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Yuan Z, Ye J, Liu B, Zhang L. Unraveling the role of autophagy regulation in Crohn's disease: from genetic mechanisms to potential therapeutics. ADVANCED BIOTECHNOLOGY 2024; 2:14. [PMID: 39883213 PMCID: PMC11740883 DOI: 10.1007/s44307-024-00021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/29/2024] [Accepted: 03/10/2024] [Indexed: 01/31/2025]
Abstract
Autophagy serves as the primary intracellular degradation mechanism in which damaged organelles and self-cytoplasmic proteins are transported to the lysosome for degradation. Crohn's disease, an idiopathic chronic inflammatory disorder of the gastrointestinal tract, manifests in diverse regions of the digestive system. Recent research suggests that autophagy modulation may be a new avenue for treating Crohn's disease, and several promising small-molecule modulators of autophagy have been reported as therapeutic options. In this review, we discuss in detail how mutations in autophagy-related genes function in Crohn's disease and summarize the modulatory effects on autophagy of small-molecule drugs currently used for Crohn's disease treatment. Furthermore, we delve into the therapeutic potential of small-molecule autophagy inducers on Crohn's disease, emphasizing the prospects for development in this field. We aim to highlight the significance of autophagy modulation in Crohn's disease, with the aspiration of contributing to the development of more efficacious treatments that can alleviate their suffering, and improve their quality of life.
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Affiliation(s)
- Ziyue Yuan
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Jing Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bo Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
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2
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Tran S, Juliani J, Fairlie WD, Lee EF. The emerging roles of autophagy in intestinal epithelial cells and its links to inflammatory bowel disease. Biochem Soc Trans 2023; 51:811-826. [PMID: 37052218 PMCID: PMC10212545 DOI: 10.1042/bst20221300] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/14/2023]
Abstract
Landmark genome-wide association studies (GWAS) identified that mutations in autophagy genes correlated with inflammatory bowel disease (IBD), a heterogenous disease characterised by prolonged inflammation of the gastrointestinal tract, that can reduce a person's quality of life. Autophagy, the delivery of intracellular components to the lysosome for degradation, is a critical cellular housekeeping process that removes damaged proteins and turns over organelles, recycling their amino acids and other constituents to supply cells with energy and necessary building blocks. This occurs under both basal and challenging conditions such as nutrient deprivation. An understanding of the relationship between autophagy, intestinal health and IBD aetiology has improved over time, with autophagy having a verified role in the intestinal epithelium and immune cells. Here, we discuss research that has led to an understanding that autophagy genes, including ATG16L, ATG5, ATG7, IRGM, and Class III PI3K complex members, contribute to innate immune defence in intestinal epithelial cells (IECs) via selective autophagy of bacteria (xenophagy), how autophagy contributes to the regulation of the intestinal barrier via cell junctional proteins, and the critical role of autophagy genes in intestinal epithelial secretory subpopulations, namely Paneth and goblet cells. We also discuss how intestinal stem cells can utilise autophagy. Importantly, mouse studies have provided evidence that autophagy deregulation has serious physiological consequences including IEC death and intestinal inflammation. Thus, autophagy is now established as a key regulator of intestinal homeostasis. Further research into how its cytoprotective mechanisms can prevent intestinal inflammation may provide insights into the effective management of IBD.
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Affiliation(s)
- Sharon Tran
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3086, Australia
| | - Juliani Juliani
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
| | - W. Douglas Fairlie
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3086, Australia
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
| | - Erinna F. Lee
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3086, Australia
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
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Saadh MJ, Pal RS, Arias-Gonzáles JL, Orosco Gavilán JC, JC D, Mohany M, Al-Rejaie SS, Bahrami A, Kadham MJ, Amin AH, Georgia H. A Mendelian Randomization Analysis Investigates Causal Associations between Inflammatory Bowel Diseases and Variable Risk Factors. Nutrients 2023; 15:1202. [PMID: 36904201 PMCID: PMC10005338 DOI: 10.3390/nu15051202] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
The question of whether variable risk factors and various nutrients are causally related to inflammatory bowel diseases (IBDs) has remained unanswered so far. Thus, this study investigated whether genetically predicted risk factors and nutrients play a function in the occurrence of inflammatory bowel diseases, including ulcerative colitis (UC), non-infective colitis (NIC), and Crohn's disease (CD), using Mendelian randomization (MR) analysis. Utilizing the data of genome-wide association studies (GWASs) with 37 exposure factors, we ran Mendelian randomization analyses based on up to 458,109 participants. Univariable and multivariable MR analyses were conducted to determine causal risk factors for IBD diseases. Genetic predisposition to smoking and appendectomy as well as vegetable and fruit intake, breastfeeding, n-3 PUFAs, n-6 PUFAs, vitamin D, total cholesterol, whole-body fat mass, and physical activity were related to the risk of UC (p < 0.05). The effect of lifestyle behaviors on UC was attenuated after correcting for appendectomy. Genetically driven smoking, alcohol consumption, appendectomy, tonsillectomy, blood calcium, tea intake, autoimmune diseases, type 2 diabetes, cesarean delivery, vitamin D deficiency, and antibiotic exposure increased the risk of CD (p < 0.05), while vegetable and fruit intake, breastfeeding, physical activity, blood zinc, and n-3 PUFAs decreased the risk of CD (p < 0.05). Appendectomy, antibiotics, physical activity, blood zinc, n-3 PUFAs, and vegetable fruit intake remained significant predictors in multivariable MR (p < 0.05). Besides smoking, breastfeeding, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs were associated with NIC (p < 0.05). Smoking, alcoholic drinks, vegetable and fruit intake, vitamin D, appendectomy, and n-3 PUFAs remained significant predictors in multivariable MR (p < 0.05). Our results provide new and comprehensive evidence demonstrating that there are approving causal effects of various risk factors on IBDs. These findings also supply some suggestions for the treatment and prevention of these diseases.
