|
1
|
Mostafa RE, Shaffie NM, Allam RM. Panax Ginseng alleviates thioacetamide-induced liver injury in ovariectomized rats: Crosstalk between inflammation and oxidative stress. PLoS One 2021; 16:e0260507. [PMID: 34843587 PMCID: PMC8629276 DOI: 10.1371/journal.pone.0260507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/09/2021] [Indexed: 12/21/2022] Open
Abstract
Liver diseases impose a substantial health problem. Female hormones play a crucial role in the protection against chronic inflammatory diseases. Fifty female rats were allocated into five groups (n = 10). Group I comprised sham-operated rats. The remaining groups underwent ovariectomy at the beginning of the experiment. Group II served as the ovariectomy-control group. Groups III, IV & V received thioacetamide (TAA; 300 mg/kg; i.p.) to induce liver injury 6 weeks after ovariectomy. Group III served as the TAA-control group. Groups IV & V received panax ginseng (100 and 300 mg/kg/day, p.o.) for 6 weeks post TAA administration. All groups were investigated for liver function tests along with total antioxidant capacity (TAC), tumor necrosis factor-α (TNF-α) and advanced glycation end products (AGEs). Histopathological examination of liver tissues was performed followed by immunohistochemical staining for nuclear factor kappa-B (NF-kβ p65) and myeloperoxidase (MPO). Ovariectomized-rats showed a non-significant change in the measured parameters while TAA administration resulted in significant liver damage. Panax ginseng at both dose levels significantly improved the serum liver function tests and TAC along with decreasing the AGEs and TNF-α. It also restored the histopathological picture of liver tissue and decreased hepatic tissue inflammation via reduction of MPO and NF-kβ p65 immunoreactivity. The current study is the first to elucidate the effect of panax ginseng against TAA-induced liver injury in ovariectomized rats which mimic aged post-menopausal estrogen-deficient females. The study demonstrates the crosstalk between AGEs, NF-kβ and MPO in the modulation of inflammation. Panax ginseng possesses antioxidant and anti-inflammatory properties.
Collapse
Affiliation(s)
- Rasha E. Mostafa
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Nermeen M. Shaffie
- Department of Pathology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Rasha M. Allam
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| |
Collapse
|
|
2
|
Kandikattu HK, Venkateshaiah SU, Mishra A. Chronic Pancreatitis and the Development of Pancreatic Cancer. Endocr Metab Immune Disord Drug Targets 2021; 20:1182-1210. [PMID: 32324526 DOI: 10.2174/1871530320666200423095700] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/31/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.
Collapse
Affiliation(s)
- Hemanth K Kandikattu
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Sathisha U Venkateshaiah
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Anil Mishra
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| |
Collapse
|
|
3
|
Ricardo Carvalho VP, Figueira da Silva J, Buzelin MA, Antônio da Silva Júnior C, Carvalho Dos Santos D, Montijo Diniz D, Binda NS, Borges MH, Senna Guimarães AL, Rita Pereira EM, Gomez MV. Calcium channels blockers toxins attenuate abdominal hyperalgesia and inflammatory response associated with the cerulein-induced acute pancreatitis in rats. Eur J Pharmacol 2021; 891:173672. [PMID: 33190801 DOI: 10.1016/j.ejphar.2020.173672] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 11/26/2022]
Abstract
Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2-blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins-antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats.
Collapse
Affiliation(s)
| | - Juliana Figueira da Silva
- Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Marcelo Araújo Buzelin
- Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | | | - Duana Carvalho Dos Santos
- Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Danuza Montijo Diniz
- Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Nancy Scardua Binda
- Laboratório de Farmacologia, Departamento de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | | | - André Luiz Senna Guimarães
- Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Montes Claros, Montes Claros, MG, Brazil
| | - Elizete Maria Rita Pereira
- Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil
| | - Marcus Vinicius Gomez
- Nucleo de Pós-graduação, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil.
| |
Collapse
|
|
4
|
Koliakos NN, Renieris G, Sotiropoulos D, Pavlou K, Droggiti DE, Gkavogianni T, Charalampopoulos A, Giamarellos-Bourboulis EJ. Immunomodulation Through Beta-D-glucan in Chemically-induced Necrotizing Pancreatitis. J Surg Res 2021; 261:74-84. [PMID: 33421796 DOI: 10.1016/j.jss.2020.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 11/19/2020] [Accepted: 12/07/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND Although the ability of β-D-glucan and monophosphoryl lipid A (MPLA) to modulate immune responses has been studied in human primary cells, their effect on sterile inflammation models such as necrotizing pancreatitis has never been investigated. MATERIALS AND METHODS 85 male New Zealand rabbits were assigned into following groups: A: control, B: pretreatment with β-D-glucan 3 d before pancreatitis, C: pretreatment with MPLA 3 d before pancreatitis, D: pretreatment with β-D-glucan and laminarin 3 d before pancreatitis, E: treatment with β-D-glucan 1 d after pancreatitis, and F: MPLA 1 d after pancreatitis. Pancreatitis was induced by sodium taurocholate injection into the pancreatic duct and parenchyma. Survival was recorded for 21 d. On days 1, 3, and 7, blood was collected for amylase measurement. Peripheral blood mononuclear cells were isolated and stimulated for tumor necrosis factor alpha and interleukin 10 production. Pancreatic necrosis and tissue bacterial load were assessed. RESULTS 21-d survival was prolonged after pretreatment or treatment with β-D-glucan; this benefit was lost with laminarin administration. At sacrifice, pancreatic inflammatory alterations were more prominent in the control group. Bacterial load was lower after pretreatment or treatment with β-D-glucan and MPLA. Tumor necrosis factor alpha production from stimulated peripheral blood mononuclear cells was significantly decreased, whereas interleukin 10 production remained unaltered after pretreatment or treatment with β-D- glucan. CONCLUSIONS β-D-glucan reduces mortality of experimental pancreatitis in vivo. This is mediated through attenuation of cytokine production and prevention of bacterial translocation.
Collapse
Affiliation(s)
- Nikolaos N Koliakos
- 3rd Department of Surgery, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Georgios Renieris
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Dimitrios Sotiropoulos
- 3rd Department of Surgery, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Kalliopi Pavlou
- Department of Pathology, Evangelismos Hospital, Athens, Greece
| | - Dionysia-Eirini Droggiti
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Theologia Gkavogianni
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Anestis Charalampopoulos
- 3rd Department of Surgery, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | | |
Collapse
|
|
5
|
Serum TLR9 and NF- κB Biochemical Markers in Patients with Acute Pancreatitis on Admission. Emerg Med Int 2020; 2020:1264714. [PMID: 32076577 PMCID: PMC7016400 DOI: 10.1155/2020/1264714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/14/2022] Open
Abstract
Aim The aim of this study was to investigate the serum TLR9 and NF-κB levels in patients for the diagnosis and prognostication of AP in the emergency department. Methods In the current study, we looked at the TLR9 and NF-κB levels in patients for the diagnosis and prognostication of AP in the emergency department. Results Of the patients with acute pancreatitis, 22 (49%) were male and 23 (51%) were female. The mean age of the patient group was 62 years, with a range of 25-95 years. The control group consisted of 19 (43.1%) male and 25 (56.9%) female patients. The serum TLR9 and NF-κB levels in patients for the diagnosis and prognostication of AP in the emergency department. p < 0.001 and 8.04 ± 1.76 vs. 4.76 ± 1.13; p < 0.001 and 8.04 ± 1.76 vs. 4.76 ± 1.13; κB levels in patients for the diagnosis and prognostication of AP in the emergency department. p < 0.001 and 8.04 ± 1.76 vs. 4.76 ± 1.13; κB levels in patients for the diagnosis and prognostication of AP in the emergency department. p < 0.001 and 8.04 ± 1.76 vs. 4.76 ± 1.13. Conclusion We demonstrated that the TLR9 and NF-κB pathway is activated in acute pancreatitis and increases the inflammatory process. This may help to further understand the pathogenesis of disorder, diagnosis, and clinical severity. We proposed that blockage of these inflammatory pathways may play a role in the prevention of the disease progression and development of inflammatory complications.κB levels in patients for the diagnosis and prognostication of AP in the emergency department.
