Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2015

Open Access 01-12-2015 | Research article

Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells

Authors: Zesi Lin, Lu-Cong Zheng, Hong-Jie Zhang, Siu Wai Tsang, Zhao-Xiang Bian

Published in: BMC Complementary Medicine and Therapies | Issue 1/2015

Login to get access

Abstract

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.
Literature
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference Mews P, Phillips P, Fahmy R, Korsten M, Pirola R, Wilson J, et al. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut. 2002;50:535–41.CrossRefPubMedPubMedCentral Mews P, Phillips P, Fahmy R, Korsten M, Pirola R, Wilson J, et al. Pancreatic stellate cells respond to inflammatory cytokines: potential role in chronic pancreatitis. Gut. 2002;50:535–41.CrossRefPubMedPubMedCentral
4.
go back to reference 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. 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.
6.
go back to reference Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003;52:275–82.CrossRefPubMedPubMedCentral Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, et al. Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut. 2003;52:275–82.CrossRefPubMedPubMedCentral
7.
go back to reference Patel M, Fine DR. Fibrogenesis in the pancreas after acinar cell injury. Scand J Surg. 2005;94:108–11.PubMed Patel M, Fine DR. Fibrogenesis in the pancreas after acinar cell injury. Scand J Surg. 2005;94:108–11.PubMed
8.
go back to reference Witt H. Chronic pancreatitis and cystic fibrosis. Gut. 2003;52 Suppl 2:ii31–41.PubMed Witt H. Chronic pancreatitis and cystic fibrosis. Gut. 2003;52 Suppl 2:ii31–41.PubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference Kardum N, Konić-Ristić A, Savikin K, Spasić S, Stefanović A, Ivanišević J, et al. Effects of polyphenol-rich chokeberry juice on antioxidant/pro-oxidant status in healthy subjects. J Med Food. 2014;17:869–74.CrossRefPubMed Kardum N, Konić-Ristić A, Savikin K, Spasić S, Stefanović A, Ivanišević J, et al. Effects of polyphenol-rich chokeberry juice on antioxidant/pro-oxidant status in healthy subjects. J Med Food. 2014;17:869–74.CrossRefPubMed
12.
go back to reference Rizvi SI, Jha R. Strategies for the discovery of anti-aging compounds. Expert Opin Drug Discov. 2011;6:89–102.CrossRefPubMed Rizvi SI, Jha R. Strategies for the discovery of anti-aging compounds. Expert Opin Drug Discov. 2011;6:89–102.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.PubMed 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.PubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference Sparmann G, Hohenadl C, Tornoe J, Jaster R, Fitzner B, Koczan D, et al. Generation and characterization of immortalized rat pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G211–9.CrossRefPubMed Sparmann G, Hohenadl C, Tornoe J, Jaster R, Fitzner B, Koczan D, et al. Generation and characterization of immortalized rat pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;287:G211–9.CrossRefPubMed
19.
go back to reference 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.PubMed 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.PubMed
20.
go back to reference Li H, Liang C, Chen Q, Yang Z. Rhein: a potential biological therapeutic drug for intervertebral disc degeneration. Med Hypotheses. 2011;77:1105–7.CrossRefPubMed Li H, Liang C, Chen Q, Yang Z. Rhein: a potential biological therapeutic drug for intervertebral disc degeneration. Med Hypotheses. 2011;77:1105–7.CrossRefPubMed
21.
go back to reference Yang X, Sun G, Yang C, Wang B. Novel rhein analogues as potential anticancer agents. ChemMedChem. 2011;6:2294–301.CrossRefPubMed Yang X, Sun G, Yang C, Wang B. Novel rhein analogues as potential anticancer agents. ChemMedChem. 2011;6:2294–301.CrossRefPubMed
22.
go back to reference Dong MX, Jia Y, Zhang YB, Li CC, Geng YT, Zhou L, et al. Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation. World J Gastroenterol. 2009;15:4753–62.CrossRefPubMedPubMedCentral Dong MX, Jia Y, Zhang YB, Li CC, Geng YT, Zhou L, et al. Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation. World J Gastroenterol. 2009;15:4753–62.CrossRefPubMedPubMedCentral
23.
go back to reference Chong L, Zhang W, Nie Y, Yu G, Liu L, Lin L, et al. Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway. Inflammation. 2014;37:1476–85.CrossRefPubMedPubMedCentral Chong L, Zhang W, Nie Y, Yu G, Liu L, Lin L, et al. Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway. Inflammation. 2014;37:1476–85.CrossRefPubMedPubMedCentral
24.
25.
go back to reference Zhai X, Qiao H, Guan W, Li Z, Cheng Y, Jia X, et al. 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.CrossRefPubMed Zhai X, Qiao H, Guan W, Li Z, Cheng Y, Jia X, et al. 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.CrossRefPubMed
26.
go back to reference Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005;280:17187–95.CrossRefPubMed Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem. 2005;280:17187–95.CrossRefPubMed
27.
go back to reference Li WY, Ng YF, Zhang H, Guo ZD, Guo DJ, Kwan YW, et al. Emodin elicits cytotoxicity in human lung adenocarcinoma A549 cells through inducing apoptosis. Inflammopharmacology. 2014;22:127–34.CrossRefPubMed Li WY, Ng YF, Zhang H, Guo ZD, Guo DJ, Kwan YW, et al. Emodin elicits cytotoxicity in human lung adenocarcinoma A549 cells through inducing apoptosis. Inflammopharmacology. 2014;22:127–34.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
29.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
30.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
31.
go back to reference Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006;25:6680–4.CrossRefPubMed Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006;25:6680–4.CrossRefPubMed
32.
go back to reference Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch. 2005;446:475–82.CrossRefPubMed Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch. 2005;446:475–82.CrossRefPubMed
33.
go back to reference Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, et al. 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.CrossRefPubMed Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, et al. 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.CrossRefPubMed
Metadata
Title
Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells
Authors
Zesi Lin
Lu-Cong Zheng
Hong-Jie Zhang
Siu Wai Tsang
Zhao-Xiang Bian
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2015
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-015-0789-y

Other articles of this Issue 1/2015

BMC Complementary Medicine and Therapies 1/2015 Go to the issue