Severity Of Cerulein-induced Acute Pancreatitis Research Articles

Sleeve Gastrectomy Attenuates the Severity of Cerulein-Induced Acute Pancreatitis in Obese Rats.

Obesity is one of the most important risk factors for acute pancreatitis. Based on the effect of sleeve gastrectomy (SG) on improving body weight and blood lipids, we investigated whether SG is beneficial in improving pancreatitis in obese rats. Two studies were used to evaluate the effect of SG on the first onset of pancreatitis and acute episodes of recurrent pancreatitis in obese rats. A high-fat diet (HFD) for 8 weeks resulted in obesity in rats. Study 1: Obese rats were treated with SG and sham surgery. Pancreatitis was induced by intraperitoneal injection of cerulein at 6 weeks after surgery. The severity of pancreatitis was assessed by histological examination, cytokines, and infiltration of inflammatory cells. Study 2 performed the same procedure as in study 1, except that rats were intraperitoneally injected with a small dose of cerulein three times a week for 6 weeks before surgery to induce recurrent pancreatitis. The body weight, food intake, and blood lipids of SG rats in study 1 and study 2 were significantly lower than those of sham rats during the 6 weeks after surgery. Compared with sham rats, SG rats in both studies had fewer inflammatory cytokines, inflammatory cell infiltration, and pathological injury in the pancreas after cerulein-induced acute pancreatitis. SG reduces the severity of the first onset of pancreatitis and the seriousness of acute episodes of recurrent pancreatitis. The improvement of lipid metabolism and body weight by SG may play an important role in this effect.

MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice.

Milk fat globule-EGF factor 8 (MFG-E8) is a secreted glycoprotein that regulates tissue homeostasis, possesses potent anti-inflammatory properties, and protects against tissue injury. The human pancreas expresses MFG-E8; however, the role of MFG-E8 in the pancreas remains unclear. We examined the expression of MFG-E8 in the pancreas at baseline and during cerulein-induced acute pancreatitis in mice and determined whether MFG-E8 attenuates the progression of pancreatitis, a serious inflammatory condition that can be life-threatening. We administered cerulein to wild-type (WT) and Mfge8 knockout (KO) mice to induce pancreatitis. Immunoblot analysis showed that MFG-E8 is constitutively expressed in the murine pancreas and is increased in mice with cerulein-induced acute pancreatitis. In situ hybridization revealed that ductal epithelial cells in the mouse pancreas express Mfge8 transcripts at baseline. During pancreatitis, Mfge8 transcripts were abundantly expressed in acinar cells and endothelial cells in addition to ductal epithelial cells. Knocking out Mfge8 in mice exacerbated the severity of cerulein-induced acute pancreatitis and delayed its resolution. In contrast, administration of recombinant MFG-E8 attenuated cerulein-induced acute pancreatitis and promoted repair of pancreatic injury in Mfge8 KO mice. Taken together, our study suggests that MFG-E8 protects the pancreas against inflammatory injury and promotes pancreatic tissue repair. MFG-E8 may represent a novel therapeutic target in acute pancreatitis.

Loss of chymotrypsin-like protease (CTRL) alters intrapancreatic protease activation but not pancreatitis severity in mice

The digestive enzyme chymotrypsin protects the pancreas against pancreatitis by reducing harmful trypsin activity. Genetic deficiency in chymotrypsin increases pancreatitis risk in humans and pancreatitis severity in mice. Pancreatic chymotrypsin is produced in multiple isoforms including chymotrypsin B1, B2, C and chymotrypsin-like protease (CTRL). Here we investigated the role of CTRL in cerulein-induced pancreatitis in mice. Biochemical experiments with recombinant mouse enzymes demonstrated that CTRL cleaved trypsinogens and suppressed trypsin activation. We generated a novel CTRL-deficient strain (Ctrl-KO) using CRISPR-Cas9 genome engineering. Homozygous Ctrl-KO mice expressed no detectable CTRL protein in the pancreas. Remarkably, the total chymotrypsinogen content in Ctrl-KO mice was barely reduced indicating that CTRL is a low-abundance isoform. When given cerulein, Ctrl-KO mice exhibited lower intrapancreatic chymotrypsin activation and a trend for higher trypsin activation, compared with C57BL/6N mice. Despite the altered protease activation, severity of cerulein-induced acute pancreatitis was similar in Ctrl-KO and C57BL/6N mice. We conclude that CTRL is a minor chymotrypsin isoform that plays no significant role in cerulein-induced pancreatitis in mice.