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Affiliation(s)
- Mohamed J. Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan;
- Applied Science Research Center, Applied Science Private University, Amman 11152, Jordan
| | - Rashmi Saxena Pal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144001, Punjab, India;
| | - José Luis Arias-Gonzáles
- Department of Social Sciences, Faculty of Social Studies, Pontifical University of Peru, San Miguel 15088, Peru;
| | | | - Darshan JC
- Department of Pharmacy Practice, Yenepoya Pharmacy College & Research Centre, Yenepoya Deemed to Be University, Mangalore 575018, Karnataka, India;
| | - Mohamed Mohany
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh 1145, Saudi Arabia; (M.M.); (S.S.A.-R.)
| | - Salim S. Al-Rejaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 55760, Riyadh 1145, Saudi Arabia; (M.M.); (S.S.A.-R.)
| | - Abolfazl Bahrami
- Biomedical Center for Systems Biology Science Munich, Ludwig Maximilians University, 80333 Munich, Germany
| | | | - Ali H. Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt;
| | - Hrosti Georgia
- Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany
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Ma J, Teng Y, Huang Y, Tao X, Fan Y. Autophagy plays an essential role in ultraviolet radiation-driven skin photoaging. Front Pharmacol 2022; 13:864331. [PMID: 36278173 PMCID: PMC9582953 DOI: 10.3389/fphar.2022.864331] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 09/05/2022] [Indexed: 11/23/2022] Open
Abstract
Photoaging is characterized by a chronic inflammatory response to UV light. One of the most prominent features of cutaneous photoaging is wrinkling, which is due primarily to a loss of collagen fibers and deposits of abnormal degenerative elastotic material within the dermis (actinic elastosis). These changes are thought to be mediated by inflammation, with subsequent upregulation of extracellular matrix-degrading proteases and down-regulation of collagen synthesis. Autophagy is a vital homeostatic cellular process of either clearing surplus or damaged cell components notably lipids and proteins or recycling the content of the cells’ cytoplasm to promote cell survival and adaptive responses during starvation and other oxidative and/or genotoxic stress conditions. Autophagy may also become a means of supplying nutrients to maintain a high cellular proliferation rate when needed. It has been suggested that loss of autophagy leads to both photodamage and the initiation of photoaging in UV exposed skin. Moreover, UV radiation of sunlight is capable of regulating a number of autophagy-linked genes. This review will focus on the protective effect of autophagy in the skin cells damaged by UV radiation. We hope to draw attention to the significance of autophagy regulation in the prevention and treatment of skin photoaging.
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Rein T. Harnessing autophagy to fight SARS-CoV-2: An update in view of recent drug development efforts. J Cell Biochem 2021; 123:155-160. [PMID: 34668225 PMCID: PMC9088732 DOI: 10.1002/jcb.30166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/09/2021] [Accepted: 10/12/2021] [Indexed: 01/18/2023]
Abstract
Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.
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Affiliation(s)
- Theo Rein
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
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DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease. Dig Dis Sci 2021; 66:3375-3390. [PMID: 33184797 DOI: 10.1007/s10620-020-06697-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 10/24/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. METHODS DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. RESULTS DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn's disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. CONCLUSIONS During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage.
