Impairment of PGC-1 Alpha Up-Regulation Enhances Nitrosative Stress in the Liver during Acute Pancreatitis in Obese Mice

Acute pancreatitis is an inflammatory process of the pancreatic tissue that often leads to distant organ dysfunction. Although liver injury is uncommon in acute pancreatitis, obesity is a risk factor for the development of hepatic complications. The aim of this work was to evaluate the role of PGC-1α in inflammatory response regulation in the liver and its contribution to the detrimental effect of obesity on the liver during acute pancreatitis. For this purpose, we induced acute pancreatitis by cerulein in not only wild-type (WT) and PGC-1α knockout (KO) mice, but also in lean and obese mice. PGC-1α levels were up-regulated in the mice livers with pancreatitis. The increased PGC-1α levels were bound to p65 to restrain its transcriptional activity toward Nos2. Lack of PGC-1α favored the assembly of the p65/phospho-STAT3 complex, which promoted Nos2 expression during acute pancreatitis. The increased transcript Nos2 levels and the pro-oxidant liver status caused by the down-regulated expression of the PGC-1α-dependent antioxidant genes enhanced nitrosative stress and decreased energy charge in the livers of the PGC-1α KO mice with pancreatitis. It is noteworthy that the PGC-1α levels lowered in the obese mice livers, which increased the Nos2 mRNA expression and protein nitration levels and decreased energy charge during pancreatitis. In conclusion, obesity impairs PGC-1α up-regulation in the liver to cause nitrosative stress during acute pancreatitis.

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Platelet-Activating Factor Mediates Pancreatic Function Derangement in Caerulein-Induced Pancreatitis in Rats

Clinical Science ◽

10.1042/cs0870085 ◽

1994 ◽

Vol 87 (1) ◽

pp. 85-90 ◽

Cited By ~ 13

Author(s):

Ricardo Alonso ◽

Angel Montero ◽

Miguel Arévalo ◽

Luis J. García ◽

Concepción Sánchez-Vicente ◽

...

Keyword(s):

Acute Pancreatitis ◽

Platelet Activating Factor ◽

Blood Platelet ◽

Pancreatic Tissue ◽

Portal Blood ◽

Blood Levels ◽

Inflammatory Infiltration ◽

Subcutaneous Injections ◽

Protein Output

1. We have assessed the role of platelet-activating factor in caerulein-induced acute pancreatitis (four subcutaneous injections of caerulein at a dose of 20 μg/kg) by measuring platelet-activating factor levels in portal blood, pancreatic tissue and peritoneal exudate in rats with and without pancreatitis. 2. We have also observed the effect of the platelet-activating factor antagonist, BN-52021, on the hyper-amylasaemia and exocrine pancreatic secretion impairment associated with pancreatitis. 3. In rats with pancreatitis the basal pancreatic flow rate was increased (1.63 ± 0.41 versus 0.25 ± 0.03 μl/min). Total protein output was similar in both untreated (5.98 ± 1.93 μg/min) and caerulein-injected (6.5 ± 2.0 μg/min) animals. Amylase output was lower in rats with pancreatitis (19.6 ± 4.8 μ-units/min) than in controls (39.4 ± 16.6 μ-units/min). 4. Caerulein-treated animals had significantly higher serum amylase levels than untreated animals. BN-52021 significantly reduced the caerulein-induced hyperamylasaemia. 5. Portal blood platelet-activating factor levels increased in rats with pancreatitis and in rats infused with cholecystokinin. Rats injected with caerulein and BN-52021 had portal blood levels of platelet-activating factor that were lower than those with pancreatitis. 6. Morphological derangements associated with pancreatitis (inflammatory infiltration and cell vacuolization) were also markedly reduced in BN-52021-treated animals. 7. The results of this study suggest that platelet-activating factor is involved in the development of caerulein-induced acute pancreatitis in rats.

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The Role of TLR-4 and Galectin-3 Interaction in Acute Pancreatitis

Serbian Journal of Experimental and Clinical Research ◽

10.2478/sjecr-2019-0067 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Milica Dimitrijevic Stojanovic ◽

Bojan Stojanovic ◽

Nebojsa Arsenijevic ◽

Bojana Stojanovic

Keyword(s):

Acute Pancreatitis ◽

Immune Cells ◽

Pancreatic Tissue ◽

Experimental Models ◽

Innate Immune ◽

Type I ◽

Innate Immune Cells ◽

Enhanced Production ◽

Galectin 3

AbstractToll-like receptor-4 (TLR-4) is a member of evolutionarily conserved type I transmembrane proteins that can initiate sterile inflammatory cascade in the pancreas. Expression of TLR-4 is up-regulated in pancreatic tissue, as well as, on peripheral blood innate immune cells in human and experimental models of acute pancreatitis. TLR-4 plays important pro-inflammatory roles during development of acute pancreatitis: it recognize alarmins released from injured acinar cells and promotes activation and infiltration of innate immune cells after the premature and intraacinar activation of tripsinogen. Galectin-3 is β-galactoside-binding lectin that plays pro-inflammatory roles in a variety autoimmune diseases, acute bacterial infections and during tumorigenesis. It is reported that Galectin-3 is alarmin in experimental models of neuroinflammation and binds to TLR-4 promoting the pro-inflammatory phenotype of microglia. Also, in experimental model of acute pancreatitis Galectin-3 is colocalized with TLR-4 on innate inflammatory cells resulted in enhanced production of inflammatory cytokines, TNF-α and IL-1β, increased infiltration of pro-inflammatory N1 neutrophils, macrophages and dendritic cells and increased damage of pancreatic tissue. This review paper discusses the role of TLR-4/Gal-3 axis in the pathogenesis of acute pancreatitis.