Silymarin Attenuates the Severity of Cerulein-Induced Acute Pancreatitis.

In this study, we investigated the anti-inflammatory effects of silymarin on cerulein-induced acute pancreatitis (AP) in mice. Cerulein (50 μg/kg) was injected intraperitoneally once hourly for 6 hours to induce AP. To investigate the prophylactic effects of silymarin, dimethyl sulfoxide or silymarin (25, 50, and 100 mg/kg) was injected intraperitoneally 1 hour before cerulein injection. To investigate the therapeutic effects of silymarin, dimethyl sulfoxide or silymarin (100 mg/kg) was injected intraperitoneally 1, 3, or 5 hours after the first cerulein injection. Blood, pancreas, and lungs were harvested 6 hours after the last cerulein injection. Pre- and posttreatment with silymarin decreased the pancreas weight/body weight ratio and serum amylase activity. Furthermore, silymarin treatment inhibited pancreas and lung injury and neutrophil infiltration during cerulein-induced AP. In addition, silymarin inhibited increased secretion of proinflammatory cytokines such as interleukin 1β, interleukin 6, and tumor necrosis factor α. Finally, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB were activated by cerulein, and only p38 in MAPK was inhibited by silymarin. These findings suggest that silymarin attenuates the severity of AP through inhibition of p38 MAPKs and that silymarin could be a potential prophylactic and therapeutic agent for the treatment of AP.

A small-molecule activator of mitochondrial aldehyde dehydrogenase 2 reduces the severity of cerulein-induced acute pancreatitis

Acute pancreatitis (AP) is one of the leading causes of hospital admission for gastrointestinal disorders. Although lipid peroxides are produced in AP, it is unknown if targeting lipid peroxides prevents AP. This study aimed to investigate the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a critical enzyme for lipid peroxide degradation, in AP and the possible underlying mechanisms. Cerulein was used to induce AP in C57BL/6 J male mice and pancreatic acinar cells were used to elucidate underlying mechanisms in vitro. Pancreatic enzymes in the serum, lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and Bcl-2, Bax and cleaved caspase-3 were measured. ALDH2 activation with a small-molecule activator, Alda-1, reduced the levels of the pancreatic enzymes in the serum and the lipid peroxidation products MDA and 4-HNE. In addition, Alda-1 decreased Bax and cleaved caspase-3 expression and increased Bcl-2 expression in vivo and in vitro. In conclusion, ALDH2 activation by Alda-1 has a protective effect in cerulein-induced AP by mitigating apoptosis in pancreatic acinar cells by alleviating lipid peroxidation.

β1 Syntrophin Supports Autophagy Initiation and Protects against Cerulein-Induced Acute Pancreatitis

Syntrophins are a family of proteins forming membrane-anchored scaffolds and serving as adaptors for various transmembrane and intracellular signaling molecules. To understand the physiological roles of β1 syntrophin, one of the least characterized members, we generated mouse models to eliminate β1 syntrophin specifically in the endocrine or exocrine pancreas. β1 syntrophin is dispensable for the morphology and function of insulin-producing β cells. However, mice with β1 syntrophin deletion in exocrine acinar cells exhibit increased severity of cerulein-induced acute pancreatitis. Reduced expression of cystic fibrosis transmembrane conductance regulator and dilation of acinar lumen are potential predisposition factors. During the disease progression, a relative lack of autophagy is associated with deficiencies in both actin assembly and endoplasmic reticulum nucleation. Our findings reveal, for the first time, that β1 syntrophin is a critical regulator of actin cytoskeleton and autophagy in pancreatic acinar cells and is potently protective against cerulein-induced acute pancreatitis.