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Lamers CR, de Roos NM, Koppelman LJM, Hopman MTE, Witteman BJM. Patient experiences with the role of physical activity in inflammatory bowel disease: results from a survey and interviews. BMC Gastroenterol 2021; 21:172. [PMID: 33853535 PMCID: PMC8046271 DOI: 10.1186/s12876-021-01739-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/29/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Physical activity may affect disease activity in patients with inflammatory bowel disease. We used a survey to investigate this association and performed interviews to get a better understanding of patient experiences, and therefore the nature of this association. METHODS Patients with Crohn's disease (CD, n = 176) and ulcerative colitis (UC, n = 162) completed the short Crohn's Disease Activity (sCDAI) or Patient Simple Clinical Colitis Activity Index (P-SCCAI) and the Short Questionnaire to Assess Health-enhancing physical activity (SQUASH). Associations were investigated by multiple linear regression. Semi-structured interviews (7 CD, 7 UC) were conducted to assess patient experiences with the role of physical activity in their disease. RESULTS The majority of survey participants were in remission (70%) and adhered to the Dutch physical activity guidelines (61%). In Crohn's disease, the total physical activity score was inversely associated with disease activity, even after adjustment for confounders (β = - 0.375; p = 0.013). No association between physical activity and disease activity was found in ulcerative colitis. Of the interviewees, 86% experienced beneficial effects of physical activity, such as improved general fitness, quality of life and self-image. However, during periods of active disease they struggled to find the motivation and perseverance to be physically active due to physical barriers. CONCLUSIONS Crohn's disease participants with a higher physical activity level had a lower disease activity. This inverse association was not found in ulcerative colitis. Interviews revealed that IBD patients generally experience beneficial effects from physical activity, although the barriers caused by active disease may put them off to be physically active.
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Affiliation(s)
- Carlijn R Lamers
- Department of Gastroenterology and Hepatology, Hospital Gelderse Vallei, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands. .,Division of Human Nutrition and Health, Wageningen University and Research (WUR), Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - Nicole M de Roos
- Division of Human Nutrition and Health, Wageningen University and Research (WUR), Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Lola J M Koppelman
- Division of Human Nutrition and Health, Wageningen University and Research (WUR), Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Maria T E Hopman
- Department of Physiology, Radboud University Medical Center, Philips Van Leydenlaan 15, 6500 HB, Nijmegen, The Netherlands
| | - Ben J M Witteman
- Department of Gastroenterology and Hepatology, Hospital Gelderse Vallei, Willy Brandtlaan 10, 6716 RP, Ede, The Netherlands.,Division of Human Nutrition and Health, Wageningen University and Research (WUR), Stippeneng 4, 6708 WE, Wageningen, The Netherlands
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Zhao J, Wang H, Zhou J, Qian J, Yang H, Zhou Y, Ding H, Gong Y, Qi X, Jiao Y, Ying P, Tang L, Sun Y, Zhu W. miR-130a-3p, a Preclinical Therapeutic Target for Crohn's Disease. J Crohns Colitis 2021; 15:647-664. [PMID: 33022049 DOI: 10.1093/ecco-jcc/jjaa204] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Crohn's disease [CD] is a chronic, relapsing and incurable inflammatory disorder. Micro RNAs [miRNAs], which modulate gene expression by binding to mRNAs, may make significant contributions to understanding the complex pathobiology and aetiology of CD. This study aimed to investigate the therapeutic role and mechanism of miR-130a-3p in CD. METHODS Differentially expressed miRNAs in colon tissues of CD patients and normal controls [NCs] were screened using an miRNA microarray and then validated by quantitative reverse transcriptase-PCR [qRT-PCR]. The functional role of miR-130a-3p in the pathogenesis of CD was then demonstrated by in vitro and in vivo studies. The target genes of miR-130a-3p and the associated signalling pathways were identified using bioinformatics analysis and experimental verification of the interactions between the target predicted by the algorithms and dysregulated mRNAs. The therapeutic role of miR-130a-3p in trinitro-benzene-sulfonic acid [TNBS]-induced colitis models was further investigated. RESULTS Our data demonstrated that miR-130a-3p is the most significantly upregulated miRNA and that miR-130a knockout significantly protects mice against TNBS-induced colitis. Gain- and loss-of-function studies indicated that miR-130a-3p promotes CD development by targeting ATG16L1 via the NF-κB pathway. Furthermore, an miR-130a-3p inhibitor significantly suppressed NLRP3 inflammasome activity by inducing autophagy in a mouse macrophage cell line [RAW264.7]. Therapeutically, an miR-130a-3p inhibitor effectively ameliorated the severity of TNBS-induced colitis. CONCLUSION Our study reveals that miR-130a-3p promotes CD progression via the ATG16L1/NF-κB pathway and serves as a potential preclinical therapeutic target in CD.
