scholarly journals Lycopene Inhibits Oxidative Stress-Mediated Inflammatory Responses in Ethanol/Palmitoleic Acid-Stimulated Pancreatic Acinar AR42J Cells

2021 ◽  
Vol 22 (4) ◽  
pp. 2101
Author(s):  
Jaeeun Lee ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Fatty Acid ◽  
Nadph Oxidase ◽  
Mitochondrial Dysfunction ◽  
Palmitoleic Acid ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Ros Production ◽  
Zymogen Activation

High alcohol intake results in the accumulation of non-oxidative ethanol metabolites such as fatty acid ethyl esters (FAEEs) in the pancreas. High FAEE concentrations mediate pancreatic acinar cell injury and are associated with alcoholic pancreatitis. Treatment with ethanol and the fatty acid palmitoleic acid (EtOH/POA) increased the levels of palmitoleic acid ethyl ester and induced zymogen activation and cytokine expression in pancreatic acinar cells. EtOH/POA induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated reactive oxygen species (ROS) production and pancreatic acinar cell injury. Lycopene, a bright-red carotenoid, is a potent antioxidant due to its high number of conjugated double bands. This study aimed to investigate whether lycopene inhibits the EtOH/POA-induced increase in ROS production, zymogen activation, and expression of the inflammatory cytokine IL-6 in EtOH/POA-stimulated pancreatic acinar AR42J cells. EtOH/POA increased the ROS levels, NADPH oxidase and NF-κB activities, zymogen activation, IL-6 expression, and mitochondrial dysfunction, which were inhibited by lycopene. The antioxidant N-acetylcysteine and NADPH oxidase 1 inhibitor ML171 suppressed the EtOH/POA-induced increases in ROS production, NF-κB activation, zymogen activation, and IL-6 expression. Therefore, lycopene inhibits EtOH/POA-induced mitochondrial dysfunction, zymogen activation, and IL-6 expression by suppressing NADPH oxidase-mediated ROS production in pancreatic acinar cells.

Effect of oxidative stress on cellular functions and cytosolic free calcium of rat pancreatic acinar cells

1997 ◽  
Vol 272 (6) ◽  
pp. G1489-G1498 ◽  
Author(s):  
H. Klonowski-Stumpe ◽  
R. Schreiber ◽  
M. Grolik ◽  
H. U. Schulz ◽  
D. Haussinger ◽  
...  
Keyword(s):  
Cell Injury ◽  
Cell Damage ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Free Calcium ◽  
Cellular Functions ◽  
Cytosolic Free Calcium ◽  
Catalyzed Oxidation ◽  
Sustained Increase

The present study evaluates the effect of free radicals generated by xanthine oxidase-catalyzed oxidation of hypoxanthine on cellular function of isolated rat pancreatic acinar cells. The results show that a rapid and sustained increase in intracellular Ca2+ concentration ([Ca2+]i) preceded all other morphological and functional alterations investigated. Radical-induced [Ca2+]i increase was largely inhibited by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, which prevents Ca2+ release from intracellular stores, but not by Ca2(+)-depleted medium. Radicals released Ca2+ from thapsigargin-insensitive, ryanodine-sensitive intracellular stores, whereas the secretagogue caerulein at physiological concentrations mainly released Ca2+ from thapsigargin-sensitive stores. In contrast to effects of the secretagogue, radical-induced Ca2+ changes did not cause luminal protein secretion but cell death. In single-cell measurements, both secretagogue and radicals induced oscillations of [Ca2+]i. Radical-induced oscillations had a lower frequency but similar amplitude when compared with caerulein-induced oscillations. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and ryanodine, which prevented the radical-induced Ca2+ increase without altering the generation of radicals, markedly reduced the radical-induced cell damage. These results suggest that the Ca2+ increase mediates the radical-induced cell injury. The studies also indicate that not only the extent and duration but also the origin of [Ca2+]i release as well as the frequency of Ca2+ oscillations may determine whether a pancreatic acinar cell will secrete or die.

