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Li X, Yan Z, Cao X, Chen X, Guan Z, Tang S, Fan J, Duan L, Xu X, Zhang H. Dachaihu Decoction alleviates chronic pancreatitis by regulating MAPK signaling pathway: Insights from network pharmacology and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118833. [PMID: 39306212 DOI: 10.1016/j.jep.2024.118833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/14/2024] [Accepted: 09/14/2024] [Indexed: 09/27/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chronic pancreatitis (CP), a syndrome characterized by inflammatory fibrosis, can impair both the internal and external secretory functions of the pancreas. The global incidence of this disease is gradually increasing. However, the exact pathogenesis remains unclear, resulting in a lack of targeted clinical therapies. According to the principles of traditional Chinese medicine, CP can be attributed to Shaoyang and Yangming syndromes, which manifest as abdominal pain and hypochondriac distension. Dachaihu Decoction (DCHD) is a classic formula from the "Treatise on Febrile and Miscellaneous Disease." It is frequently prescribed for conditions associated with combined Shaoyang and Yangming syndromes. However, the specific mechanisms by which DCHD prevents and treats CP remain unclear and require further investigation. AIM OF THE STUDY Using a holistic methodology, including network pharmacology, molecular docking, transcriptomic profiling, and animal experimentation, we explored the potential therapeutic mechanisms of DCHD in CP. MATERIALS AND METHODS In a mouse model, caerulein was used to induce CP, and DCHD was administered via gastric lavage to assess its therapeutic effect on pancreatic injury caused by caerulein-induced CP. Subsequently, pancreatic tissues were collected for transcriptomic analysis. Screening of DCHD-active ingredient-target pathways for CP treatment was conducted using network pharmacology and further preliminary validation was performed using molecular docking techniques. Additionally, in vivo and in vitro validation was conducted using animal and cells experiments based on the predicted results. RESULTS Our findings suggest that DCHD ameliorates pancreatic acinar cell injury, pancreatic inflammation, and fibrosis in mice with CP. Network pharmacology identified 385 potential targets of DCHD associated with CP. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the therapeutic effect of DCHD on CP may be linked to the mitogen-activated protein kinase (MAPK) signaling pathway. Transcriptomic data supported this finding, as it confirmed that DCHD inhibited the pancreatic MAPK signaling pathway in CP. Molecular docking studies further revealed that the top ten active components of DCHD exhibited strong docking activity with key molecules within the MAPK signaling pathway. Finally, animal experiments confirmed that DCHD effectively reduced the phosphorylation of P38, Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) in pancreatic tissues. In addition, the expression of p-P38, p-JNK, and p-ERK was reduced in pancreatic stellate cells and macrophages in the DCHD group. We further treated CP mice, human pancreatic stellate cell line (hPSCs), and macrophage cell line RAW264.7 with the active component baicalin from DCHD, and found that baicalin effectively reduced pancreatic damage in CP. Additionally, the expression of key proteins in the MAPK signaling pathway was significantly decreased in both hPSCs and RAW264.7. CONCLUSION In summary, DCHD plays an important role in the treatment of chronic pancreatitis, and it may become a promising drug against the progression of CP. The role of DCHD in alleviating pancreatic inflammatory cell infiltration and fibrosis may be related to the regulation of the MAPK signaling pathway.
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Affiliation(s)
- Xu Li
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zhangli Yan
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xin Cao
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xin Chen
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zheng Guan
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Shangan Tang
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jianwei Fan
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Lifang Duan
- Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Xiaofan Xu
- Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, China.
| | - Hong Zhang
- Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, China; Shaanxi International Cooperation Base, Shaanxi University of Chinese Medicine, Xianyang, China.
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Wang H, Qi L, Han H, Li X, Han M, Xing L, Li L, Jiang H. Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies. Acta Pharm Sin B 2024; 14:4756-4775. [PMID: 39664424 PMCID: PMC11628839 DOI: 10.1016/j.apsb.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.
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Affiliation(s)
- Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Han Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Xuena Li
- College of Pharmacy, Yanbian University, Yanji 133000, China
| | - Mengmeng Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing 210009, China
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hulin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- College of Pharmacy, Yanbian University, Yanji 133000, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
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Iyer S, Enman M, Sahay P, Dudeja V. Novel therapeutics to treat chronic pancreatitis: targeting pancreatic stellate cells and macrophages. Expert Rev Gastroenterol Hepatol 2024; 18:171-183. [PMID: 38761167 DOI: 10.1080/17474124.2024.2355969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/13/2024] [Indexed: 05/20/2024]
Abstract
INTRODUCTION Chronic pancreatitis (CP) is a persistent, recurrent, and progressive disorder that is characterized by chronic inflammation and irreversible fibrosis of the pancreas. It is associated with severe morbidity, resulting in intense abdominal pain, diabetes, exocrine and endocrine dysfunction, and an increased risk of pancreatic cancer. The etiological factors are diverse and the major risk factors include smoking, chronic alcoholism, as well as other environmental and genetic factors. The treatment and management of CP is challenging, and no definitive curative therapy is currently available. AREAS COVERED This review paper aims to provide an overview of the different cell types in the pancreas that is known to mediate disease progression and outline potential novel therapeutic approaches and drug targets that may be effective in treating and managing CP. The information presented in this review was obtained by conducting a NCBI PubMed database search, using relevant keywords. EXPERT OPINION In recent years, there has been an increased interest in the development of novel therapeutics for CP. A collaborative multi-disciplinary approach coupled with a consistent funding for research can expedite progress of translating the findings from bench to bedside.