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Affiliation(s)
- Jie Zhao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China.,Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Honggang Wang
- Department of General Surgery, Taizhou People's Hospital, Medical School of Nantong University, Taizhou, Jiangsu, China
| | - Jin Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jun Qian
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Haojun Yang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Yan Zhou
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Hao Ding
- Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Yu Gong
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Xiaoyang Qi
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Yuwen Jiao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Pu Ying
- Department of Orthopedics, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Jiangsu, China
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ye Sun
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
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Seo DH, Che X, Kim S, Kim DH, Ma HW, Kim JH, Kim TI, Kim WH, Kim SW, Cheon JH. Triggering Receptor Expressed on Myeloid Cells-1 Agonist Regulates Intestinal Inflammation via Cd177 + Neutrophils. Front Immunol 2021; 12:650864. [PMID: 33767714 PMCID: PMC7985452 DOI: 10.3389/fimmu.2021.650864] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022] Open
Abstract
Triggering receptor expressed on myeloid cell-1 (TREM-1) signaling is expressed on neutrophils and monocytes that is necessary for the successful antimicrobial response and resolution of inflammation in the gut. In this study, we determined the effect of an anti-TREM-1 agonistic antibody (α-TREM-1) on colitis and identify its underlying mechanism of action. Administration of α-TREM-1 alleviated colitis in mice and resolved dysbiosis, which required TLR4/Myd88 signaling. α-TREM-1 increased the production of neutrophil extracellular traps and interleukin-22 by CD177+ neutrophils, which led to pathogen clearance and protection of the intestinal barrier. TREM-1 activation using an α-TREM-1 antibody protects against colitis by rebalancing the microbiota and protecting the epithelium against the immune response as well as modulates the function of neutrophils and macrophages. These results highlight the importance of the TREM-1 pathway in intestinal homeostasis and suggest that α-TREM-1 treatment may be an effective therapeutic strategy for inflammatory bowel disease.
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Affiliation(s)
- Dong Hyuk Seo
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Xiumei Che
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Soochan Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Da Hye Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyun Woo Ma
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Hyeon Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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Piovani D, Danese S, Peyrin-Biroulet L, Bonovas S. Environmental, Nutritional, and Socioeconomic Determinants of IBD Incidence: A Global Ecological Study. J Crohns Colitis 2020; 14:323-331. [PMID: 31504350 DOI: 10.1093/ecco-jcc/jjz150] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS The wide variation in inflammatory bowel disease [IBD] incidence across countries entails an opportunity to recognise global disease determinants and hypothesise preventive policies. METHODS We fitted multivariable models to identify putative environmental, nutritional, and socioeconomic determinants associated with the incidence of IBD (i.e. ulcerative colitis [UC] and Crohn's disease [CD]). We used the latest available country-specific incidence rates, and aggregate data for 20 determinants, from over 50 countries accounting for more than half of the global population. We presented the associations with exponentiated beta coefficients (exp[β]) indicating the relative increase of disease incidence per unit increase in the predictor variables. RESULTS Country-specific incidence estimates demonstrate wide variability across the world, with a median of 4.8 new UC cases (interquartile range [IQR] 2.4-9.3), and 3.5 new CD cases [IQR 0.8-5.7] per 100 000 population per year. Latitude (exp[β] 1.05, 95% confidence interval [CI] 1.04‒1.06, per degree increase), prevalence of obesity [1.05, 1.02‒1.07, per 1% increase], and of tobacco smoking [0.97, 0.95‒0.99, per 1% increase] explained 71.5% of UC incidence variation across countries in the adjusted analysis. The model for CD included latitude [1.04, 1.02‒1.06], expenditure for health (1.03, 1.01‒1.05, per 100 purchasing power parity [PPP]/year per capita increase), and physical inactivity prevalence [1.03, 1.00‒1.06, per 1% increase], explaining 58.3% of incidence variation across countries. Besides expenditure for health, these associations were consistent in low/middle- and high-income countries. CONCLUSIONS Our analysis highlights factors able to explain a substantial portion of incidence variation across countries. Further high-quality research is warranted to develop global strategies for IBD prevention.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and INSERM U954, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy
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11
