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Swetha K, Indumathi MC, Kishan R, Siddappa S, Chen CH, Marathe GK. Selenium Mitigates Caerulein and LPS-induced Severe Acute Pancreatitis by Inhibiting MAPK, NF-κB, and STAT3 Signaling via the Nrf2/HO-1 Pathway. Biol Trace Elem Res 2025:10.1007/s12011-025-04531-2. [PMID: 39907886 DOI: 10.1007/s12011-025-04531-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Severe acute pancreatitis (SAP) leads to systemic inflammation, resulting in multiorgan damage. Acute lung injury and acute respiratory distress syndrome develop in one-third of SAP patients, with a high mortality rate of 60% due to secondary complications. Patients with pancreatitis often have selenium deficiency, and selenium supplements may provide beneficial effects. This study examined the protective role of selenium in a model of SAP induced by caerulein + lipopolysaccharide (cae + LPS). Mice were administered selenium (1 mg/kg) before being challenged with caerulein (6 injections of 50 μg/kg) and LPS (10 mg/kg). At 3 h after the last caerulein injection, blood was collected for estimating pancreatic enzymes and cytokine levels, and the mice were euthanized. We performed morphological and histological studies, measured levels of protease and oxidative stress markers and conducted western blot, ELISA, and RT-qPCR analyses. We examined lung tissue histologically and estimated myeloperoxidase levels. Selenium pretreatment significantly reduced pancreatic enzyme levels such as amylase, lipase, and proteases (specifically MMPs) and reversed tissue injury in the pancreas and lungs caused by cae + LPS. In addition, selenium-treated mice showed decreased levels of inflammatory markers and chemokines. Examination of the downstream inflammatory pathways confirmed the protective effect of selenium, which mediates its anti-inflammatory and antioxidant action by inhibiting the major inflammatory signaling pathways (MAPKs, NF-κB, and STAT3) and activating the phosphorylation of Nrf2 via Nrf2/HO-1 pathways. These findings suggest that selenium may be a potential therapeutic option for treating SAP-associated secondary complications.
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Affiliation(s)
- Kamatam Swetha
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri Mysore, 570006, India
| | | | - Raju Kishan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri Mysore, 570006, India
| | - Shiva Siddappa
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore, 570015, India
| | - Chu-Huang Chen
- Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, 77030, USA
| | - Gopal K Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri Mysore, 570006, India.
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri Mysore, 570006, India.
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Choi JW, Shin J, Zhou Z, Song HJ, Bae GS, Kim MS, Park SJ. Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production. Int Immunopharmacol 2024; 136:112284. [PMID: 38823179 DOI: 10.1016/j.intimp.2024.112284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/14/2024] [Indexed: 06/03/2024]
Abstract
Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/β-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.
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Affiliation(s)
- Ji-Won Choi
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Joonyeon Shin
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Ziqi Zhou
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Research Center of Traditional Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Ho-Joon Song
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Gi-Sang Bae
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Research Center of Traditional Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Min Seuk Kim
- Department of Oral Physiology, Institute of Biomaterial-Implant, School of Dentistry, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Sung-Joo Park
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Research Center of Traditional Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea.
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Zhang P, Yin X, Wang X, Wang J, Na G, Ирина Павловна К. Paeonol protects against acute pancreatitis by Nrf2 and NF-κB pathways in mice. J Pharm Pharmacol 2022; 74:1618-1628. [PMID: 36170125 DOI: 10.1093/jpp/rgac065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES Paeonol (PAE) is an active ingredient with anti-inflammatory and antioxidant properties. This study was designed to investigate the effect of PAE on acute pancreatitis (AP). METHODS AP was induced by the intraperitoneal injection of 20% l-arginine (4 g/kg) for 6 h. Mice were pretreated with PAE (25, 50 or 100 mg/kg) intragastrically for 5 days. The histological damage and alterations of biochemical indicators, inflammatory cytokines and oxidative stress factors in AP mice were detected. The Nrf2 and NF-κB pathways were examined to illustrate the potential mechanism. KEY FINDINGS In AP model, we found that PAE attenuated histological injury of pancreatic tissues, reduced the serum levels of α-amylase and increased Ca2+ contents in a dose-dependent manner. The white blood cell content, and IL-1β, IL-6 and TNF-α levels in the serum of AP mice were reduced by PAE. Furthermore, PAE caused a reduction of MPO and MDA levels, accompanied by an increase in SOD activity in the pancreas of AP mice. We also demonstrated that the alterations of Nrf2 and NF-κB pathways in AP mice were reversed by PAE. CONCLUSIONS PAE attenuates inflammation and oxidative stress in the development of AP by the regulation of Nrf2 and NF-κB pathways.
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Affiliation(s)
- Peng Zhang
- College of Life Engineering, Shenyang Institute of Technology, Fushun, China.,Animal Science and Veterinary Medicine Institute, Primorskaya State Academy of Agriculture, Ussuriysk, Russia
| | - Xing Yin
- College of Life Engineering, Shenyang Institute of Technology, Fushun, China
| | - Xinxin Wang
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Jiaqing Wang
- College of Life Engineering, Shenyang Institute of Technology, Fushun, China
| | - Guangning Na
- College of Life Engineering, Shenyang Institute of Technology, Fushun, China
| | - Короткова Ирина Павловна
- Animal Science and Veterinary Medicine Institute, Primorskaya State Academy of Agriculture, Ussuriysk, Russia
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Deng H, Yu X, Gao K, Liu Y, Tong Z, Liu Y, Li W. Dynamic Nomogram for Predicting Thrombocytopenia in Adults with Acute Pancreatitis. J Inflamm Res 2021; 14:6657-6667. [PMID: 34916817 PMCID: PMC8667610 DOI: 10.2147/jir.s339981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Objective Thrombocytopenia increases the risk of hemorrhage in patients with acute pancreatitis (AP), leading to poor clinical outcomes. Currently, there is no reliable tool for the early assessment of thrombocytopenia in these patients. We aimed to develop a nomogram based on available clinical parameters and validate its efficacy in predicting thrombocytopenia. Methods This was a retrospective study. All the data were extracted from an electronic database from May 2018 to May 2019. Patients with a diagnosis of AP and staying in the intensive care unit for more than 3 days were retrospectively analyzed. A clinical signature was built based on reproducible features, using the least absolute shrinkage and selection operator method (LASSO), and logistic regression established the model (P < 0.05). Nomogram performance was determined by its discrimination, calibration, and clinical usefulness. Results A total of 594 eligible patients were enrolled, of whom 399 were allocated to the training sets and the 195 in the test sets. The clinical features, including blood urea nitrogen (BUN), fibrinogen (FIB), and antithrombase III, were significantly associated with the incidence of thrombocytopenia after acute pancreatitis (p < 0.05) in training sets. The individualized nomogram showed good discrimination in the training sample (area under the receiver operating characteristic curve [AUC], 0.881) and in the validation sample (AUC, 0.883) with good calibration. Conclusion The proposed nomogram has good performance for predicting thrombocytopenia in patients with acute pancreatitis and may facilitate clinical decision-making.
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Affiliation(s)
- Hongbin Deng
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xianqiang Yu
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Kun Gao
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yang Liu
- Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
| | - Zhihui Tong
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yuxiu Liu
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weiqin Li
- Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People's Republic of China.,School of Medicine, Southeast University, Nanjing, People's Republic of China.,Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China
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Takauji S, Konishi H, Fujiya M, Ueno N, Tanaka H, Sato H, Isozaki S, Kashima S, Moriichi K, Mizukami Y, Okumura T. Polyphosphate, Derived from Lactobacillus brevis, Modulates the Intestinal Microbiome and Attenuates Acute Pancreatitis. Dig Dis Sci 2021; 66:3872-3884. [PMID: 33492535 DOI: 10.1007/s10620-020-06747-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/23/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.
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Affiliation(s)
- Shuhei Takauji
- Department of Emergency Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Mikihiro Fujiya
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan.
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan.
| | - Nobuhiro Ueno
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Hiroki Tanaka
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Hiroki Sato
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Shotaro Isozaki
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Shin Kashima
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Kentaro Moriichi
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Yusuke Mizukami
- Cancer Genetics, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1, Midorigaoka Higashi, Asahikawa, 078-8510, Japan
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Zhang Z, Li D, Cao Y, Wang Y, Wang F, Zhang F, Zheng S. Biodegradable Hypocrellin B nanoparticles coated with neutrophil membranes for hepatocellular carcinoma photodynamics therapy effectively via JUNB/ROS signaling. Int Immunopharmacol 2021; 99:107624. [PMID: 34343939 DOI: 10.1016/j.intimp.2021.107624] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 03/27/2021] [Accepted: 03/28/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is an inflammation-induced and chemotherapy-resistant common liver cancer, and a major cause of death. Some natural products have been found to be used as photosensitizers in photodynamic therapy of HCC. Due to its specific molecular structure diversities and biological activities, current status of HCC treatment with nature production remains unsatisfactory, owing largely to the toxicity, side effect and inefficiency to drug targeting. Herein, we show a nanoparticle-based broad-spectrum anti-inflammatory strategy that naïve neutrophil membrane-coated PLGA nanoparticles (NM-HB NPs) were constructed for synchronous nearinfrared fluorescence (NIR FL) imaging and photodynamic therapy (PDT) for HCC. Moreover, NM-HB NPs inhibited the expression of JUNB and promoted the ROS production. JUNB depletion enhanced the anti-HCC effect of NM-HB NPs. Importantly, it was shown that NM-HB NPs are well targeted to the tumor site and overcomes the blood circulation and immune elimination in vivo and vitro. In a mouse model of HCC, the neutrophil membrane-coated nanoparticles (NM-HB NPs) show significant therapeutic efficacy by PDT and suppressing tumor tissue increase. All results demonstrated that NM coated HB NPs representing a viable and effective treatment option for HCC.