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Affiliation(s)
- Srikanth Iyer
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Macie Enman
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Preeti Sahay
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
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Alavi M, Mejia-Bautista A, Tang M, Bandovic J, Rosenberg AZ, Bialkowska AB. Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis. Cancers (Basel) 2023; 15:5427. [PMID: 38001687 PMCID: PMC10670257 DOI: 10.3390/cancers15225427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of KrasG12D mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and KrasG12D mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without KrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.
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Affiliation(s)
- Maryam Alavi
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
| | - Ana Mejia-Bautista
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
| | - Meiyi Tang
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
| | - Jela Bandovic
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21217, USA;
| | - Agnieszka B. Bialkowska
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
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Zhang Y, Zhang WQ, Liu XY, Zhang Q, Mao T, Li XY. Immune cells and immune cell-targeted therapy in chronic pancreatitis. Front Oncol 2023; 13:1151103. [PMID: 36969002 PMCID: PMC10034053 DOI: 10.3389/fonc.2023.1151103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
In recent years, studies have attempted to understand the immune cells and mechanisms underlying the pathogenesis of chronic pancreatitis (CP) by constructing a model of CP. Based on these studies, the innate immune response is a key factor in disease pathogenesis and inflammation severity. Novel mechanisms of crosstalk between immune and non-immune pancreatic cells, such as pancreatic stellate cells (PSC), have also been explored. Immune cells, immune responses, and signaling pathways in CP are important factors in the development and progression of pancreatitis. Based on these mechanisms, targeted therapy may provide a feasible scheme to stop or reverse the progression of the disease in the future and provide a new direction for the treatment of CP. This review summarizes the recent advances in research on immune mechanisms in CP and the new advances in treatment based on these mechanisms.
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Han S, Conwell DL, Li L, Cervantes A, Hart PA, Cruz-Monserrate Z, Hao W, Lesinski GB, Mace T, Palermo TM, Saloman JL, Yadav D, Vege SS, Topazian M. The phase 1/2 trial of indomethacin in chronic pancreatitis (The PAIR trial): Protocol for a parallel multi-center randomized controlled trial. Pancreatology 2023; 23:42-47. [PMID: 36535851 PMCID: PMC9839482 DOI: 10.1016/j.pan.2022.12.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 09/03/2022] [Accepted: 12/12/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND/OBJECTIVES Current treatments for chronic pancreatitis focus on symptom management and therapeutics targeting disease reversal are lacking. Given the role of the cyclooxygenase-2 (COX-2) enzyme in producing prostaglandin E2 (PGE2), a key component in the inflammatory pathway of chronic pancreatitis, this study evaluates the physiologic effect of oral indomethacin, a COX-2 inhibitor, on PGE2 levels in pancreatic fluid. METHODS This pilot two-center randomized controlled trial seeks to examine 32 subjects with chronic pancreatitis who have no contraindications to indomethacin. Subjects will be randomized to either oral indomethacin 50 mg twice a day or placebo twice a day for a total of 28 days. Baseline (pre-treatment) assessment of pain and quality of life will be performed using the Brief Pain Inventory and the PROMIS-10 questionnaires, respectively. Biological specimens including blood, urine, and saliva will be collected at pre-treatment and post-treatment(day 28). Endoscopic pancreatic function testing with concomitant pancreatic fluid collection will also be performed pre- and post-treatment to assess the change in pancreatic fluid PGE2 levels. The relationship between pancreatic fluid PGE2 levels with blood and saliva PGE2 levels will be examined. CONCLUSIONS This study will elucidate the effect of oral indomethacin on PGE2 levels in the pancreas to assess its role in the inflammatory pathway of chronic pancreatitis. Should indomethacin significantly reduce PGE2 levels, this may represent a potential disease-altering treatment for chronic pancreatitis.