Collapse
|
|
6
|
Godugu C, Pasari LP, Khurana A, Anchi P, Saifi MA, Bansod SP, Annaldas S. Crocin, an active constituent of
Crocus sativus
ameliorates cerulein induced pancreatic inflammation and oxidative stress. Phytother Res 2019; 34:825-835. [DOI: 10.1002/ptr.6564] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 10/08/2019] [Accepted: 11/06/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Chandraiah Godugu
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| | - Lakshmi P. Pasari
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| | - Amit Khurana
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| | - Pratibha Anchi
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| | - Mohd A. Saifi
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| | - Sapana P. Bansod
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| | - Shivaraju Annaldas
- Department of Regulatory ToxicologyNational Institute of Pharmaceutical Education and Research Balanagar, Hyderabad Telangana India
| |
Collapse
|
|
7
|
Munir F, Jamshed MB, Shahid N, Muhammad SA, Bhandari A, Zhang Q. Protective effects of maresin 1 against inflammation in experimentally induced acute pancreatitis and related lung injury. Am J Physiol Gastrointest Liver Physiol 2019; 317:G333-G341. [PMID: 31125268 DOI: 10.1152/ajpgi.00078.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Severe acute pancreatitis (SAP) is an inflammatory disorder that progresses with local and systemic difficulties accompanied by a relatively high mortality rate. In recent years, maresin 1 (MaR1) has been shown to be a macrophage mediator with effective proresolving and anti-inflammatory properties that prevents the occurrence of various inflammatory conditions. The purpose of this study was to investigate the role of MaR1 in SAP and related lung injury. Experimental SAP was induced in mice with a combination of cerulean and lipopolysaccharide. MaR1 was administered 30 min before the primary injection of cerulean. Biochemical markers and histological injury scores were used to evaluate the severity of acute pancreatitis. To determine the degree of inflammation, serum cytokines and myeloperoxidase activity in pancreas and lung tissues were measured. Western blot analysis detected the activation of NF-κB. After MaR1 pretreatment, the activities of amylase, lipase, TNF-α, IL-1β, and IL-6 were decreased in serum, and the myeloperoxidase activity both in pancreas and in lung tissues significantly decreased, whereas the activity of anti-inflammatory cytokine IL-10 in serum was increased. MaR1-pretreated mice reduced the activation of pancreatic NF-κB and decreased the severity of pancreatic and lung-related injuries. These results confirm that MaR1 alleviated inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimentally induced acute pancreatitis and exerted anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of SAP.NEW & NOTEWORTHY These results provided us evidence to confirm that maresin 1 (MaR1) can alleviate inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimental induced acute pancreatitis and exerts certain anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of severe acute pancreatitis.
Collapse
Affiliation(s)
- Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Muhammad Babar Jamshed
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Numan Shahid
- Department of General Surgery, The School of International Studies of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahaudin Zakariya University, Multan, Punjab, Pakistan
| | - Adheesh Bhandari
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - QiYu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| |
Collapse
|
|
8
|
Zhao G, Zhuo YZ, Cui LH, Li CX, Chen SY, Li D, Liu JH, Li DH, Cui NQ, Zhang SK. Modified Da-chai-hu Decoction regulates the expression of occludin and NF-κB to alleviate organ injury in severe acute pancreatitis rats. Chin J Nat Med 2019; 17:355-362. [PMID: 31171270 DOI: 10.1016/s1875-5364(19)30041-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Indexed: 02/07/2023]
Abstract
Modified Da-chai-hu Decoction (MDD), a traditional Chinese medicinal formulation, which was empirically generated from Da-chai-hu decoction, has been utilized to treat severe acute pancreatitis (SAP) for decades. The aim of the present study was to explore its potential organprotective mechanism in SAP. In the present study, rat SAP model was induced by retrograde injection of 3.5% sodium taurocholate into the biliopancreatic duct, MDD (23.35 g/kg body weight, twelve times the clinical dose) were orally given at 2 h before and 10 h after injection. At 12 h after model induction, blood was taken from vena cava for analysis of amylase, diamine oxidase (DAO), pulmonary surfactant protein-A (SP-A), and C-reactive protein (CRP). Histopathological change of pancreas, ileum and lung was assayed by H&E staining, myeloperoxidase (MPO) activity were determinated using colorimetric assay, and the expressions of occludin and nuclear factor-κB (NF-κB) were detected by real-time RT-PCR and western blot, respectively. In addition, the tissue concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that in SAP rats, MDD significantly alleviated histopathological damage, depressed the MPO activity and the concentrations of TNF-α, IL-1β, and MCP-1 of pancreas, ileum and lung, and reduced the serum levels of amylase [(3283.4 ± 585.5) U·L-1vs (5626.4 ± 795.1)U·L-1], DAO [(1100.1 ± 334.3) U·L-1vs (1666.4 ± 525.3) U·L-1] and CRP [(7.6 ± 1.2) μg·mL-1vs (17.8 ± 3.8) μg·mL-1]. However, the serum SP-A concentration [(106.1 ± 16.6) pg·mL-1vs (90.1 ± 14.9) pg·mL-1] was elevated when treated SAP rats with MDD. Furthermore, MDD increased the occludin expression and reduced the NF-κB expression in pancreas, ileum and lung of SAP rats. Our findings suggested that MDD administration was an effective therapeutic approach for SAP treatment. It could up-regulate occludin expression to protect intercellular tight junction and down-regulate NF-κB expression to inhibit inflammatory reaction of pancreas, ileum and lung.
Collapse
Affiliation(s)
- Guang Zhao
- Hepatobiliary and Pancreatic Surgery, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China; Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China
| | - Yu-Zhen Zhuo
- Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China; Institute of Integrated Traditional Chinese and Western medicine, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China
| | - Li-Hua Cui
- Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China; Institute of Integrated Traditional Chinese and Western medicine, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China
| | - Cai-Xia Li
- Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China; Institute of Integrated Traditional Chinese and Western medicine, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China
| | - Sha-Yan Chen
- Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China; Department of Clinical Laboratory, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China
| | - Dan Li
- Hepatobiliary and Pancreatic Surgery, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China; Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China
| | - Jun-Hong Liu
- Institute of Integrated Traditional Chinese and Western medicine, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China
| | - Di-Hua Li
- Institute of Integrated Traditional Chinese and Western medicine, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China
| | - Nai-Qiang Cui
- Hepatobiliary and Pancreatic Surgery, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China; Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China
| | - Shu-Kun Zhang
- Nankai Clinical College, Tianjin Medical University, Tianjin 300107, China; Institute of Integrated Traditional Chinese and Western medicine, Tianjin Nankai Hospital, Tianjin Hospital of Integrated Traditional Chinese and Western medicine, Tianjin 300100, China.
| |
Collapse
|
|
9
|
Merry TL, Petrov MS. The rise of genetically engineered mouse models of pancreatitis: A review of literature. Biomol Concepts 2018; 9:103-114. [DOI: 10.1515/bmc-2018-0011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022] Open
Abstract
AbstractPancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans.