scholarly journals Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury

2012 ◽  
Vol 302 (8) ◽  
pp. G898-G905 ◽  
Author(s):  
Kamaldeen A. Muili ◽  
Mahwish Ahmad ◽  
Abrahim I. Orabi ◽  
Syeda M. Mahmood ◽  
Ahsan U. Shah ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Injury ◽  
Acinar Cells ◽  
High Amplitude ◽  
Pancreatic Acinar Cell ◽  
Critical Event ◽  
Amylase Secretion ◽  
Zymogen Activation ◽  
Inhibitory Peptide ◽  
A Subunit

Acute pancreatitis is a major health burden for which there are currently no targeted therapies. Premature activation of digestive proenzymes, or zymogens, within the pancreatic acinar cell is an early and critical event in this disease. A high-amplitude, sustained rise in acinar cell Ca2+ is required for zymogen activation. We previously showed in a cholecystokinin-induced pancreatitis model that a potential target of this aberrant Ca2+ signaling is the Ca2+-activated phosphatase calcineurin (Cn). However, in this study, we examined the role of Cn on both zymogen activation and injury, in the clinically relevant condition of neurogenic stimulation (by giving the acetylcholine analog carbachol) using three different Cn inhibitors or Cn-deficient acinar cells. In freshly isolated mouse acinar cells, pretreatment with FK506, calcineurin inhibitory peptide (CiP), or cyclosporine (CsA) blocked intra-acinar zymogen activation ( n = 3; P < 0.05). The Cn inhibitors also reduced leakage of lactate dehydrogenase (LDH) by 79%, 62%, and 63%, respectively ( n = 3; P < 0.05). Of the various Cn isoforms, the β-isoform of the catalytic A subunit (CnAβ) was strongly expressed in mouse acinar cells. For this reason, we obtained acinar cells from CnAβ-deficient mice (CnAβ−/−) and observed an 84% and 50% reduction in trypsin and chymotrypsin activation, respectively, compared with wild-type controls ( n = 3; P < 0.05). LDH release in the CnAβ-deficient cells was reduced by 50% ( n = 2; P < 0.05). The CnAβ-deficient cells were also protected against zymogen activation and cell injury induced by the cholecystokinin analog caerulein. Importantly, amylase secretion was generally not affected by either the Cn inhibitors or Cn deficiency. These data provide both pharmacological and genetic evidence that implicates Cn in intra-acinar zymogen activation and cell injury during pancreatitis.

Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-κB

2006 ◽  
Vol 291 (6) ◽  
pp. G1113-G1119 ◽  
Author(s):  
Raina Devi Ramnath ◽  
Madhav Bhatia
Keyword(s):  
Acute Pancreatitis ◽  
Substance P ◽  
Acinar Cell ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Chemokine Production ◽  
Pancreatic Acini ◽  
Monocyte Chemoattractant Protein 1

Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1α (MIP-1α), as well as MIP-2. Furthermore, SP also increased NF-κB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-κB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-κB inhibitor NF-κB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-κB dependent.

scholarly journals Alcohols enhance caerulein-induced zymogen activation in pancreatic acinar cells

2002 ◽  
Vol 282 (3) ◽  
pp. G501-G507 ◽  
Author(s):  
Zhao Lu ◽  
Suresh Karne ◽  
Thomas Kolodecik ◽  
Fred S. Gorelick
Keyword(s):  
Acinar Cell ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Dependent Manner ◽  
Zymogen Activation ◽  
Concentration Dependent Manner ◽  
Pancreatic Acini ◽  
A Chain ◽  
Peak Value