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Affiliation(s)
- Samuel Han
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Darwin L Conwell
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Liang Li
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alejandra Cervantes
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Wenrui Hao
- Department of Mathematics, Pennsylvania State University, University Park, PA, USA
| | - Gregory B Lesinski
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - Thomas Mace
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Tonya M Palermo
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA
| | - Jami L Saloman
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
| | - Santhi Swaroop Vege
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Mark Topazian
- Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, USA
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Xiang H, Yu H, Zhou Q, Wu Y, Ren J, Zhao Z, Tao X, Dong D. Macrophages: A rising star in immunotherapy for chronic pancreatitis. Pharmacol Res 2022; 185:106508. [DOI: 10.1016/j.phrs.2022.106508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/10/2022] [Indexed: 11/29/2022]
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Durst M, Graf TR, Graf R, Kron M, Arras M, Zechner D, Palme R, Talbot SR, Jirkof P. Analysis of Pain and Analgesia Protocols in Acute Cerulein-Induced Pancreatitis in Male C57BL/6 Mice. Front Physiol 2021; 12:744638. [PMID: 34880773 PMCID: PMC8645955 DOI: 10.3389/fphys.2021.744638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/21/2021] [Indexed: 11/13/2022] Open
Abstract
Pancreatitis is known to be painful in humans and companion animals. However, the extent of pain in experimental mouse models of acute pancreatitis is unknown. Consequently, the severity classification of acute pancreatitis in mice is controversially discussed and standardized pain management is missing. In this study, we investigated acute Cerulein-induced pancreatitis with pain-specific and well-being orientated parameters to detect its impact on mice. Male C57BL/6J male mice were injected with Cerulein; animals that received saline injections served as control group. The animals were observed for weight change and water intake. To assess pain, behaviors like stretch-and-press and reduced rearing, the Mouse Grimace Scale, and von Frey hypersensitivity were assessed. Fecal corticosterone metabolites and burrowing behavior were assessed to detect changes in the animal’s well-being. Pancreatitis severity was evaluated with amylase and lipase in the blood and pancreas histology. To investigate whether different analgesics can alleviate signs of pain, and if they influence pancreas inflammation, animals received Buprenorphine, Paracetamol in combination with Tramadol, or Metamizole in the drinking water. The calculated intake of these analgesics via drinking reached values stated to be efficient for pain alleviation. While pancreatitis did not seem to be painful, we detected acute pain from Cerulein injections that could not be alleviated by analgesics. The number of inflammatory cells in the pancreas did not differ with the analgesic administered. In conclusion: (1) Cerulein injections appear to be acutely painful but pain could not be alleviated by the tested analgesics, (2) acute pancreatitis induced by our protocol did not induce obvious signs of pain, (3) analgesic substances had no detectable influence on inflammation. Nevertheless, protocols inducing more severe or even chronic pancreatitis might evoke more pain and analgesic treatment might become imperative. Considering our results, we recommend the use of Buprenorphine via drinking water in these protocols. Further studies to search for efficient analgesics that can alleviate the acute pain induced by Cerulein injections are needed.
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Affiliation(s)
- Mattea Durst
- Centre for Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Theresia Reding Graf
- Pancreas Research Laboratory, Department of Visceral Surgery & Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Rolf Graf
- Pancreas Research Laboratory, Department of Visceral Surgery & Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Mareike Kron
- Centre for Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Margarete Arras
- Centre for Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Dietmar Zechner
- Rudolf-Zenker-Institute of Experimental Surgery, University Medical Center, Rostock, Germany
| | - Rupert Palme
- Unit of Physiology, Pathophysiology and Experimental Endocrinology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Steven R Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, Hanover, Germany
| | - Paulin Jirkof
- Centre for Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Office for Animal Welfare & 3R, University of Zurich, Zurich, Switzerland
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Mukherjee D, DiVincenzo MJ, Torok M, Choueiry F, Kumar RJ, Deems A, Miller JL, Hinton A, Geraghty C, Maranon JA, Kulp SK, Coss C, Carson WE, Conwell DL, Hart PA, Cooperstone JL, Mace TA. Soy-tomato enriched diet reduces inflammation and disease severity in a pre-clinical model of chronic pancreatitis. Sci Rep 2020; 10:21824. [PMID: 33311549 PMCID: PMC7733503 DOI: 10.1038/s41598-020-78762-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 μg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP (p = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels (p < 0.05). Mice with CP fed a soy-tomato diet had a reduction in inflammatory factors (TNF-α, IL-1β, IL-5) and suppressive immune populations (myeloid-derived suppressor cells; MDSC) compared to control diet fed mice (p < 0.05). Infra-red sensing to monitor spontaneous activity of mice showed that soy-tomato enriched diet improved total activity and overall health of mice with CP (p = 0.055) and CP mice on a control diet were determined to spend more time at rest (p = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.
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Affiliation(s)
| | - Mallory J DiVincenzo
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
- Department of Veterinary Biosciences, The Ohio State University, Columbus, USA
| | - Molly Torok
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Fouad Choueiry
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Rahul J Kumar
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Anna Deems
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Jenna L Miller
- Department of Food Science and Technology, The Ohio State University, Columbus, USA
| | - Alice Hinton
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, USA
| | - Connor Geraghty
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | | | - Samuel K Kulp
- College of Pharmacy, The Ohio State University, Columbus, USA
| | | | | | - Darwin L Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 420 W 12th Ave., Columbus, OH, 43210, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 420 W 12th Ave., Columbus, OH, 43210, USA
| | - Jessica L Cooperstone
- Department of Food Science and Technology, The Ohio State University, Columbus, USA
- Departments of Horticulture and Crop Science, The Ohio State University, Columbus, OH, 43210, USA
| | - Thomas A Mace
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 420 W 12th Ave., Columbus, OH, 43210, USA.
