Exploring chemical space for lead identification by propagating on chemical similarity network.

Motivation: Lead identification is a fundamental step to prioritize candidate compounds for downstream drug discovery process. Machine learning (ML) and deep learning (DL) approaches are widely used to identify lead compounds using both chemical property and experimental information. However, ML or DL methods rarely consider compound similarity information directly since ML and DL models use abstract representation of molecules for model construction. Alternatively, data mining approaches are also used to explore chemical space with drug candidates by screening undesirable compounds. A major challenge for data mining approaches is to develop efficient data mining methods that search large chemical space for desirable lead compounds with low false positive rate. Results: In this work, we developed a network propagation (NP) based data mining method for lead identification that performs search on an ensemble of chemical similarity networks. We compiled 14 fingerprint-based similarity networks. Given a target protein of interest, we use a deep learning-based drug target interaction model to narrow down compound candidates and then we use network propagation to prioritize drug candidates that are highly correlated with drug activity score such as IC50. In an extensive experiment with BindingDB, we showed that our approach successfully discovered intentionally unlabeled compounds for given targets. To further demonstrate the prediction power of our approach, we identified 24 candidate leads for CLK1. Two out of five synthesizable candidates were experimentally validated in binding assays. In conclusion, our framework can be very useful for lead identification from very large compound databases such as ZINC.

New phytopharmaceutical agent CJ-20001 modulates stress-induced inflammatory infiltration into gastric mucosa.

BACKGROUND/AIMS: CJ-20001 is a phytopharmaceutical agent and currently being investigated in a Phase II trial for the treatment of acute and chronic gastritis patients in Korea. In this study we addressed the protective effects of CJ-20001 against water immersion restraint stress (WIRS)-induced gastric injury in rats and studied the underlying mechanisms. METHODOLOGY: To evaluate the protective effect of CJ-20001 on stress-induced gastric lesions, rats were exposed to water immersion restraint stress. Inflammatory infiltration into gastric mucosa was examined by immunohistochemistry and in vitro invasion assay. Expression of proinflammatory cytokines was detected with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Pretreatment with CJ-20001 dose-dependently attenuated the WIRS-induced gastric lesions as demonstrated by gross pathology and histology. WIRS increased infiltration of mast cells and macrophages into the gastric mucosa and submucosal layer, whereas the inflammatory infiltration was markedly inhibited by CJ-20001 administration. An in vitro cell invasion assay showed that treatment with CJ-20001 decreased the migration of macrophages. CJ-20001 suppressed the expression of proinflammatory cytokines, IL-18, IP-10 and GRO/KC, in lipopolysaccharides (LPS)-treated macrophages. CONCLUSIONS: These data suggest that novel phytopharmaceutical agent CJ-20001 has the potent anti-inflammatory properties through inhibition of inflammatory infiltration in psycho-physiological stress-induced gastric injury.

The loss of phenol sulfotransferase 1 in hepatocellular carcinogenesis.

Biomarkers for the detection of early hepatocellular carcinoma (HCC) are urgently needed. To identify biomarkers of HCC, we performed a comparative proteomics analysis, based on 2-DE of HCC tissues and surrounding non-tumor tissues. Six xenobiotic enzymes were significantly down-regulated in the HCC tissue. Among these, phenol sulfotransferase (SULT1A1) was confirmed by Western blot analysis in 105 HCC patients. SULT1A1 showed a significant decrease in 98.1% of the HCC tissues, with 88.6% sensitivity and 66.7% specificity for the detection of HCC. Immunohistochemistry for SULT1A1 was performed and compared with glypican-3, which is a well-known marker of HCC. The results showed down-regulation of SULT1A1 and up-regulation of glypican-3 in 52.6 and 71.9% of the HCCs, and the use of both markers improved the sensitivity up to 78.9%. Moreover, SULT1A1 was useful in differentiating early HCC from benign dysplastic nodules. Clinically, the down-regulation of SULT1A1 was closely associated with an advanced International Union Against Cancer stage and high levels of serum alpha-fetoprotein. In conclusion, the results of this study demonstrate that the loss of SULT1A1 appears to be a characteristic molecular signature of HCC. SULT1A1 might be a useful biomarker for the detection of early HCC and help predict the clinical outcome of patients with HCC.