Effects of Calcium Channel Blockers on Trypsinogen Activation and Severity of Cerulein-induced Acute Pancreatitis in Rats

Acute pancreatitis is an inflammatory disease of the pancreas associated with high mortality but without a specific therapy. Intrapancreatic protease activation appears to be an early event in the development of acute pancreatitis but its association with pathogenesis has not been established. Recently it has been demonstrated that an enormous rise in the cytoplasmic Ca2+ levels of pancreatic acinar cells could be associated with the development of acute pancreatitis, thereby suggesting that Ca2+ channel could be a potential target for treatment. In this study, the protective effects of calcium channel blockers such as 2-aminoethoxydiphenyl borate, dantrolene and verapamil were investigated in cerulein-induced acute pancreatitis in vivo. Rats were divided into five groups. Group 1 (control), group 2 (cerulein, 100 µg/kg), group 3 (cerulein+ 2-aminoethoxydiphenyl borate, mg/kg), group 4 (cerulein+dantrolene, 10 mg/kg) and group 5 (cerulein+verapamil, 2.5 mg/kg). Activities of amylase, lipase, cathepsin B, pancreatic secretory trypsin inhibitor and trypsin and levels of trypsinogen activation peptide and trypsinogen were measured addition to histological examination of the sections of pancreas. The results showed that cerulein increased the amylase, lipase and trypsin activities and trypsinogen activation peptide levels significantly. Administration of calcium channel blockers significantly protected the pancreas from histological damage (p<0.05). The results of this study demonstrated that calcium channel blockers can mitigate early protease activation and pancreas injury. It was suggested regulation of calcium channels would be relevant to maintain pancreatic acinar cell homeostasis and further research is necessary to understand the protective effects of calcium channel blockers.

The effect of quercetin on cerulein-induced acute pancreatitis

OBJECTIVE: The aim of this study was to evaluate the protective and therapeutic effects of quercetin on pancreatic injury in cerulein-induced acute pancreatitis. METHOD: Thirty-two rats were randomly divided into four groups, eight per group: (CT): untreated controls, (CER) treated with cerulein, 50 µg/kg body weight; (Q+CER) pre-treatment with quercetin, 100 mg/kg body weight, followed by cerulein, 50 µg/kg; (CER+Q) post-treatment, cerulein followed by quercetin, same doses. Cerulein was divided into four doses, given at 1-hour intervals by intraperitoneal injection. Quercetin was given either 1-hour before (in pre-treatment group) or 1-hour after (in post-treatment group) cerulein. Pancreatic malondialdehyde (MDA), carbonyl, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), reduced and oxidized glutathione (GSH and GSSG, respectively) were measured. Histology of the pancreas was studied. RESULTS: (1) MDA, carbonyl, MPO, TNF-a and IL-6 levels were significantly higher in CER vs CT rats. (2) MDA, carbonyl, MPO and TNF-α decreased significantly in pre-treated rats vs. CER. (3) MDA, MPO, TNF-α, IL-6 were significantly lower in post-treated rats vs. CER. (4) The reduced vs. oxidized glutathione ratio (GSH/GSSG) of was significantly lower CER vs. CT rats. (5) Pre- and post-treatment with quercetin significantly increased this ratio. (6) Pancreatic histology showed that quercetin had no significant effect on the histological image of the pâncreas CONCLUSION: These results suggest that quercetin can attenuate the severity of cerulein-induced acute pancreatitis by acting as an antioxidant and anti-inflammatory agent and combating oxidative stress. Further studies are needed to clearly explain its utility on acute pancreatitis.

