Lycopene protects pancreatic acinar cells against severe acute pancreatitis by abating the oxidative stress through JNK pathway

Oxidative stress is a major risk factor for acute pancreatitis. Reactive oxygen species (ROS) mediate expression of inflammatory cytokines such as interleukin-6 (IL-6) which reflects the severity of acute pancreatitis. The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway is activated to induce the expression of antioxidant enzymes such as NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) as a cytoprotective response to oxidative stress. In addition, binding of Kelch-like ECH-associated protein 1 (Keap1) to Nrf2 promotes degradation of Nrf2. Docosahexaenoic acid (DHA)—an omega-3 fatty acid—exerts anti-inflammatory and antioxidant effects. Oxidized omega-3 fatty acids react with Keap1 to induce Nrf2-regulated gene expression. In this study, we investigated whether DHA reduces ROS levels and inhibits IL-6 expression via Nrf2 signaling in pancreatic acinar (AR42J) cells stimulated with cerulein, as an in vitro model of acute pancreatitis. The cells were pretreated with or without DHA for 1 h and treated with cerulein (10−8 M) for 1 (ROS levels, protein levels of NQO1, HO-1, pNrf2, Nrf2, and Keap1), 6 (IL-6 mRNA expression), and 24 h (IL-6 protein level in the medium). Our results showed that DHA upregulates the expression of NQO1 and HO-1 in cerulein-stimulated AR42J cells by promoting phosphorylation and nuclear translocation of Nrf2. DHA increased interaction between Keap1 and Nrf2 in AR42J cells, which may increase Nrf2 activity by inhibiting Keap1-mediated sequestration of Nrf2. In addition, DHA-induced expression of NQO1 and HO-1 is related to reduction of ROS and IL-6 levels in cerulein-stimulated AR42J cells. In conclusion, DHA inhibits ROS-mediated IL-6 expression by upregulating Nrf2-mediated expression of NQO1 and HO-1 in cerulein-stimulated pancreatic acinar cells. DHA may exert positive modulatory effects on acute pancreatitis by inhibiting oxidative stress and inflammatory cytokine production by activating Nrf2 signaling in pancreatic acinar cells.

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The role of intracellular Ca2+ signaling in the exocrine pancreatic damage during acute pancreatitis

10.14232/phd.10488 ◽

2020 ◽

Author(s):

Júlia Fanczal

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Bile Acid ◽

Bile Acids ◽

Digestive Enzyme ◽

Acinar Cells ◽

Mitochondrial Damage ◽

Enzyme Activation ◽

Pancreatic Acinar Cells ◽

Biliary Pancreatitis

Acute biliary pancreatitis poses a significant clinical challenge as currently no specific pharmaceutical treatment exists. Disturbed intracellular Ca2+ signalling caused by bile acids is a hallmark of the disease, which induces increased reactive oxygen species (ROS) production, mitochondrial damage, intra-acinar digestive enzyme activation and cell death. Because of this mechanism of action, prevention of toxic cellular Ca2+ overload is a promising therapeutic target. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. However, the expression and possible functions of TRPM2 in the exocrine pancreas remain unknown. Here we found that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar, which can be activated by increased oxidative stress induced by H2O2 treatment. TRPM2 activity was found to contribute to bile acid-induced extracellular Ca2+ influx in acinar cells. The generation of intracellular ROS in response to bile acids was remarkably higher in pancreatic acinar cells. This activity promoted acinar cell necrosis in vitro independently from mitochondrial damage or mitochondrial fragmentation. In addition, bile-acid-induced experimental pancreatitis was less severe in TRPM2 knockout mice, whereas the lack of TRPM2 had no protective effect in cerulein-induced acute pancreatitis. Our results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.

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Protective effects of baicalin on caerulein-induced AR42J pancreatic acinar cells by attenuating oxidative stress through miR-136-5p downregulation

Science Progress ◽

10.1177/00368504211026118 ◽

2021 ◽

Vol 104 (2) ◽

pp. 003685042110261

Author(s):

Zhu-fen Zhao ◽

Ye Zhang ◽

Yang Sun ◽

Chun-hai Zhang ◽

Ming-wei Liu

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Relative Survival ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Amylase Level ◽

Sod1 Gene ◽

Expression Levels ◽

Thiazolyl Blue Tetrazolium Bromide ◽

Gene And Protein Expression

Baicalin, the main active component of Scutellaria baicalensis, has antioxidant and anti-apoptotic effects and is used to treat acute pancreatitis; however, its specific mechanism is unclear. This study aims to determine the protective effect and underlying mechanism of baicalin on AR42J pancreatic acinar cell injury. AR42J acinar cells (caerulein, 10 nmol/L) were induced in vitro to establish a cell model for acute pancreatitis. Cell relative survival was measured by thiazolyl blue tetrazolium bromide, and cell apoptosis and death were examined by flow cytometry. The expression levels of superoxide dismutase1 (SOD1), Bax, survivin, Bcl-2, caspase-3, and caspase-7 proteins were analyzed by Western blot, and those of SOD1 mRNA and miR-136-5p were determined by RT-PCR. The activities of GSH, SOD1, ROS, and MDA were also investigated. Compared with those of the caerulein group, the relative survival rate and activity of AR42J pancreatic acinar cells with different baicalin concentrations were significantly increased ( p < 0.05), and the supernatant amylase level was markedly decreased ( p < 0.05). In addition, the ROS and MDA activities and mir-136-5p expression were significantly decreased, and the GSH activities and SOD1 gene and protein expression levels were markedly increased ( p < 0.05). These results suggest that baicalin reduced the caerulein-induced death of AR42J acinar cells and alleviated the caerulein-induced injury in pancreatic acinar cells by inhibiting oxidative stress. The mechanism may be related to the decreased expression of Mir-136-5p and the increased expression of SOD1 gene and protein.