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Affiliation(s)
- Zhiqiang Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Dan Li
- School of Materials and Chemical Engineering, Zhongyuan University of Technology, Zhengzhou 450007, China
| | - Yiming Cao
- College of Pharmaceutical Science, Shandong University of Traditional Chinese Medicine, Jinan 250300, China
| | - Yupeng Wang
- College of Pharmaceutical Science, Shandong University of Traditional Chinese Medicine, Jinan 250300, China
| | - Feixia Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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Abstract
OBJECTIVES The mechanisms underlying pathogenesis of acute pancreatitis (AP) are still not completely understood. An early, critical feature of AP is aberrant calcium (Ca) signaling, termed Ca overload, within pancreatic acinar cells. This study aimed to develop a model system in rats for AP induction to study the contribution of the Na-Ca exchanger 1 (NCX1) ion channel in AP pathogenesis. METHODS To establish a rat model of AP induction, cerulein or L-arginine were intraperitoneally injected and tissue was histologically analyzed by hematoxylin and eosin staining. A cell culture-based model for AP induction was similarly created through cerulein treatment of AR42J cells. Induction of AP was also examined following exposure to the NXC1-targeted inhibitor KB-R7943. The expression of each gene was detected by Western blotting, immunofluorescence, immunohistochemistry, or quantitative reverse transcription polymerase chain reaction. Transcriptional regulation by nuclear factor (NF)-κB was detected using an NCX1 promoter-fusion dual luciferase reporter system. Cytosolic Ca was measured using a fluorescent calcium indicator. RESULTS We found that cerulein induced NCX1 expression via activation of nuclear factor NF-κB, which potentially binds to the NCX1 promoter to induce its transcription. CONCLUSIONS Our findings reveal a regulatory pathway through NF-κB/NCX1 governing Ca overload in AP development, thus providing potential targets for AP treatment.
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Cao X, Hu Y, Luo S, Wang Y, Gong T, Sun X, Fu Y, Zhang Z. Neutrophil-mimicking therapeutic nanoparticles for targeted chemotherapy of pancreatic carcinoma. Acta Pharm Sin B 2019; 9:575-589. [PMID: 31193785 PMCID: PMC6543032 DOI: 10.1016/j.apsb.2018.12.009] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 10/26/2018] [Accepted: 12/20/2018] [Indexed: 12/20/2022] Open
Abstract
Due to the critical correlation between inflammation and carcinogenesis, a therapeutic candidate with anti-inflammatory activity may find application in cancer therapy. Here, we report the therapeutic efficacy of celastrol as a promising candidate compound for treatment of pancreatic carcinoma via naïve neutrophil membrane-coated poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles. Neutrophil membrane-coated nanoparticles (NNPs) are well demonstrated to overcome the blood pancreas barrier to achieve pancreas-specific drug delivery in vivo. Using tumor-bearing mice xenograft model, NNPs showed selective accumulations at the tumor site following systemic administration as compared to nanoparticles without neutrophil membrane coating. In both orthotopic and ectopic tumor models, celastrol-loaded NNPs demonstrated greatly enhanced tumor inhibition which significantly prolonged the survival of tumor bearing mice and minimizing liver metastases. Overall, these results suggest that celastrol-loaded NNPs represent a viable and effective treatment option for pancreatic carcinoma.
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Key Words
- 5-FU, fluorouracil
- CLT, celastrol
- Celastrol
- DAPI, 4′,6-diamidino-2-phenylindole
- DiD, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine perchlorate
- IKKα, IκB kinase α
- IKKβ, IκB kinase β
- IL-1β, interleukin 1 beta
- IL-6, interleukin 6
- Inflammation
- NF-κB, nuclear factor kappa B
- NIK, NF kappa B inducing kinase
- NNPs, neutrophil membrane-coated nanoparticles
- NPs, nanoparticles without neutrophil membrane coating
- Naïve neutrophils membrane
- PEG-PLGA nanoparticle
- PEG-PLGA, poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid)
- PI, propidium iodide
- Pancreatic carcinoma
- TAK1, TGF-β-activated kinase 1
- TEM, transmission electronic microscopy
- TNF-α, tumor necrosis factor alpha
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Affiliation(s)
| | | | | | | | | | | | - Yao Fu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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A Network Pharmacology Approach to Uncover the Potential Mechanism of Yinchensini Decoction. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:2178610. [PMID: 30671125 PMCID: PMC6317126 DOI: 10.1155/2018/2178610] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 10/26/2018] [Accepted: 11/26/2018] [Indexed: 01/30/2023]
Abstract
Objective To predict and explore the potential mechanism of Yinchensini decoction (YCSND) based on systemic pharmacology. Method TCMSP database was searched for the active constituents and related target proteins of YCSND. Cytoscape 3.5.1 was used to construct the active ingredient-target interaction of YCSND and network topology analysis, with STRING online database for protein-protein interaction (PPI) network construction and analysis; and collection from the UniProt database of target protein gene name, with the DAVID database for the gene ontology (GO) functional analysis, KEGG pathway enrichment analysis mechanism and targets of YCSND. Results The results indicate the core compounds of YCSND, namely, kaempferol, 7-Methoxy-2-methyl isoflavone, and formononetin. And its core targets are prostaglandin G/H synthase 2, estrogen receptor, Calmodulin, heat shock protein HSP 90, etc. PPI network analysis shows that the key components of the active ingredients of YCSND are JUN, TP53, MARK1, RELA, MYC, and so on. The results of the GO analysis demonstrate that extracellular space, cytosol, and plasma membrane are the main cellular components of YCSND. Its molecular functions are mainly acting on enzyme binding, protein heterodimerization activity, and drug binding. The biological process of YCSND is focused on response to drug, positive regulation of transcription from RNA polymerase II promoter, the response to ethanol, etc. KEGG results suggest that the pathways, including pathways in cancer, hepatitis B, and pancreatic cancer, play a key role in YCSND. Conclusion YCSND exerts its drug effect through various signaling pathways and acts on kinds of targets. By system pharmacology, the potential role of drugs and the mechanism of action can be well predicted.
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Shi C, Hou C, Zhu X, Huang D, Peng Y, Tu M, Li Q, Miao Y. SRT1720 ameliorates sodium taurocholate-induced severe acute pancreatitis in rats by suppressing NF-κB signalling. Biomed Pharmacother 2018; 108:50-57. [PMID: 30216799 DOI: 10.1016/j.biopha.2018.09.035] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 09/05/2018] [Accepted: 09/05/2018] [Indexed: 01/27/2023] Open
Abstract
Severe acute pancreatitis (SAP) is a medical emergency that is often associated with multiple organ failure and high mortality. Although an SAP diagnosis requires prompt treatment, therapeutic options remain limited. SRT1720 is a newly formulatedSIRT1 activator that exerts multiple pharmacological activities with beneficial health effects. However, its potential as an SAP treatment has not been explored. The current study assessed the effect of SRT1720 on a rat model of sodium taurocholate-induced SAP and explored the underlying mechanism. SAP was induced in rats by retrograde injection of a 3.5% sodium taurocholate solution (1 ml/kg) in the biliopancreatic duct. SRT1720 (5 mg/kg) was administered intraperitoneally after sodium taurocholate exposure. Serum samples were analysed for inflammatory cytokine levels and select enzymatic activities using the enzyme-linked immunosorbent assay and commercial enzyme activity assay kits, respectively; protein expression levels were evaluated by western blotting; mRNA levels of biomarkers were determined by quantitative real-time PCR; histopathological changes were analysed by haematoxylin and eosin staining and immunohistochemistry.SRT1720 treatment significantly reduced serum amylase, lipase, pancreatic histological scores, proinflammatory cytokine (TNF-α and IL-6) levels, and expression of NF-κB and p65 in sodium taurocholate-induced SAP rats. Importantly, the treatment stimulated SIRT1 and IκBα levels in pancreatic tissue. Our data suggest that SRT1720 protects rats from sodium taurocholate-induced SAP by suppressing the NF-κB signalling pathway.
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Affiliation(s)
- Chenyuan Shi
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Chaoqun Hou
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiaole Zhu
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Dongya Huang
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yunpeng Peng
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Min Tu
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Qiang Li
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Yi Miao
- Pancreas Centre, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu Province, China.
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11
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Wang Y, Chen M. Fentanyl Ameliorates Severe Acute Pancreatitis-Induced Myocardial Injury in Rats by Regulating NF-κB Signaling Pathway. Med Sci Monit 2017; 23:3276-3283. [PMID: 28680032 PMCID: PMC5510983 DOI: 10.12659/msm.902245] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Acute pancreatitis (AP) is a sudden inflammation of the pancreas. It results in multiple, severe complications, and 15–20% of patients develop severe acute pancreatitis (SAP) with mortality as high as 30%. Consequently, it is imperative to develop an effective therapy for SAP. Material/Methods We used 30 adult male Sprague Dawley (SD) rats. Rats were randomly divided into 3 groups – sham, SAP, and fentanyl+SAP – with 10 rats in each group. An automatic biochemical analyzer was used to analyze the concentration of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to assess the cell apoptosis rate. Pathological changes in pancreas/heart were detected with hematoxylin and eosin (HE) staining. Western immunoblot assay was used to analyze protein levels of interleukin (IL)-1β, IL-6, and IκB. Results Fentanyl pre-treatment inhibits SAP-induced elevation of CK-MB/LDH concentrations in serum. Compared with the sham group, SAP generates a higher brown/yellow staining rate, which is abated by fentanyl. In the pancreas, SAP generated more serious interstitial edema/hemorrhage and fat necrosis than in the sham group, which are attenuated by fentanyl. Likewise, compared to the sham group, SAP generates swelled/disordered myocardial fibers and congested blood vessels in myocardium, which are ameliorated by fentanyl. In the sham group, there was little IL-1β/IL-6, and fentanyl significantly inhibited SAP-induced up-regulation of IL-1β/IL-6 levels. Compared with the sham group, SAP significantly reduced IκB level, which was rescued by fentanyl. Conclusions Fentanyl effectively alleviates SAP-induced pancreas and heart injuries through regulating the nuclear factor-κB (NF-κB) signaling pathway.
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Affiliation(s)
- Yayun Wang
- Department of Cardiology, The Central Hospital of Wuhan, Wuhan, Hubei, China (mainland)
| | - Manhua Chen
- Department of Cardiology, The Central Hospital of Wuhan, Wuhan, Hubei, China (mainland)
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12
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Guibing R, Xiping Z, Xiaowen D, Dehong Z, Hongjiang Y, Xiaoru M, Wenju M, Xiangming H, Shuai Z. EFFECTS OF SALVIA MILTIORRHIZAE ON THE KIDNEY OF RATS WITH SEVERE ACUTE PANCREATITIS AND OBSTRUTIVE JAUNDICE. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES : AJTCAM 2017; 14:103-124. [PMID: 28573227 PMCID: PMC5446434 DOI: 10.21010/ajtcam.v14i2.12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background: Severe acute pancreatitis (SAP) and obstructive jaundice (OJ) are frequent recurring diseases that bring about huge threat to human health. Some reports have demonstrated that Salviae miltiorrhizae can protect multiple organs of SAP and OJ model animals or patients, but their related mechanisms were not clear. In this study, we observed the effects of Salvia miltiorrhizae injection on apoptosis and NF-κB expression in kidney and explored the protective effect and mechanism of Salvia miltiorrhizae on the kidney of SAP or OJ rats. The results obtained will provide a theoretical basis for clinical application of Salvia miltiorrhizae. Material and Methods: A total of 288 rats were used for SAP -and OJ-associated experiments. The mortality rates of rats, the contents of serum BUN and CREA, the expression levels of Bax, NF-κB proteins and the apoptosis index were observed, respectively. Results: The pathological changes in the kidney of SAP or OJ rats in treated group were mitigated to varying degrees. At 6 and 12 hours after operation in SAP rats or on 21 and 28 days after operation in OJ rats, the contents of serum CREA in treated group were significantly lower than those in model control group; At 3 and 6 hours after operation, the staining intensity of Bax protein of kidney in treated group was significantly lower than that in model control group; on 14 days after operation, the apoptosis index in the kidney of OJ rats in treated group was significantly lower than that in model control group. Conclusion: Salvia miltiorrhizae can exert protective effects on the kidney of SAP and OJ rats.