Collapse
Affiliation(s)
- Troy L. Merry
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Maxim S. Petrov
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
10
|
Tiruveedi VL, Bale S, Khurana A, Godugu C. Withaferin A, a novel compound of Indian ginseng (Withania somnifera), ameliorates Cerulein-induced acute pancreatitis: Possible role of oxidative stress and inflammation. Phytother Res 2018; 32:2586-2596. [PMID: 30307087 DOI: 10.1002/ptr.6200] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/29/2018] [Accepted: 08/27/2018] [Indexed: 02/06/2023]
Abstract
Acute pancreatitis is an inflammatory disorder of the pancreas that may precipitate due to various reasons such as chronic alcoholism, gall stone obstruction, and life style. Current treatment options offer limited efficacy, as they provide only symptomatic relief. This study is an attempt to study the effects of Withaferin A (WFA) against Cerulein-induced acute pancreatitis in mice. Animals were pretreated with WFA via intraperitoneal route, for 7 days. Plasma amylase and lipase, tissue malondialdehyde (MDA), and glutathione were evaluated for all groups. Western blot analysis; haematoxylin and eosin staining of the liver, lung, and pancreas; immunohistochemistry for nitrotyrosine; and myeloperoxidase activity were performed. Haematoxylin and eosin stained sections significantly revealed the altered architecture and thereby damage in the pancreas, lungs, and liver that has been low in treatment groups. Increased myeloperoxidase and nitrotyrosine have also been reduced upon treatment with WFA. Increased levels of MDA, NO, and expression of myeloperoxidase and nitrotyrosine in the parameters estimated add evidence to the role of oxidative stress and inflammation in acute pancreatitis. WFA evidently altered these conditions upon pretreatment. Our study shows that this novel steroidal compound has potent anti-inflammatory property. Natural compounds can therefore be good remedies against many diseases if incorporated in routine diet as dietary supplement.
Collapse
Affiliation(s)
- Vijaya Lakshmi Tiruveedi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Swarna Bale
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Amit Khurana
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| |
Collapse
|
|
11
|
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.
Collapse
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)
| |
Collapse
|
|
12
|
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.
Collapse
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.
| |
Collapse
|
|
13
|
Immunopathogenesis of pancreatitis. Mucosal Immunol 2017; 10:283-298. [PMID: 27848953 DOI: 10.1038/mi.2016.101] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 10/06/2016] [Indexed: 02/04/2023]
Abstract
The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic- or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstream induction of T cells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.
Collapse
|
|
14
|
Abstract
OBJECTIVES Inflammation plays a key role in pancreatitis. Earlier studies from our laboratory showed that experimental pancreatitis activated the pancreatic apelin-APJ axis robustly in mice. Apelin signaling reduced neutrophil invasion and the activation of pancreatic nuclear factor (NF)-κB in mice with experimental pancreatitis. METHODS The aim of this study was to assess whether apelin-induced inhibition of pancreatic NF-κB activation was linked mechanistically to apelin's inhibition of pancreatic inflammatory mediator up-regulation in mice with cerulein-induced chronic pancreatitis (CP). Whether apelin's inhibitory effects were associated with the inhibition of NF-κB binding to the promoter region of IL-1β was examined. The effects of apelin exposure on pancreatic IκB degradation/replenishment and membrane levels of phosphorylated protein kinase C were measured. RESULTS Results demonstrated that apelin inhibited the up-regulation of pancreatic tumor necrosis factor α, macrophage inflammatory protein-1 α/β, and IL-1β expression significantly in mice with CP. Chromatin immunoprecipitation assay findings showed that apelin inhibited NF-κB binding to a putative NF-κB binding site in the IL-1β promoter. Apelin exposure reduced the pancreatic membrane levels of phosphorylated protein kinase C-δ and enhanced the replenishment of pancreatic IκB proteins. CONCLUSIONS Together, these findings indicated that the inhibition of NF-κB activation by apelin was a mechanism behind the reduced pancreatic levels of inflammatory mediators in CP mice exposed to apelin.
Collapse
|
|
15
|
Yuan P, He XH, Rong YF, Cao J, Li Y, Hu YP, Liu Y, Li D, Lou W, Liu MF. KRAS/NF-κB/YY1/miR-489 Signaling Axis Controls Pancreatic Cancer Metastasis. Cancer Res 2016; 77:100-111. [PMID: 27793842 DOI: 10.1158/0008-5472.can-16-1898] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 10/15/2016] [Accepted: 10/19/2016] [Indexed: 11/16/2022]
Abstract
KRAS activation occurring in more than 90% of pancreatic ductal adenocarcinomas (PDAC) drives progression and metastasis, but the underlying mechanisms involved in these processes are still poorly understood. Here, we show how KRAS acts through inflammatory NF-κB signaling to activate the transcription factor YY1, which represses expression of the tumor suppressor gene miR-489. In PDAC cells, repression of miR-489 by KRAS signaling inhibited migration and metastasis by targeting the extracellular matrix factors ADAM9 and MMP7. miR-489 downregulation elevated levels of ADAM9 and MMP7, thereby enhancing the migration and metastasis of PDAC cells. Together, our results establish a pivotal mechanism of PDAC metastasis and suggest miR-489 as a candidate therapeutic target for their attack. Cancer Res; 77(1); 100-11. ©2016 AACR.
Collapse
Affiliation(s)
- Peng Yuan
- Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, CAS Center for Excellence in Molecular Cell Science, Shanghai, China.,Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiao-Hong He
- Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, CAS Center for Excellence in Molecular Cell Science, Shanghai, China.,Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ye-Fei Rong
- Department of Pancreatic Surgery, Zhong Shan Hospital, Shanghai, China
| | - Jing Cao
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Yong Li
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Yun-Ping Hu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dangsheng Li
- Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Wenhui Lou
- Department of Pancreatic Surgery, Zhong Shan Hospital, Shanghai, China.
| | - Mo-Fang Liu
- Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, CAS Center for Excellence in Molecular Cell Science, Shanghai, China. .,Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| |
Collapse
|
|
16
|
Liu Y, Zhou D, Long FW, Chen KL, Yang HW, Lv ZY, Zhou B, Peng ZH, Sun XF, Li Y, Zhou ZG. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol 2016; 310:G303-9. [PMID: 26702138 DOI: 10.1152/ajpgi.00355.2014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 12/03/2015] [Indexed: 02/05/2023]
Abstract
Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.
Collapse
Affiliation(s)
- Yong Liu
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Zhou
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Fei-Wu Long
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Ke-Ling Chen
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hong-Wei Yang
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhao-Yin Lv
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Zhou
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi-Hai Peng
- Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China; and
| | - Xiao-Feng Sun
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Oncology, Department of Clinical and Experiment Medicine, Linköping University, Linköping, Sweden
| | - Yuan Li
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China;
| | - Zong-Guang Zhou
- Institute of Digestive Surgery and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
17
|
Abstract
Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas frequently associated with metabolic causes, contributing factors, or consequences, including hypertriglyceridemia, obesity, and disorders of intermediary metabolism, respectively. To date, there is no specific therapy for this disease. Future optimal therapy should correct both inflammatory and metabolic components of the disease. Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that control inflammatory and metabolic pathways via ligand-dependent and ligand-independent mechanisms. There are 3 known subtypes, PPAR-α, PPAR-β/δ, and PPAR-γ, which are differentially expressed in various tissues. The PPARs interact closely with other transcription factors such as nuclear factor κB and signal tranducers and activators of transcription that have pivotal roles in the pathobiology of AP. In this comprehensive review, we summarize the role of PPARs in AP, highlighting important in vitro and in vivo experimental findings. Finally, we propose future research directions as well as potential translational use of PPAR agonists in the treatment of AP.
Collapse
|
|
18
|
Wang Y, Liu W, Liu X, Sheng M, Pei Y, Lei R, Zhang S, Tao R. Role of liver in modulating the release of inflammatory cytokines involved in lung and multiple organ dysfunction in severe acute pancreatitis. Cell Biochem Biophys 2015; 71:765-76. [PMID: 25260395 DOI: 10.1007/s12013-014-0261-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The objective of this study was to understand the role of liver in modulating remote organ dysfunction during severe acute pancreatitis (SAP). We used sodium taurocholate and endotoxin to induce SAP in the rats and confirmed the development of this condition by measuring serum and ascite levels of the biomarkers of liver and lung damage. Our results showed that expression of tumor necrosis factor (TNF)-α was up-regulated sequentially, first in the gut, then in the liver, and finally in lung. Moreover, the SAP-induced increase in the expressions of TNF-α and IL-6 occurring in gut, liver, and lung was directly related to the increase in time. However, in liver and lung, the transcriptional activity of NF-κB and expression of TNF-α at 4 and 8 h were not increased. The distribution sequence of the pro-inflammatory cytokines to various organs was determined by their detection in the blood from portal vein and inferior vena cava. Although liver received TNF-α during 0.5-8 h of the SAP induction, the release of this cytokine into vena cava was not increased in this period of time. In conclusion, our results suggest that the aggravation of SAP leading to development of MODS exhibited the gut-liver-lung cytokine axis. Furthermore, this study indicates that liver performs both protective and stimulatory activities in the modulation of pro-inflammatory cytokine generation and their distribution to remote organs, such as lungs.
