Green tea polyphenol (–)‐epigallocatechin‐3‐gallate inhibits ethanol‐induced activation of pancreatic stellate cells

Asaumi, Hiroshi; Watanabe, Shiro; Taguchi, Masashi; Tashiro, Mitsuo; Nagashio, Yoshikuni; Nomiyama, Yoko; Nakamura, Hayato; Ōtsuki, Makoto

doi:10.1111/j.1365-2362.2006.01599.x

Cited by 41 publications

(41 citation statements)

References 43 publications

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“…In a recent study, Masamune et al (2006) have demonstrated that curcumin, the yellow pigment in curry, inhibits PSC proliferation. Furthermore, other groups provided evidence that compounds like statins, taurine, or the green tea extract epigallocatechin gallate could also block the proliferation of PSCs in experimental in vitro or in vivo models, but the exact cellular mechanisms are still not fully understood (Jaster et al, 2003;Asaumi et al, 2006;Shirahige et al, 2007). Note that all of these mentioned substances are potent inducers of the cytoprotective enzyme HO-1 in several cell types, but no information is available concerning their effects on HO-1 in the pancreas (Olszanecki and Marcinkiewicz, 2004;Wu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Schwer¹,

Guerrero²,

Humar³

et al. 2008

J Pharmacol Exp Ther

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Activation of pancreatic stellate cells (PSCs) is the key process in the development of pancreatic fibrosis, a common feature of chronic pancreatitis and pancreatic cancer. In recent studies, curcumin has been shown to inhibit PSC proliferation via an extracellular signal-regulated kinase (ERK)1/2-dependent mechanism. In addition, curcumin is a potent inducer of the cytoprotective enzyme heme oxygenase-1 (HO-1) in other cell types. Therefore, the aims of this study were to 1) characterize the effect of curcumin on HO-1 gene expression in PSCs, 2) explore whether HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation, and 3) clarify the involvement of the mitogen-activated protein kinase (MAPK) family in this context. Cultured rat PSCs were incubated with curcumin and assessed for HO-1 up-regulation by Northern blot analysis, immunoblotting, and activity assays. The effect of HO-1 on platelet-derived growth factor (PDGF)-induced PSC proliferation and MAPK activation was determined by immunoblotting, cell proliferation assays, and cell count analyses. Curcumin induced HO-1 gene expression in PSCs in a timeand dose-dependent manner and inhibited PDGF-mediated ERK1/2 phosphorylation and PSC proliferation. These effects were blocked by treatment of PSCs with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA. Our data provide evidence that HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation. Therefore, therapeutic up-regulation of HO-1 could represent a mode for inhibition of PSC proliferation and thus may provide a novel strategy in the prevention of pancreatic fibrosis.Pancreatic fibrosis is a common histopathological feature in chronic pancreatitis and pancreatic cancer. It is now generally accepted that pancreatic stellate cells (PSCs) play a crucial role in the fibrogenic process (Omary et al., 2007). In response to profibrogenic stimuli, PSCs undergo transdifferentiation from quiescent phenotypes into highly proliferative myofibroblast-like cells, which express the cytoskeletal protein ␣-smooth muscle actin and synthesize increased amounts of extracellular matrix components (Apte et al., 1998;Bachem et al., 1998). Recent studies have identified platelet-derived growth factor (PDGF)-BB as the most potent mitogen for pancreatic stellate cells in culture, and its effects have been extensively studied (Apte et al., 1998;Luttenberger et al., 2000). PDGF stimulates PSC cell proliferation by activating key effectors, including ras, raf, and the extracellular signal-regulated kinase (ERK)1/2 cascade (Jaster et al., 2002;Masamune et al., 2003a). Data from recent studies suggest that p38 mitogenactivated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase (JNK) signaling pathways might also play a role in PSC proliferation ((Masamune et al., 2003b((Masamune et al., , 2004. Thus, modulation of MAPK activation is considered a potential strategy to inhibit PSC growth.Heme oxygenases (HOs) are the rate-limiting enzymes...

