Chronic pancreatitis as an inflammatory process characterized by morphological changes, pancreatic dysfunction, and pain. During pancreatic injury and repair the Notch signaling pathway is reinstated. The current study analyzed this pathway in chronic pancreatitis and characterized its influence on fibrogenesis. Real-time quantitative PCR and immunohistochemistry were used for expression studies. Notch activation was determined by a specific luciferase-HES-1-reporter gene constructs. Cells were stimulated with alcohol, glucose, bile acids, and steroids. Notch-2, -3, and -4 mRNA, were overexpressed in chronic pancreatitis specimens. The ligands Jagged-1, -2, and Delta-1 were highly overexpressed. Jagged-1 and Notch receptors were observed in nerves, regenerating exocrine cells, and endocrine cells. Delta staining was present in ductal but not in acinus cells and not in nerves. Activation of Notch signaling was detectable upon cell stimulation with glucose, steroids, and bile acids. High glucose levels were further associated with increased collagen-I production. The Notch pathway is reactivated during chronic pancreatitis. Among the stimuli activating the Notch pathway are steroids, high glucose levels, and bile acids. These findings suggest a possible role of the Notch pathway during pancreatic regeneration since Jagged-1 inhibits inducible collagen-1 production, suggesting a new mechanism of tissue repair in this disease.
"These findings are consistent with earlier studies that had shown that Notch signaling could be activated by TLR stimulation  in macrophages. We also determined that exposure of bile acids to TLR4-deficient IEC-6 cells as well as to crypts from TLR4-deficient mice reversed the goblet cell phenotype, a finding that is particularly relevant given that bile acids can activate Notch in the gastrointestinal epithelium [78, 79], and that increased bile acids were associated with reduced goblet cells in newborn rats and increased NEC severity . These findings together indicate that TLR4 can regulate goblet cell differentiation and suggest the possibility that bile acids may serve as intermediates in the regulation of Notch. "
[Show abstract][Hide abstract] ABSTRACT: Necrotizing enterocolitis (NEC) is a challenging disease to treat, and caring for patients afflicted by it remains both frustrating and difficult. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and appear to take the caregiver by surprise. In seeking to understand the molecular and cellular processes that lead to NEC development, we have identified a critical role for the receptor for bacterial lipopolysaccharide (LPS) toll like receptor 4 (TLR4) in the pathogenesis of NEC, as its activation within the intestinal epithelium of the premature infant leads to mucosal injury and reduced epithelial repair. The expression and function of TLR4 were found to be particularly elevated within the intestinal mucosa of the premature as compared with the full-term infant, predisposing to NEC development. Importantly, factors within both the enterocyte itself, such as heat shock protein 70 (Hsp70), and in the extracellular environment, such as amniotic fluid, can curtail the extent of TLR4 signaling and reduce the propensity for NEC development. This review will highlight the critical TLR4-mediated steps that lead to NEC development, with a focus on the proinflammatory responses of TLR4 signaling that have such devastating consequences in the premature host.