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Role of the Immune System and the Circadian Rhythm in the Pathogenesis of Chronic Pancreatitis: Establishing a Personalized Signature for Improving the Effect of Immunotherapies for Chronic Pancreatitis. Pancreas 2020; 49:1024-1032. [PMID: 32833942 DOI: 10.1097/mpa.0000000000001626] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatitis, in both acute and chronic forms, poses a major therapeutic challenge and is associated with great morbidity and several complications. The nature of pancreatic injury in chronic pancreatitis (CP) and the wide range of causative processes that lead to CP have made effective therapy a true unmet need. Multiple physiological, genetic, environmental, and behavioral factors contribute to the development of CP. As a result, several fields of research are aimed at identifying and addressing the factors that contribute to pancreatic injury. In this article, we review the current understanding of the pathogenesis and natural history of CP. We focus on the autonomous nervous system, immune system, and role of a chronobiological therapeutic approach to alleviate symptoms and prevent or reverse pancreatic injury associated with CP. We aim to demonstrate that individualizing chronopharmacological treatments for CP is a promising direction for future treatment using immune, nervous, and circadian systems.
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Choi JW, Jeong JH, Jo IJ, Kim DG, Shin JY, Kim MJ, Choi BM, Shin YK, Song HJ, Bae GS, Park SJ. Preventive Effects of Gardenia jasminoides on Cerulein-Induced Chronic Pancreatitis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:987-1003. [PMID: 32431181 DOI: 10.1142/s0192415x20500470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1[Formula: see text]g/kg) or saline (control group) were intraperitoneally injected 1[Formula: see text]h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.
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Affiliation(s)
- Ji-Won Choi
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea.,Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan 54538, Republic of Korea
| | - Jun-Hyeok Jeong
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea
| | - Il-Joo Jo
- Division of Beauty Sciences, Wonkwang University School of Natural Sciences, Iksan 54538, Republic of Korea
| | - Dong-Gu Kim
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan 54538, Republic of Korea
| | - Joon Yeon Shin
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea
| | - Myoung-Jin Kim
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea
| | - Byung-Min Choi
- Department of Biochemistry, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea
| | - Yong Kook Shin
- Major in Integrated Oriental Medical Bioscience, College of Health Biotechnology, Semyung University, Jecheon 27136, Republic of Korea
| | - Ho-Joon Song
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea
| | - Gi-Sang Bae
- Department of Pharmacology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea.,Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan 54538, Republic of Korea
| | - Sung-Joo Park
- Department of Herbology, Wonkwang University School of Korean Medicine, Iksan 54538, Republic of Korea.,Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksan 54538, Republic of Korea
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12
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Bansod S, Aslam Saifi M, Khurana A, Godugu C. Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating β-catenin/Smad in a sirtuin-dependent way. Pharmacol Res 2020; 156:104756. [PMID: 32194177 DOI: 10.1016/j.phrs.2020.104756] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/28/2019] [Accepted: 03/13/2020] [Indexed: 12/18/2022]
Abstract
Chronic pancreatitis (CP) is one of the leading causes of mortality worldwide with no clinically approved therapeutic interventions. The present study was designed to investigate the protective effect of nimbolide (NB), an active constituent of neem tree (Azadirachta indica), by targeting β-catenin/Smad/SIRT1 in cerulein-induced CP model. The effects of NB was investigated on cerulein (50 μg/kg/hr*6 exposures /day, 3 days a week for 3 weeks) induced CP in mice. Amylase and lipase activity were measured and histopathological evaluation was performed. Collagen deposition in the pancreatic tissue was estimated by hydroxyproline assay, and collagen specific staining picrosirius red and Masson's trichrome. Cerulein-induced CP was significantly controlled by NB treatment, as shown by the downregulation of β-catenin/Smad signaling in a SIRT1 dependent manner. NB treatment significantly decreased α-SMA, MMP-2, collagen1a, fibronectin, TGF-β1, p-Smad-2/3 expression and extracellular matrix (ECM) deposition in pancreatic tissue. However, the protective effects of NB on cerulein-induced CP were undermined by nicotinamide (NMD) or splitomicin, sirtuin 1 (SIRT1) inhibitors treatment. NB treatment modulated protein expression by activating SIRT1 and decreasing the expression of β-catenin/Smad proteins in CP mice. However, the expression of SIRT1 in pancreatic tissue was elevated by NB treatment and it was decreased by NMD or splitomicin treatment. In summary, our results strongly suggest that NB exerted promising protective effects in cerulein-induced CP model by inhibiting β-catenin/Smad in a sirtuin-dependent manner, which could be attributed to its anti-inflammatory and antifibrotic effects. Our study suggests that NB could be an effective therapeutic intervention for the treatment of CP.