Protective effects of Commiphora myrrha on acute pancreatitis

ABSTRACT Objectives : Commiphora myrrha (CM) has been used in traditional medicine for treating diseas e such as obesity, hyperlipidemia, atherosclerosis, diabetes and osteoart hritis. However, the protective effects of CM on acute pancreatitis (AP) has not been reported. Thus, the aim of this study was to evaluate the protective effects of CM water extract on cerulein-induced AP.Methods : AP was induced in mice via intraperitoneal injection of supram aximal concentrations of the stable cholecystokinin analogue cerulein (50 µg/kg) every hour for 6 times. Water extract of CM (0.1, 0.2, or 0.5 g/kg) was administrated intraperitoneally 1 h prior to the first injection of cerulein. The mice were killed at 6 h after the final cerulein injection. Pancreas was rapidly remove d for morphologic and histochemical examination, myeloperoxidase (MPO) assay. Blood samples were taken to determ ine serum amylase and lipase activities.Results : Administration of CM significantly inhibited pancreatic weight /body weight ratio, pancreas histological injury. And CM administration inhibited the serum digestive enz yme elevation such as amylase and lipase on cerulein-induced pancreatitis. In addition, Pancreas MPO activi ty which indicates neutrophil infiltration was inhibited by CM extract on cerulein-induced pancreatitis.Conclusions : In conclusion, our results could suggest that pre-treatment of CM reduces the severity of cerulein-induced AP. Therefore, CM could be used as a protectiv e agent against AP. Also, this study could give a clinical basis that CM could be a drug or agent to prevent AP.Key words : Commiphora myrrha, Acute pancreatitis, Cerulein, Amylase, Lipase

Downregulation of GRP78 and XIAP is correlated with apoptosis during cerulein-induced acute pancreatitis in rats via regulation of caspase activation

Our aim in the present study was to investigate the potential roles of the 78-kDa glucose-regulated protein (GRP78) and the X-linked inhibitor of apoptosis protein (XIAP) in the regulation of apoptosis during cerulein-induced acute pancreatitis (CAP). A rat CAP model was induced by injection of cerulein (50 μg/kg), and the severity of CAP was estimated by measuring serum amylase and lipase, pancreatic edema and histological changes. Pancreatic acinar cell apoptosis was determined by terminal-deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) assay, and the expression of GRP78, XIAP and the apoptotic genes caspase-3, -7 and -9 were determined by real-time quantitative PCR and western blotting. After induction with cerulein, increased serum amylase and lipase, pancreatic edema, inflammation and apoptosis were observed in CAP rats. Furthermore, the mRNA and protein levels of GRP78 and XIAP were significantly downregulated in CAP rats, while the mRNA levels of caspase-3, -7 and -9, as well as the cell apoptotic index were markedly increased when compared with control rats (P<0.05). The expression of GRP78 and XIAP was negatively correlated with caspase expression in CAP (P<0.05). This study suggests that the downregulation of GRP78 and XIAP were correlated with apoptosis in pancreatic acinar cells, and that this may occur through the regulation of caspase activation during CAP.

Acenocoumarol increases the severity of cerulein-induced acute pancreatitis in rats

s / Pancreatology 12 (2012) 502–597 509 Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Early diagnosis is rare and treatment options are limited. The Notch pathway has recently emerged as a candidate drug target. Notch signalling is important in PDAC initiation and maintenance. This provides a rationale for further analysis of Notch signalling in PDAC carcinogenesis Aims: Based on the known roles of Notch in development and stem cell biology, we investigated the effects of GSI IX on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. Methods: We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. In addition, sorted CD44+/EpCAM+ cells were subcutaneously injected into the nude mice (NMRI-nu/nu) and treated with vehicle or with GSI IX. The effect of GSI on Xenograft tumors, EMT markers, and cell proliferation was evaluated. Results: GSI IX inhibited pancreatic cancer cell proliferation, migration and invasion in a dose-dependent manner. Apoptosis was induced after GSI IX treatment and EMT markers reversed partially. GSI IX significantly inhibited the growth of pancreatic tumor initiating CD44+/EpCAM+ cells in vitro and in a xenograft mouse model. Conclusion: Our data support the central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.