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Schwer¹,

Guerrero²,

Humar³

et al. 2008

J Pharmacol Exp Ther

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“…Epigallocatechin-3-gallare (EGCG) 76 is an antioxidant polyphenol purifi ed from green tea and curcumin, 77 and it is a major component of turmeric. The polyphenol family has anti-infl ammatory, antifi brotic, and anticancer properties.…”

Section: Polyphenolmentioning

confidence: 99%

Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

Shimizu

2008

J Gastroenterol

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Pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis and in the desmoplastic reaction of pancreatic cancer. When PSCs are stimulated by oxidative stress, ethanol and its metabolite acetaldehyde, and cytokines, the phenotype of quiescent fat-storing cells converts to myofibroblastlike activated PSCs, which then produce extracellular matrix, adhesion molecules, and various chemokines in response to cytokines and growth factors. Recent data suggest that PSCs have a phagocytic function. Plateletderived growth factor is a potent stimulator of PSC proliferation. Transforming growth factor beta, activin A, and connective tissue growth factor also play a role in PSC-mediated pancreatic fibrogenesis through autocrine and paracrine loops. Following pancreatic damage, pathophysiological processes that occur in the pancreas, including pancreas tissue pressure, hyperglycemia, intracellular reactive oxygen species production, activation of protease-activated receptor 2, induction of cyclooxygenase 2, and bacterial infection play a role in sustaining pancreatic fibrosis through increased PSC proliferation and collagen production by PSCs. Targeting PSCs might be an effective therapeutic approach in chronic pancreatitis. Various substances including vitamin A, vitamin E, polyphenols, peroxisome proliferator-activated receptor gamma ligands, and inhibitors of the renin-angiotensin system show great promise of being useful in the treatment of chronic pancreatitis.

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“…A similarly low level of evidence exists for green tea and green tea extracts. Animal models show a protective effect of green tea polyphenols and aqueous extracts from green and black tea [47,48], but no convincing clinical trial or epidemiologic data supporting this effect in humans are currently available.…”

Section: Chronic Pancreatitismentioning

confidence: 99%

Environmental Risk Factors for Chronic Pancreatitis and Pancreatic Cancer

Nitsche

Simon

Weiss

et al. 2011

Dig Dis

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Chronic pancreatitis has long been thought to be mainly associated with immoderate alcohol consumption. The observation that only ∼10% of heavy drinkers develop chronic pancreatitis not only suggests that other environmental factors, such as tobacco smoke, are potent additional risk factors, but also that the genetic component of pancreatitis is more common than previously presumed. Either disease-causing or protective traits have been indentified for mutations in different trypsinogen genes, the gene for the trypsin inhibitor SPINK1, chymotrypsinogen C, and the cystic fibrosis transmembane conductance regulator (CFTR). Other factors that have been proposed to contribute to pancreatitis are obesity, diets high in animal protein and fat, as well as antioxidant deficiencies. For the development of pancreatic cancer, preexisting chronic pancreatitis, more prominently hereditary pancreatitis, is a risk factor. The data on environmental risk factors for pancreatic cancer are, with the notable exception of tobacco smoke, either sparse, unconfirmed or controversial. Obesity appears to increase the risk of pancreatic cancer in the West but not in Japan. Diets high in processed or red meat, diets low in fruits and vegetables, phytochemicals such as lycopene and flavonols, have been proposed and refuted as risk or protective factors in different trials. The best established and single most important risk factor for cancer as well as pancreatitis and the one to clearly avoid is tobacco smoke.

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Green tea polyphenol (–)‐epigallocatechin‐3‐gallate inhibits ethanol‐induced activation of pancreatic stellate cells

Abstract: Our results suggest that green tea and polyphenols could prevent pancreatic fibrosis by inhibiting PSC activation through the antioxidative effect.

Cited by 41 publications

References 43 publications

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis

Environmental Risk Factors for Chronic Pancreatitis and Pancreatic Cancer

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