Activation of zymogens within the pancreatic acinar cell is an early feature of acute pancreatitis. Supraphysiological concentrations of cholecystokinin (CCK) cause zymogen activation and pancreatitis. The effects of the CCK analog, caerulein, and alcohol on trypsin and chymotrypsin activation in isolated pancreatic acini were examined. Caerulein increased markers of zymogen activation in a time- and concentration-dependent manner. Notably, trypsin activity reached a peak value within 30 min, then diminished with time, whereas chymotrypsin activity increased with time. Ethanol (35 mM) sensitized the acinar cells to the effects of caerulein (10−10 to 10−7 M) on zymogen activation but had no effect alone. The effects of ethanol were concentration dependent. Alcohols with a chain length of ≥2 also sensitized the acinar cell to caerulein; the most potent was butanol. Branched alcohols (2-propanol and 2-butanol) were less potent than aliphatic alcohols (1-propanol and 1-butanol). The structure of an alcohol is related to its ability to sensitize acinar cells to the effects of caerulein on zymogen activation.

scholarly journals Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

2013 ◽  
Vol 288 (29) ◽  
pp. 21065-21073 ◽  
Author(s):  
Kamaldeen A. Muili ◽  
Shunqian Jin ◽  
Abrahim I. Orabi ◽  
John F. Eisses ◽  
Tanveer A. Javed ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acinar Cell ◽  
Cell Injury ◽  
Nuclear Translocation ◽  
Calcineurin Inhibitors ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Luciferase Reporter ◽  
Biliary Pancreatitis

Biliary pancreatitis is the most common etiology of acute pancreatitis, accounting for 30–60% of cases. A dominant theory for the development of biliary pancreatitis is the reflux of bile into the pancreatic duct and subsequent exposure to pancreatic acinar cells. Bile acids are known to induce aberrant Ca2+ signals in acinar cells as well as nuclear translocation of NF-κB. In this study, we examined the role of the downstream Ca2+ target calcineurin on NF-κB translocation. Freshly isolated mouse acinar cells were infected for 24 h with an adenovirus expressing an NF-κB luciferase reporter. The bile acid taurolithocholic acid-3-sulfate caused NF-κB activation at concentrations (500 μm) that were associated with cell injury. We show that the NF-κB inhibitor Bay 11-7082 (1 μm) blocked translocation and injury. Pretreatment with the Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, the calcineurin inhibitors FK506 and cyclosporine A, or use of acinar cells from calcineurin Aβ-deficient mice each led to reduced NF-κB activation with taurolithocholic acid-3-sulfate. Importantly, these manipulations did not affect LPS-induced NF-κB activation. A critical upstream regulator of NF-κB activation is protein kinase C, which translocates to the membranes of various organelles in the active state. We demonstrate that pharmacologic and genetic inhibition of calcineurin blocks translocation of the PKC-δ isoform. In summary, bile-induced NF-κB activation and acinar cell injury are mediated by calcineurin, and a mechanism for this important early inflammatory response appears to be upstream at the level of PKC translocation.

scholarly journals A novel protein kinase D inhibitor attenuates early events of experimental pancreatitis in isolated rat acini

2011 ◽  
Vol 300 (1) ◽  
pp. G120-G129 ◽  
Author(s):  
Edwin C. Thrower ◽  
Jingzhen Yuan ◽  
Ashar Usmani ◽  
Yannan Liu ◽  
Courtney Jones ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Protein Kinase ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Protein Kinase D ◽  
Amylase Secretion ◽  
Zymogen Activation ◽  
Isolated Rat ◽  
Novel Protein