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Role and mechanism of matrine alone and combined with acitretin for HaCaT cells and psoriasis-like murine models. Chin Med J (Engl) 2020; 132:2079-2088. [PMID: 31460901 PMCID: PMC6793800 DOI: 10.1097/cm9.0000000000000412] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Acitretin and matrine have been used in the treatment of psoriasis in China. This study was designed to investigate the role and related mechanisms of matrine alone and in combination with acitretin in the treatment of psoriasis in vitro and in vivo. METHODS HaCaT cells were treated with matrine at different concentrations of 0 (blank control), 0.2, 0.4, 0.8, and 1.6 mg/mL for 24, 48, 72 h, respectively. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium cell viability assay was used to assess the growth and proliferation of HaCaT cells. Cell cycle and apoptosis were detected by flow cytometry. Expression of protein was detected by Western blotting. Autophagy was observed by transmission electron microscopy. Then HaCaT cells were assigned to normal saline (NS) control group, matrine (0.4 mg/mL) group, acitretin (10 μmol/L) group, and matrine plus acitretin group, and the above methods were repeated. In animal experiments, the cumulative score (erythema, scaling, thickening) as a measure of the severity of inflammation was used to measure the skin performance of mice after treated with matrine 50 mg/kg, acitretin 4.5 mg/kg or combination of the two drugs on the psoriasis-like mouse models, respectively. Pathological findings of the lesions were observed, and the protein expressions in the lesions were detected by immunohistochemistry. RESULTS Cell proliferation inhibition was seen in HaCaT cells with treatment of matrine in a dose- and time-dependent manner (P < 0.01, respectively). Cell cycle G0/G1 phase arrest was observed in a dose-dependent way (P < 0.01). The expression of p21 (P < 0.05), LC3II/I (P < 0.01), and Beclin 1 (P < 0.01) increased and the expression of cyclin D1 (P < 0.05) decreased with increasing doses of matrine. Compared with the blank control, more autophagosomes were seen in HaCaT cells treated with matrine at 0.4 mg/mL by transmission electron microscopy (2.667 ± 1.202 vs. 21.33 ± 1.453, t = 9.899, P < 0.01). Cell proliferation inhibition and degree of the G0/G1 phase arrest was significantly higher in matrine plus acitretin group than those in matrine, acitretin, or the NS control group (P < 0.01, respectively). Compared with matrine or acitretin group, the expression of p21 (P < 0.05, P < 0.05) and LC3II/I (P < 0.01, P < 0.05) in matrine plus acitretin group increased significantly and the expression of cyclin D1 (P < 0.01, P < 0.05) and p62 (P < 0.05, P < 0.05) was reduced significantly. Compared with matrine or acitretin, matrine plus acitretin significantly down-regulated the phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway (P < 0.05) and its downstream p-p70S6K (P < 0.05). In addition, the cumulative score of mice in the matrine plus acitretin group was significantly better than that in the matrine or acitretin group (1.480 ± 0.230 vs. 2.370 ± 0.241, P < 0.01; 1.480 ± 0.230 vs. 2.888 ± 0.341, P < 0.01). The expression of LC3 protein in the matrine plus acitretin group was also higher than that in the matrine, acitretin, or the NS control group (P < 0.05, respectively). CONCLUSIONS Matrine has therapeutic potentials for psoriasis. Matrine and acitretin show synergistic effect via cell cycle arrest and autophagy induction by PI3K/Akt/mTOR pathway.
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Moon JM, Kang EA, Han K, Hong SW, Soh H, Park S, Lee J, Lee HJ, Im JP, Kim JS. Trends and risk factors of elderly-onset Crohn’s disease: A nationwide cohort study. World J Gastroenterol 2020; 26:404-415. [PMID: 32063689 PMCID: PMC7002904 DOI: 10.3748/wjg.v26.i4.404] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/09/2020] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The incidence of inflammatory bowel disease (IBD) is increasing in Asia. Numerous risk factors associated with IBD development have been investigated.
AIM To investigate trends and environmental risk factors of Crohn’s disease (CD) diagnosed in persons aged ≥ 40 years in South Korea.
METHODS Using the National Health Insurance Service database, a total of 14060821 persons aged > 40 years who underwent national health screening in 2009 were followed up until December 2017. Patients with newly diagnosed CD were enrolled and compared with non-CD cohort. CD was identified according to the International Classification of Diseases 10th revision and the rare/intractable disease registration program codes from the National Health Insurance Service database. The mean follow-up periods was 7.39 years. Age, sex, diabetes, hypertension, smoking, alcohol consumption, regular exercise, body mass index, anemia, chronic kidney disease (CKD) and dyslipidemia were adjusted for in the multivariate analysis model.
RESULTS During the follow-up, 1337 (1.33/100000) patients developed CD. Men in the middle-aged group (40-64 years) had a higher risk than women [adjusted hazard ratio (aHR) 1.46, 95% confidence interval (CI): 1.29-1.66]; however, this difference tended to disappear as the age of onset increases. In the middle-aged group, patients with a history of smoking [aHR 1.46, 95%CI: 1.19-1.79) and anemia (aHR 1.85, 95%CI: 1.55-2.20) had a significantly higher CD risk. In the elderly group (age, ≥ 65 years), ex-smoking and anemia also increased the CD risk (aHR 1.68, 95%CI: 1.22-2.30) and 1.84 (95%CI: 1.47-2.30, respectively). Especially in the middle-aged group, those with CKD had a statistically elevated CD risk (aHR 1.37, 95%CI: 1.05-1.79). Alcohol consumption and higher body mass index showed negative association trend with CD incidence in both of the age groups. [Middle-aged: aHR 0.77 (95%CI: 0.66-0.89) and aHR 0.73 (95%CI: 0.63-0.84), respectively] [Elderly-group: aHR 0.57 (95%CI: 0.42-0.78) and aHR 0.84 (95%CI 0.67-1.04), respectively]. For regular physical activity and dyslipidemia, negative correlation between CD incidences was proved only in the middle-aged group [aHR 0.88 (95%CI: 0.77-0.89) and aHR 0.81 (95%CI: 0.68-0.96), respectively].