Retraction: Blockage of intracellular proton extrusion with proton pump inhibitor induces apoptosis in gastric cancer.

The following article from Cancer Science, 'Blockage of intracellular proton extrusion with proton pump inhibitor induces apoptosis in gastric cancer' by Marie Yeo, Dong-Kyu Kim, Hee Jin Park, Sung Won Cho, Jae Youn Cheong and Kwang Jae Lee (doi: 10.1111/j.1349-7006.2007.00642.x), published online on 23 October 2007 on Blackwell Synergy (http://www.blackwell-synergy.com), has been retracted by agreement between the authors, the journal Editor in Chief, Takashi Tsuruo, and Blackwell Publishing. All authors wish to retract this paper because of the use of RGM-1 without the prior permission of the original establisher.

Blockage of intracellular proton extrusion with proton extrusions with proton pump inhibitor induces apoptosis in gastric cancer.

Proton pump inhibitors have been used for treatment of acid-related gastroesophageal diseases and they act as potent inhibitors of gastric acid pump, H(+)/K(+)-ATPase. Since cancer cells in vivo often exist in an ischemic microenvironment with a lower pH, maintenance of cellular pH is important for cell survival. In this study, we evaluated whether blocking of proton extrusion with proton pump inhibitors could inhibit the viability of gastric cancer cells. Treatment of human gastric cancer cells with proton pump inhibitors significantly attenuated cell viability in a time- and dose-dependent manner. The pro-apoptotic activity of proton pump inhibitors was mediated by release of cytochrome c and caspases activation. Gastric cancer cells showed the resistance to acidity of culture medium, which was related with a remarkable increase of extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the acidic condition. This ERK1/2 phosphorylation was completely inhibited by pretreatment with proton pump inhibitors, suggesting that its inhibitory action on phosphorylation of ERK1/2 might contribute to the induction of apoptosis in gastric cancer cells. In conclusion, our results suggest novel therapeutic approaches for gastric cancer with proton pump inhibitors.

Pepsin detection in the sputum/saliva for the diagnosis of gastroesophageal reflux disease in patients with clinically suspected atypical gastroesophageal reflux disease symptoms.

BACKGROUND/AIMS: Atypical manifestations of gastroesophageal reflux disease (GERD) are diverse. We aimed to determine whether pepsin detection in the sputum/saliva could be useful for diagnosing GERD in patients with clinically suspected atypical GERD symptoms. METHODS: Patients with clinically suspected atypical GERD symptoms provided sputum/saliva collected before bedtime, at the time of those symptoms, and after awakening for pepsin measurement by Western blot analysis. All subjects received 24-hour esophageal pH monitoring, and then 40 mg of esomeprazole was given twice a day for 2 weeks. RESULTS: The pepsin test was positive in 20 out of 40 patients, with pepsin detected mainly in the samples collected at the time of symptoms (45%). Samples collected from healthy volunteers (n = 8) were all negative for pepsin. 24-hour pH-metry was positive in 9 patients (23%). Based on 24-hour pH-metry data, the sensitivity and negative predictive value of the pepsin test were excellent in most of typical and atypical symptom groups, whereas its specificity and positive predictive value were relatively low, particularly in atypical symptom groups. CONCLUSIONS: Pepsin measurement in the sputum/saliva collected at the time of symptoms provides a sensitive, non-invasive method for diagnosing GERD in patients with clinically suspected atypical GERD symptoms.

Identification of NUCKS1 as a putative oncogene and immunodiagnostic marker of hepatocellular carcinoma.