Collapse
Affiliation(s)
- Yilin Wang
- Center for Organ Transplantation and Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 7W Surgical Building, 197 2nd Ruijin Road, Shanghai, 200025, China
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Orabi AI, Sah S, Javed TA, Lemon KL, Good ML, Guo P, Xiao X, Prasadan K, Gittes GK, Jin S, Husain SZ. Dynamic imaging of pancreatic nuclear factor κB (NF-κB) activation in live mice using adeno-associated virus (AAV) infusion and bioluminescence. J Biol Chem 2015; 290:11309-20. [PMID: 25802340 PMCID: PMC4416837 DOI: 10.1074/jbc.m115.647933] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Indexed: 12/19/2022] Open
Abstract
Nuclear factor κB (NF-κB) is an important signaling molecule that plays a critical role in the development of acute pancreatitis. Current methods for examining NF-κB activation involve infection of an adenoviral NF-κB-luciferase reporter into cell lines or electrophoretic mobility shift assay of lysate. The use of adeno-associated viruses (AAVs) has proven to be an effective method of transfecting whole organs in live animals. We examined whether intrapancreatic duct infusion of AAV containing an NF-κB-luciferase reporter (AAV-NF-κB-luciferase) can reliably measure pancreatic NF-κB activation. We confirmed the infectivity of the AAV-NF-κB-luciferase reporter in HEK293 cells using a traditional luciferase readout. Mice were infused with AAV-NF-κB-luciferase 5 weeks before induction of pancreatitis (caerulein, 50 μg/kg). Unlike transgenic mice that globally express NF-κB-luciferase, AAV-infused mice showed a 15-fold increase in pancreas-specific NF-κB bioluminescence following 12 h of caerulein compared with baseline luminescence (p < 0.05). The specificity of the NF-κB-luciferase signal to the pancreas was confirmed by isolating the pancreas and adjacent organs and observing a predominant bioluminescent signal in the pancreas compared with liver, spleen, and stomach. A complementary mouse model of post-ERCP-pancreatitis also induced pancreatic NF-κB signals. Taken together these data provide the first demonstration that NF-κB activation can be examined in a live, dynamic fashion during pancreatic inflammation. We believe this technique offers a valuable tool to study real-time activation of NF-κB in vivo.
Collapse
Affiliation(s)
| | - Swati Sah
- From the Department of Pediatrics and
| | | | | | | | - Ping Guo
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Xiangwei Xiao
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Krishna Prasadan
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - George K Gittes
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | | | | |
Collapse
|
|
20
|
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]
|
|
21
|
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.
Collapse
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
| |
Collapse
|
|
22
|
McCorkell KA, May MJ. NEMO-binding domain peptide inhibition of inflammatory signal-induced NF-κB activation in vivo. Methods Mol Biol 2015; 1280:505-525. [PMID: 25736769 DOI: 10.1007/978-1-4939-2422-6_30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
NF-κB comprises a family of transcription factors that regulate the expression of diverse gene families essential for inflammatory and immune responses as well as cell survival and cell death pathways. Aberrant NF-κB transcriptional activity plays pivotal roles in a large number of human pathologies, including a variety of cancers and chronic inflammatory diseases. Therefore, there has been a large increase in studies aimed at identifying and testing drugs or small molecule inhibitors that would specifically block NF-κB activation in inflammatory diseases and cancer. In this chapter, we describe an in vivo system to test the inhibitory effects of the NEMO-binding domain (NBD) peptide on NF-κB activation specifically in the vascular endothelium and lymphocytes in mice. We demonstrate that pretreatment of mice with the NBD peptide reduces the NF-κB induced gene expression of cell adhesion molecules and DNA-binding activity following systemic LPS stimulation. These methods can be further used to test alternate inhibitors for effects on NF-κB signaling in murine endothelium and immune cells.
Collapse
Affiliation(s)
- Kelly A McCorkell
- Department of Animal Biology, The University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street (OVH 200E), Philadelphia, PA, 19104, USA
| | | |
Collapse
|
|
23
|
Immune Mechanisms of Pancreatitis. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00088-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
24
|
Li J, Yang WJ, Huang LM, Tang CW. Immunomodulatory therapies for acute pancreatitis. World J Gastroenterol 2014; 20:16935-16947. [PMID: 25493006 PMCID: PMC4258562 DOI: 10.3748/wjg.v20.i45.16935] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/24/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis.
Collapse
|
|
25
|
Pala HG, Erbas O, Pala EE, Artunc Ulkumen B, Akman L, Akman T, Oltulu F, Yavasoglu A. The effects of sunitinib on endometriosis. J OBSTET GYNAECOL 2014; 35:183-7. [DOI: 10.3109/01443615.2014.941345] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
26
|
Habineza Ndikuyeze G, Gaurnier-Hausser A, Patel R, Baldwin AS, May MJ, Flood P, Krick E, Propert KJ, Mason NJ. A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma. PLoS One 2014; 9:e95404. [PMID: 24798348 PMCID: PMC4010398 DOI: 10.1371/journal.pone.0095404] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 03/25/2014] [Indexed: 01/03/2023] Open
Abstract
Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.
Collapse
Affiliation(s)
- Georges Habineza Ndikuyeze
- Division of Hematology/Oncology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Anita Gaurnier-Hausser
- Office of Professional Studies in the Health Sciences, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Reema Patel
- Antech Diagnostics, New Hyde Park, New York, United States of America
| | - Albert S. Baldwin
- TheraLogics, Inc., Chapel Hill, North Carolina, United States of America
- Lineberger Comprehensive Cancer Center and Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Michael J. May
- Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Patrick Flood
- 7-020G Katz Centre for Pharmacy and Health Research, The University of Alberta, Edmonton, Alberta, Canada
| | - Erika Krick
- Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Kathleen J. Propert
- Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Nicola J. Mason
- Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- * E-mail:
| |
Collapse
|
|
27
|
The protective effects of Shen-Fu injection on experimental acute pancreatitis in a rat model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:248786. [PMID: 24738018 PMCID: PMC3964904 DOI: 10.1155/2014/248786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 01/24/2014] [Accepted: 01/31/2014] [Indexed: 01/03/2023]
Abstract
Objectives. In the present study, we investigated the protective effects of Shen-Fu injection (SFI) on a caerulein-induced rat pancreatitis (AP) model.
Methods. SFI was given to rats in the SFI treated group through intraperitoneal injection. Blood and pancreas samples were collected for serological and histopathological studies. Results. Our results showed that AP caused significant decrease in tissue glutathione (GSH) and serum IL-4 and IL-10, while pancreatic malondialdehyde (MDA) and myeloperoxidase (MPO) were increased. Furthermore, TNF-α, IL-1β, amylase, and lipase levels were also significantly increased. On the other hand, SFI treatment reserved all these biochemical indices as well as histopathologic alterations that were induced by caerulein.
Conclusion. Our findings suggest that the SFI protects against caerulein-induced AP in rats via modulation of cytokines, oxidative stress, and Nuclear Factor-kappa B (NF-κB) activity.