CONCLUSION History of cigarette smoking, anemia, underweight and CKD are possible risk factors for CD in Asians aged > 40 years.
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Affiliation(s)
- Jung Min Moon
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Eun Ae Kang
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Kyungdo Han
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Seung Wook Hong
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Hosim Soh
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Seona Park
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Jooyoung Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Hyun Jung Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Jong Pil Im
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Joo Sung Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
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Larabi A, Barnich N, Nguyen HTT. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy 2020; 16:38-51. [PMID: 31286804 PMCID: PMC6984609 DOI: 10.1080/15548627.2019.1635384] [Citation(s) in RCA: 510] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 06/11/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023] Open
Abstract
One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic composition of the host and the intestinal microbiota, under impact of specific environmental factors, lead to chronic intestinal inflammation. Genome-wide association studies, followed by functional studies, have identified a role for numerous autophagy genes in IBD, especially in Crohn disease. Studies using in vitro and in vivo models, in addition to human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation, appropriate intestinal immune responses and anti-microbial protection. This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria. A better understanding of the role of autophagy in IBD pathogenesis may provide better sub-classification of IBD phenotypes and novel approaches for disease management.Abbreviations: AIEC: adherent-invasive Escherichia coli; AMPK: AMP-activated protein kinase; ATF6: activating transcription factor 6; ATG: autophagy related; Atg16l1[ΔIEC] mice: mice with Atg16l1 depletion specifically in intestinal epithelial cells; Atg16l1[HM] mice: mice hypomorphic for Atg16l1 expression; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; CALCOCO2: calcium binding and coiled-coil domain 2; CASP: caspase; CD: Crohn disease; CGAS: cyclic GMP-AMP synthase; CHUK/IKKA: conserved helix-loop-helix ubiquitous kinase; CLDN2: claudin 2; DAPK1: death associated protein kinase 1; DCs: dendritic cells; DSS: dextran sulfate sodium; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK: eukaryotic translation initiation factor 2 alpha kinase; ER: endoplasmic reticulum; ERBIN: Erbb2 interacting protein; ERN1/IRE1A: ER to nucleus signaling 1; FNBP1L: formin binding protein 1-like; FOXP3: forkhead box P3; GPR65: G-protein coupled receptor 65; GSK3B: glycogen synthase kinase 3 beta; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IFN: interferon; IL: interleukin; IL10R: interleukin 10 receptor; IRGM: immunity related GTPase M; ISC: intestinal stem cell; LAMP1: lysosomal-associated membrane protein 1; LAP: LC3-associated phagocytosis; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; LRRK2: leucine-rich repeat kinase 2; MAPK: mitogen-activated protein kinase; MHC: major histocompatibility complex; MIF: macrophage migration inhibitory factor; MIR/miRNA: microRNA; MTMR3: myotubularin related protein 3; MTOR: mechanistic target of rapamycin kinase; MYD88: myeloid differentiation primary response gene 88; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NPC: Niemann-Pick disease type C; NPC1: NPC intracellular cholesterol transporter 1; OMVs: outer membrane vesicles; OPTN: optineurin; PI3K: phosphoinositide 3-kinase; PRR: pattern-recognition receptor; PTPN2: protein tyrosine phosphatase, non-receptor type 2; PTPN22: protein tyrosine phosphatase, non-receptor type 22 (lymphoid); PYCARD/ASC: PYD and CARD domain containing; RAB2A: RAB2A, member RAS oncogene family; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RIPK2: receptor (TNFRSF)-interacting serine-threonine kinase 2; ROS: reactive oxygen species; SNPs: single nucleotide polymorphisms; SQSTM1: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Th: T helper 1; TIRAP/TRIF: toll-interleukin 1 receptor (TIR) domain-containing adaptor protein; TLR: toll-like receptor; TMEM173/STING: transmembrane protein 173; TMEM59: transmembrane protein 59; TNF/TNFA: tumor necrosis factor; Treg: regulatory T; TREM1: triggering receptor expressed on myeloid cells 1; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type; XBP1: X-box binding protein 1; XIAP: X-linked inhibitor of apoptosis.