Although the molecular mechanisms underpinning hepatocellular carcinoma (HCC) are unknown, gene copy number and associated mRNA expression changes are frequently reported. Comparative genomic hybridization arrays spotted with 4041 bacterial artificial chromosome clones were used to assess copy number changes in 45 HCC tissues. Seventy more HCC tissues were used to validate candidate genes by using western blots and immunohistochemistry. A total of 259 clones were associated with copy number changes that significantly differed between normal liver and HCC samples. The chromosomal region 1q32.1 containing the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) gene was associated with tumor vascular invasion. Western blot analysis demonstrated that NUCKS1 was up-regulated in 37 of 70 (52.8%) HCC tissues compared with adjacent non-tumor tissues, and over-expressed in a vast majority of HCCs (44/52, 84.6%) as determined by immunohistochemical staining. Furthermore, immunostaining of both NUCKS1 and glypican-3 improved the diagnostic prediction of HCC. Knock-down of NUCKS1 by siRNA implied the decrease in cell viability of the Hep3B cell line and reduced tumor formation in a xenograft mouse model. NUCKS1 was identified as a potential oncogene at chromosomal 1q32.1 in patients with HCC, and it might be a valuable immunodiagnostic marker for HCC.

Synergism of Helicobacter pylori infection and stress on the augmentation of gastric mucosal damage and its prevention with alpha-tocopherol.

Despite evidence that Helicobacter pylori (H. pylori) infection is closely associated with stress in gastric ulcer patients, the underlying mechanism why ulcer recurrence after stress is augmented especially in patients with H. pylori remains unknown. In this study, we found that oxidative stress played a critical role in the augmented mucosal damage provoked by water immersion restraint stress (WIRS) in H. pylori infection and that an antioxidant, alpha-tocopherol, could ameliorate the aggravation of stress-associated gastric mucosal damage. Two hundred forty SD rats were divided into two groups according to H. pylori inoculation, and after 24 weeks of H. pylori infection, the water immersion restraint stress was imposed for 30, 120, or 480 min, respectively. To evaluate the therapeutic effects of an antioxidant, alpha-tocopherol was administrated 40 mg/kg daily prior to imposing WIRS. Remarkably increased hemorrhagic lesions and bleeding indexes were noted in the H. pylori-infected group with statistical significance (P < 0.05) compared to the noninfected group at the same duration of WIRS. Significantly higher oxidative stress documented by iNOS, lipid peroxides, and GSH level was detected in gastric homogenates of the H. pylori-infected group. Proteomic analysis using 2-dimensional electrophoresis showed a decrease of HSP27 and other chaperone proteins. alpha-Tocopherol pretreatment significantly prevented the gastric mucosal damage, caused by WIRS in the presence of H. pylori. alpha-Tocopherol induced HSP27 expression, which was well correlated with downregulation of iNOS mRNA. Conclusively, the presence of H. pylori caused significant deterioration of stress-induced gastric mucosal lesions through increased oxidative stress and thus antioxidant treatment such as alpha-tocopherol protected the gastric injuries.

Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells.

PURPOSE: To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusion is critical for cancer cell survival. Gastric H+/K(+)-ATPase exchanges luminal K+ for cytoplasmic H+ and is the enzyme primarily responsible for gastric acidification. On the basis of the fact that blocking the clearance of acidic metabolites are known to induce the cell death, we hypothesized that pantoprazole (PPZ), one of gastric H+/K(+)-ATPase inhibitors used frequently to treat acid-related diseases, could inhibit growth of tumor cells. EXPERIMENTAL DESIGN: Genomic DNA fragmentation, terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay, and annexin V staining were performed to detect PPZ-induced apoptosis. Mitogen-activated protein kinase activation and heat shock proteins expression were determined by immunoblot with specific antibodies. The antitumor effect of PPZ was evaluated in vivo by a xenograft model of nude mice. RESULTS: After PPZ treatment, apoptotic cell death was seen selectively in cancer cells and was accompanied with extracellular signal-regulated kinase deactivation. By contrast, normal gastric mucosal cells showed the resistance to PPZ-induced apoptosis through the overexpression of antiapoptotic regulators including HSP70 and HSP27. In a xenograft model of nude mice, administration of PPZ significantly inhibited tumorigenesis and induced large-scale apoptosis of tumor cells. CONCLUSIONS: PPZ selectively induced in vivo and in vitro apoptotic cell death in gastric cancer, suggesting that proton pump inhibitors could be used for selective anticancer effects.