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

Scientific Reports ◽

10.1038/s41598-019-53293-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 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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Nitric oxide protects the ultrastructure of pancreatic acinar cells in the course of caerulein-induced acute pancreatitis

International Journal of Experimental Pathology ◽

10.1046/j.1365-2613.1999.00126.x ◽

2001 ◽

Vol 80 (6) ◽

pp. 317-324 ◽

Cited By ~ 16

Author(s):

Anna Andrzejewska ◽

Grazyna Jurkowska

Keyword(s):

Nitric Oxide ◽

Acute Pancreatitis ◽

Acinar Cells ◽

Pancreatic Acinar Cells

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Differential Cytotoxicity, ER/Oxidative Stress, Dysregulated AMPKα Signaling and Mitochondrial Stress by Ethanol and its Metabolites in Human Pancreatic Acinar Cells

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.14595 ◽

2021 ◽

Author(s):

Mukund P. Srinivasan ◽

Kamlesh K Bhopale ◽

Anna A Caracheo ◽

Lata Kaphalia ◽

Gopalakrishnan Loganathan ◽

...

Keyword(s):

Oxidative Stress ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Mitochondrial Stress

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TRANSCRIPTION FACTOR PROFILING OF PANCREATIC ACINAR CELLS FOLLOWING TNF-α INDUCTION OF ACUTE PANCREATITIS.

Shock ◽

10.1097/00024382-200306001-00057 ◽

2003 ◽

Vol 19 (Supplement) ◽

pp. 20

Author(s):

L. Vona-Davis ◽

K. Magabo ◽

B. Jackson ◽

T. Evans ◽

D. Riggs ◽

...

Keyword(s):

Acute Pancreatitis ◽

Transcription Factor ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Tnf Α

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Acinar Akt1 in pancreatic acinar cells supports proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis

Pancreatology ◽

10.1016/j.pan.2019.05.268 ◽

2019 ◽

Vol 19 ◽

pp. S101

Author(s):

Rong Chen ◽

Ermanno Malagola ◽

Maren Dietrich ◽

Richard Zuellig ◽

Marta Bombardo ◽

...

Keyword(s):

Acute Pancreatitis ◽

Acinar Cells ◽

Pancreatic Acinar Cells ◽

Acinar To Ductal Metaplasia

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High-Fat Diet Aggravates the Intestinal Barrier Injury via TLR4-RIP3 Pathway in a Rat Model of Severe Acute Pancreatitis

Mediators of Inflammation ◽

10.1155/2019/2512687 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Ying-ru Su ◽

Yu-pu Hong ◽

Fang-chao Mei ◽

Chen-yang Wang ◽

Man Li ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Inflammatory Response ◽

Severe Acute Pancreatitis ◽

High Fat Diet ◽

Sodium Taurocholate ◽

Intestinal Barrier ◽

High Body Mass Index ◽

High Fat ◽

Junction Protein

Objective. For patients with severe acute pancreatitis (SAP), a high body mass index (BMI) increases the possibility of infection derived from the intestine. In this study, we evaluate whether TAK242 can alleviate severe acute pancreatitis-associated injury of intestinal barrier in high-fat diet-fed rats. Methods. A SAP model was established by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Thirty Sprague-Dawley (SD) adult rats were randomly divided into five groups: standard rat chow (SRC) normal (SN), SRC SAP (SAP), high-fat diet normal (HN), HFD SAP (HSAP), and TLR4 inhibitor pretreatment HFD SAP (HAPT) groups. Intraperitoneal injection of 3 mg/kg TAK242 was administered 30 minutes before SAP model establishment in the HAPT group. Rats were sacrificed 12 hours after SAP modeling, followed by blood and pancreatic and distal ileum tissue collection for further analyses. Changes in the pathology responses of the rats in each group were assessed. Result. Analyses of serum amylase, lipase, cholesterol, triglyceride, IL-1β, IL-6, DAO, and serum endotoxin as well as tight junction protein expression including zonula occluden-1 and occludin indicated that high-fat diet aggravated SAP-induced intestinal barrier injury via increasing inflammatory response. In addition, the level of necroptosis was significantly higher in the SAP group compared with the SN group while the HSAP group exhibited more necroptosis compared with the SAP group, indicating the important role of necroptosis in pancreatitis-associated gut injury and illustrating that high-fat diet aggravated necroptosis of the ileum. Pretreatment with TLR4 inhibitor significantly alleviated inflammatory response and reduced necroptosis and level of oxidative stress while improving intestinal barrier function. Conclusion. High-fat diet aggravated SAP-induced intestinal barrier injury via inflammatory reactions, necroptosis, and oxidative stress. Inhibition of TLR4 by TAK242 reduced inflammation, alleviated necroptosis, and lowered the level of oxidative stress and then protected the intestinal barrier dysfunction from SAP in high-fat diet-fed rats.

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