"In particular, over-expression of Notch-1 has been shown to facilitate lung fibroblast transition into myofibroblasts . On the other hand, it has been reported that Notch-1 can inhibit the conversion of hepatic stellate cells and 10T1/2 fibroblasts into myofibroblasts , that Jagged-1 over-expressing fibroblasts are refractory to the profibrotic effects of TGF-β1- , and that inhibition of Notch signaling by a highly active γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) promotes cardiac fibroblast-myofibroblast transition . Along this line of evidence, it has been recently demonstrated that TGF-β1 limits Notch-1 activation in mouse fibroblasts by inducing the expression of ADAM12 , , a member of metalloprotease-disintegrin family, which is capable of cleaving Notch ectodomain after ligand-receptor interaction , . "
[Show abstract][Hide abstract] ABSTRACT: The hormone relaxin (RLX) is produced by the heart and has beneficial actions on the cardiovascular system. We previously demonstrated that RLX stimulates mouse neonatal cardiomyocyte growth, suggesting its involvement in endogenous mechanisms of myocardial histogenesis and regeneration. In the present study, we extended the experimentation by evaluating the effects of RLX on primary cultures of neonatal cardiac stromal cells. RLX inhibited TGF-β1-induced fibroblast-myofibroblast transition, as judged by its ability to down-regulate α-smooth muscle actin and type I collagen expression. We also found that the hormone up-regulated metalloprotease (MMP)-2 and MMP-9 expression and downregulated the tissue inhibitor of metalloproteinases (TIMP)-2 in TGF-β1-stimulated cells. Interestingly, the effects of RLX on cardiac fibroblasts involved the activation of Notch-1 pathway. Indeed, Notch-1 expression was significantly decreased in TGF-β1-stimulatedfibroblasts as compared to the unstimulated controls; this reduction was prevented by the addition of RLX to TGF-β1-stimulated cells. Moreover, pharmacological inhibition of endogenous Notch-1 signaling by N-3,5-difluorophenyl acetyl-L-alanyl-2-phenylglycine-1,1-dimethylethyl ester (DAPT), a γ-secretase specific inhibitor, as well as the silencing of Notch-1 ligand, Jagged-1, potentiated TGF-β1-induced myofibroblast differentiation and abrogated the inhibitory effects of RLX. Interestingly, RLX and Notch-1 exerted their inhibitory effects by interfering with TGF-β1 signaling, since the addition of RLX to TGF-β1-stimulated cells caused a significant decrease in Smad3 phosphorylation, a typical downstream event of TGF-β1 receptor activation, while the treatment with a prevented this effect. These data suggest that Notch signaling can down-regulate TGF-β1/Smad3-induced fibroblast-myofibroblast transition and that RLX could exert its well known anti-fibrotic action through the up-regulation of this pathway. In conclusion, the results of the present study beside supporting the role of RLX in the field of cardiac fibrosis, provide novel experimental evidence on the molecular mechanisms underlying its effects.
PLoS ONE 05/2013; 8(5):e63896. DOI:10.1371/journal.pone.0063896 · 3.23 Impact Factor
"In addition to controlling cell fate, several studies indicate that Notch influences tissue formation and morphogenesis during development by regulating the balance between a progenitor or precursor pool and differentiating progeny (Dallas et al., 2005; Fre et al., 2005; Mammucari et al., 2005; van Es et al., 2005). In principal, a similar process could contribute to tissue regeneration (Kohler et al., 2004; Raya et al., 2004; Su et al., 2006; Nakamura and Chiba, 2007; Poss, 2007). Because the signals that control fetal and early neonatal cardiomyocyte replication and the subsequent postnatal withdrawal from cell cycle are unclear, we explored whether Notch reactivation might trigger and sustain the cell cycle of neonatal dividing and quiescent cardiomyocytes. "
[Show abstract][Hide abstract] ABSTRACT: The inability of heart muscle to regenerate by replication of existing cardiomyocytes has engendered considerable interest in identifying developmental or other stimuli capable of sustaining the proliferative capacity of immature cardiomyocytes or stimulating division of postmitotic cardiomyocytes. Here, we demonstrate that reactivation of Notch signaling causes embryonic stem cell-derived and neonatal ventricular cardiomyocytes to enter the cell cycle. The proliferative response of neonatal ventricular cardiomyocytes declines as they mature, such that late activation of Notch triggers the DNA damage checkpoint and G2/M interphase arrest. Notch induces recombination signal-binding protein 1 for Jkappa (RBP-Jkappa)-dependent expression of cyclin D1 but, unlike other inducers, also shifts its subcellular distribution from the cytosol to the nucleus. Nuclear localization of cyclin D1 is independent of RBP-Jkappa. Thus, the influence of Notch on nucleocytoplasmic localization of cyclin D1 is an unanticipated property of the Notch intracellular domain that is likely to regulate the cell cycle in multiple contexts, including tumorigenesis as well as cardiogenesis.
The Journal of Cell Biology 11/2008; 183(1):129-41. DOI:10.1083/jcb.200806104 · 9.83 Impact Factor
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