The selective cyclooxygenase-2 inhibitor nimesulide prevents Helicobacter pylori-associated gastric cancer development in a mouse model.

PURPOSE: Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice. EXPERIMENTAL DESIGN: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide. RESULTS: Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone. CONCLUSIONS: Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.

[Perspective of Helicobacter pylori research: molecular pathogenesis of Helicobacter pylori virulence factors].

Helicobacter pylori (H. pylori) causes chronic gastritis in human stomach, a minority of which progress to peptic ulcer disease, atrophic gastritis, or gastric malignancies. Clinical outcomes of H. pylori infection has been shown to depend on the variability of H. pylori virulence factors, host susceptibility, environmental factors and their interactions. This review provides an update on the molecular pathogenesis of H. pylori infection, focused on H. pylori virulence factors, H. pylori-gastric epithelium interactions, and modulation of host cell signaling. Understanding of H. pylori molecular pathogenic mechanism will facilitate the development of novel treatment strategies for eradication of the bacterium and prevention of H. pylori-induced gastropathy.

[Proteomic approach in gastrointestinal and liver research].

In the post-genomic era, the focus of research is now moving to functional genomics employing the information on predicted gene products provided by genome sequencing. Proteomics, the global analysis of structures, functions, and interactions of whole cellular proteins, draws the special attention as a tool for documenting the disease pathogenesis or progression. The high-throughput technology has become feasible by considerable improvement of two dimensional electrophoresis and mass fingerprinting. Thus proteome techniques can be used as tools to study the disease processes, develop new biomakers for diagnosis and early detection of diseases, and accelerate drug development. In this review, we discuss the background and techniques of proteomics, and potential applications to the research of gastrointestinal diseases.

Loss of SM22 is a characteristic signature of colon carcinogenesis and its restoration suppresses colon tumorigenicity in vivo and in vitro.

BACKGROUND: We previously found the down-expression of SM22 in an experimental animal model of colorectal cancer by performing a proteomic analysis. In this study, we addressed the expression and molecular mechanisms of SM22 in human colorectal cancer. METHODS: To evaluate the expression of SM22 in colon cancers, Western blot and immunohistochemistry were performed in 13 normal, 14 adenomas, and 44 adenocarcinomas. To address the role of SM22 in colon carcinogenesis, SM22 was restored in the colon cancer cells by the transfection with the pIRES2 vector containing full-length SM22 cDNA and tested for tumorigenicity in vivo and in vitro. RESULTS: SM22 was found to be significantly down-regulated in adenocarcinoma (58%) compared with adenoma (21.4%) and normal (15.3%). The loss of SM22 correlated with poor differentiation of tumor (P = 0.009) and lymph node metastasis (P = 0.029). Restoration of SM22 expression inhibited cell migration, colony-forming ability of cancer cells, and induced retardation of in vivo tumor growth in a xenograft model. CONCLUSIONS: Loss of SM22 is a molecular signature of colon cancer and is closely associated with progression, differentiation, and metastasis of colon cancer. The restoration of SM22 leads to an inhibition of colon carcinogenesis in vivo and in vitro, suggesting that SM22 might potentially function as a novel tumor suppressor.

Ginseng, the root of Panax ginseng C.A. Meyer, protects ethanol-induced gastric damages in rat through the induction of cytoprotective heat-shock protein 27.