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Affiliation(s)
- Anaïs Larabi
- M2iSH, UMR 1071 Inserm, INRA USC 2018, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Nicolas Barnich
- M2iSH, UMR 1071 Inserm, INRA USC 2018, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
| | - Hang Thi Thu Nguyen
- M2iSH, UMR 1071 Inserm, INRA USC 2018, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
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14
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Zhao J, Wang H, Yang H, Zhou Y, Tang L. Autophagy induction by rapamycin ameliorates experimental colitis and improves intestinal epithelial barrier function in IL-10 knockout mice. Int Immunopharmacol 2019; 81:105977. [PMID: 31677991 DOI: 10.1016/j.intimp.2019.105977] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND An impairment of the intestinal barrier function is one of the major characteristics of Crohn's disease (CD). This study aimed to evaluate the impact of autophagy induction by rapamycin on the intestinal epithelial barrier function in CD model mice. METHODS IL-10 knockout (IL-10 KO) mice were used as the human CD models in this study. All the mice were randomly assigned into four groups, (a) wild-type (WT) group; (b) IL-10 KO group; (c) IL-10 KO + rapamycin group and (d) IL-10 KO + 3-methyladenine (3-MA), containing 6 mice in each group. The disease activity index (DAI), histology, pro-inflammatory cytokines and chemotactic factors in colon tissues, intestinal and colonic permeability, distributions and expressions of tight junction (TJ) proteins, epithelial apoptosis of mice in four groups were evaluated and compared. RESULTS Autophagy induction by rapamycin treatment ameliorated DAI and histological colitis, decreased pro-inflammatory cytokines (TNF-α, IFN-γ and IL-17) and chemotactic factors (CXCL-1 and CXCL-2), decreased intestinal and colonic permeability, improved the distribution and expression of TJ proteins in IL-10 KO mice. CONCLUSION Autophagy induction by rapamycin significantly improved intestinal barrier function and protected IL-10 KO mice from the experimental chronic colitis.
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Affiliation(s)
- Jie Zhao
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, PR China; Department of General Surgery, The First Affiliated Hospital of Soochow University, PR China
| | - Honggang Wang
- Department of General Surgery, Taizhou People's Hospital, Taizhou People's Hospital, Medical School of Nantong University, PR China
| | - Haojun Yang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, PR China
| | - Yan Zhou
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, PR China
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, PR China.
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Piovani D, Danese S, Peyrin-Biroulet L, Nikolopoulos GK, Lytras T, Bonovas S. Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses. Gastroenterology 2019; 157:647-659.e4. [PMID: 31014995 DOI: 10.1053/j.gastro.2019.04.016] [Citation(s) in RCA: 486] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/15/2019] [Accepted: 04/15/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Multiple environmental factors have been associated with the development of inflammatory bowel diseases (IBDs). We performed an umbrella review of meta-analyses to summarize available epidemiologic evidence and assess its credibility. METHODS We systematically identified and appraised meta-analyses of observational studies examining environmental factors and risk of IBD (Crohn's disease [CD] or ulcerative colitis [UC]). For each meta-analysis, we considered the random effects estimate, its 95% confidence interval, the estimates of heterogeneity, and small-study effects, and we graded the evidence according to prespecified criteria. Methodologic quality was assessed with AMSTAR (ie, A Measurement Tool to Assess Systematic Reviews) 2. RESULTS We examined 183 estimates in 53 meta-analyses of 71 environmental factors related to lifestyles and hygiene, surgeries, drug exposures, diet, microorganisms, and vaccinations. We identified 9 factors that increase risk of IBD: smoking (CD), urban living (CD and IBD), appendectomy (CD), tonsillectomy (CD), antibiotic exposure (IBD), oral contraceptive use (IBD), consumption of soft drinks (UC), vitamin D deficiency (IBD), and non-Helicobacter pylori-like enterohepatic Helicobacter species (IBD). We identified 7 factors that reduce risk of IBD: physical activity (CD), breastfeeding (IBD), bed sharing (CD), tea consumption (UC), high levels of folate (IBD), high levels of vitamin D (CD), and H pylori infection (CD, UC, and IBD). Epidemiologic evidence for all of these associations was of high to moderate strength; we identified another 11 factors associated with increased risk and 16 factors associated with reduced risk with weak credibility. Methodologic quality varied considerably among meta-analyses. Several associations were based on findings from retrospective studies, so it is not possible to determine if these are effects of IBD or the results of recall bias. CONCLUSIONS In an umbrella review of meta-analyses, we found varying levels of evidence for associations of different environmental factors with risk of IBD. High-quality prospective studies with analyses of samples from patients with recent diagnoses of IBD are needed to determine whether these factors cause or are results of IBD and their pathogenic mechanisms.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Inflammatory Bowel Disease Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Inflammatory Bowel Disease Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and INSERM U954, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | | | - Theodore Lytras
- Hellenic Center for Disease Control and Prevention, Athens, Greece
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Inflammatory Bowel Disease Center, Humanitas Clinical and Research Center-IRCCS, Milan, Italy.