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Affiliation(s)
- Ren Guibing
- Department of Oncological Surgery, Affiliated Hospital, Logistics University of the Chinese People's Armed Police Force, Tianjin, 300162, PR China
| | - Zhang Xiping
- Wenzhou Medical University, Wenzhou, 325035, Zhejiang Province, PR China.,Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
| | - Ding Xiaowen
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
| | - Zou Dehong
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
| | - Yang Hongjiang
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
| | - Meng Xiaoru
- Department of Oncological Surgery, Affiliated Hospital, Logistics University of the Chinese People's Armed Police Force, Tianjin, 300162, PR China
| | - Mo Wenju
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
| | - He Xiangming
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
| | - Zhao Shuai
- Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, PR China
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13
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Qian D, Wei G, Xu C, He Z, Hua J, Li J, Hu Q, Lin S, Gong J, Meng H, Zhou B, Teng H, Song Z. Bone marrow-derived mesenchymal stem cells (BMSCs) repair acute necrotized pancreatitis by secreting microRNA-9 to target the NF-κB1/p50 gene in rats. Sci Rep 2017; 7:581. [PMID: 28373667 PMCID: PMC5428835 DOI: 10.1038/s41598-017-00629-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 03/08/2017] [Indexed: 02/07/2023] Open
Abstract
Acute pancreatitis (AP) is a common acute abdominal disease, 10-20% of which can evolve into severe AP (SAP) causing significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential of repairing SAP, but the detailed mechanism remains unknown. We demonstrate here that microRNA-9 (miR-9) modified BMSCs (pri-miR-9-BMSCs) can significantly reduce the pancreatic edema, infiltration, hemorrhage, necrosis, the release of amylase and lipase. Meanwhile, decreased local/systemic inflammatory response (TNF-α↓, IL-1β↓, IL-6↓, HMGB1↓, MPO↓, CD68↓, IL-4↑, IL-10↑, and TGF-β↑) and enhanced regeneration of damaged pancreas (Reg4↑, PTF1↑, and PDX1↑) are also promoted. But these effects diminish or disappear after antagonizing miR-9 (TuD). Besides, we find that miR-9 is negatively correlated with AP and miR-9 agomir which can mimic the effects of pri-miR-9-BMSCs and protect injured pancreas. Furthermore, we investigate that BMSCs deliver miR-9 to the injured pancreas or peripheral blood mononuclear cell (PBMC), which can target the NF-κB1/p50 gene and inhibit the NF-κB signaling pathway (p-P65↓, NF-κB1/p50↓, IκBα↑, IκBβ↑). Taken together, these results show that miR-9 is a key paracrine factor of BMSCs attenuating SAP targeting the NF-κB1/p50 gene and suppressing the NF-κB signaling pathway.
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Affiliation(s)
- Daohai Qian
- Department of General Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, 241001, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China.,Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy, Los Angeles, California, 90089, USA
| | - Ge Wei
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Chenglei Xu
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhigang He
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Jie Hua
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Jian Li
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Qili Hu
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Shengping Lin
- Intensive Care Unit, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Jian Gong
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Hongbo Meng
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Bo Zhou
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Hongfei Teng
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhenshun Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Affiliated to Tongji University School of Medicine, Shanghai, 200072, China.
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14
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Liu Z, Liu J, Zhao K, Shi Q, Zuo T, Wang G, Wang W. Role of Daphnetin in Rat Severe Acute Pancreatitis Through the Regulation of TLR4/NF-[Formula: see text]B Signaling Pathway Activation. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2016; 44:149-63. [PMID: 26916920 DOI: 10.1142/s0192415x16500105] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Severe acute pancreatitis (SAP) often results in multiple-organ dysfunction syndrome with high mortality. There is no effective clinical therapy for SAP, yet daphnetin, a coumarin extracted from Dracaena marginata, has analgesic and anti-inflammatory effects, and has been used clinically in several diseases. The objective of this study was to investigate the role and underlying mechanisms of daphnetin in a rat SAP model. Male Wistar rats were pretreated with daphnetin via intraperitoneal injection, 30[Formula: see text]min before retrograde infusion of 5% sodium taurocholate into the biliopancreatic duct. Twelve hours after sodium taurocholate administration, rats were sacrificed and tissues and blood were harvested. Then, histological, chemical, and molecular analyses were performed. Daphnetin treatment reduced the levels of serum alanine transaminase and creatinine (CR), increased superoxide dismutase(SOD) activity, and decreased neutrophil infiltration and cell apoptosis of the pancreatic tissues in rat SAP. Daphnetin treatment significantly decreased expression of pro-inflammatory cytokines and increased expression of anti-inflammatory cytokines in rat SAP. Molecular analyses revealed that daphnetin reduced TLR4 expression and inhibited NF-[Formula: see text]B signaling pathway activation. These findings demonstrate that daphnetin attenuates acute pancreatic injury by regulating the TLR4/NF-[Formula: see text]B signaling pathway and inflammation in rat SAP model. Daphnetin may be a potential therapeutic agent for SAP.
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Affiliation(s)
- Zhiyong Liu
- * Department of General Surgery, Wuhan University, Renmin Hospital, Wuhan 430060, China.,‡ Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Jiao Liu
- † Department of Critical Care Medicine, Wuhan University, Renmin Hospital, Wuhan 430060, China.,‡ Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Kailiang Zhao
- * Department of General Surgery, Wuhan University, Renmin Hospital, Wuhan 430060, China
| | - Qiao Shi
- * Department of General Surgery, Wuhan University, Renmin Hospital, Wuhan 430060, China
| | - Teng Zuo
- * Department of General Surgery, Wuhan University, Renmin Hospital, Wuhan 430060, China
| | - Guirong Wang
- ‡ Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Weixing Wang
- * Department of General Surgery, Wuhan University, Renmin Hospital, Wuhan 430060, China
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Xu M, Wang KN, Wu K, Wang XP. Pyrrolidine Dithiocarbamate Inhibits Nuclear Factor κB and Toll-Like Receptor 4 Expression in Rats with Acute Necrotizing Pancreatitis. Gut Liver 2016; 9:411-6. [PMID: 25287011 PMCID: PMC4413976 DOI: 10.5009/gnl14050] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background/Aims To investigate the expression of Toll-like receptor 4 (TLR4) in the pancreases of rats with acute necrotizing pancreatitis (ANP) and any changes upon treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor κB (NF-κB), as well as to determine the relationship between TLR4 and NF-κB in ANP pathogenesis. Methods A total of 72 SD rats were randomly divided into three groups, namely, the control (sham-operation), ANP, and ANP with PDTC pretreatment groups. The PDTC-pretreated group was intraperitoneally injected with PDTC at a dose of 100 mg/kg 1 hour before the induction of ANP. The expressions of TLR4 and NF-κB in pancreatic tissue were evaluated by immunohistochemistry and Western blot analysis. The mRNA levels of cytokines tumor necrosis factor α, interleukin (IL)-1β, and IL-6 were measured by reverse transcription polymerase chain reaction. Results The expressions of TLR4, NF-κB, and cytokine (NF-κB target) genes in the pancreatic tissue increased more significantly in the ANP groups than in the sham-operation group at 3, 6, and 12 hours. Pretreatment with PDTC alleviated the inflammatory activation in the pancreas with ANP, causing a significant decrease in the expressions of TLR4, NF-κB, and cytokine genes in the pancreatic tissue. Conclusions The expressions of TLR4 and NF-κB were increased in the pancreases of rats with ANP. PDTC not only inhibits NF-κB but also suppresses the expression of TLR4 and downregulates the expression of the related cytokine genes.
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Affiliation(s)
- Min Xu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai, China
| | - Kun-Ning Wang
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai, China
| | - Kai Wu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai, China
| | - Xing-Peng Wang
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai, China
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16
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Feng C, Li B, Wang LL, Chen LI, Zhou X, Lv FQ, Li TS. Effect of peritoneal lavage with ulinastatin on the expression of NF-κB and TNF-α in multiple organs of rats with severe acute pancreatitis. Exp Ther Med 2015; 10:2029-2034. [PMID: 26668591 PMCID: PMC4665968 DOI: 10.3892/etm.2015.2802] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 06/22/2015] [Indexed: 01/15/2023] Open
Abstract
The aim of the present study was to investigate the effect of peritoneal lavage with ulinastatin on the expression levels of nuclear factor κB (NF-κB) and tumor necrosis factor (TNF)-α in multiple organs of rats with severe acute pancreatitis (SAP). Male Wistar rats were randomly divided into the following groups: Sham-operated (C), SAP model (SAP), saline lavage (SL), intravenous ulinastatin (IU) and peritoneal lavage with ulinastatin (UL). The SAP model was induced by the retrograde infusion of 5% sodium taurocholate into the biliopancreatic ducts of the rats. Intraperitoneal lavage or injection was performed immediately following the establishment of the SAP model in groups SL, IU and UL. Intraperitoneal lavage with or without ulinastatin was performed for 3 h. The survival time of half of the rats in each group was recorded over a 12-h period. At 3 h after the induction of SAP, inflammatory mediators and the expression levels of NF-κB and TNF-α in multiple organs of the rats in each group were also detected. The survival rates of the rats in group UL at 6 h and 9 h were increased compared with those in group SAP, and were also higher than that in groups SL and IU. The levels of serum inflammatory mediators were effectively reduced in groups SL, IU and UL, the greatest effects were observed in group UL. The expression levels of NF-κB and TNF-α in multiple organs were significantly lower in group UL compared with other groups. Intraperitoneal lavage with ulinastatin significantly ameliorated the inflammatory reaction and inhibited NF-κB and TNF-α expression in multiple organs of SAP model rats.