Effect of Echium amoenum Fisch. et Mey a Traditional Iranian Herbal Remedy in an Experimental Model of Acute Pancreatitis

Acute pancreatitis is a morbid inflammatory condition of pancreas with limited specific therapy. Enhanced oxidative stress plays an important role in induction and progression of acute pancreatitis. So reducing oxidative stress may relieve this pathogenic process. Echium amoenum Fisch. and Mey has been implemented in Iranian folk medicine for several centuries. Antioxidant, analgesic, immunomodulatory, and anxiolytic properties of E. amoenum suggest that this plant may have beneficial effects in the management of acute pancreatitis. The aim of this study was to evaluate the protective effect of petals of E. amoenum extract (EAE) on a murine model of pancreatitis. Acute pancreatitis was induced by five intraperitoneal (i.p.) injection of cerulein (50 μg/kg) with 1h intervals which was characterized by pancreatic inflammation and increase in the serum level of digestive enzymes, in comparison to normal mice. EAE (100, 200, and 400 mg/kg) was administered i.p., 30 minutes before induction of pancreatitis. Pretreatment with EAE (400 mg/kg) reduced significantly the inflammatory response of cerulein-induced acute pancreatitis by ameliorating pancreatic edema, amylase and lipase serum levels, proinflammatory cytokines, myeloperoxidase activity, lipid peroxidation and pathological alteration. These results show that EAE attenuates the severity of cerulein-induced acute pancreatitis with an anti-inflammatory, immunomodulatory and antioxidant effects.

Metabolomic analysis to discover candidate therapeutic agents against acute pancreatitis

Novel and effective drugs against acute pancreatitis are required. Therefore, we examined the changes in the metabolite levels in the serum and pancreatic tissue of mice with cerulein- and arginine-induced pancreatitis using gas-chromatography/mass-spectrometry (GC/MS) and investigated whether these alterations affected the severity of acute pancreatitis. In the cerulein-induced pancreatitis model, 93 and 129 metabolites were detected in the serum and pancreatic tissue, respectively. In the l-arginine-induced acute pancreatitis model, 120 and 133 metabolites were detected in the serum and pancreatic tissue, respectively. Among the metabolites, the concentrations of tricarboxylic acid (TCA) cycle intermediates and amino acids were altered in pancreatitis, and in pancreatic tissue, the levels of the intermediates involved in the initial part of the TCA cycle were increased and those of the intermediates involved in the latter part of the TCA cycle were decreased. Some metabolites exhibited similar changes in both pancreatitis mouse models, e.g., the levels of glutamic acid and O-phosphoethanolamine were significantly decreased in the pancreatic tissue. Supplementation with glutamic acid and O-phosphoethanolamine attenuated the severity of cerulein-induced acute pancreatitis. Our results suggest that GC/MS-based metabolomics is capable of accurately representing the status of acute pancreatitis, leading to the discovery of therapeutic agents for pancreatitis.

Pioglitazone, a PPAR-γ activator, attenuates the severity of cerulein-induced acute pancreatitis by modulating early growth response-1 transcription factor