Ginseng, the root of Panax ginseng C.A. Meyer, has been reported to exert preventive effects on gastropathy via anti-oxidative and anti-inflammatory actions. In this study, we investigated the protective effects of ginseng against ethanol-induced gastric damages in rat. To examine the preventive effect of ginseng, rats received two different ginseng extracts, A and B, 1 h prior to the administration of ethanol. Pretreatment of rats with ginseng extract A and B attenuated the ethanol-induced gastric lesions by 111 +/- 48 and 142 +/- 47 mm(2) compared to control group (164 +/- 54 mm(2)). Significant induction of cytoprotective heat-shock proteins HSP27 and HSP70 was found in the ginseng-administrated rats, suggesting that the restoration of the proteins might contribute to prevention of ethanol-induced gastric injuries. It is, therefore, suggested that ginseng has a protective effect against ethanol-induced gastric damages by induction of heat-shock proteins 70 and 27.

Inhibitory activities and attenuated expressions of 5-LOX with red ginseng in Helicobacter pylori-infected gastric epithelial cells.

Our recent studies documented that red ginseng extract (RGE, isolates from steamed and dried Panax ginseng, C.A. Meyer) can inhibit Helicobacter pylori-induced mitogen-activated protein kinase (MAPK) signaling with repressing either nuclear factor (NF)-kappaB-DNA binding activity or releases of IL-8 and COX-2 in gastric epithelial cells (Dig Dis Sci 50:1218-1227, 2005). We extended the experiment to prove whether RGE influences 5-lipoxygenase (5-LOX) pathway, thereby suppressing the biosynthesis of 5(S)-HETE. The 5-LOX enzyme activities were measured by thin layer chromatography using (14)C-labeled arachidonic acid (AA) and quantified by reverse phase-high performance liquid chromatography in human gastric adenocarcinoma (AGS) cells cocultured with H pylori (ATCC 43504 strain) with or without pretreatment of RGE. Western blotting analyses for MAPK signaling and 5-LOX, reverse transcriptase polymerase chain reaction for interleukin-8, and electrophoretic mobility shift assay for NF-kappaB-DNA binding were done, respectively. H pylori infection increased exclusively 5-LOX enzyme activity and RGE inhibited H pylori-stimulated 5-LOX activity, resulting in suppression of 5(S)-HETE generations from AA. RGE inactivated c-jun phosphorylation and repressed redox-sensitive transcriptional activation, led to reduced expression of IL-8 and 5-LOX mRNA in gastric mucosal cells, of which action was very similar to known LOX inhibitor, 200 mumol of geraniin. RGE could be phytoceutical against H pylori infection-associated gastric inflammation through its LOX-inhibiting actions, inhibitory 5-LOX enzyme activity, and attenuating its expression.

Genetic polymorphism of interferon-gamma, interferon-gamma receptor, and interferon regulatory factor-1 genes in patients with hepatitis B virus infection.

The natural history of hepatitis B virus (HBV) infection is probably related to host immune factors. Interferon-gamma (IFN-gamma) plays significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of IFN-gamma, IFN-gamma receptor (IFNGR)-1 and 2, and interferon regulatory factor (IRF)-1 genes. Between March 2002 and December 2002, 614 Korean patients were enrolled in two different groups: an HBV clearance group (n = 201), who were hepatitis B surface antigen (HBsAg) negative with antibodies to HBsAg and hepatitis B core antigen, and an HBV persistence group (n = 413), who were repeatedly HBsAg positive. We assessed polymorphisms in the IFN-gamma gene at position +874, in the IFNGR-1 gene at positions -56 and +95, in the IFNGR-2 gene at the second position of codon 64 (Gln64Arg), and in the IRF-1 gene promoter (-410, -388), and the genotype distributions of the HBV clearance and persistence groups were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with the IFN-gamma, IFNGR-1 and 2, and IRF-1 gene polymorphisms under the codominant, dominant, and recessive models.

Loss of transgelin in repeated bouts of ulcerative colitis-induced colon carcinogenesis.