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Affiliation(s)
- Cong Feng
- Department of Emergency, PLA General Hospital, Beijing 100853, P.R. China ; Li-Shi Road Outpatient Department, Second Artillery General Hospital of the PLA, Beijing 100820, P.R. China
| | - Bei Li
- Department of Emergency, PLA General Hospital, Beijing 100853, P.R. China
| | - Li-Li Wang
- Department of Emergency, PLA General Hospital, Beijing 100853, P.R. China
| | - L I Chen
- Department of Emergency, PLA General Hospital, Beijing 100853, P.R. China
| | - Xuan Zhou
- Department of Emergency, PLA General Hospital, Beijing 100853, P.R. China
| | - Fa-Qin Lv
- Department of Ultrasound, PLA General Hospital, Beijing 100853, P.R. China
| | - Tan-Shi Li
- Department of Emergency, PLA General Hospital, Beijing 100853, P.R. China
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17
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Lv J, Gu WL, Chen CX. Effect of gentiopicroside on experimental acute pancreatitis induced by retrograde injection of sodium taurocholate into the biliopancreatic duct in rats. Fitoterapia 2015; 102:127-33. [DOI: 10.1016/j.fitote.2015.03.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 02/28/2015] [Accepted: 03/02/2015] [Indexed: 01/04/2023]
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18
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Qiu L, Yin G, Cheng L, Fan Y, Xiao W, Yu G, Xing M, Jia R, Sun R, Ma X, Hu G, Wang X, Tang M, Zhao Y. Astragaloside IV ameliorates acute pancreatitis in rats by inhibiting the activation of nuclear factor-κB. Int J Mol Med 2015; 35:625-36. [PMID: 25604657 PMCID: PMC4314416 DOI: 10.3892/ijmm.2015.2070] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 01/08/2015] [Indexed: 11/30/2022] Open
Abstract
This study aimed to investigate the effects of astragaloside IV (AS-IV; 3-O-β-D-xylopyranosyl-6-O-β-D-glucopyranosylcycloastragenol), which has been reported to have comprehensive pharmacological functions, on sodium taurocholate (NaTc)/L-arginine (L-Arg)-induced acute pancreatitis (AP) in rats in vivo and in rat pancreatic acinar cells in vitro. NaTc-induced experimental AP was induced in rats by injecting 4% NaTc (0.1 ml/100 g) in the retrograde direction of the biliopancreatic duct. L-Arg-induced experimental AP was induced in rats by 2 intraperitoneal injections of 20% L-arg (3 g/kg), with an interval of 1 h between the injections. The rats were pre-treated AS-IV (50 mg/kg) or the vehicle (DMSO) 2 h prior to the induction of AP. Enzyme-linked immunosorbent assay, H&E staining, myeloperoxidase (MPO) activity, reverse transcription-quantitative PCR, western blot analysis and immunohistochemistry were used to evaluate the effects of AS-IV on AP. The results revealed that treatment with AS-IV significantly reduced serum amylase and lipase levels, pancreatic pathological alterations, the secretion of pro-inflammatory cytokines, MPO activity, and the protein expression of nuclear factor-κB (NF-κB) in vivo. Moreover, pre-treatment with AS-IV significantly increased the expression levels of manganese superoxide dismutase and cuprum/zinc superoxide dismutase. In the in vitro experiment, treatment of the cells with AS-IV aslo reduced rat pancreatic acinar cell necrosis and nuclear NF-κB activity, and enhanced the protein expression of superoxide dismutase. In conclusion, this study indicates that the protective effects of AS-IV on experimental AP in rats may be closely related to the inhibition of NF-κB. In addition, our results indicate that AS-IV may exert potential antioxidant effects on AP. Therefore, AS-IV may be an effective therapeutic agent for AP.
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Affiliation(s)
- Lei Qiu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Guojian Yin
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Li Cheng
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai 200080, P.R. China
| | - Yuting Fan
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Wenqin Xiao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Ge Yu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai 200080, P.R. China
| | - Miao Xing
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai 200080, P.R. China
| | - Rongrong Jia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Ruiqing Sun
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xiuying Ma
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai 200080, P.R. China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai First People's Hospital, Shanghai JiaoTong University, Shanghai 200080, P.R. China
| | - Maochun Tang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yan Zhao
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Neuhöfer P, Liang S, Einwächter H, Schwerdtfeger C, Wartmann T, Treiber M, Zhang H, Schulz HU, Dlubatz K, Lesina M, Diakopoulos KN, Wörmann S, Halangk W, Witt H, Schmid RM, Algül H. Deletion of IκBα activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology 2013; 144:192-201. [PMID: 23041330 DOI: 10.1053/j.gastro.2012.09.058] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Revised: 09/18/2012] [Accepted: 09/22/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice. METHODS IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin. RESULTS Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis. CONCLUSIONS Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
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Affiliation(s)
- Patrick Neuhöfer
- II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität Munich, Munich, Germany
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Muzammil S, Cooper HC. Acute pancreatitis and fibromyalgia: Cytokine link. NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES 2012; 3:206-8. [PMID: 22540093 PMCID: PMC3336914 DOI: 10.4297/najms.2011.3205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Context: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Acute pancreatitis is a severe condition and in most cases gallstones disease represents approximately half of the cases of acute pancreatitis, and 20-25% are related to alcohol abuse. Small numbers of cases are caused by a variety of other reasons but a few cases have no obvious cause, referred to as ‘idiopathic’. Here we present a case where fibromyalgia might be linked to acute pancreatitis. We believe this has not been reported in this context in literature. Case Report: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Patient had a cholecystectomy eight years previously. Patient feels tired almost all the time due to her fibromyalgia and requires family support for daily routine. Patient's blood results showed alanine transaminase 527 IU/L, alkaline phosphatase 604 IU/L, bilirubin 34 μmol/L, amylase 2257 IU/L, C-reactive protein 19 mg/L, Gamma-Glutamyl transpeptidase 851 IU/L, renal function and electrolytes were within normal limits. The patient was admitted to the high dependency unit with a diagnosis of acute pancreatitis. Conclusion: There is a known increase in levels of cytokines in patients with fibromyalgia. Part of the pathophysiology of acute pancreatitis is related to raised cytokines and immune deregulations. We hypothesize that elevated levels of cytokines in fibromyalgia has led to acute pancreatitis in our patient. Further epidemiological research on the incidence of pancreatitis in cytokine mediated conditions such as fibromyalgia is required.
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Affiliation(s)
- Sadat Muzammil
- Mid Cheshire Hospitals NHS Foundation Trust, Crewe, Cheshire CW1 4QJ, England, UK
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Jingmin O, Xiping Z, Chun W, Ping Y, Qian Y. Study of dexamethasone, baicalin and octreotide on brain injury of rats with severe acute pancreatitis. Inflamm Res 2011; 61:265-75. [PMID: 22166920 DOI: 10.1007/s00011-011-0408-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2010] [Revised: 11/05/2011] [Accepted: 11/28/2011] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE To investigate the protecting effects of dexamethasone (DXM), baicalin and octreotide on brain injury of rats with severe acute pancreatitis (SAP) and explore their underlying mechanism. METHODS This experiment was divided into two different parts: (1) In the first part, 90 SAP rats were randomly divided into a model control group and a DXM treated group (n = 45, respectively). (2) In the second part, 135 SAP rats were randomly divided into a model control group, a baicalin treated group and an octreotide treated group (n = 45, respectively). In two different experiments, the same number of normal rats were considered as the sham-operated group (n = 45, respectively). At 3, 6 and 12 h after operation, the pathological changes in the brain were observed. The expression levels of nuclear factor-κB (NF-κB), Bax and Bcl-2 proteins were detected and apoptosis indexes were calculated, using brain tissue microarray section. RESULTS (1) First part: The expression levels of Bax and Bcl-2 were significantly higher in the DXM treated group than those in the model control group at different time points, while the content of NF-κB protein and pathological changes were significantly lower in the treated group than those in the model control group (P < 0.05, P < 0.01 or P < 0.001). But the apoptotic indexes of brain tissue were not significantly different at different time points (P > 0.05). (2) Second part: At all time points after operation, the expression levels of NF-κB in the brain of treated groups were, to varying degrees, significantly lower than those in the model control group while the expression levels of Bcl-2 protein in baicalin and octreotide group were significantly higher than those in model control group (P < 0.01, P < 0.01 and P < 0.05, respectively). At 12 h after operation, the expression level of Bax protein in baicalin treated group was significantly higher than those in model control group and octreotide treated group (P < 0.05 and P < 0.01, respectively). CONCLUSIONS Dexamethasone, baicalin and octreotide can exert protective effects against brain injury in SAP rats mainly through inhibiting the expression of NF-κB protein.
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Affiliation(s)
- Ou Jingmin
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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Yun SW, Bae GS, Kim MS, Park KC, Koo BS, Kim BJ, Kim TH, Seo SW, Shin YK, Lee SH, Song HJ, Park SJ. Melittin inhibits cerulein-induced acute pancreatitis via inhibition of the JNK pathway. Int Immunopharmacol 2011; 11:2062-72. [PMID: 21939783 DOI: 10.1016/j.intimp.2011.08.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 07/21/2011] [Accepted: 08/28/2011] [Indexed: 12/29/2022]
Abstract
The major compound of bee venom, melittin, has been used as an anti-inflammatory reagent for decades. However, the potential of melittin to ameliorate acute pancreatitis (AP) is unknown. Our aim was to investigate the effect of melittin on cerulein-induced AP. Pre- and post-treatment with melittin inhibited histological changes in the pancreas and lungs during cerulein-induced AP. Pancreatic weight/body weight ratios; digestive enzymes, including amylase and lipase; serum and pancreatic cytokine expression; and myeloperoxidase activity were decreased. In addition, treatment with melittin inhibited the activation of c-Jun NH(2)-terminal protein kinase (JNK) in the pancreas during cerulein-induced pancreatitis. In accordance with the results of in vivo experiments, melittin reduced cerulein-induced cell death, and production of inflammatory cytokines. In conclusion, our results suggest that melittin attenuated AP and AP-associated lung injury through the inhibition of JNK activation.
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Affiliation(s)
- Seung-Won Yun
- ChungBuk Oriental Medicine Center, Jecheon, 390-250, ChungBuk, South Korea
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Abstract
Severe acute pancreatitis (SAP) is an acute abdominal disease that is characterized by sudden onset, quick progression, many complications and high mortality. Multiple organ dysfunction syndrome (MODS) is still regarded as the main cause of death in SAP patients. Nowadays, the mortality rate for patients with SAP in developed countries is 22.7%. In the early 21st century, the mortality reached 15.60%-23.77% in mainland China. However, the etiology, pathogenesis and pathophysiology of SAP remains unclear, resulting in puzzle or perplexity in choosing and developing treatment strategies for SAP. This paper reviews recent progress in understanding the pathogenesis of SAP.