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Protective Effects of Rhubarb in Rats with Acute Pancreatitis and the Role of Its Active Compound Rhein on Mitochondria of Exocrine Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/7321352 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jianlei Zhao ◽

George Li ◽

Wenbi Xiong ◽

Litao Liu ◽

Jin Xiang ◽

...

Keyword(s):

Acute Pancreatitis ◽

Active Compound ◽

Stellate Cell ◽

Blood Perfusion ◽

Pancreatic Tissue ◽

Protective Effects ◽

Mtor Signaling Pathway ◽

Activity Inhibition ◽

Potential Link

Da-Cheng-Qi-Decoction (DCQD) has been used in the treatment of acute pancreatitis (AP) in China for many years. The aim of the current study was to examine the principal ingredient rhubarb of DCQD and its potential link to the pancreatic repair effects in rats with AP. The pancreatitis was induced in SD rats by intraperitoneal injections of cerulein. The results showed that rhubarb significantly increased blood perfusion of pancreatic tissue, reversed mitochondrial damage, and promoted pancreatic acinar and stellate cell proliferation. In addition, the rhein (from rhubarb) had high distribution in pancreas tissue and protected mitochondria in AR42J cells via the activation of PI3K/AKT/mTOR signaling pathway and activity inhibition of AMPK (P < 0.05). The results provide some preclinical evidence on the protective effects of DCQD for the treatment of acute pancreatitis. Rhein is regarded to be the active compound of rhubarb and can be expected to be a new compound for the treatment of AP.

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Role of Interleukin-17 in Acute Pancreatitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.674803 ◽

2021 ◽

Vol 12 ◽

Author(s):

Guanqun Li ◽

Hongze Chen ◽

Liwei Liu ◽

Peng Xiao ◽

Yu Xie ◽

...

Keyword(s):

Acute Pancreatitis ◽

Poor Prognosis ◽

Acinar Cells ◽

Therapeutic Strategies ◽

Pancreatic Tissue ◽

Vital Role ◽

Interleukin 17 ◽

Systemic Manifestations ◽

Pathogenic Process

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.

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Mesenchymal Stem Cells Inhibits the Shh/GLi (Sonic Hedgehog/GLi) Axis and Promotes Repair of Tissue Injury in Severe Acute Pancreatitis

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2915 ◽

2022 ◽

Vol 12 (2) ◽

pp. 386-392

Author(s):

Bo Qian ◽

Hongmei Zhang ◽

Jijun Zhang ◽

Chao Bai ◽

Wencai Sun

Keyword(s):

Stem Cells ◽

Acute Pancreatitis ◽

Mesenchymal Stem Cells ◽

Severe Acute Pancreatitis ◽

Sonic Hedgehog ◽

Tissue Injury ◽

Pancreatic Tissue ◽

Control Group ◽

Tissue Necrosis ◽

Regulated Expression

Mesenchymal stem cells (MSCs) are indicated to severe pancreatitis (SAP), whilst level of Shh/GLi axis varies in severe acute pancreatitis (SAP). However, little is known the interaction between MSCs and Shh in SAP. In this study, we established animal model of SAP in 10 rats and transplanted MSCs into 10 rats, with another 10 sham-operated rats as control group. The pathological changes of rat pancreatic tissue were observed. ELISA was conducted to determine the MPO level of pancreatic inflammation, and Western blot to detect the expression level of Shh, Gli1 and Gli2 in tissues. Administration of MSCs remarkably alleviated the pancreatic tissue necrosis and inflammation and decreased blood loss in SAP rats. Up-regulated expression of Shh, Gli1 and Gli2 was observed in SAP tissues when compared to tissues in control group, but their expressions declined in the presence of MSCs, and 24 hour later returned to normal levels. Collectively, MSCs regulates the balance of Shh/GLi axis by decreasing Shh and Gli1, thereby attenuating progression and symptoms of SAP.

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Role of Biomarkers in Diagnosis and Prognostic Evaluation of Acute Pancreatitis

Journal of Biomarkers ◽

10.1155/2015/519534 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 26

Author(s):

Susanta Meher ◽

Tushar Subhadarshan Mishra ◽

Prakash Kumar Sasmal ◽

Satyajit Rath ◽

Rakesh Sharma ◽

...

Keyword(s):

Acute Pancreatitis ◽

Biochemical Markers ◽

Necrotizing Pancreatitis ◽

Pancreatic Tissue ◽

Pancreatic Acinar Cell ◽

Early Assessment ◽

Prognostic Evaluation ◽

Reactive Protein ◽

Life Threatening

Acute pancreatitis is a potentially life threatening disease. The spectrum of severity of the illness ranges from mild self-limiting disease to a highly fatal severe necrotizing pancreatitis. Despite intensive research and improved patient care, overall mortality still remains high, reaching up to 30–40% in cases with infected pancreatic necrosis. Although little is known about the exact pathogenesis, it has been widely accepted that premature activation of digestive enzymes within the pancreatic acinar cell is the trigger that leads to autodigestion of pancreatic tissue which is followed by infiltration and activation of leukocytes. Extensive research has been done over the past few decades regarding their role in diagnosis and prognostic evaluation of severe acute pancreatitis. Although many standalone biochemical markers have been studied for early assessment of severity, C-reactive protein still remains the most frequently used along with Interleukin-6. In this review we have discussed briefly the pathogenesis and the role of different biochemical markers in the diagnosis and severity evaluation in acute pancreatitis.

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