Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulator

2003 ◽  
Vol 14 (1) ◽  
pp. 59-72 ◽  
Author(s):  
Baoan Ji ◽  
Xue-qing Chen ◽  
David E. Misek ◽  
Rork Kuick ◽  
Samir Hanash ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Rt Pcr ◽  
Novel Genes ◽  
In Vivo Models ◽  
Severity Of The Disease ◽  
Deficient Mice

We hypothesized that genes expressed in pancreatic acinar cells during the initiation of acute pancreatitis determine the severity of the disease. Therefore, we utilized microarrays to identify those genes commonly induced in rat pancreatic acinar cells within 1–4 h in two in vivo models, caerulein and taurocholate administration. This strategy yielded 51 known genes representing a complex array of molecules, including those that are likely to either reduce or increase the severity of the disease. Novel genes identified in the current study included ATF3, BRF1, C/EBPβ, CGRP, EGR-1, ephrinA1, villin2, ferredoxin, latexin, lipocalin, MKP-1, NGFI-B, RhoA, tissue factor (TF), and syndecan. To validate these microarray results, the role of EGR-1 was further investigated using quantitative RT-PCR, Western blotting, and immunocytochemistry. EGR-1 expression occurred within acinar cells and correlated with the development of caerulein-induced acute pancreatitis in rats. Furthermore, the levels of the inflammation-related genes MCP-1, PAI, TF, IL-6, and ICAM-1 and the extent of lung inflammation were reduced during the initiation of caerulein-induced acute pancreatitis in EGR-1-deficient mice. Thus this study identified EGR-1 and several other novel genes likely to be important in the development and severity of acute pancreatitis.

scholarly journals Insulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jason I. E. Bruce ◽  
Rosa Sánchez-Alvarez ◽  
Maria Dolors Sans ◽  
Sarah A. Sugden ◽  
Nathan Qi ◽  
...  
Keyword(s):  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Atp Depletion ◽  
Pancreatic Acinar Cells ◽  
In Vivo Models ◽  
Knock Out ◽  
Endogenous Insulin ◽  
Knock Out Mice ◽  
Atp Supply

AbstractAcute pancreatitis (AP) is serious inflammatory disease of the pancreas. Accumulating evidence links diabetes with severity of AP, suggesting that endogenous insulin may be protective. We investigated this putative protective effect of insulin during cellular and in vivo models of AP in diabetic mice (Ins2Akita) and Pancreatic Acinar cell-specific Conditional Insulin Receptor Knock Out mice (PACIRKO). Caerulein and palmitoleic acid (POA)/ethanol-induced pancreatitis was more severe in both Ins2Akita and PACIRKO vs control mice, suggesting that endogenous insulin directly protects acinar cells in vivo. In isolated pancreatic acinar cells, insulin induced Akt-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) which upregulated glycolysis thereby preventing POA-induced ATP depletion, inhibition of the ATP-dependent plasma membrane Ca2+ ATPase (PMCA) and cytotoxic Ca2+ overload. These data provide the first mechanistic link between diabetes and severity of AP and suggest that phosphorylation of PFKFB2 may represent a potential therapeutic strategy for treatment of AP.

scholarly journals The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells

2015 ◽  
Vol 465 (3) ◽  
pp. 405-412 ◽  
Author(s):  
Svetlana Voronina ◽  
David Collier ◽  
Michael Chvanov ◽  
Ben Middlehurst ◽  
Alison J. Beckett ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Vacuole Formation

Endocytic vacuoles are ‘initiating’ organelles in the development of acute pancreatitis. In the present study, we identified the important roles of store-operated Ca2+ influx and Ca2+-dependent proteases (calpains) in the formation of these organelles.

scholarly journals Comprehensive analysis of microRNA signature of mouse pancreatic acini: overexpression of miR-21-3p in acute pancreatitis

2016 ◽  
Vol 311 (5) ◽  
pp. G974-G980 ◽  
Author(s):  
Ajay Kumar Dixit ◽  
Anne E. Sarver ◽  
Zuobiao Yuan ◽  
John George ◽  
Usman Barlass ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mouse Models ◽  
Expression Profile ◽  
Mirna Expression ◽  
Acinar Cells ◽  
Mirna Expression Profile ◽  
Comprehensive Analysis ◽  
Pancreatic Acinar Cells ◽  
Pancreatic Acini ◽  
Severity Of The Disease

In the current study, we have characterized the global miRNA expression profile in mouse pancreatic acinar cells and during acute pancreatitis using next-generation RNA sequencing. We identified 324 known and six novel miRNAs that are expressed in mouse pancreatic acinar cells. In the basal state, miR-148a-3p, miR-375-3p, miR-217-5p, and miR-200a-3p were among the most abundantly expressed, whereas miR-24-5p and miR-421-3p were the least abundant. Treatment of acinar cells with caerulein (100 nM) and taurolithocholic acid 3-sulfate [TLC-S (250 μM)] induced numerous changes in miRNA expression profile. In particular, we found significant overexpression of miR-21-3p in acini treated with caerulein and TLC-S. We further looked at the expression of miR-21-3p in caerulein, l-arginine, and caerulein + LPS-induced acute pancreatitis mouse models and found 12-, 21-, and 50-fold increased expression in the pancreas, respectively. In summary, this is the first comprehensive analysis of global miRNA expression profile of mouse pancreatic acinar cells in normal and disease conditions. Our analysis shows that miR-21-3p expression level correlates with the severity of the disease.

