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Ebert, Matthias P.; Kasper, Haino Uwe; Hernberg, Sara; Frieß, Helmut; Büchler, Markus W.; Roessner, Albert; Korc, Murray; Malfertheiner, Peter

doi:10.1023/a:1018867209170

Cited by 40 publications

(4 citation statements)

References 25 publications

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“…Currently, numerous in vivo and in vitro studies have provided strong evidence for a pivotal role for pancreatic stellate cells (PSCs) in fibrogenesis associated with acute and chronic pancreatitis [8]–[11]. In addition to the elimination of the conditions inducing acinar cell injury (e.g., alcohol) and the reduction of the inflammatory response of the host, therapeutic targeting of PSCs may represent a promising new strategy for reducing fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

L-Cysteine Administration Attenuates Pancreatic Fibrosis Induced by TNBS in Rats by Inhibiting the Activation of Pancreatic Stellate Cell

Yang

Shen

et al. 2012

PLoS ONE

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Background and AimsRecent studies have shown that activated pancreatic stellate cells (PSCs) play a major role in pancreatic fibrogenesis. We aimed to study the effect of L-cysteine administration on fibrosis in chronic pancreatitis (CP) induced by trinitrobenzene sulfonic acid (TNBS) in rats and on the function of cultured PSCs.MethodsCP was induced by TNBS infusion into rat pancreatic ducts. L-cysteine was administrated for the duration of the experiment. Histological analysis and the contents of hydroxyproline were used to evaluate pancreatic damage and fibrosis. Immunohistochemical analysis of α-SMA in the pancreas was performed to detect the activation of PSCs in vivo. The collagen deposition related proteins and cytokines were determined by western blot analysis. DNA synthesis of cultured PSCs was evaluated by BrdU incorporation. We also evaluated the effect of L-cysteine on the cell cycle and cell activation by flow cytometry and immunocytochemistry. The expression of PDGFRβ, TGFβRII, collagen 1α1 and α-SMA of PSCs treated with different concentrations of L-cysteine was determined by western blot. Parameters of oxidant stress were evaluated in vitro and in vivo. Nrf2, NQO1, HO-1, IL-1β expression were evaluated in pancreas tissues by qRT-PCR.ResultsThe inhibition of pancreatic fibrosis by L-cysteine was confirmed by histological observation and hydroxyproline assay. α-SMA, TIMP1, IL-1β and TGF-β1 production decreased compared with the untreated group along with an increase in MMP2 production. L-cysteine suppressed the proliferation and extracellular matrix production of PSCs through down-regulating of PDGFRβ and TGFβRII. Concentrations of MDA+4-HNE were decreased by L-cysteine administration along with an increase in GSH levels both in tissues and cells. In addition, L-cysteine increased the mRNA expression of Nrf2, NQO1 and HO-1 and reduced the expression of IL-1β in L-cysteine treated group when compared with control group.ConclusionL-cysteine treatment attenuated pancreatic fibrosis in chronic pancreatitis in rats.

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Section: Introductionmentioning

confidence: 99%

L-Cysteine Administration Attenuates Pancreatic Fibrosis Induced by TNBS in Rats by Inhibiting the Activation of Pancreatic Stellate Cell

Yang

Shen

et al. 2012

PLoS ONE

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“…Experimental and clinical investigations of HGF have revealed that aberrant HGF/Met signaling contribute to the tumorigenesis of various neoplasms such as sarcomas (Rong et al, 1993;Maier et al, 1996), carcinomas (Ebert et al, 1994), gliomas (Rosen et al, 1996) and leukemias (Hino et al, 1996). For example, coexpression of human Met and HGF caused normal cell lines such as NIH3T3 ®broblasts and C127 cells to become tumorigenic in nude mice and acquire an invasive and metastatic phenotype (Tsarfaty et al, 1994;Rong et al, 1994;Je ers et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

et al. 1997

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In this study, we have localized an enhancer element in the 5'-¯anking region of the HGF gene promoter and have identi®ed its functional transcriptional factors. Through transient transfection of NIH3T3 ®broblast cells and gel mobility shift assays, the functional binding site was localized to a short region (7318 to 7303 bp from the transcription start site) which has a CTCCC sequence. This motif is also conserved in the human HGF promoter and acts as a binding site for the Sp family of transcription factors. In the presence of NIH3T3 nuclear protein extracts, this enhancer region formed speci®c DNA-protein complexes which were totally abrogated by excess amounts of consensus Sp1 oligonucleotide. In gel mobility supershift assays, antiSp1 and anti-Sp3 antibodies speci®cally recognized these complexes as was evident by their slower migration. Sitespeci®c mutation of this binding motif resulted in total loss of Sp1 and Sp3 binding and a concomitant loss of enhancer function within the context of the HGF promoter. Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. DNaseI hypersensitive analysis of freshly isolated nuclei from NIH3T3 cells revealed that ®ve hypersensitive sites (HSS) are present within the 2 kb region immediately upstream of the HGF promoter. One of these sites was mapped to position 70.3 kb from the transcription start site. These data show that both Sp1 and Sp3 transcription factors upregulate HGF promoter activity by binding to the Sp1 binding site at position 7318 to 7303 bp in the HGF gene promoter.

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“…PDGF-β represents the most potent mitogen for PSCs, both PDGF-β and the PDGF-β receptor have been shown to be over expressed in human CP 18 . However, we are unaware of any studies that investigated the role of the PDGF-β variants in CP.…”

Section: Discussionmentioning

confidence: 99%

Are Genetic Variants in the Platelet-Derived Growth Factor β Gene Associated With Chronic Pancreatitis?

Muddana¹,

Park²,

Lamb³

et al. 2010

Pancreas

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Objectives Platelet derived growth factor β (PDGF-β) is a major signal in proliferation and matrix synthesis through activated PSCs, leading to fibrosis of the pancreas. Recurrent acute pancreatitis (RAP) appears to predispose to chronic pancreatitis (CP) in some patients but not others. We tested the hypothesis that two known PDGF-β polymorphisms are associated with progression from RAP to CP. We also tested the hypothesis that PDGF-β polymorphisms in combination with environmental risk factors such as alcohol and smoking are associated with CP. Methods 382 patients with CP (n=176) and RAP (n=206) and 251 controls were evaluated. PDGF-β polymorphisms +286 A/G (rs#1800818) seen in 5′-UTR and +1135 A/C (rs#1800817) in first intron were genotyped using single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach and confirmed by DNA sequencing. Results The genotypic frequencies for PDGF-β polymorphisms in position +286 and +1135 were found to be similar in controls and patients with RAP and CP. There was no difference in genotypic frequencies among RAP, CP and controls in subjects in the alcohol and smoking subgroups. Conclusions Known variations in the PDGF-β gene do not have a significant effect on promoting or preventing fibrogenesis in pancreatitis. Further evaluation of this important pathway is warranted.

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Cited by 40 publications

References 25 publications

L-Cysteine Administration Attenuates Pancreatic Fibrosis Induced by TNBS in Rats by Inhibiting the Activation of Pancreatic Stellate Cell

L-Cysteine Administration Attenuates Pancreatic Fibrosis Induced by TNBS in Rats by Inhibiting the Activation of Pancreatic Stellate Cell

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

Are Genetic Variants in the Platelet-Derived Growth Factor β Gene Associated With Chronic Pancreatitis?

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