Novel protein kinase C isoforms (PKC δ and ε) mediate early events in acute pancreatitis. Protein kinase D (PKD/PKD1) is a convergent point of PKC δ and ε in the signaling pathways triggered through CCK or cholinergic receptors and has been shown to activate the transcription factor NF-κB in acute pancreatitis. For the present study we hypothesized that a newly developed PKD/PKD1 inhibitor, CRT0066101, would prevent the initial events leading to pancreatitis. We pretreated isolated rat pancreatic acinar cells with CRT0066101 and a commercially available inhibitor Gö6976 (10 μM). This was followed by stimulation for 60 min with high concentrations of cholecystokinin (CCK, 0.1 μM), carbachol (CCh, 1 mM), or bombesin (10 μM) to induce initial events of pancreatitis. PKD/PKD1 phosphorylation and activity were measured as well as zymogen activation, amylase secretion, cell injury and NF-κB activation. CRT0066101 dose dependently inhibited secretagogue-induced PKD/PKD1 activation and autophosphorylation at Ser-916 with an IC50 ∼3.75–5 μM but had no effect on PKC-dependent phosphorylation of the PKD/PKD1 activation loop (Ser-744/748). Furthermore, CRT0066101 reduced secretagogue-induced zymogen activation and amylase secretion. Gö6976 reduced zymogen activation but not amylase secretion. Neither inhibitor affected basal zymogen activation or secretion. CRT0066101 did not affect secretagogue-induced cell injury or changes in cell morphology, but it reduced NF-κB activation by 75% of maximal for CCK- and CCh-stimulated acinar cells. In conclusion, CRT0066101 is a potent and specific PKD family inhibitor. Furthermore, PKD/PKD1 is a potential mediator of zymogen activation, amylase secretion, and NF-κB activation induced by a range of secretagogues in pancreatic acinar cells.

Secretin differentially sensitizes rat pancreatic acini to the effects of supramaximal stimulation with caerulein

2005 ◽  
Vol 289 (4) ◽  
pp. G713-G721 ◽  
Author(s):  
G. Perides ◽  
A. Sharma ◽  
A. Gopal ◽  
X. Tao ◽  
K. Dwyer ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Injury ◽  
Digestive Enzyme ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
High Dose ◽  
Zymogen Activation ◽  
Pancreatic Acini ◽  
Intracellular Ca ◽  
Supramaximal Stimulation

Supramaximal stimulation of the rat pancreas with CCK, or its analog caerulein, triggers acute pancreatitis and a number of pancreatitis-associated acinar cell changes including intracellular activation of digestive enzyme zymogens and acinar cell injury. It is generally believed that some of these various acinar cell responses to supramaximal secretagogue stimulation are interrelated and interdependent. In a recent report, Lu et al. ( 8 ) showed that secretin, by causing generation of cAMP and activation of PKA, sensitizes acinar cells to secretagogue-induced zymogen activation, and, as a result, submaximally stimulating concentrations of caerulein can, in the presence of secretin, trigger intracellular zymogen activation. We found that secretin also sensitizes acinar cells to secretagogue-induced cell injury and to subapical F-actin redistribution but that it did not alter the caerulein concentration dependence of other pancreatitis-associated changes such as the induction of a peak plateau intracellular [Ca2+] rise, inhibition of secretion, activation of ERK1/2, and activation of NF-κB. The finding that secretin sensitizes acinar cells to both intracellular zymogen activation and cell injury is consistent with the concept that these two early events in pancreatitis are closely interrelated and, possibly, interdependent. On the other hand, the finding that, in the presence of secretin, caerulein can trigger subapical F-actin redistribution without inhibiting secretion challenges the concept that disruption of the subapical F-actin web is causally related to high-dose secretagogue-induced inhibition of secretion in pancreatic acinar cells.

scholarly journals The ryanodine receptor is expressed in human pancreatic acinar cells and contributes to acinar cell injury

2014 ◽  
Vol 307 (5) ◽  
pp. G574-G581 ◽  
Author(s):  
Christopher M. Lewarchik ◽  
Abrahim I. Orabi ◽  
Shunqian Jin ◽  
Dong Wang ◽  
Kamaldeen A. Muili ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Acinar Cell ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Tissue ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Muscarinic Agonist ◽  
Basal Region ◽  
Release Channel