P–664 Bone morphogenetic protein–7 (BMP–7) reduces E2 and P4 production of human luteinized granulosa cells by down-regulating the expression of the steroidogenic enzymes StAR and 3B-HSD

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
C S Yildiz ◽  
O Oktem
Keyword(s):  
Granulosa Cells ◽  
Activin A ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Steroidogenic Enzymes ◽  
In Vivo Models ◽  
Viability Assay

Abstract Study question What is the biological role of BMP–7 on the granulosa cells after luteinization? Summary answer BMP–7 down regulates the steroidogenic enzymes and reduces E2 and P4 output of luteinized granulosa cells. What is known already BMP–7 is a member of TGF-B super family that is mainly produced by theca cells in the ovary. It promotes the transition of primordials into primary follicles, and the growth and preantral and antral follicles, and inhibits progesterone (P4) production during FSH-induced growth phase of Graafian follicles (luteinization inhibitor). However, limited data is available regarding the role of this hormone on the molecular luteal characteristics of granulosa cells after ovulation and luteinization processes. We therefore aimed to address this issue in the current study. Study design, size, duration A basic science study on the corpus luteum biology Participants/materials, setting, methods Human luteal granulosa cells were obtained from 10 normo-responder IVF patients undergoing ovarian stimulation with rec-FSH and GnRH antagonist protocol and cultured with recombinant forms of BMP–7, hCG and activin-A for 24h. The presence of cognate receptors for these hormones were validated using RT-PCR. The expression of the steroidogenic enzymes were analyzed with quantitative immunoblotting, real-time RT-PCR and confocal microscopy. E2 and P4 production of the cells were measured using ECLIA method. Main results and the role of chance BMP–7 significantly down-regulated the expression of StAR and 3b-HSD in immunoblotting and confocal images and caused a substantial decrease in P4 production in the luteal GCs in a dose dependent manner. It did not cause any notable change in aromatase expression, however E2 output declined in parallel with P4 due to the reduced expression of StAR, which is the rate limiting enzyme in steroidogenesis. hCG significantly up-regulated StAR and 3b-HSD expression and enhanced P4 output whereas activin-A did the opposite effect. Viability assay with Yo-PRO–1 uptake assay did not reveal any significant differences in the viability of the cells before and after treatment with these hormones. Limitations, reasons for caution In-vitro findings requires validation using in-vivo models. Wider implications of the findings: Reversal of luteinization and down-regulation of steroidogenesis with BMP–7 and other hormones with similar actions warrant further investigation to test their in-vivo effects in order to develop new strategies against ovarian hyperstimulation syndrome (OHSS). Trial registration number Not applicable

scholarly journals MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

2022 ◽  
Vol 9 ◽  
Author(s):  
Yifan Ren ◽  
Wuming Liu ◽  
Jia Zhang ◽  
Jianbin Bi ◽  
Meng Fan ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Milk Fat ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Cellular Homeostasis ◽  
Pancreatic Exocrine

Excessive endoplasmic reticulum (ER) stress contributes significantly to the pathogenesis of exocrine acinar damage in acute pancreatitis. Our previous study found that milk fat globule EGF factor 8 (MFG-E8), a lipophilic glycoprotein, alleviates acinar cell damage during AP via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining cellular homeostasis. However, MFG-E8’s role in ER stress in pancreatic exocrine acinar cells has not been evaluated. To study this, thapsigargin, brefeldin A, tunicamycin and cerulein + LPS were used to induce ER stress in rat pancreatic acinar cells in vitro. L-arginine- and cerulein + LPS-induced acute pancreatitis in mice were used to study ER stress in vivo. The results showed that MFG-E8 dose-dependently inhibited ER stress under both in vitro and in vivo conditions. MFG-E8 knockout mice suffered more severe ER stress and greater inflammatory response after L-arginine administration. Mechanistically, MFG-E8 increased phosphorylation of FAK and STAT3 in cerulein + LPS-treated pancreatic acinar cells. The presence of specific inhibitors of αvβ3/5 integrin, FAK or STAT3 abolished MFG-E8’s effect on cerulein + LPS-induced ER stress in pancreatic acinar cells. In conclusion, MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells.

scholarly journals Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells

2008 ◽  
Vol 181 (7) ◽  
pp. 1065-1072 ◽  
Author(s):  
Daisuke Hashimoto ◽  
Masaki Ohmuraya ◽  
Masahiko Hirota ◽  
Akitsugu Yamamoto ◽  
Koichi Suyama ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Knockout Mice ◽  
Early Stage ◽  
Acinar Cells ◽  
Conditional Knockout ◽  
Pancreatic Acinar Cells ◽  
Trypsinogen Activation ◽  
Conditional Knockout Mice ◽  
Cellular Environment

Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70–77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.

scholarly journals Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

scholarly journals Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Chantal B. Lucini ◽  
Ralf J. Braun
Keyword(s):  
Cell Death ◽  
Oxygen Species ◽  
In Vivo Models ◽  
Dependent Cell ◽  
Cell Death Mechanisms ◽  
Sting Pathway ◽  
Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

scholarly journals Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ali A. Aghdassi ◽  
Daniel S. John ◽  
Matthias Sendler ◽  
Christian Storck ◽  
Cindy van den Brandt ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Serine Protease ◽  
Acinar Cells ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Pancreatic Acinar Cells ◽  
Neutrophil Granulocyte ◽  
Zymogen Activation ◽  
Trypsinogen Activation ◽  
Extracellular Matrix Components

AbstractAcute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG−/− mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG−/− mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.

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