Collapse
|
|
28
|
Protective Effects of Sivelestat in a Caerulein-Induced Rat Acute Pancreatitis Model. Inflammation 2013; 36:1348-56. [DOI: 10.1007/s10753-013-9674-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
|
|
29
|
Muili KA, Jin S, Orabi AI, Eisses JF, Javed TA, Le T, Bottino R, Jayaraman T, Husain SZ. Pancreatic acinar cell nuclear factor κB activation because of bile acid exposure is dependent on calcineurin. J Biol Chem 2013; 288:21065-21073. [PMID: 23744075 DOI: 10.1074/jbc.m113.471425] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Biliary pancreatitis is the most common etiology of acute pancreatitis, accounting for 30-60% of cases. A dominant theory for the development of biliary pancreatitis is the reflux of bile into the pancreatic duct and subsequent exposure to pancreatic acinar cells. Bile acids are known to induce aberrant Ca(2+) signals in acinar cells as well as nuclear translocation of NF-κB. In this study, we examined the role of the downstream Ca(2+) target calcineurin on NF-κB translocation. Freshly isolated mouse acinar cells were infected for 24 h with an adenovirus expressing an NF-κB luciferase reporter. The bile acid taurolithocholic acid-3-sulfate caused NF-κB activation at concentrations (500 μm) that were associated with cell injury. We show that the NF-κB inhibitor Bay 11-7082 (1 μm) blocked translocation and injury. Pretreatment with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, the calcineurin inhibitors FK506 and cyclosporine A, or use of acinar cells from calcineurin Aβ-deficient mice each led to reduced NF-κB activation with taurolithocholic acid-3-sulfate. Importantly, these manipulations did not affect LPS-induced NF-κB activation. A critical upstream regulator of NF-κB activation is protein kinase C, which translocates to the membranes of various organelles in the active state. We demonstrate that pharmacologic and genetic inhibition of calcineurin blocks translocation of the PKC-δ isoform. In summary, bile-induced NF-κB activation and acinar cell injury are mediated by calcineurin, and a mechanism for this important early inflammatory response appears to be upstream at the level of PKC translocation.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Rita Bottino
- Internal Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Thotalla Jayaraman
- Internal Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | | |
Collapse
|
|
30
|
Luan ZG, Ma XC, Zhang H, Zhang C, Guo RX. Protective effect of ethyl pyruvate on pancreas injury in rats with severe acute pancreatitis. J Surg Res 2013; 181:76-84. [DOI: 10.1016/j.jss.2012.05.066] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Revised: 04/20/2012] [Accepted: 05/22/2012] [Indexed: 12/22/2022]
|
|
31
|
Chen J, Cai QP, Shen PJ, Yan RL, Wang CM, Yang DJ, Fu HB, Chen XY. Netrin-1 protects against L-Arginine-induced acute pancreatitis in mice. PLoS One 2012; 7:e46201. [PMID: 23029434 PMCID: PMC3459888 DOI: 10.1371/journal.pone.0046201] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Accepted: 08/28/2012] [Indexed: 12/28/2022] Open
Abstract
Acute pancreatitis (AP) is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with infiltration of leukocytes. The neuronal guidance protein, netrin-1, has been shown to control leukocyte trafficking and modulate inflammatory responses in several inflammation-based diseases. The present study was aimed toward investigating the effects of netrin-1 in an in vivo model of AP in mice. AP was induced in C57BL/6 mice by administration of two intraperitoneal injections of L-Arginine (4 g/kg). Mice were treated with recombinant mouse netrin-1 at a dose of 1 µg/mouse or vehicle (0.1% BSA) intravenously through the tail vein immediately after the second injection of L-Arginine, and every 24 h thereafter. Mice were sacrificed at several time intervals from 0 to 96 h after the induction of pancreatitis. Blood and tissue samples of pancreas and lung were collected and processed to determine the severity of pancreatitis biochemically and histologically. Immunohistochemical staining demonstrated that netrin-1 was mainly expressed in the islet cells of the normal pancreas and the AP model pancreas, and the pancreatic expression of netrin-1 was down-regulated at both the mRNA and protein levels during the course of AP. Exogenous netrin-1 administration significantly reduced plasma amylase levels, myeloperoxidase activity, pro-inflammatory cytokine production, and pancreas and lung tissue damages. Furthermore, netrin-1 administration did not cause significant inhibition of nuclear factor-kappa B activation in the pancreas of L-Arginine-induced AP. In conclusion, our novel data suggest that netrin-1 is capable of improving damage of pancreas and lung, and exerting anti-inflammatory effects in mice with severe acute pancreatitis. Thus, our results indicate that netrin-1 may constitute a novel target in the management of AP.
Collapse
Affiliation(s)
- Ji Chen
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qing-ping Cai
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pi-jie Shen
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Rong-lin Yan
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chang-ming Wang
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - De-jun Yang
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hong-bing Fu
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xue-yun Chen
- Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| |
Collapse
|
|
32
|
Gamble C, McIntosh K, Scott R, Ho KH, Plevin R, Paul A. Inhibitory kappa B Kinases as targets for pharmacological regulation. Br J Pharmacol 2012; 165:802-19. [PMID: 21797846 PMCID: PMC3312479 DOI: 10.1111/j.1476-5381.2011.01608.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 06/20/2011] [Accepted: 07/02/2011] [Indexed: 01/04/2023] Open
Abstract
The inhibitory kappa B kinases (IKKs) are well recognized as key regulators of the nuclear factor kappa B (NF-κB) cascade and as such represent a point of convergence for many extracellular agents that activate this pathway. The IKKs generally serve to transduce pro-inflammatory and growth stimulating signals that contribute to major cellular processes but also play a key role in the pathogenesis of a number of human diseases. Therefore, the catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. IKK isoforms are assembled as variable multi-subunit IKK complexes that regulate not only NF-κB dimers, but also protein substrates out-with this cascade. Consequently, close consideration of how these individual complexes transduce extracellular signals and more importantly what impact small molecule inhibitors of the IKKs have on functional outcomes are demanded. A number of adenosine triphosphate (ATP)-competitive IKKβ-selective inhibitors have been developed but have demonstrated a lack of activity against IKKα. A number of these chemicals have also exhibited detrimental outcomes such as cellular toxicity and immuno-suppression. The impact of small molecule inhibitors of IKK catalytic activity will therefore be reappraised, examining the advantages and potential disadvantages to this type of intervention strategy in the treatment of diseases such as arthritis, intestinal inflammation and cancer. Furthermore, we will outline some emerging strategies, particularly the disruption of protein-protein interactions within the IKK complex, as an alternative route towards the development of novel pharmacological agents. Whether these alternatives may negate the limitations of ATP-competitive molecules and potentially avoid the issues of toxicity will be discussed.
Collapse
Affiliation(s)
- Carly Gamble
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK
| | | | | | | | | | | |
Collapse
|
|
33
|
Bedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A, Ibrahim J, Cieza-Rubio NE, Henning JR, Barilla R, Rehman A, Pachter HL, Medina-Zea MV, Cohen SM, Frey AB, Acehan D, Miller G. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology 2011; 141:1915-26.e1-14. [PMID: 21801698 PMCID: PMC3202684 DOI: 10.1053/j.gastro.2011.07.033] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Revised: 06/21/2011] [Accepted: 07/18/2011] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS The cellular mediators of acute pancreatitis are incompletely understood. Dendritic cells (DCs) can promote or suppress inflammation, depending on their subtype and context. We investigated the roles of DC in development of acute pancreatitis. METHODS Acute pancreatitis was induced in CD11c.DTR mice using caerulein or L-arginine; DCs were depleted by administration of diphtheria toxin. Survival was analyzed using Kaplan-Meier method. RESULTS Numbers of major histocompatibility complex II(+)CD11c(+) DCs increased 100-fold in pancreata of mice with acute pancreatitis to account for nearly 15% of intrapancreatic leukocytes. Intrapancreatic DCs acquired a distinct immune phenotype in mice with acute pancreatitis; they expressed higher levels of major histocompatibility complex II and CD86 and increased production of interleukin-6, membrane cofactor protein-1, and tumor necrosis factor-α. However, rather than inducing an organ-destructive inflammatory process, DCs were required for pancreatic viability; the exocrine pancreas died in mice that were depleted of DCs and challenged with caerulein or L-arginine. All mice with pancreatitis that were depleted of DCs died from acinar cell death within 4 days. Depletion of DCs from mice with pancreatitis resulted in neutrophil infiltration and increased levels of systemic markers of inflammation. However, the organ necrosis associated with depletion of DCs did not require infiltrating neutrophils, activation of nuclear factor-κB, or signaling by mitogen-activated protein kinase or tumor necrosis factor-α. CONCLUSIONS DCs are required for pancreatic viability in mice with acute pancreatitis and might protect organs against cell stress.