Though ulcerative colitis (UC)-associated colon cancer develops from dysplastic lesions caused by chronic inflammation, the specific mechanistic link between chronic inflammation and carcinogenesis in colon has not been integrated into molecular understanding. We therefore established an experimental animal model for colitic cancer, and used proteomic analysis, based on 2-DE and MALDI-TOF MS, to identify proteins involved in colitic cancer. In our model, 6-week-old C57BL/6J mice were exposed to 15 cycles of dextran sodium sulfate (DSS), with each cycle consisting of 0.7% DSS for 1 week followed by distilled water for 10 days. Colorectal tumors developed in 22 of 24 mice (91.6%), with a tumor multiplicity of 1.727 per tumor-bearing mouse. Comparative 2-DE analysis showed that 38 protein spots were differentially expressed in colon tumors and normal colon. We identified 27 of these proteins, including GRP94, HSC70, enolase, prohibitin, and transgelin. The reduction of transgelin expression in mouse colon tumors was confirmed by Western blotting and immunohistochemistry. We also found that transgelin expression was significantly reduced in human colon tumors compared with adjacent nontumorous tissues. In conclusion, these results suggest that loss of transgelin could be a candidate for biomarker of repeated colitis-associated colon cancer.

Rescue of Helicobacter pylori-induced cytotoxicity by red ginseng.

Helicobacter pylori has been known to provoke gastric inflammation, ulceration, and DNA damage, based on which WHO defined H. pylori as a class I carcinogen. Although ginseng, the root of Panax ginseng C.A. Meyer, has been reported to possess antiadhesion or antimicrobial activity against H. pylori, in this study, we examined the protective effect of red ginseng extracts (RGE) against H. pylori-induced cytotoxicity and DNA damage. RGE significantly attenuated both H. pylori-induced DNA damage assessed by comet assay and apoptosis measured by DNA fragmentation. Inactivation of ERK1/2 signaling and attenuation of caspase-3 activation and PARP cleavage were revealed with RGE against H. pylori infection. RGE decreased H. pylori-stimulated IL-8 gene expression, which resulted from the transcriptional regression of NF-kappaB. In conclusion, RGE showed significant gastroprotective effects against H. pylori-associated gastric mucosal cell damage, suggesting that red ginseng could be used as a medicinal phytonutrient against H. pylori infection.

Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling.

OBJECTIVES: Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury, which is a result of the imbalance between synthesis and degradation of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta) plays a central role in biosynthesis and turnover of the ECM. In this study, we evaluated the role of TGF-beta signaling in pancreatic fibrosis induced by repetitive acute pancreatic injuries with mice of dominant-negative mutant of TGF-beta receptor II selectively in pancreas. METHODS: TGF-beta signaling was inactivated by overexpressing a dominant-negative mutant form of TGF-beta type II receptor (pS2-dnR II) only in the pancreas under control of pS2/TFF1 promoter. Pancreatic fibrosis was induced by repeated intraperitoneal injections of 40 microg/kg cerulein for 5 or 10 weeks. RESULTS: Repeated administration of cerulein induced significant pancreatic fibrosis, but of which fibrosis was remarkably attenuated in pS2-dnR II mice compared with wild-type littermates (P < 0.01). The ameliorated fibrosis was due to the reduction of synthesis of ECM proteins such as collagen type I, fibronectin, and ICAM-1. DNA binding activity of transcriptional factors including nuclear factor (NF)-kappaB and AP-1, responsible for the induction of immediate early genes of inflammatory responses, were significantly decreased in pS2-dnR II mice. While TGF-beta1 treatment in isolated pancreatic stellate cells (PSCs) stimulated the expression of alpha-SMA and fibronectin, PSCs transfected with TGF-beta dnRII showed attenuation of the ECM components. CONCLUSION: Conditional loss of TGF-beta signaling selectively in the pancreas led to a failure in fibrogenic responses of repeated injections of cerulein, signifying that the modulation of TGF-beta signaling could be the therapeutic target for the prevention of chronic fibrosing pancreatitis.