Physiological calcium (Ca2+) signals within the pancreatic acinar cell regulate enzyme secretion, whereas aberrant Ca2+ signals are associated with acinar cell injury. We have previously identified the ryanodine receptor (RyR), a Ca2+ release channel on the endoplasmic reticulum, as a modulator of these pathological signals. In the present study, we establish that the RyR is expressed in human acinar cells and mediates acinar cell injury. We obtained pancreatic tissue from cadaveric donors and identified isoforms of RyR1 and RyR2 by qPCR. Immunofluorescence staining of the pancreas showed that the RyR is localized to the basal region of the acinar cell. Furthermore, the presence of RyR was confirmed from isolated human acinar cells by tritiated ryanodine binding. To determine whether the RyR is functionally active, mouse or human acinar cells were loaded with the high-affinity Ca2+ dye (Fluo-4 AM) and stimulated with taurolithocholic acid 3-sulfate (TLCS) (500 μM) or carbachol (1 mM). Ryanodine (100 μM) pretreatment reduced the magnitude of the Ca2+ signal and the area under the curve. To determine the effect of RyR blockade on injury, human acinar cells were stimulated with pathological stimuli, the bile acid TLCS (500 μM) or the muscarinic agonist carbachol (1 mM) in the presence or absence of the RyR inhibitor ryanodine. Ryanodine (100 μM) caused an 81% and 47% reduction in acinar cell injury, respectively, as measured by lactate dehydrogenase leakage ( P < 0.05). Taken together, these data establish that the RyR is expressed in human acinar cells and that it modulates acinar Ca2+ signals and cell injury.

scholarly journals Astaxanthin Inhibits Interleukin-6 Expression in Cerulein/Resistin-Stimulated Pancreatic Acinar Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Min Seung Kwak ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Acute Pancreatitis ◽  
Nadph Oxidase ◽  
Interleukin 6 ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Dependent Manner ◽  
Ros Production ◽  
Ar42j Cells ◽  
Proinflammatory Mediators ◽  
Nadph Oxidase 1

Acute pancreatitis is a common clinical condition with increasing the proinflammatory mediators, including interleukin-6 (IL-6). Obesity is a negative prognostic factor in acute pancreatitis. Obese patients with acute pancreatitis have a higher systemic inflammatory response rate. Levels of serum resistin, an adipocytokine secreted by fat tissues, increase with obesity. Cerulein, a cholecystokinin analog, induces calcium (Ca2+) overload, oxidative stress, and IL-6 expression in pancreatic acinar cells, which are hallmarks of acute pancreatitis. A recent study showed that resistin aggravates the expression of inflammatory cytokines in cerulein-stimulated pancreatic acinar cells. We aimed to investigate whether resistin amplifies cerulein-induced IL-6 expression and whether astaxanthin (ASX), an antioxidant carotenoid with anti-inflammatory properties, inhibits ceruelin/resistin-induced IL-6 expression in pancreatic acinar AR42J cells. We found that resistin enhanced intracellular Ca2+ levels, NADPH oxidase activity, intracellular reactive oxygen species (ROS) production, NF-κB activity, and IL-6 expression in cerulein-stimulated AR42J cells, which were inhibited by ASX in a dose-dependent manner. The calcium chelator BAPTA-AM inhibited cerulein/resistin-induced NADPH oxidase activation and ROS production. Antioxidant N-acetyl cysteine (NAC) and ML171, a specific NADPH oxidase 1 inhibitor, suppressed cerulein/resistin-induced ROS production, NF-κB activation, and IL-6 expression. In conclusion, ASX inhibits IL-6 expression, by reducing Ca2+ overload, NADPH oxidase-mediated ROS production, and NF-κB activity in cerulein/resistin-stimulated pancreatic acinar cells. Consumption of ASX-rich foods could be beneficial for preventing or delaying the incidence of obesity-associated acute pancreatitis.

scholarly journals Pancreatogenic Diabetes: Triggering Effects of Alcohol and HIV

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 108
Author(s):  
Moses New-Aaron ◽  
Murali Ganesan ◽  
Raghubendra Singh Dagur ◽  
Kusum K. Kharbanda ◽  
Larisa Y. Poluektova ◽  
...  
Keyword(s):  
Multiorgan Failure ◽  
Acinar Cells ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Alcoholic Pancreatitis ◽  
People Living With Hiv ◽  
Zymogen Activation ◽  
Pancreatogenic Diabetes ◽  
Hiv Entry ◽  
Living With Hiv

Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5 (CCR5) into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol’s effects on acinar cells.

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