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Tsai MJ, Chen C, Chen SH, Huang YT, Chiu TH. Pomalidomide suppresses cerulein-induced acute pancreatitis in mice. J Gastroenterol 2011; 46:822-33. [PMID: 21437599 DOI: 10.1007/s00535-011-0394-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Accepted: 02/24/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Ming Jen Tsai
- Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien 970, Taiwan.
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Li YY, Li XJ, Lv S, Li K, Li YN, Gao ZR, Feng JY, Chen CJ, Schaefer C. Ascitic fluid and serum from rats with acute pancreatitis injure rat pancreatic tissues and alter the expression of heat shock protein 60. Cell Stress Chaperones 2010; 15:583-91. [PMID: 20146106 PMCID: PMC3006631 DOI: 10.1007/s12192-010-0170-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 01/06/2010] [Accepted: 01/11/2010] [Indexed: 01/14/2023] Open
Abstract
Acute pancreatitis (AP) is an inflammatory process in which cytokines and chemokines are involved. After onset, extrapancreatic stimuli can induce the expression of cytokines in pancreatic acinar cells, thereby amplifying this inflammatory loop. To further determine the role and mechanism of irritating agents in the pathogenesis of AP, rat pancreatic tissues were stimulated with ascitic fluid (APa) and serum (APs) from rats with AP or with lipopolysaccharide (LPS). In addition, the alteration of heat shock protein 60 (HSP60) expression was evaluated. Rat pancreas was removed and meticulously snipped to fragments. The snips were cultured for up to 48 h. During this period, the tissue viability as well as amylase and TNF-alpha levels in the supernatant and the HSP60 expression in the pancreatic tissue before and after stimulation by APa, APs, and LPS were assayed time-dependently. At different time-points during the culture, the viability and the amylase activity in the pancreatic tissue remained largely stable. After stimulation with APa, APs, or LPS for 1 h, the pancreatic tissues showed some damage, and this was followed by a sharp decrease in the viability accompanied by increased levels of amylase and TNF-alpha in the culture medium 2 or 4 h after stimulation (p < 0.05). In contrast, both the HSP60 mRNA and protein levels had a relatively high expression in the freshly prepared tissue fragments (0 h). As the culturing period was extended, the expression of HSP60 mRNA decreased only slightly; at the same time, the HSP60 protein levels decreased over a prolonged culture time, significantly so from 12 through 48 h (p < 0.05). After stimulation with APs, APa, or LPS, both the expression of HSP60 mRNA and protein in the tissue fragments increased slightly at 1 h and decreased significantly thereafter at 2 and 4 h (p < 0.05). APa, APs, or LPS induce injuries on isolated pancreatic tissues, accompanied by an altered HSP60 expression pattern in a time-dependent manner.
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Affiliation(s)
- Yong-Yu Li
- Institute of Digestive Disease, Department of Pathophysiology, School of Medicine, Tongji University, 1239 Si Ping Road, Shanghai 200092, China.
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Antioxidant inhibits HMGB1 expression and reduces pancreas injury in rats with severe acute pancreatitis. Dig Dis Sci 2010; 55:2529-36. [PMID: 19997973 DOI: 10.1007/s10620-009-1073-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2009] [Accepted: 11/20/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND Pathogenesis of severe acute pancreatitis is still unclear, which leads to a lack of proper treatment in severe acute pancreatitis therapeutic strategy. OBJECTIVE To investigate the effect of treatment with antioxidant pyrrolidine dithiocarbamate on pancreas injury in rats with severe acute pancreatitis and its possible mechanism. METHODS A total of 144 male Sprague-Dawley rats were randomly allocated into a sham operation group (n=48), a severe acute pancreatitis group (n=48), and a pyrrolidine dithiocarbamate-treated group (n=48). All the rats were killed at 1, 3, 6, 12, 24, and 48 h after operation. The pancreas histopathologies were observed and serum amylase levels were tested. Meanwhile, the nuclear factor-kappaB activation, tumor necrosis factor-alpha levels and high-mobility group box protein-1 expression levels in pancreatic tissue were studied. RESULTS Animals receiving pyrrolidine dithiocarbamate had significantly improved pancreas histopathology and lower serum amylase levels (p<0.05). In the severe acute pancreatitis group, pancreas tumor necrosis factor-alpha levels reached a peak at 6 h after operation and afterwards rapidly declined to normal levels. However, high-mobility group box protein-1 levels in pancreatic tissue increased remarkably at the 12th hour, reached a peak at 24 h, and maintained up to 48 h post-severe acute pancreatitis. Compared to the severe acute pancreatitis group, the pancreas nuclear factor-kappaB activity, tumor necrosis factor-alpha, high-mobility group box protein-1 levels in the pyrrolidine dithiocarbamate-treated group all remarkably decreased (p<0.05). CONCLUSIONS High-mobility group box protein-1 seems to act as a late cytokine mediator in the pathogenesis of severe acute pancreatitis. Pyrrolidine dithiocarbamate might inhibit the activation of nuclear factor-kappaB to blockade tumor necrosis factor-alpha, thereby indirectly suppressing the high-mobility group box protein-1 and reducing pancreatic tissue damage in rats with severe acute pancreatitis.
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Bu LM, Tang MC, Xu M. Advances in understanding the role of cyclooxygenase-2 in the pathogenesis of acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2010; 18:1919-1922. [DOI: 10.11569/wcjd.v18.i18.1919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Activation and release of digestive enzymes and pancreatic microcirculatory disturbance are initiators of acute pancreatitis. The expression of cyclooxygenase-2 (COX-2) has been detected in inflammatory response induced by many stimulating factors. COX-2 can promote the development of early inflammation and induce pancreatic microcirculatory disturbance.
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Twait E, Williard DE, Samuel I. Dominant negative p38 mitogen-activated protein kinase expression inhibits NF-kappaB activation in AR42J cells. Pancreatology 2010; 10:119-28. [PMID: 20453549 PMCID: PMC2899148 DOI: 10.1159/000290656] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2009] [Accepted: 02/13/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND The role of the p38 mitogen-activated protein (MAP) kinase in acute pancreatitis pathogenesis is controversial. We hypothesize that p38 plays a role in regulating NF-kappaB activation in exocrine pancreatic cells. METHODS AR42J cells incorporating an NF-kappaB-responsive luciferase reporter, with and without adenoviral transduction of DNp38, were stimulated with cholecystokinin (CCK) or tumor necrosis factor-alpha (TNF-alpha) prior to measuring NF-kappaB activation. RESULTS CCK- or TNF-alpha-stimulated NF-kappaB-dependent gene transcription (luciferase assay) was substantially subdued by DNp38 expression. These findings were confirmed by electrophoretic mobility shift assay. Nuclear translocation of the p65 NF-kappaB subunit following agonist stimulation was evident (supershift). Characterization studies showed excellent adenoviral infection efficiency and cell viability in our AR42J cell model. Agonist-stimulated dose- and time-dependent p38 activation, with inhibition by DNp38 expression, was also confirmed. CONCLUSION The p38 MAP kinase regulates NF-kappaB pathway activation in exocrine pancreatic cells, and thus potentially plays a role in the mechanism of acute pancreatitis pathogenesis..
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Affiliation(s)
| | | | - Isaac Samuel
- *Isaac Samuel, MD, FRCS, FACS, Department of Surgery, VAMC & UI CCOM, 200 Hawkins Drive, 4625 JCP (Surgery), Iowa City, IA 52242 (USA), Tel. +1 319 356 7359, Fax +1 319 356 8378, E-Mail
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Abstract
OBJECTIVES Nardostachys jatamansi belonging to the family Valerianaceae has been used as a remedy for stomach and skin ailments in Korea. The effect of N. jatamansi on acute pancreatitis (AP) has not been defined. Therefore, we investigated the effect of N. jatamansi on cerulein-induced AP. METHODS In the pretreatment group, N. jatamansi was administered orally to mice at 10 and 20 mg/kg for 5 days, and the mice were intraperitoneally injected with the stable cholecystokinin analogue cerulein hourly for 6 hours. In the posttreatment group, cerulein was injected hourly for 6 hours, and N. jatamansi was administered at the indicated time (1, 3, and 5 hours after the first cerulein injection) and dose (10 and 20 mg/kg) during the cerulein injection. Blood samples were taken 6 hours later to determine the serum amylase, the lipase, and the cytokine levels. The pancreas and the lung were rapidly removed for morphologic examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. RESULTS Nardostachys jatamansi treatment attenuated the AP, as shown by the histological examination results of the pancreas and the lung, reductions in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and messenger RNA expressions of inflammatory mediators. CONCLUSIONS These results suggest that N. jatamansi attenuates the severity of AP and pancreatitis-associated lung injury.
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Zhang CX, Guo XF, Qin YM. Huangqi Injection reduces NF-κB activity and down-regulates TNF-α mRNA expression in rats with acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2010; 18:1051-1055. [DOI: 10.11569/wcjd.v18.i10.1051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of Huangqi Injection on nuclear factor-κB (NF-κB) activity and NF-κB and tumor necrosis factor-α (TNF-α) mRNA expression in rats with acute pancreatitis.
METHODS: Sixty male Sprague-Dawley rats were randomly divided into five groups: sham-operation group, model control group, and low- [0.10 mL/(100 g•d)], medium- [0.15 mL/(100 g•d)] and high-dose [0.20 mL/(100 g•d)] Huangqi Injection groups. Acute pancreatitis was induced by injection of 5% sodium taurocholate [0.10 mL/(100 g•d)] into the pancreatic duct of rats. Huangqi Injection was injected into the tail vein 30 min before sodium taurocholate injection in the three treatment groups. The rats were killed 6 h after sodium taurocholate injection. The histomorphologic structure of the pancreas was observed under an optical microscope, and the severity of pancreatitis was evaluated using a pathologic grading system. The NF-κB activity in pancreatic acinar cells was determined by immunohistochemistry. The expression of NF-κB and TNF-α mRNAs in the pancreas was measured by reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: Compared with the sham-operation group, the pathologic grading score, NF-κB activity and TNF-α mRNA expression level increased obviously in the model group (both P < 0.01). The pathologic grading score, NF-κB activity and TNF-α mRNA expression level were significantly lower in the treatment groups than in the model group (all P < 0.05 or 0.01). A positive correlation was noted between NF-κB activity and TNF-α mRNA expression level (r = 0.542, P < 0.05). No significant difference was noted in NF-κB mRNA expression level among each group (all P > 0.01).