Collapse
Affiliation(s)
- Andrea S. Bedrosian
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Andrew H. Nguyen
- Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Michael Hackman
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Michael K. Connolly
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Ashim Malhotra
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Junaid Ibrahim
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Napoleon E. Cieza-Rubio
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Justin R. Henning
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Rocky Barilla
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Adeel Rehman
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - H. Leon Pachter
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Marco V. Medina-Zea
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Steven M. Cohen
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Alan B. Frey
- Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - Devrim Acehan
- Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| | - George Miller
- Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016,Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016
| |
Collapse
|
|
34
|
|
|
35
|
Wu CX, Sun H, Liu Q, Guo H, Gong JP. LPS induces HMGB1 relocation and release by activating the NF-κB-CBP signal transduction pathway in the murine macrophage-like cell line RAW264.7. J Surg Res 2011; 175:88-100. [PMID: 21571302 DOI: 10.1016/j.jss.2011.02.026] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 02/06/2011] [Accepted: 02/09/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND High mobility group protein B1 (HMGB1) is an important late inflammatory mediator in sepsis. Understanding the mechanisms that regulate HMGB1 release from cells and their downstream signal transduction pathways may lead to the ability to develop anti-HMGB1 therapies to treat inflammation. MATERIALS AND METHODS We stimulated murine macrophage-like RAW 264.7 cells with lipopolysaccharide (LPS) and LPS+ ethylpyruvate (EP) and examined the resulting HMGB1 expression and release. We also studied the expression of related signal transduction factors (NF-κB, p38 MAPK, and CBP). RESULTS AND CONCLUSION Gene expression of HMGB1 mRNA in RAW264.7 cell showed no significant change at 0-18 h after stimulation with LPS, but increased significantly at 24, 36, and 48 h. HMGB1 mRNA expression in the LPS+EP group was significantly lower than in LPS alone. HMGB1 was distributed mainly in the nucleus; the cytoplasmic level was low before LPS stimulation. After stimulation with LPS, cytoplasmic HMGB1 increased gradually and plateaued at a high level at 12-48 h. Nuclear HMGB1 decreased gradually at 12-24 h, then increased, maintaining a comparatively high level at 36-48 h. EP prevented this pattern significantly. LPS induced p38 MAPK activation and NF-κB signal pathways first, followed by CBP activation. Activated CBP acetylated HMGB1 was stored in a crino-lysosome and secreted activated NF-κB resulted in increased transcription and synthesis of HMGB1, but the expression of up-regulated HMGB1 mRNA was delayed. Extracellular HMGB1 originated from early synthetic reserves present in the nucleus. New HMGB1 protein was synthesized in the nucleus and transferred into the cytoplasm, causing an increase in HMGB1 in the nucleus and cytoplasm. EP inhibits HMGB1 mRNA up-regulation and release from LPS- stimulated macrophages. The molecular function of EP is to attenuate the activation p38 MAPK, NF-κB, and CBP signaling pathways.
Collapse
Affiliation(s)
- Chuan-Xin Wu
- Department of Hepatobiliary Surgery, Chongqing Medical University, Second Affiliated Hospital, Chongqing, China
| | | | | | | | | |
Collapse
|
|
36
|
Abstract
OBJECTIVE It has long been recognized that autoimmunity is often associated with immunodeficiency. The mechanism underlying this paradox is not well understood. Bcl-3 (B-cell lymphoma 3) is an atypical member of the IκB (inhibitor of the nuclear factor-κB) family that is required for lymphoid organogenesis and germinal center responses. Mice deficient in Bcl-3 are immunodeficient because of the microarchitectural defects of their lymphoid organs. The goal of this study is to define the potential roles of Bcl-3 in type 1 diabetes. RESEARCH DESIGN AND METHODS Bcl-3-deficient NOD mice were generated by backcrossing Bcl-3-deficient C57BL/6 mice to NOD mice. Spontaneous and induced type 1 diabetes were studied in these mice by both pathologic and immunologic means. The effect of Bcl-3 on inflammatory gene transcription was evaluated in a promoter reporter assay. RESULTS We found that Bcl-3-deficient NOD and C57BL/6 mice were, paradoxically, more susceptible to autoimmune diabetes than wild-type mice. The increase in diabetes susceptibility was caused by Bcl-3 deficiency in hematopoietic cells but not nonhematopoietic cells. Bcl-3 deficiency did not significantly affect anti-islet Th1 or Th2 autoimmune responses, but markedly increased inflammatory chemokine and T helper 17 (Th17)-type cytokine expression. Upon transfection, Bcl-3 significantly inhibited the promoter activities of inflammatory chemokine and cytokine genes. CONCLUSIONS These results indicate that in addition to mediating lymphoid organogenesis, Bcl-3 prevents autoimmune diabetes by inhibiting inflammatory chemokine and cytokine gene transcription. Thus, a single Bcl3 gene mutation leads to both autoimmunity and immunodeficiency.
Collapse
MESH Headings
- Animals
- B-Cell Lymphoma 3 Protein
- Cell Differentiation
- Chemokines/genetics
- Crosses, Genetic
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Experimental/physiopathology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 1/prevention & control
- Gene Expression Regulation
- Genes, Reporter
- Genetic Predisposition to Disease
- Genotype
- Luciferases/genetics
- Major Histocompatibility Complex
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mutation
- Promoter Regions, Genetic
- Proto-Oncogene Proteins/deficiency
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription Factors/deficiency
- Transcription Factors/genetics
- Transcription Factors/physiology
Collapse
Affiliation(s)
- Qingguo Ruan
- From the Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Shi-Jun Zheng
- From the Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Scott Palmer
- From the Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Ruaidhri J. Carmody
- From the Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Youhai H. Chen
- From the Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- Corresponding author: Youhai H. Chen,
| |
Collapse
|
|
37
|
Liu SL, Liao WJ, Wu LQ. N-acetylcysteine protects against liver injury in rats with severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2010; 18:1046-1050. [DOI: 10.11569/wcjd.v18.i10.1046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [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 explore whether N-acetylcysteine (NAC) reduces liver injury in rats with severe acute pancreatitis (SAP).
METHODS: Fifty-four Sprague-Dawley rats were randomized into sham-operation group, SAP group and NAC treatment group. SAP was induced in rats by retrograde injection of 4% sodium taurocholate into the pancreatic duct. Rats in the NAC treatment group received an intravenous injection of NAC (200 mg/kg) one hour after sodium taurocholate injection. All the animals were sacrificed at 3, 6 and 12 h after SAP induction. The activation of nuclear factor-κB (NF-κB) in the liver was determined by immunohistochemistry. The hepatic expression of inducible nitric oxide synthase (iNOS) mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). Meanwhile, plasma amylase and liver function (ALT and AST) were measured.
RESULTS: SAP induction significantly enhanced NF-κB binding activity and up-regulated iNOS mRNA expression in the liver of rats. NAC treatment for different durations could significantly suppress the activation of NF-κB (3 h: 0.32 ± 0.05 vs 0.46 ± 0.04, 6 h: 0.56 ± 0.07 vs 0.97 ± 0.18 and 12 h: 0.87 ± 0.14 vs 1.13 ± 0.11, respectively; all P < 0.05) and reduce the levels of plasma amylase, ALT and AST.
CONCLUSION: NF-κB activation and iNOS mRNA expression are associated with liver injury in SAP. NAC protects against SAP-induced liver injury perhaps by blocking the activation of NF-κB.
