, Xu XR, Chen YM, Li HB. Resources and biological activities of natural polyphenols. Nutrients. 2014; 6:6020-47.
• [19]Guo MZ, Li XS, Xu HR, Mei ZC, Shen W, Ye XF. Rhein inhibits liver fibrosis induced by carbon tetrachloride in rats. Acta Pharmacol Sin. 2002; 23:739-44.
• [20]Li H, Liang C, Chen Q, Yang Z. Rhein: a potential biological therapeutic drug for intervertebral disc degeneration. Med Hypotheses. 2011; 77:1105-7.
• [21]Yang X, Sun G, Yang C, Wang B. Novel rhein analogues as potential anticancer agents. ChemMedChem. 2011; 6:2294-301.
• [22]Dong MX, Jia Y, Zhang YB, Li CC, Geng YT, Zhou L, Li XY, Liu JC, Niu YC. Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation. World J Gastroenterol. 2009; 15:4753-62.
• [23]Chong L, Zhang W, Nie Y, Yu G, Liu L, Lin L, Wen S, Zhu L, Li C. Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway. Inflammation. 2014; 37:1476-85.
• [24]Troselj KG, Kujundzic RN. Curcumin in combined cancer therapy. Curr Pharm Des. 2014; 20:6682-96.
• [25]Zhai X, Qiao H, Guan W, Li Z, Cheng Y, Jia X, Zhou Y. Curcumin regulates peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression by AMPK pathway in hepatic stellate cells in vitro. Eur J Pharmacol. 2015; 746:56-62.
• [26]Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005; 280:17187-95.
• [27]Li WY, Ng YF, Zhang H, Guo ZD, Guo DJ, Kwan YW, Leung GP, Lee SM, Yu PH, Chan SW. Emodin elicits cytotoxicity in human lung adenocarcinoma A549 cells through inducing apoptosis. Inflammopharmacology. 2014; 22:127-34.
• [28]Li WY, Chan RY, Yu PH, Chan SW. Emodin induces cytotoxic effect in human breast carcinoma MCF-7 cell through modulating the expression of apoptosis-related genes. Pharm Biol. 2013; 51:1175-81.
• [29]Masamune A, Suzuki N, Kikuta K, Satoh M, Satoh K, Shimosegawa T. Curcumin blocks activation of pancreatic stellate cells. J Cell Biochem. 2006; 97:1080-93.
• [30]Tsang SW, Zhang H, Lin Z, Mu H, Bian ZX. Anti-fibrotic effect of trans-resveratrol on pancreatic stellate cells. Biomed Pharmacother. 2015; 71:91-7.
• [31]Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006; 25:6680-4.
• [32]Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch. 2005; 446:475-82.
• [33]Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, Chen J, Tu M, Lu Z, Wei J, Jiang K, Miao Y. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer. 2013; 132(5):993-1003.