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Affiliation(s)
- Sapana Bansod
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Amit Khurana
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India.
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Serotonin-RhoA/ROCK axis promotes acinar-to-ductal metaplasia in caerulein-induced chronic pancreatitis. Biomed Pharmacother 2020; 125:109999. [PMID: 32070876 DOI: 10.1016/j.biopha.2020.109999] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/02/2020] [Accepted: 02/06/2020] [Indexed: 12/15/2022] Open
Abstract
The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.
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Torabizadeh SA, Rezaeifar M, Jomehzadeh A, Nabizadeh Haghighi F, Ansari M. Radioprotective Potential of Sulindac Sulfide to Prevent DNA Damage Due to Ionizing Radiation. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:4127-4134. [PMID: 31827319 PMCID: PMC6902880 DOI: 10.2147/dddt.s218022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 11/15/2019] [Indexed: 11/23/2022]
Abstract
Introduction: The ionizing radiation exposure of the normal cell causes damage to DNA, which leads to cell dysfunction or even cell death. However, it is necessary to identify new radio protectives in order to protect normal cells. Sulindac sulfide (SS) is a metabolite of sulindac (a non-steroidal anti-inflammatory drug) known as a cyclooxygenase inhibitor. Free radicals and reactive oxygen species are generated in the IR-exposed cells. Also, the induced inflammation process causes damage in DNA. Purpose In this research, the radioprotective effect of SS was investigated against genotoxicity and lipid peroxidation induced by ionizing radiation in the human blood lymphocytes. Methods In this study, the human blood samples were pretreated with SS at different concentrations (10, 25, 50, 100 and 250 μM) and then were exposed to IR at a dose of 1.5 Gy. The micronucleus (MN) assay was used to indicate the radioprotective effects of SS on exposed cells. Total antioxidant activity of the SS was measured by using FRAP and DPPH assay. Also, the malondialdehyde (MDA) levels and the activity of superoxide dismutase (SOD) on the exposed cells were evaluated. Results It was found that SS decreased the percentage of MN induced by IR in exposed cells. Maximum reduction in the frequency of MN was observed at 250 μM of SS (87%) that provides the highest degree of protection against IR. On the other hand, pretreatment at 250 μM of SS inhibited IR-induced oxidative stress, which led to a decrease in the MN frequencies and MDA levels, while SOD activity showed an increase in the exposed cells. Conclusion It could be concluded that SS as a good radioprotective agent protects the human normal cells against the oxidative stress and genetic damage induced by IR.
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Affiliation(s)
- Seyedeh Atekeh Torabizadeh
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehdi Rezaeifar
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Jomehzadeh
- Department of Medical Physics, Faculty of Medicine, Medical Physics Department, Radiotherapy & Oncology Unit, Shafa Kerman Hospital, Kerman University of Medical Sciences, Kerman, Iran
| | - Farzaneh Nabizadeh Haghighi
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mehdi Ansari
- Drug and Food Control Department, Kerman University of Medical Sciences, Kerman, Iran
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Novovic S, Borch A, Werge M, Karran D, Gluud L, Schmidt PN, Hansen EF, Nøjgaard C, Jensen AB, Jensen FK, Frøkjær JB, Hansen MB, Jørgensen LN, Drewes AM, Olesen SS. Characterisation of the fibroinflammatory process involved in progression from acute to chronic pancreatitis: study protocol for a multicentre, prospective cohort study. BMJ Open 2019; 9:e028999. [PMID: 31439604 PMCID: PMC6707691 DOI: 10.1136/bmjopen-2019-028999] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Chronic pancreatitis (CP) is thought to present the end stage of a continuous disease process evolving from acute pancreatitis (AP), over recurrent AP, to early and end-stage CP. Due to the irreversible nature of CP, early detection and prevention is key. Prospective assessment based on advanced imaging modalities as well as biochemical markers of inflammation, fibrosis and oxidative stress may provide a better understanding of the underlying pathological processes and help identify novel biomarkers of disease with the ultimate goal of early diagnosis, intervention and prevention of disease progression. This paper describes the protocol of a prospective multicentre cohort study investigating the fibroinflammatory process involved in progression from acute to CP using state-of-the-art diagnostic imaging modalities and circulating biomarkers of inflammation, fibrosis and oxidative stress. METHODS AND ANALYSIS Adult control subjects and patients at different stages of CP according to the M-ANNHEIM system will be recruited from outpatient clinics at the participating sites and form three cohorts: controls (n=40), suspected CP (n=60) and definitive CP (n=60). Included patients will be followed prospectively for 15 years with advanced MRI and contrast-enhanced endoscopic ultrasound with elastography, assessment of endocrine and exocrine pancreatic function, biochemical and nutritional assessment, and evaluation of pain processing using quantitative sensory testing. Blood samples for a biobank will be obtained. The purpose of the biobank is to allow analyses of potential circulating biomarkers of disease progression, including markers of inflammation, fibrosis and oxidative stress. ETHICS AND DISSEMINATION Permissions from the Regional Science Ethics committee and the Regional Data Protection Agency have been obtained. We will submit the results of the study for publication in peer-reviewed journals regardless of whether the results are positive, negative or inconclusive.