CONCLUSION: NF-κB activity and TNF-α mRNA expression are closely related with the severity of acute pancreatitis. Active NF-κB may play an important role in the pathogenesis of acute pancreatitis by up-regulating TNF-α mRNA expression. Huangqi Injection can significantly decrease NF-κB activity and TNF-α mRNA expression and therefore alleviate pancreatic injury in rats with acute pancreatitis.
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Abstract
OBJECTIVES Nuclear factor-kappaB (NF-kappaB) is a potent mediator in several steps of acute pancreatitis. Leflunomide is a novel immunomodulating drug that is also a potent inhibitor of NF-kappaB activation. The aim of this study was to investigate the effects of leflunomide pretreatment in severe necrotizing pancreatitis in rats. METHODS Fifty rats were randomly divided into 5 groups. Severe necrotizing pancreatitis was induced by retrograde injection of 3% sodium taurocholate into the common biliopancreatic duct. Leflunomide (10 mg/kg) was given intragastrically for 2 doses before the experiment. Serum amylase activity, pancreatic histopathologic condition, malondialdehyde level, myeloperoxidase enzyme activity, nitric oxide level, and pulmonary changes were assessed. RESULTS Leflunomide pretreatment significantly ameliorated pancreatic hemorrhage, edema, and neutrophil infiltration and decreased histopathological score compared with the untreated severe necrotizing pancreatitis group (pathological score [mean +/- SEM]: 6.70 +/- 1.19 vs 12.36 +/- 1.08 in the leflunomide treated and untreated groups, respectively, P < 0.01). Pulmonary changes was decreased in the leflunomide treated group (3.90 +/- 0.45 vs 4.75 +/- 0.25, respectively). Change in pulmonary alveolar distention was significant. Although serum amylase levels also decreased, the difference was not significant (5922 +/- 3290 vs 15547 +/- 5090 U/mL). CONCLUSIONS Leflunomide is a beneficial agent in the severe form of acute pancreatitis in rats and should be considered as a potential agent for treatment of acute pancreatitis.
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Li YY, Ochs S, Gao ZR, Malo A, Chen CJ, Lv S, Gallmeier E, Göke B, Schäfer C. Regulation of HSP60 and the role of MK2 in a new model of severe experimental pancreatitis. Am J Physiol Gastrointest Liver Physiol 2009; 297:G981-9. [PMID: 20501446 DOI: 10.1152/ajpgi.00225.2009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The objective of this study was to investigate the role of MAPKAP kinase 2 (MK2) and heat shock protein (HSP) HSP60 in the pathogenesis of a new model of severe acute pancreatitis (AP). MK2 plays a significant role in the regulation of cytokines. It has been shown that induction and expression of several HSPs can protect against experimental pancreatitis. Interplay between both systems seems of high interest. Mice with a homozygous deletion of the MK2 gene were used. Severe AP was induced by combined intraperitoneal injections of cerulein with lipopolysaccharide (LPS). Severity of AP was assessed by biochemical markers and histology. The serum IL-6 and lung myeloperoxidase (MPO) levels were determined for assessing the extent of systemic inflammatory response. Expression of HSP25, HSP60, HSP70, and HSP90 was analyzed by Western blotting. Repeated injections of cerulein alone or cerulein plus LPS (Cer+LPS) resulted in local inflammatory responses in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the Cer+LPS group. Compared with the C57Bl wild-type mice, the MK2-/- mice presented with significant milder pancreatitis and attenuated responses of serum amylase and trypsinogen activity. Furthermore, serum IL-6 was decreased as well as lung MPO activity. Injection of LPS alone displayed neither pancreatic inflammatory responses nor alterations of pancreatic enzyme activities but evidently elevated serum IL-6 levels and increased lung MPO activity. In contrast hereto, in the MK2-/- mice, these changes were much milder. Increased expression of HSP25 and HSP60 occurred after induction of AP. Especially, HSP60 was robustly elevated after Cer+LPS treatment, in both MK2-/- and wild-type mice. Thus the homozygous deletion of the MK2 gene ameliorates the severity of acute pancreatitis and accompanying systemic inflammatory reactions in a new model of severe acute pancreatitis. Our data support the hypothesis that MK2 participates in the multifactorial regulation of early inflammatory responses in AP, independently of the regulation of stress proteins like HSP25 and HSP60 and most likely due to its effect on cytokine regulation.
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Affiliation(s)
- Yong-Yu Li
- Department of Pathophysiology, School of Medicine, Tongji University, Shanghai, China
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Effect of Korean red ginseng on superoxide dismutase inhibitor-induced pancreatitis in rats: a histopathologic and immunohistochemical study. Pancreas 2009; 38:661-6. [PMID: 19531970 DOI: 10.1097/mpa.0b013e3181a9eb85] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Korean red ginseng (KRG) is a representative herbal remedy in Korea. We examined the effects of KRG treatment on superoxide dismutase inhibitor-induced experimental pancreatitis. METHODS Sprague-Dawley rats and KRG from the roots of a 6-year-old fresh Panax ginseng C. A. Meyer plant were used in this study. Pancreatitis was induced by intraperitoneal injection of diethyldithiocarbamate for 4 weeks. Korean red ginseng was fed orally to rats for the next 3 weeks. At week 7, all rats were killed, and pancreatic tissues were analyzed. RESULTS No histological alterations were detected in the pancreata of normal and KRG control groups. Tissues from the non-KRG-treated pancreatitis group exhibited marked pancreatic damage including changes in histological architecture, acinar cell necrosis and degeneration, and cytoplasmic vacuolization. However, tissues from the KRG-treated pancreatitis group exhibited no cellular damage and had normal histological pancreatic architecture. Immunohistochemical examination revealed that the expressions of nuclear factor kappaB, tumor necrosis factor alpha, inducible nitric oxide synthase, and the oxidant stress markers, malondialdehyde and 4-hydroxynonenal, were significantly decreased in the KRG-treated pancreatitis group as compared with the non-KRG-treated pancreatitis group. CONCLUSIONS Our results suggest that KRG has antioxidant therapeutic effects on superoxide dismutase inhibitor-induced pancreatitis by inhibition of nuclear factor kappaB.
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Andersson R, Axelsson J, Norrman G, Wang X. Gut barrier failure in critical illness: Lessons learned from acute pancreatitis. ACTA ACUST UNITED AC 2009. [DOI: 10.1080/17471060500233034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Li YY, Lu XY, Li XJ, Li YN, Li K, Chen CJ. Intervention of pyrrolidine dithiocarbamate and tetrandrine on cellular calcium overload of pancreatic acinar cells induced by serum and ascitic fluid from rats with acute pancreatitis. J Gastroenterol Hepatol 2009; 24:155-65. [PMID: 19196399 DOI: 10.1111/j.1440-1746.2008.05592.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM To investigate the effects of serum and ascitic fluid from rats with acute pancreatitis (AP) on cellular free calcium concentration ([Ca(2+)]i) of isolated rat pancreatic acinar cells, and the intervention of pyrrolidine dithiocarbamate (PDTC) and tetrandrine (Tet) to cellular calcium overload in AP. METHODS AP was induced in Sprague-Dawley rats with a retrograde pancreatic duct injection of 3% sodium deoxycholate, and confirmed by histopathological examination and amylase activity assay. The rat serum and ascitic fluid were collected at 1, 5 and 10 h after AP induction, and used as irritants on isolated rat pancreatic acinar cells. The effects on intracellular [Ca(2+)]i, and cell viability were examined. Then, the antagonistic effects of different concentrations of PDTC and Tet were assessed. RESULTS The irritation with AP serum and ascitic fluid reduced the survival rate of the isolated rat pancreatic acinar cells and increased the cellular [Ca(2+)]i significantly (P < 0.05). As AP induction course prolonged, the stimulation effect of the AP serum and ascitic fluid intensified. In the pretreated acinar cells with PDTC or Tet, the decreased cell vitality reverted. The elevation of [Ca(2+)]i in the acinar cells significantly ameliorated (significant, P < 0.05; very significant, P < 0.01). CONCLUSION The serum and ascitic fluid from AP rats drastically elevate the [Ca(2+)]i in isolated pancreatic acinar cells and decrease cell vitality, while the pretreatment of cells with PDTC and Tet offsets the calcium overload irritated by the AP serum and ascitic fluid and protects these isolated acinar cells.
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Affiliation(s)
- Yong-Yu Li
- Department of Pathophysiology, Institute of Digestive Disease, Medical School of Tongji University, Shanghai, China.
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Viterbo D, Bluth MH, Lin YY, Mueller CM, Wadgaonkar R, Zenilman ME. Pancreatitis-associated protein 2 modulates inflammatory responses in macrophages. THE JOURNAL OF IMMUNOLOGY 2008; 181:1948-58. [PMID: 18641332 DOI: 10.4049/jimmunol.181.3.1948] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Pancreatitis-associated proteins (PAP) are stress-induced secretory proteins that are implicated in immunoregulation. Previous studies have demonstrated that PAP is up-regulated in acute pancreatitis and that gene knockdown of PAP correlated with worsening severity of pancreatitis, suggesting a protective effect for PAP. In the present study, we investigated the effect of PAP2 in the regulation of macrophage physiology. rPAP2 administration to clonal (NR8383) and primary macrophages were followed by an assessment of cell morphology, inflammatory cytokine expression, and studies of cell-signaling pathways. NR8383 macrophages which were cultured in the presence of PAP2 aggregated and exhibited increased expression of IL-1, IL-6, TNF-alpha, and IL-10; no significant change was observed in IL-12, IL-15, and IL-18 when compared with controls. Chemical inhibition of the NFkappaB pathway abolished cytokine production and PAP facilitated nuclear translocation of NF-kappaB and phosphorylation of IkappaB alpha inhibitory protein suggesting that PAP2 signaling involves this pathway. Cytokine responses were dose dependent. Interestingly, similar findings were observed with primary macrophages derived from lung, peritoneum, and blood but not spleen. Furthermore, PAP2 activity was inhibited by the presence of serum, inhibition which was overcome with increased PAP2. Our results demonstrate a new function for PAP2: it stimulates macrophage activity and likely modulates the inflammatory environment of pancreatitis.