The purpose of this study was to test the hypothesis that activation of endogenous peroxisome proliferator-activated receptor (PPARγ) inhibits induction of early growth response factor-1 (Egr-1), which is rapidly induced in the pancreas following cerulein intraperitoneal injection. Acute pancreatitis was induced in mice by hourly intraperitoneal injection of cerulein. Pioglitazone was administered prophylactically and pancreatic inflammation was assessed. AR42J cells were stimulated with caerulein 10⁻⁸ M co-incubated in presence of different concentration of pioglitazone. The expression of PPARγ, Egr-1, and the target genes of Egr-1 were studied by real-time reverse transcriptase polymerase chain reaction (PCR), Western blot, and immunohistochemistry. In vitro, a PPAR-γ activator (pioglitazone) strikingly diminished Egr-1 mRNA and protein expression corresponding to Egr-1. In vivo, treatment with pioglitazone prior to the intraperitoneal injection of cerulein induction of Egr-1 and its target genes such as, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). The inhibitory effect of pioglitazone on Egr-1 expression induced by cerulein was almost fully restored by GW9662. Activation of PPAR-γ suppressed the activation of Egr-1 and its inflammatory gene targets and provided potent protection against pancreas injury. These data suggest a new mechanism in which PPAR-γ activation may decrease tissue inflammation in response to a cerulein insult.

2′,4′,6′-Tris(methoxymethoxy) chalcone (TMMC) attenuates the severity of cerulein-induced acute pancreatitis and associated lung injury

Acute pancreatitis (AP) is an inflammatory disease involving acinar cell injury and rapid production and release of inflammatory cytokines, which play a dominant role in local pancreatic inflammation and systemic complications. 2',4',6'-Tris (methoxymethoxy) chalcone (TMMC), a synthetic chalcone derivative, displays potent anti-inflammatory effects. Therefore, we aimed to investigate whether TMMC might affect the severity of AP and pancreatitis-associated lung injury in mice. We used the cerulein hyperstimulation model of AP. Severity of pancreatitis was determined in cerulein-injected mice by histological analysis and neutrophil sequestration. The pretreatment of mice with TMMC reduced the severity of AP and pancreatitis-associated lung injury and inhibited several biochemical parameters (activity of amylase, lipase, trypsin, trypsinogen, and myeloperoxidase and production of proinflammatory cytokines). In addition, TMMC inhibited pancreatic acinar cell death and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 by inhibiting NF-κB and extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation. Neutralizing antibodies for TNF-α, IL-1β, and IL-6 inhibited cerulein-induced cell death in isolated pancreatic acinar cells. Moreover, pharmacological blockade of NF-κB/ERK1/2 reduced acinar cell death and production of TNF-α, IL-1β, and IL-6 in isolated pancreatic acinar cells. In addition, posttreatment of mice with TMMC showed reduced severity of AP and lung injury. Our results suggest that TMMC may reduce the complications associated with pancreatitis.

Piperine ameliorates the severity of cerulein-induced acute pancreatitis by inhibiting the activation of mitogen activated protein kinases

Piperine is a phenolic component of black pepper ( Piper nigrum) and long pepper ( Piper longum), fruits used in traditional Asian medicine. Our previous study showed that piperine inhibits lipopolysaccharide-induced inflammatory responses. In this study, we investigated whether piperine reduces the severity of cerulein-induced acute pancreatitis (AP). Administration of piperine reduced histologic damage and myeloperoxidase (MPO) activity in the pancreas and ameliorated many of the examined laboratory parameters, including the pancreatic weight (PW) to body weight (BW) ratio, as well as serum levels of amylase and lipase and trypsin activity. Furthermore, piperine pretreatment reduced the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 during cerulein-induced AP. In accordance with in vivo results, piperine reduced cell death, amylase and lipase activity, and cytokine production in isolated cerulein-treated pancreatic acinar cells. In addition, piperine inhibited the activation of mitogen-activated protein kinases (MAPKs). These findings suggest that the anti-inflammatory effect of piperine in cerulein-induced AP is mediated by inhibiting the activation of MAPKs. Thus, piperine may have a protective effect against AP.