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Affiliation(s)
- Srdan Novovic
- Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark
| | - Anders Borch
- Abdominal Center K, Bispebjerg Hospital, Kobenhavn, Denmark
| | - Mikkel Werge
- Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark
| | - David Karran
- Abdominal Center K, Bispebjerg Hospital, Kobenhavn, Denmark
| | - Lise Gluud
- Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark
| | - Palle Nordblad Schmidt
- Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark
| | - Erik Feldager Hansen
- Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark
| | - Camilla Nøjgaard
- Department of Gastroenterology and Gastrointestinal Surgery, Hvidovre Hospital, Hvidovre, Denmark
| | | | | | - Jens Brøndum Frøkjær
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | | | | | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Søren Schou Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
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Klauss S, Schorn S, Teller S, Steenfadt H, Friess H, Ceyhan GO, Demir IE. Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison. FASEB J 2018; 32:fj201800241RR. [PMID: 29863911 DOI: 10.1096/fj.201800241rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Chronic pancreatitis (CP) is an utmost complex disease that is pathogenetically linked to pancreas-intrinsic ( e.g., duct obstruction), environmental-toxic ( e.g., alcohol, smoking), and genetic factors. Studying such a complex disease naturally requires validated experimental models. In the past 2 decades, the various animal models of CP usually addressed either the pancreas-intrinsic ( e.g., the caerulein model), the environmental-toxic ( e.g., diet-induced models), or the genetic component of CP. As such, these models were far from mirroring CP in its full spectrum, and the correct choice of models was vital for valid scientific conclusions on CP. The quest for mechanistic, genetic models gave rise to models based on gene modification and transgene insertion, such as the PRSS1 and the IL-1β/IL-1β models. Recently, we witnessed the development of highly exciting models that rely on the importance of autophagy in CP, that is, the murine pancreas-specific Atg5 and LAMP2 knockout models. Today, critical comparison of these several models is more important than ever for guiding research on CP in an efficient direction. The present review outlines the characteristics of the new genetic models in comparison with the well-known classic models for CP, notes the caveats in the choice of models, and also indicates novel directions for model development.-Klauss, S., Schorn, S., Teller, S., Steenfadt, H., Friess, H., Ceyhan, G. O., Demir, I. K. Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison.
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Affiliation(s)
- Sarah Klauss
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Stephan Schorn
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Steffen Teller
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Hendrik Steenfadt
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice: Targeting RAGE and CXCL12/CXCR4 Axis. J Neuroimmune Pharmacol 2017; 12:693-707. [DOI: 10.1007/s11481-017-9757-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 07/20/2017] [Indexed: 12/11/2022]
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Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol 2017; 23:382-405. [PMID: 28210075 PMCID: PMC5291844 DOI: 10.3748/wjg.v23.i3.382] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.
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Kozak A, Talar-Wojnarowska R, Kaczka A, Borkowska A, Czupryniak L, Małecka-Panas E, Gąsiorowska A. Utility of different serum fibrosis markers in diagnosing patients with chronic pancreatitis and pancreatic adenocarcinoma. World J Gastrointest Oncol 2016; 8:635-641. [PMID: 27574557 PMCID: PMC4980655 DOI: 10.4251/wjgo.v8.i8.635] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/21/2016] [Accepted: 06/16/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To estimate the levels of serum cytokines in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) patients in order to evaluate their usefulness as possible biomarkers.
METHODS: The study included 167 Caucasian patients: 74 with PDAC (28 men and 42 women, aged 30-88 years), 78 with CP (50 men and 21 women, aged 20-79 years) and 15 age-matched healthy controls hospitalized in the Department of Digestive Tract Diseases, Medical University of Lodz, Poland between 2006 and 2013. Serum MCP-1, transforming growth factor (TGF)-β1, HA and s-Fr were measured in patients with CP (n = 78), PDAC (n = 74) and healthy controls (n = 15) using ELISA (Corgenix United Kingdom Ltd R and D Systems). The severity of CP was assessed according to the Cambridge classification.