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Affiliation(s)
- Domenico Viterbo
- Department of Surgery, Downstate Medical Center, State University of New York, Brooklyn, NY 11203, USA
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Campo GM, Avenoso A, Campo S, Nastasi G, Traina P, D'Ascola A, Calatroni A. Chondroitin-4-sulphate reduced oxidative injury in caerulein-induced pancreatitis in mice: the involvement of NF-kappaB translocation and apoptosis activation. Exp Biol Med (Maywood) 2008; 233:741-52. [PMID: 18408139 DOI: 10.3181/0711-rm-318] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Activation of nuclear factor kappaB (NF-kappaB) and caspases may greatly amplify inflammation and cell damage in addition to that directly exerted by free radicals. Since reactive oxygen species (ROS) are involved in acute pancreatitis, we studied whether the administration of chondroitin-4-sulphate (C4S), in addition to its antioxidant activity, was able to modulate NF-kappaB and caspase activation in an experimental model of caerulein-induced acute pancreatitis in mice. Hyperstimulating doses of caerulein (50 microg/ kg), five injections per mouse given at hourly intervals produced the following: high serum lipase and amylase activity; lipid peroxidation, evaluated by 8-isoprostane concentrations; loss of antioxidant defenses such as glutathione reductase (GR) activity; NF-kappaB activation and loss of cytoplasmic IkappaBalpha protein; increases in tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), caspase-3, and caspase-7 gene expression and their related protein; accumulation and activation of neutrophils in the damaged tissue, evaluated by elastase (ELA) determination; and pancreatic injury, evaluated by histologic analysis. Pretreatment of mice with different doses of C4S, given 1 hr before caerulein injections and 1 and 2 hrs after the last caerulein injection, reduced lipid peroxidation, inhibited NF-kappaB translocation and cytoplasmic IkappaBalpha protein loss, decreased TNF-alpha, IL-6, and caspase gene expression and their related protein levels, limited endogenous antioxidant depletion, and reduced tissue neutrophils accumulation and tissue damage. Since molecules with antioxidant activity can block NF-kappaB and apoptosis activation, we suggest that C4S administration is able to block NF-kappaB and caspase activation by reducing the oxidative burst.
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Affiliation(s)
- Giuseppe M Campo
- Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, 98125, Messina, Italy.
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Abstract
OBJECTIVES Bee venom (BV) has frequently been used as a remedy for inflammatory diseases. The aim of this study was to investigate the effect of BV on cholecystokinin octapeptide (CCK-8)-induced acute pancreatitis (AP) in rats. METHODS The BV pretreatment group: 0.25 mg/kg BV was administered subcutaneously, followed by 75 mug/kg CCK-8 subcutaneously 3 times after 1, 3, and 5 hours. This whole procedure was repeated for 5 days. CONTROL GROUP CCK-8 subcutaneously 3 times after 1, 3, and 5 hours for 5 days. The BV posttreatment group: CCK-8 subcutaneously 3 times at an interval of 2 hours for 3 days, and then 0.25 mg/kg of BV was administered subcutaneously. CONTROL GROUP CCK-8 subcutaneously 3 times at an interval of 2 hours for 3 days. RESULTS The BV pretreatment and posttreatment ameliorated many of the examined laboratory parameters (the pancreatic weight [PW]/body weight [BW] ratio, the serum amylase and lipase activity) and reduced histological damages in pancreas. Furthermore, BV pretreatment reduced the production of tumor necrosis factor-alpha, interleukin 1, and interleukin 6 and also decreased pancreatic nuclearfactor-kappaB binding activity compared with saline-treated group in the AP model. The BV also increased heat shock protein 60 (HSP60) and heat shock protein 72 (HSP72) compared with the saline-treated group in the AP model. CONCLUSIONS These findings suggest that the anti-inflammatory effect of BV in CCK-8-induced AP seems to be mediated by inhibiting nuclear factor-kappaB binding activity, and that BV may have a protective effect against AP.
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Samuel I, Tephly L, Williard DE, Carter AB. Enteral exclusion increases MAP kinase activation and cytokine production in a model of gallstone pancreatitis. Pancreatology 2008; 8:6-14. [PMID: 18235211 PMCID: PMC2829292 DOI: 10.1159/000114850] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2007] [Accepted: 11/06/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND We have previously demonstrated that enteral exclusion augments pancreatic p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor-alpha (TNF-alpha) production after bile-pancreatic duct ligation in rats. METHODS In the present study, we evaluated c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation, and cytokine production, in pancreata of duct-ligated rats with and without duodenal bile-pancreatic juice replacement from a donor rat. We hypothesized that enteral exclusion of bile-pancreatic juice activates stress kinases and induces cytokine production in ligation-induced acute pancreatitis. RESULTS Increased JNK and ERK activation after ligation are inhibited by bile-pancreatic juice replacement. Increases in pancreatic production of IL-1beta and IL-12 after ligation are significantly subdued by replacement. In additional in vitro studies, we show that cholecystokinin- or TNF-alpha-stimulated nuclear transcription factor kappa-B activation in AR42J cells is inhibited by dominant negative ERK2. CONCLUSIONS Our novel findings using our Donor Rat Model indicate that bile-pancreatic juice exclusion induces MAP kinase activation and exacerbates cell stress and inflammation in this experimental model of gallstone pancreatitis. and IAP.
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Affiliation(s)
- Isaac Samuel
- Department of Surgery, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
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40
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Jordan S, Hutchings MI, Mascher T. Cell envelope stress response in Gram-positive bacteria. FEMS Microbiol Rev 2008; 32:107-46. [PMID: 18173394 DOI: 10.1111/j.1574-6976.2007.00091.x] [Citation(s) in RCA: 278] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Affiliation(s)
- Sina Jordan
- Department of General Microbiology, Georg-August-University, Grisebachstrasse 8, Göttingen, Germany
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41
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Dang SC, Zhang JX, Mao ZF, Qu JG, Wang XQ, Zhu B. Dynamic changes in the levels of serum interleukin-2 and interleukin-10 and the expression of Fas in the intestinal mucosa of rats with severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2007; 15:3697-3702. [DOI: 10.11569/wcjd.v15.i35.3697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the dynamic changes in the levels of serum interleukin (IL)-2 and IL-10 sFas and IL-2/IL-10 in rats with severe acute pancreatitis (SAP), and to explore the expression of Fas in the intestinal mucosa of rats with severe acute pancreatitis.
METHODS: A total of 64 Sprague-Dawley (SD) rats were randomly divided into normal control group and SAP group. A SAP model was induced by injection of 50 g/L sodium taurocholate under the pancreatic membrane. The normal control group received isovolumetric injection of 9 g/L physiological saline solution using the same method. Blood samples from the rats in each group were obtained via the superior mesenteric vein to measure the levels of IL-2, IL-10 and sFas, and to calculate the value of IL-2/IL-10. The levels of IL-2, IL-10 and sFas were determined by ELISA. The severity of pancreas and intestinal mucosal injury was evaluated by pathologic score. The expression of Fas in intestinal mucosal tissue was determined by immunohistochemistry.
RESULTS: The levels of serum IL-2 in the SAP group were significantly higher than those in the normal control group at 0.5 h after injury (3.53 ± 0.62 ng/L vs 2.79 ± 0.51 ng/L, 4.35 ± 1.11 ng/L vs 2.93 ± 0.89 ng/L, 6.94 ± 1.55 ng/L vs 4.81 ± 1.23 ng/L, 4.80 ± 1.10 ng/L vs 3.41 ± 0.72 ng/L, P < 0.01) and peaked at 6 h after injury. The levels of serum IL-10 in the SAP group were significantly higher than those in the normal control group at 6 h after injury (494.98 ± 11.23 ng/L vs 89.18 ± 32.52 ng/L, 93.28 ± 25.81 ng/L vs 77.15 ± 22.60 ng/L, P < 0.01). The IL-2/IL-10 ratio in the SAP group was significantly higher than that in the normal control group at 0.5 h and 2 h after injury, and significantly lower than that in the normal control group at 6 h after injury (P < 0.01), after which this ratio returned to the control level (P > 0.05). The pathological changes were significantly aggravated in the SAP group compared with the normal group. Immunohistochemistry staining showed. Fas from normal intestinal tissue. Fas expression in intestinal tissue gradually increased 0.5 h after the induction of pancreatitis, and its a peak at 12 h after induction.
CONCLUSION: Fas is involved in the pathogenesis of pancreatitis-associated intestinal injury. The mechanisms underlying this involvement of Fas may be related to Fas-mediated T helper cell apoptosis.
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Abstract
Biliary cancer comprise carcinoma of the gallbladder as well as the intrahepatic, hilar and extrahepatic bile ducts. Furthermore, many different etiologies and risk factors are contributing to the inhomogeneity of this disease. It is often diagnosed at an advanced stage when potentially curative resection is not feasible. Due to the lack of randomised Phase III studies, there is no standard regimen for chemotherapy in biliary cancer. Recent investigations into the underlying molecular mechanisms involved in biliary carcinogenesis and tumour growth have contributed greatly to our understanding of biliary cancer. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic and preventive strategies may be developed. Although fluoropyrimidines and gemcitabine remain the backbone of routine chemotherapy in advanced disease, new agents such as epidermal growth factor receptor blockers and angiogenesis inhibitors may hold promise for improving the outcome for patients with biliary cancer.
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Affiliation(s)
- Florian Eckel
- Technical University of Munich, Department of Internal Medicine, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany.
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Zhong B, Strnad P, Toivola DM, Tao GZ, Ji X, Greenberg HB, Omary MB. Reg-II is an exocrine pancreas injury-response product that is up-regulated by keratin absence or mutation. Mol Biol Cell 2007; 18:4969-78. [PMID: 17898082 PMCID: PMC2096595 DOI: 10.1091/mbc.e07-02-0180] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The major keratins in the pancreas and liver are keratins 8 and 18 (K8/K18), but their function seemingly differs in that liver K8/K18 are essential cytoprotective proteins, whereas pancreatic K8/K18 are dispensable. This functional dichotomy raises the hypothesis that K8-null pancreata may undergo compensatory cytoprotective gene expression. We tested this hypothesis by comparing the gene expression profile in pancreata of wild-type and K8-null mice. Most prominent among the up-regulated genes in K8-null pancreas was mRNA for regenerating islet-derived (Reg)-II, which was confirmed by quantitative reverse transcription-polymerase chain reaction and by an anti-Reg-II peptide antibody we generated. Both K8-null and wild-type mice express Reg-II predominantly in acinar cells as determined by in situ hybridization and immunostaining. Analysis of Reg-II expression in various keratin-related transgenic mouse models showed that its induction also occurs in response to keratin cytoplasmic filament collapse, absence, or ablation of K18 Ser52 but not Ser33 phosphorylation via Ser-to-Ala mutation, which represent situations associated with predisposition to liver but not pancreatic injury. In wild-type mice, Reg-II is markedly up-regulated in two established pancreatitis models in response to injury and during the recovery phase. Thus, Reg-II is a likely mouse exocrine pancreas cytoprotective candidate protein whose expression is regulated by keratin filament organization and phosphorylation.