Collapse
|
|
38
|
Yang B, Zeng WZ, Wu XL. Advances in research on the signaling pathways involved in activation and phenotypic transformation of hepatic stellate cells and their inhibitors. Shijie Huaren Xiaohua Zazhi 2009; 17:2283-2291. [DOI: 10.11569/wcjd.v17.i22.2283] [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
Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. It is believed that activation and phenotypic transformation of hepatic stellate cells (HSCs) play a central role in the development and resolution of liver fibrosis. Many cytokines and related signaling pathways are involved in the phenotypic transformation and proliferation of HSCs. In recent years, great advances have been made in the study of these signaling pathways and their specific inhibitors, thereby providing a new avenue for clinical therapy of liver fibrosis. However, as the mechanisms underlying the roles of these signaling pathways are very complicated, further intensive studies are still essential. In this article, we will review the advances in research on the signaling pathways involved in activation and phenotypic transformation of hepatic stellate cells and their inhibitors.
Collapse
|
|
39
|
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]
|
|
40
|
Liu XJ, Long YM, Chen K, Xie WR, Wang H. Inhibitory effects of cell-permeable PTD-NBD peptide on lipopolysaccharide-induced inflammation of pancreatic acinar cell line AR42J. Shijie Huaren Xiaohua Zazhi 2009; 17:1931-1935. [DOI: 10.11569/wcjd.v17.i19.1931] [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
AIM: To explore the effects of cell permeable PTD-NBD peptide on rat pancreatic acinus AR42J cell induced by lipopolysaccharide.
METHODS: AR42J cell lines were stimulated by lipopolysaccharide with a dose of 10 mg/L for 24 h. The wild type PTD-NBD peptide was incubated with AR42J cells with different concentrations (10-1-102 mg/L) before the inflammation induced by lipopolysaccharide. At the same time, the mutant type PTD-NBD peptide, PTD and NBD peptide were used as control peptide fragments. The expressions of ICAM-1 and IL-1β mRNA were detected using reverse transcription-polymerase chain reaction (RT-PCR), and IL-1β protein was measured by enzyme-linked immunosorbent assay (ELISA).
RESULTS: The PTD-NBD (WT) peptide inhibited the expression of ICAM-1 and IL-1β mRNA (0.449 ± 0.088, 0.526 ± 0.077), but also decreased the IL-1β protein level (278.82 ± 61.80 ng/L) in a dose-dependent manner. NBD (1.132 ± 0.069), PTD- NBD (MT) (1.158 ± 0.095) and PTD (1.206 ± 0.078) did not inhibit the expression of ICAM-1 mRNA. NBD (0.993 ± 0.065), PTD- NBD (MT) (1.143 ± 0.086) and PTD (1.128 ± 0.117) did not inhibit the expression of IL-1β mRNA. NBD (898.08 ± 74.65 ng/L), PTD-NBD (MT) (945.25 ± 42.49 ng/L) and PTD (947.86 ± 38.66 ng/L) failed to inhibit the expression of IL-1β protein.
CONCLUSION: The wild type PTD-NBD peptide is able to inhibit the expression of ICAM-1and IL-1β induced by LPS on AR42J cell lines in a dose-dependent manner. We confirmed PTD-NBD peptide can take effect on acinus cell directly. The result showed the early event and new therapeutic pathway of acute pancreatitis.
Collapse
|
|
41
|
|
|
42
|
Long YM, Chen K, Liu XJ, Xie WR, Wang H. Cell-permeable Tat-NBD peptide attenuates rat pancreatitis and acinus cell inflammation response. World J Gastroenterol 2009; 15:561-9. [PMID: 19195057 PMCID: PMC2653342 DOI: 10.3748/wjg.15.561] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Revised: 10/24/2008] [Accepted: 11/01/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of Tat-NEMO-binding domain (NBD) peptide on taurocholate-induced pancreatitis and lipopolysaccharide (LPS)-stimulated AR42J acinus cells inflammatory response in rats. METHODS Sodium taurocholate (5%) was used to induce the pancreatitis model. Forty-eight rats from the taurocholate group received an intravenous bolus of 13 mg/kg Tat-NBD (wild-type, WT) peptide, Tat-NBD (mutant-type, MT) peptide, NBD peptide or Tat peptide. The pancreatic histopathology was analyzed by hematoxylin staining. LPS was added to the culture medium to stimulate the AR42J cells. For pretreatment, cells were incubated with different peptides for 2 h before LPS stimulation. Expression of IL-1beta and TNF-alpha mRNA was analyzed using a semi-quantitative reverse-transcript polymerase chain reaction (RT-PCR) method. IL-1beta and TNF-alpha protein in culture medium were detected by enzyme linked immunosorbent assay (ELISA). NF-kappaB DNA-binding in pancreas was examined by electrophoretic mobility shift assays. P65 expression of AR42J was determined by Strept Actividin-Biotin Complex (SABC) method. RESULTS Pretreatment with Tat-NBD (WT) peptide at a concentration of 13 mg/kg body wt showed beneficial effect in pancreaitis model. LPS (10 mg/L) resulted in an increase of IL-1beta mRNA, IL-1beta protein, TNF-alpha mRNA and TNF-alpha protein, whereas significantly inhibitory effects were observed when cells were incubated with Tat-NBD (WT). Consisting with p65 expression decrease analyzed by SABC method, NF-kappaB DNA-binding activity significantly decreased in Tat-NBD (WT) pretreatment group, especially at the largest dose. No significant changes were found in the control peptide group. CONCLUSION Our result supports that active NF-kappaB participates in the pathogenesis of STC-induced acute pancreatitis in rats. Tat-NBD (WT) peptide has anti-inflammatory effects in this model and inhibits the inflammation of acinus simulated by LPS.
Collapse
|
|
43
|
Jackson LN, Zhou Y, Qiu S, Wang Q, Evers BM. Alternative medicine products as a novel treatment strategy for inflammatory bowel disease. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2009; 36:953-65. [PMID: 19051360 DOI: 10.1142/s0192415x08006375] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Inflammatory bowel disease (IBD) affects the mucosal lining of the gastrointestinal tract; the etiology is unknown and treatment is directed at systemic immunosuppression. Natural products, including medicinal herbs, have provided approximately half of the drugs developed for clinical use over the past 20 years. The purpose of our current study was to determine the effects of a novel combination of herbal extracts on intestinal inflammation using a murine model of IBD. Female Swiss-Webster mice were randomized to receive normal water or 5% dextran sulfate sodium (DSS) drinking water to induce colitis. Mice were treated with either a novel combination of herbal aqueous extracts or vehicle control per os (po) or per rectum (pr) every 24 hours for 7-8 days. Disease activity index score (DAI) was determined daily; mice were sacrificed and colons were analyzed by H & E staining, MPO assay, and cytokine (TNF-alpha, IL-6) ELISAs. Mice treated with the combination of herbal extracts, either po or pr, had significantly less rectal bleeding and lower DAI scores compared to the vehicle-treated group. Moreover, colonic ulceration, leukocytic infiltration, and cytokine levels (TNF-alpha and IL-6) were also decreased in the colons of herbal-treated mice, reflected by H & E staining, MPO assay, and cytokine ELISA. Treatment with the combination of medicinal herbs decreases leukocyte infiltration and mucosal ulceration, ameliorating the course of acute colonic inflammation. This herbal remedy may prove to be a novel and safe therapeutic alternative in the treatment of IBD.
Collapse
Affiliation(s)
- Lindsey N Jackson
- Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
| | | | | | | | | |
Collapse
|
|
44
|
Abstract
The nuclear factor kappa B (NF-kappaB) transcription factors are activated by a range of stimuli including pro-inflammatory cytokines. Active NF-kappaB regulates the expression of genes involved in inflammation and cell survival and aberrant NF-kappaB activity plays pathological roles in certain types of cancer and diseases characterized by chronic inflammation. NF-kappaB signaling is an attractive target for the development of novel anti-inflammatory or anti-cancer drugs and we discuss here how the method of peptide transduction has been used to specifically target NF-kappaB. Peptide transduction relies on the ability of certain small cell-penetrating peptides (CPPs) to enter cells, and a panel of CPP-linked inhibitors (CPP-Is) has been developed to directly inhibit NF-kappaB signaling. Remarkably, several of these NF-kappaB-targeting CPP-Is are effective in vivo and therefore offer exciting potential in the clinical setting.