RESULTS: Both patients with CP and PDAC had a significantly higher mean TGF-β1 serum level (1066 ± 582 and 888 ± 356 vs 264 ± 93, P < 0.0001), mean s-Fr (2.42 ± 1.385 and 2.41 ± 1.275 vs 0.6 ± 0.370, P < 0.0001) and mean HA (199 ± 254 and 270 ± 358 vs 40 ± 26, P < 0.0001) compared to controls. There was no difference in mean MCP-1 between all the groups. There were no significant differences in any cytokine levels between the PC and PDAC groups. No significant differences between serum cytokines depending on age, gender or smoking status were found in CP patients. Mean s-Fr concentration was significantly higher in CP, lasting longer than 5 years compared to those with a shorter disease clinical course (2.639 ± 1.125 vs 1.870 ± 0.970, P < 0.03). There was no correlation between tumor size, localization or TNM classification and serum TGF-β1, MCP-1, s-Fr and HA levels in patients with PDAC. No significant differences between cytokines depending on diabetes presence in CP were found. Nevertheless, mean serum TGF-β1 concentration in PDAC patients was higher in those with diabetes compared to the remaining group (986 vs 839, P = 0.043).
CONCLUSION: Serum TGF-β1, s-Fr and HA may be considered additional diagnostic markers of CP and PDAC. TGF-β1 may be useful to predict endocrine insufficiency in PDAC.
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Abstract
OBJECTIVES Animal models are essential to understand the pathogenesis of acute pancreatitis (AP) and to develop new therapeutic strategies. Although it has been shown that cerulein-induced AP is associated with pain in experimental animals, most experiments are carried out without any pain-relieving treatment because researchers are apprehensive of an interference of the analgetic agent with AP-associated inflammation. In light of the growing ethical concerns and the legal tightening regarding animal welfare during experiments, this attitude should be changed. METHODS Acute pancreatitis was induced by cerulein in the C57BL/6J and FVB/N mouse inbred strains. One group received vehicle only, and the other was treated with metamizol as analgetic agent. Pain sensation and parameters of AP were analyzed as well as the effect of metamizol in the pancreas and its actions in the brain. RESULTS We report that oral administration of metamizol protects cerulein-treated mice from abdominal pain without influencing the clinical and histopathological course of the disease. In addition, it could be shown that metamizol reduces the central pain response. CONCLUSIONS This study reveals that oral administered metamizol has no influence on the cerulein-induced AP and can be given as an analgesic to increase animal welfare in experiments with induced AP.
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An optimised mouse model of chronic pancreatitis with a combination of ethanol and cerulein. Cent Eur J Immunol 2016; 41:54-63. [PMID: 27095923 PMCID: PMC4829821 DOI: 10.5114/ceji.2016.58816] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 08/30/2015] [Indexed: 02/08/2023] Open
Abstract
Introduction Chronic pancreatitis (CP) is an intractable and multi-factorial disorder. Developing appropriate animal models is an essential step in pancreatitis research, and the best ones are those which mimic the human disorder both aetiologically and pathophysiologically. The current study presents an optimised protocol for creating a murine model of CP, which mimics the initial steps of chronic pancreatitis in alcohol chronic pancreatitis and compares it with two other mouse models treated with cerulein or ethanol alone. Material and methods Thirty-two male C57BL/6 mice were randomly selected, divided into four groups, and treated intraperitoneally with saline (10 ml/kg, control group), ethanol (3 g/kg; 30% v/v), cerulein (50 µg/kg), or ethanol + cerulein, for six weeks. Histopathological and immunohistochemical assays for chronic pancreatitis index along with real-time PCR assessments for mRNA levels of inflammatory cytokines and fibrogenic markers were conducted to verify the CP induction. Results The results indicated that CP index (CPI) was significantly increased in ethanol-cerulein mice compared to the saline, ethanol, and cerulein groups (p < 0.001). Interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), α-smooth muscle actin (α-SMA), and myeloperoxidase activity were also significantly greater in both cerulein and ethanol-cerulein groups than in the saline treated animals (p < 0.001). Immunohistochemical analysis revealed enhanced expression of TGF-β and α-SMA in ethanol-cerulein mice compared to the saline group. Conclusions Intraperitoneal (IP) injections of ethanol and cerulein could successfully induce CP in mice. IP injections of ethanol provide higher reproducibility compared to ethanol feeding. The model is simple, non-invasive, reproducible, and time-saving. Since the protocol mimics the initial phases of CP development in alcoholics, it can be used for investigating basic mechanisms and testing new therapies.
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Zhang T, Paluch K, Scalabrino G, Frankish N, Healy AM, Sheridan H. Molecular structure studies of (1 S,2 S)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol. J Mol Struct 2015; 1083:286-299. [PMID: 25750458 PMCID: PMC4308634 DOI: 10.1016/j.molstruc.2014.12.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 12/03/2014] [Accepted: 12/03/2014] [Indexed: 11/30/2022]
Abstract
The single enantiomer (1S,2S)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol (2), has recently been synthesized and isolated from its corresponding diastereoisomer (1). The molecular and crystal structures of this novel compound have been fully analyzed. The relative and absolute configurations have been determined by using a combination of analytical tools including X-ray crystallography, X-ray Powder Diffraction (XRPD) analysis and Nuclear Magnetic Resonance (NMR) spectroscopy.