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Affiliation(s)
- Bihui Zhong
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
- Division of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China; and
| | - Pavel Strnad
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
| | - Diana M. Toivola
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
- Biosciences, Department of Biology, Abo Akademi University, FI-20520, Turku, Finland
| | - Guo-Zhong Tao
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
| | - Xuhuai Ji
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
| | - Harry B. Greenberg
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
| | - M. Bishr Omary
- *Department of Medicine, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA 94304
- Stanford University Digestive Disease Center, Stanford, CA 94305
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Wang KN, Xu M. Relationship of toll-like receptor 4, nuclear factor kappa B and acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2007; 15:2684-2689. [DOI: 10.11569/wcjd.v15.i25.2684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is a serious commonly-occurring disease. Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) are closely related to the activation of many cytokines that have important roles in the occurrence and development of AP. It is already acknowledged that TLR4 and NF-κB have roles in the pathogenesis of acute necrotizing pancreatitis (ANP) because they are essential in the inducing and mediating of inflammation. It is thought that TLR4 induces LPS signaling, which leads to the activation and translocation of NF-κB, and then stimulates the production of proinflammatory cytokines that result in the occurrence of inflammation. Recently, however, new concepts about the specific signaling pathway of TLR4/NF-κB and the factors participating in it have been proposed. This review summarizes the TLR4/NF-κB signaling pathway and outlines the factors that can down- or up-regulate TLR4/NF-κB expression and other factors that activate NF-κB.
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Letoha T, Fehér LZ, Pecze L, Somlai C, Varga I, Kaszaki J, Tóth G, Vizler C, Tiszlavicz L, Takács T. Therapeutic proteasome inhibition in experimental acute pancreatitis. World J Gastroenterol 2007; 13:4452-7. [PMID: 17724800 PMCID: PMC4611577 DOI: 10.3748/wjg.v13.i33.4452] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.
METHODS: Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 × 100 μg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.
RESULTS: Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-κB (NF-κB).
Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.
CONCLUSION: Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.
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Affiliation(s)
- Tamás Letoha
- Department of Medical Chemistry, University of Szeged, Dom ter 8, H-6720, Szeged, Hungary.
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Li YY, Sibaev A, Zhou MZ, Zhu GY, Yüce B, Storr M. The Chinese herbal preparation Qing Yi Tang (QYT) improves intestinal myoelectrical activity and increases intestinal transit during acute pancreatitis in rodents. Phytother Res 2007; 21:324-31. [PMID: 17199239 DOI: 10.1002/ptr.2071] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The aim was to investigate alterations of intestinal motility in models of acute pancreatitis and to investigate the effects of the Chinese herbal preparation Qing Yi Tang (QYT) on these alterations. Upper gastrointestinal transit was evaluated in mice following induction of mild acute pancreatitis (MAP) using caerulein. Myoelectrical activity was recorded in rats after induction of severe acute pancreatitis (SAP) using sodium deoxycholate (SDOC). The contractility of jejunum segments was evaluated in the presence of SDOC, lipopolysaccharide (LPS) and trypsin. QYT accelerated the transit in MAP mice in a concentration dependent manner. Slow wave activity of smooth muscle in rat stomach and jejunum remained unchanged following SAP, but the spiking activity was significantly decreased, with bursts of 7.2 +/- 2.6/10 min compared with 47.9 +/- 13.2/10 min without SAP (p < 0.01). QYT reversed this decrease. Additionally, the amplitudes of slow waves and spikes were enhanced by QYT in SAP rats. The tension and amplitude of spontaneous contractile activity was reduced by SDOC and LPS and increased by trypsin. Gastrointestinal (GI) transit is altered by SAP but not by MAP. The Chinese herbal preparation QYT improves disturbed motility in AP by stimulating myoelectrical activity and accelerating GI transit.
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Affiliation(s)
- Yong-Yu Li
- Department of Pathophysiology, School of Medicine, Tongji University, 200092 Shanghai, China.
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Van Acker GJD, Perides G, Weiss ER, Das S, Tsichlis PN, Steer ML. Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis. J Biol Chem 2007; 282:22140-9. [PMID: 17537724 DOI: 10.1074/jbc.m702225200] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Pancreatic and lung inflammation during acute pancreatitis is a poorly understood, but clinically important, phenomenon. The proto-oncogene Tpl2 (tumor progression locus-2) has recently been shown to have important immunomodulatory effects on some inflammatory processes, but its importance to pancreatitis has not been previously examined. Our studies were designed to (a) define the effects of Tpl2 on pancreatic and lung inflammation during pancreatitis and (b) identify mechanisms and cell types responsible for those effects. We examined pancreatitis-associated Tpl2 effects in wild type and Tpl2(-/-) mice subjected to either secretagogue-induced or bile salt-induced pancreatitis. To determine the myeloid or non-myeloid lineage of cells responsible for the Tpl2 effects, we used Tpl2(-/-) chimeric mice generated by lethal irradiation followed by bone marrow transplantation. Mechanisms responsible for the effects of Tpl2 ablation on caerulein-induced proinflammatory events were evaluated under in vivo and in vitro conditions using the techniques of electrophoretic mobility shift assay, immunoblot analysis, and quantitative reverse transcription-PCR. We found that Tpl2 ablation markedly reduced pancreatic and lung inflammation in these two dissimilar models of pancreatitis, but it did not alter pancreatic injury/necrosis in either model. The reduction in caerulein-induced pancreatic inflammation is dependent upon Tpl2 ablation in non-myeloid cells and is associated with both in vivo and in vitro inhibition of MEK, JNK, and AP-1 activation and the expression of MCP-1, MIP-2, and interleukin-6. Non-myeloid cell expression of Tpl2 regulates pancreatic inflammation during pancreatitis by mediating proinflammatory signals and the generation of neutrophil chemoattracting factors.
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Affiliation(s)
- Gijs J D Van Acker
- Department of Surgery, Tufts University School of Medicine, Boston, MA 02111, USA
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48
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Baumann B, Wagner M, Aleksic T, von Wichert G, Weber CK, Adler G, Wirth T. Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. J Clin Invest 2007; 117:1502-13. [PMID: 17525799 PMCID: PMC1868787 DOI: 10.1172/jci30876] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2006] [Accepted: 03/20/2007] [Indexed: 01/01/2023] Open
Abstract
Activation of the inhibitor of NF-kappaB kinase/NF-kappaB (IKK/NF-kappaB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-kappaB target genes, including mediators of the inflammatory response such as TNF-alpha and ICAM-1. Indeed, inhibition of TNF-alpha activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-kappaB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease.
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Affiliation(s)
- Bernd Baumann
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Martin Wagner
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Tamara Aleksic
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Götz von Wichert
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Christoph K. Weber
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Guido Adler
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
| | - Thomas Wirth
- Institute of Physiological Chemistry and
Department of Internal Medicine I, University of Ulm, Ulm, Germany
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Kageyama S, Gunji W, Nakasato M, Murakami Y, Nagata M, Aoki F. Analysis of transcription factor expression during oogenesis and preimplantation development in mice. ZYGOTE 2007; 15:117-28. [PMID: 17462104 DOI: 10.1017/s096719940700411x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
SummaryThe transition from a differentiated germ cell into a totipotent zygote during oogenesis and preimplantation development is critical to the creation of a new organism. During this period, cell characteristics change dynamically, suggesting that a global alteration of gene expression patterns occurs, which is regulated by global changes in various epigenetic factors. Among these, transcription factors (TFs) are essential in the direct regulation of transcription and also play important roles in determining cell characteristics. However, no comprehensive analysis of TFs from germ cells to embryos had been undertaken. We used mRNA amplification systems and microarrays to conduct a genomewide analysis of TFs at various stages of oogenesis and preimplantation development. The greatest alteration in TFs occurred between the 1- and 2-cell stages, at which time zygotic genome activation (ZGA) occurs. Our analysis of TFs classified by structure and function revealed several specific patterns of change. Basic transcription factors, which are the general components of transcription, increased transiently at the 2-cell stage, while homeodomain (HD) TFs were expressed specifically in the oocyte. TFs containing the Rel homology region (RHR) and Ets domains were expressed at a high level in 2-cell and blastocyst embryos. Thus, the global TF dynamics that occur during oogenesis and preimplantation development seem to regulate the transition from germ-cell-type to embryo-type gene expression.
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Affiliation(s)
- S Kageyama
- Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba 277-8562, Japan
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Xue D, Zhang W, Zhang Y, Wang H, Zheng B, Shi X. Adjusting effects of baicalin for nuclear factor-kappaB and tumor necrosis factor-alpha on rats with caerulein-induced acute pancreatitis. Mediators Inflamm 2007; 2006:26295. [PMID: 17392571 PMCID: PMC1657078 DOI: 10.1155/mi/2006/26295] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Forty Wistar rats were divided into 5 groups, including the control group, the acute pancreatitis group (AP group, induced by intraperitoneal injections of caerulein), and the AP group treated with baicalin, the AP group treated with LPS, and the AP group treated with LPS and baicalin. Pathological damage of pancreatic tissue was scored with hematoxylin and eosin (HE) staining. The mRNA expression of TNF-α was measured with semiquantitative RT-PCR, and activation of NF-κB was detected with flow cytometry assay. It was shown in the results that the expression of TNF-α mRNA, activation of NF-κB, and pathological score of AP group were all obviously higher than those of control group (P < .01). In AP group treated with LPS, further rise of these values were observed (P < .01). In the AP group treated with baicalin, activation of NF-κB decreased (P < .05), and expression of TNF-α mRNA also obviously decreased (P < .01), while pancreatic pathological damage was alleviated at the same time (P < .01); similar results were observed in AP group treated with LPS and baicalin (P < .01), which indicated that baicalin might be applied to inhibit NF-κB activating and TNF-α expressing so as to treat AP.
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Affiliation(s)
- Dongbo Xue
- Department of General Surgery, First Clinical College, Harbin Medical University, Harbin 150001, China
| | - Weihui Zhang
- Department of General Surgery, First Clinical College, Harbin Medical University, Harbin 150001, China
- *Weihui Zhang:
| | - Yingmei Zhang
- Central Laboratory, First Clinical College, Harbin Medical University, Harbin 150001, China
| | - Haiyang Wang
- Department of General Surgery, First Clinical College, Harbin Medical University, Harbin 150001, China
| | - Biao Zheng
- Department of General Surgery, First Clinical College, Harbin Medical University, Harbin 150001, China
| | - Xingye Shi
- Department of General Surgery, First Clinical College, Harbin Medical University, Harbin 150001, China
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