Pomalidomide suppresses cerulein-induced acute pancreatitis in mice

An overproduction of proinflammatory mediators in severe acute pancreatitis contributes to the systemic inflammatory response, which may lead to multiorgan damage and even death. Thus, inflammatory cytokines, e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β, may be novel targets for the treatment of acute pancreatitis. The aim of this study was to investigate the therapeutic effects of pomalidomide (or CC-4047), a thalidomide analog and immunomodulatory agent, in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by intraperitoneal administration of cerulein (100 μg/kg/h × 8). Pomalidomide was administered (0.5 mg/kg orally) 1 h before the first or 1 h after the last cerulein administration. The severity of the acute pancreatitis was evaluated biochemically and morphologically. Pretreatment with pomalidomide significantly reduced the plasma levels of amylase and lipase; the histological injury; and the expression of TNF-α, IL-1β, monocyte chemotactic protein-1 (MCP-1), and inducible nitric oxide synthase (iNOS) in cerulein-induced acute pancreatitis. Post-treatment with pomalidomide also decreased the cerulein-induced elevation of plasma amylase and lipase and decreased the pancreatic damage. Treatment with pomalidomide ameliorated the severity of cerulein-induced acute pancreatitis in mice. Our data suggest that pomalidomide may become a new therapeutic agent in future clinical trials for the treatment of acute pancreatitis.

The Natural Flavonoid Quercetin Ameliorates Cerulein-Induced Acute Pancreatitis in Mice

Many plant-derived flavonoids including quercetin exhibit antioxidant and antiinflammatory properties. Proinflammatory cytokines and oxidative stress play an important role in acute pancreatitis. This study aimed to evaluate the effect of quercetin on cerulein-induced acute pancreatitis in mice. Animal groups were pretreated with quercetin (25, 50, 100 mg/kg, per os (p.o.)), thalidomide (200 mg/kg, p.o.) or vehicle (2% dimethyl sulfoxide (DMSO)) 1 h before hourly (x5) intraperitoneal injections of cerulein. A saline (0.9%, NaCl)-treated control group was included for comparison. Cerulein significantly enhanced the serum levels of amylase and lipase, and pancreatic myeloperoxidase activities, malondialdehyde and the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6, as well as the pancreatic wet weight/body weight ratio. Cerulein significantly reduced the serum levels of IL-10. Histological assessment of the pancreas showed tissue edema, neutrophil infiltration, acinar vacuolization, and cell necrosis and a marked increase in the immunoreactivity staining for TNF-alpha. Pretreatment with quercetin or thalidomide significantly attenuated the severity of cerulein-induced acute pancreatitis as evidenced by effective reductions in the pancreatic wet weight/body weight ratio, biochemical indices, proinflammatory cytokines, myeloperoxidase activity, malondialdehyde formation, and an increase in antiinflammatory cytokine IL-10. Quercetin treatment also markedly suppressed the histological changes such as pancreatic edema, inflammatory cell infiltration, acinar cell necrosis, and the expression of TNF-alpha. Taken together, these results indicate that quercetin ameliorates the severity of cerulein-induced acute pancreatitis by acting as an antiinflammatory and antioxidant agent.

Adrenomedullin as Preventive Treatment in Cerulein-induced Acute Pancreatitis

This article has been withdrawn. After further review by the journal’s editorial board and publisher, a decision has been reached that this article does not meet the minimum requirements for uniqueness when compared to a previously published paper by the same authors: ‘‘Adrenomedullin reduces the severity of cerulein-induced acute pancreatitis’’ by Ozge Ecmel Onur, Ozlem Guneysel, Haldun Akoglu, Arzu Denizbasi, and Ender Onur published in Peptides 28: 2179–2183, 2007.

Adrenomedullin reduces the severity of cerulein-induced acute pancreatitis

We investigated the effect of Adrenomedullin (AM) on cerulein-induced acute pancreatitis in rats. AM treatment (100 ng/kg per rat, subcutaneous) after one hour of cerulein injection reduced the plasma amylase levels, pancreatic weight, pancreatic malondialdehyde (MDA) levels, and the severity of the lesions microscopically. These data suggest that AM has a protective effect on cerulein-induced acute pancreatitis. These could be due to anti-inflammatory properties of AM, inhibition of proinflammatory cytokine secretion, reducing the endothelial permeability increased by reactive oxygen species, endotoxins or cytokines.