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Affiliation(s)
- Tao Zhang
- Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland
- Novel Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Krzysztof Paluch
- Centre for Pharmaceutical Engineering Science, Bradford School of Pharmacy, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford BD7 1DP, UK
| | - Gaia Scalabrino
- Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland
| | - Neil Frankish
- Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland
- Novel Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Anne-Marie Healy
- Novel Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Helen Sheridan
- Trino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Dublin 2, Ireland
- Novel Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
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Zhou X, Li YJ, Gao SY, Wang XZ, Wang PY, Yan YF, Xie SY, Lv CJ. Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21. J Cell Mol Med 2015; 19:1103-13. [PMID: 25704671 PMCID: PMC4420612 DOI: 10.1111/jcmm.12506] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 10/24/2014] [Indexed: 12/15/2022] Open
Abstract
Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF.
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Affiliation(s)
- Xue Zhou
- Department of Clinical Medicine, Binzhou Medical University, Yantai, China; Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, China
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Han YM, Park JM, Lee HJ, Kim EH, Hahm KB. Short-term Intervention to Revert Premalignant Lesions as Strategy to Prevent Gastrointestinal Cancers. J Cancer Prev 2014; 18:289-97. [PMID: 25337558 PMCID: PMC4189441 DOI: 10.15430/jcp.2013.18.4.289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 09/11/2013] [Accepted: 09/12/2013] [Indexed: 12/20/2022] Open
Abstract
"Prevention might be better than treatment in cancer treatment" is brief conclusion drawn from war on cancer through National Cancer Act of 1971 by U.S. President Richard Nixon. However, the clinical practice of chemoprevention is still in its infancy in spite of a wealth of data showing its effectiveness in experimental animals as well as in vitro mechanism research. Recent advances in either high throughput analysis including cancer genomes and tailored medicine or molecular targeted therapeutics, preventive strategies also should be changes as previous preventive strategies including phytoceuticals, life-style modification, and some empirical agents. Furthermore, molecular targeted therapeutics achieved high goal of effectiveness under the concept of therapeutic or preventive "synthetic lethality", of which extended application can be included within the scope of chemoprevention. Here, we will summarize several recent advances in chemopreventive strategy objected to justify optimism that chemoprevention will be an effective approach for the control of human cancer. siTRP (short-term intervention to revert premalignancy) strategy will be introduced for cancers in gastroenterology.
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Affiliation(s)
- Young-Min Han
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul ; College of Pharmacy, CHA University, Pocheon
| | - Jong-Min Park
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul
| | - Ho-Jae Lee
- Lee Gil Ya Cancer and Diabetes Research Institute, Gachon University, Incheon
| | - Eun-Hee Kim
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul ; Lee Gil Ya Cancer and Diabetes Research Institute, Gachon University, Incheon
| | - Ki Baik Hahm
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul ; Department of Gastroenterology, CHA Bundang Medical Center, Seongnam, Korea
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Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol 2014; 20:11160-11181. [PMID: 25170202 PMCID: PMC4145756 DOI: 10.3748/wjg.v20.i32.11160] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/27/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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Ulmasov B, Oshima K, Rodriguez MG, Cox RD, Neuschwander-Tetri BA. Differences in the degree of cerulein-induced chronic pancreatitis in C57BL/6 mouse substrains lead to new insights in identification of potential risk factors in the development of chronic pancreatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:692-708. [PMID: 23845568 DOI: 10.1016/j.ajpath.2013.05.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 03/25/2013] [Accepted: 05/11/2013] [Indexed: 12/26/2022]
Abstract
A frequently used experimental model of chronic pancreatitis (CP) recapitulating human disease is repeated injection of cerulein into mice. C57BL/6 is the most commonly used inbred mouse strain for biomedical research, but widespread demand has led to generation of several substrains with subtly different phenotypes. In this study, two common substrains, C57BL/6J and C57BL/6NHsd, exhibited different degrees of CP, with C57BL/6J being more susceptible to repetitive cerulein-induced CP as assessed by pancreatic atrophy, pancreatic morphological changes, and fibrosis. We hypothesized that the deficiency of nicotinamide nucleotide transhydrogenase (NNT) protein in C57BL/6J is responsible for the more severe C57BL/6J phenotype but the parameters of CP in NNT-expressing transgenic mice generated on a C57BL6/J background do not differ with those of wild-type C57BL/6J. The highly similar genetic backgrounds but different CP phenotypes of these two substrains presents a unique opportunity to discover genes important in pathogenesis of CP. We therefore performed whole mouse genome Affymetrix microarray analysis of pancreatic gene expression of C57BL/6J and C57BL/6NHsd before and after induction of CP. Genes with differentially regulated expression between the two substrains that might be candidates in CP progression included Mmp7, Pcolce2, Itih4, Wdfy1, and Vtn. We also identified several genes associated with development of CP in both substrains, including RIKEN cDNA 1810009J06 gene (trypsinogen 5), Ccl8, and Ccl6.
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Affiliation(s)
- Barbara Ulmasov
- Department of Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA.
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