Collapse
Affiliation(s)
- J. S. Orange
- Department of Pediatrics, University of Pennsylvania School of Medicine, The Children’s Hospital of Philadelphia 3615 Civic Center Blvd., ARC 1016H, Philadelphia, PA 19104 USA
| | - M. J. May
- Department of Animal Biology and The Mari Lowe Center for Comparative Oncology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street (OVH 200E), Philadelphia, PA 19104 USA
| |
Collapse
|
|
45
|
de Campos T, Deree J, Martins JO, Loomis WH, Shenvi E, Putnam JG, Coimbra R. Pentoxifylline attenuates pulmonary inflammation and neutrophil activation in experimental acute pancreatitis. Pancreas 2008; 37:42-9. [PMID: 18580443 DOI: 10.1097/mpa.0b013e3181612d19] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Acute pancreatitis (AP) is associated with a systemic inflammatory response. Pentoxifylline (PTX) has been shown to attenuate neutrophil activation and end-organ injury in shock states such as hemorrhage and sepsis. We hypothesized that PTX would down-regulate AP-induced lung injury. METHODS Sprague-Dawley rats underwent catheterization of the pancreatic duct. Acute pancreatitis (n = 7) and AP/PTX animals (n = 7) received a retrograde infusion of 3.5% sodium taurocholate and intravenous treatment with normal saline or normal saline and PTX (25 mg/kg), respectively. Pulmonary neutrophil degranulation and sequestration were determined by zymography and detection of myeloperoxidase. Nuclear factor kappa B and mitogen-activated protein kinase phosphorylation was determined by Western blot. Cytokine-induced neutrophil chemoattractant was quantified by enzyme linked immunosorbent assay. RESULTS Pulmonary histologic injury scores were attenuated in the AP/PTX group (P < 0.05). Plasma amylase levels remained unchanged. Pentoxifylline produced a significant decline in myeloperoxidase content and matrix metalloproteinase activity (P < 0.05). The increase in the phosphorylation of pulmonary nuclear factor kappa B, p38 mitogen-activated protein kinase, and extracellular-related signal kinase 1/2 observed after AP was not demonstrated with PTX (P < 0.05). Pentoxifylline supplementation reduced pulmonary cytokine-induced neutrophil chemoattractant levels by 50% (P < 0.05). CONCLUSIONS Pentoxifylline significantly attenuated histologic lung injury, pulmonary neutrophil activity, and proinflammatory signaling in a severe model of AP. Therefore, PTX may serve as an adjunct for the treatment of the inflammatory complications of severe AP.
Collapse
Affiliation(s)
- Tercio de Campos
- Division of Trauma and Surgical Critical Care, Department of Surgery, University of California School of Medicine, San Diego, CA, USA
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Cheng BQ, Liu CT, Li WJ, Fan W, Zhong N, Zhang Y, Jia XQ, Zhang SZ. Ethyl pyruvate improves survival and ameliorates distant organ injury in rats with severe acute pancreatitis. Pancreas 2007; 35:256-61. [PMID: 17895847 DOI: 10.1097/mpa.0b013e318064678a] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate the effect of ethyl pyruvate (EP) in improving the survival and ameliorating distant organ damage and to investigate the role of high-mobility group box (HMGB) 1 in rats with established severe acute pancreatitis (SAP). METHODS Severe acute pancreatitis was induced by retrograde infusion of sodium taurodeoxycholate (5%, 1 mL/kg) into the biliopancreatic ducts in male Wistar rats. The rats were infused intravenously with EP of 40 mg/kg, 4 mg/kg, and 0.4 mg/kg initiating 12 hours, and EP of 40 mg/kg was administered beginning 2 hours before surgery (-2 hours) and 12, 24, and 36 hours after induction of SAP; then, the mortality was recorded. Serum tumor necrosis factor alpha, interleukin (IL) 6, and IL-1beta were measured using enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured using Western immunoblotting analysis. RESULTS Serum HMGB1 levels were increased dramatically after 12 hours, remained at high levels for 72 hours, and were significantly higher in rats with SAP than in those with mild and moderate pancreatitis (P < 0.01). Treatment with EP (40 mg/kg) conferred protection from lethality of SAP (EP survival [63%] vs vehicle survival [6.3%]; P < 0.001). No survival advantage occurred when treatment was initiated 36 hours after surgery, but administration beginning 2 hours before operation (-2 hours) and 12 and 24 hours after induction of SAP significantly increased survival. Ethyl pyruvate treatment significantly decreased serum HMGB1, tumor necrosis factor alpha, IL-1beta, and IL-6 levels and ameliorated extrapancreatic organ dysfunction in rats with SAP. CONCLUSIONS Ethyl pyruvate improves survival and ameliorates distant organ injury of SAP. These beneficial effects of EP are because of the modulation of HMGB1 and other inflammatory cytokine responses.
Collapse
Affiliation(s)
- Bao-Quan Cheng
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
47
|
De Plaen IG, Liu SXL, Tian R, Neequaye I, May MJ, Han XB, Hsueh W, Jilling T, Lu J, Caplan MS. Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 2007; 61:716-21. [PMID: 17426653 DOI: 10.1203/pdr.0b013e3180534219] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Necrotizing enterocolitis (NEC) is a major cause of morbidity and death in premature infants. NEC is associated with increased levels of pro-inflammatory cytokines in plasma and tissues that are regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). It remains unknown, however, whether NF-kappaB mediates injury in neonatal NEC. We therefore examined the activation status of NF-kappaB perinatally in the small intestine and in a neonatal rat model of NEC. We found that intestinal NF-kappaB is strongly activated at birth and, in dam-fed newborn rats, is down-regulated within a day. In contrast, NF-kappaB remains strongly activated at both d 1 and d 2 in stressed animals, and this is accompanied by a significant decrease in the levels of the endogenous NF-kappaB inhibitor protein IkappaBalpha and IkappaBbeta at d 2. To determine the importance of elevated NF-kappaB activity in intestinal injury in NEC, we administered the NEMO-binding domain (NBD) peptide that selectively inhibits the critical upstream IkappaB kinase (IKK). NBD but not a control peptide decreased mortality and bowel injury in this model, supporting the hypothesis that bowel injury in NEC results from elevated NF-kappaB activity. Our findings therefore lead us to conclude that selective NF-kappaB inhibition represents a promising therapeutic strategy for NEC.
Collapse
Affiliation(s)
- Isabelle G De Plaen
- Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
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.
Collapse
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
| |
Collapse
|
|
49
|
Cosen-Binker LI, Gaisano HY. Recent insights into the cellular mechanisms of acute pancreatitis. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 21:19-24. [PMID: 17225878 PMCID: PMC2656626 DOI: 10.1155/2007/930424] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In acute pancreatitis, initiating cellular events causing acinar cell injury includes co-localization of zymogens with lysosomal hydrolases, leading to premature enzyme activation and pathological exocytosis of zymogens into the interstitial space. This is followed by processes that accentuate cell injury; triggering acute inflammatory mediators, intensifying oxidative stress, compromising the microcirculation and activating a neurogenic feedback. Such localized events then progress to a systemic inflammatory response leading to multiorgan dysfunction syndrome with resulting high morbidity and mortality. The present review discusses some of the most recent insights into each of these cellular processes postulated to cause or propagate the process of acute pancreatitis, and also the role of alcohol and genetics.
Collapse
Affiliation(s)
| | - Herbert Y Gaisano
- Correspondence: Dr Herbert Y Gaisano, University of Toronto, Room 7226, Medical Science Building, 1 King’s College Circle, Toronto, Ontario M5S 1A8. Telephone 416-978-1526, fax 416-978-8765, e-mail
| |
Collapse
|
|
50
|
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.
Collapse
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
| |
Collapse
|