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16
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Abstract
Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder-associated IBD increasingly directs treatment strategies as part of personalized medicine.
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Affiliation(s)
- Holm H Uhlig
- Department of Pediatrics, University of Oxford, Oxford OX3 9DU, United Kingdom; .,Translational Gastroenterology Unit, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, United Kingdom; .,Translational Gastroenterology Unit, University of Oxford, Oxford OX3 9DU, United Kingdom
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17
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Crohn's Disease: Potential Drugs for Modulation of Autophagy. ACTA ACUST UNITED AC 2019; 55:medicina55060224. [PMID: 31146413 PMCID: PMC6630681 DOI: 10.3390/medicina55060224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/26/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022]
Abstract
Autophagy is an intracellular process whereby cytoplasmic constituents are degraded within lysosomes. Autophagy functions to eliminate unwanted or damaged materials such as proteins and organelles as their accumulation would be harmful to the cellular system. Autophagy also acts as a defense mechanism against invading pathogens and plays an important role in innate and adaptive immunity. In physiological processes, autophagy is involved in the regulation of tissue development, differentiation and remodeling, which are essential for maintaining cellular homeostasis. Recent studies have demonstrated that autophagy is linked to various diseases and involved in pathophysiological roles, such as adaptation during starvation, anti-aging, antigen presentation, tumor suppression and cell death. The modulation of autophagy has shown greatest promise in Crohn’s disease as most of autophagy drugs involved in these diseases are currently under clinical trials and some has been approved by Food and Drug Administration. This review article discusses autophagy and potential drugs that are currently available for its modulation in Crohn’s disease.
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18
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Hooper KM, Barlow PG, Henderson P, Stevens C. Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:661-671. [PMID: 30590697 DOI: 10.1093/ibd/izy380] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. The etiology involves a combination of genetic and environmental factors resulting in abnormal immune responses to intestinal microbiota. Genetic studies have strongly linked genes involved in autophagy to CD, and genes involved in the unfolded protein response (UPR) to IBD. The UPR is triggered in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER), and autophagy plays a key role in relieving ER stress and restoring homeostasis. This review summarizes the known interactions between autophagy and the UPR and discusses the impact of these converging pathways on IBD pathogenesis. With a paucity of effective long-term treatments for IBD, targeting of synergistic pathways may provide novel and more effective therapeutic options.
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Affiliation(s)
- Kirsty M Hooper
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
| | - Peter G Barlow
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
| | - Paul Henderson
- Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, United Kingdom
| | - Craig Stevens
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
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19
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Al Azzaz J, Rieu A, Aires V, Delmas D, Chluba J, Winckler P, Bringer MA, Lamarche J, Vervandier-Fasseur D, Dalle F, Lapaquette P, Guzzo J. Resveratrol-Induced Xenophagy Promotes Intracellular Bacteria Clearance in Intestinal Epithelial Cells and Macrophages. Front Immunol 2019; 9:3149. [PMID: 30693000 PMCID: PMC6339935 DOI: 10.3389/fimmu.2018.03149] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 12/20/2018] [Indexed: 11/14/2022] Open
Abstract
Autophagy is a lysosomal degradation process that contributes to host immunity by eliminating invasive pathogens and the modulating inflammatory response. Several infectious and immune disorders are associated with autophagy defects, suggesting that stimulation of autophagy in these diseases should be beneficial. Here, we show that resveratrol is able to boost xenophagy, a selective form of autophagy that target invasive bacteria. We demonstrated that resveratrol promotes in vitro autophagy-dependent clearance of intracellular bacteria in intestinal epithelial cells and macrophages. These results were validated in vivo using infection in a transgenic GFP-LC3 zebrafish model. We also compared the ability of resveratrol derivatives, designed to improve the bioavailability of the parent molecule, to stimulate autophagy and to induce intracellular bacteria clearance. Together, our data demonstrate the ability of resveratrol to stimulate xenophagy, and thereby enhance the clearance of two invasive bacteria involved life-threatening diseases, Salmonella Typhimurium and Crohn's disease-associated Adherent-Invasive Escherichia coli. These findings encourage the further development of pro-autophagic nutrients to strengthen intestinal homeostasis in basal and infectious states.
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Affiliation(s)
- Jana Al Azzaz
- AgroSup Dijon, PAM UMR A 02.102, University Bourgogne Franche-Comté, Dijon, France
| | - Aurélie Rieu
- AgroSup Dijon, PAM UMR A 02.102, University Bourgogne Franche-Comté, Dijon, France
| | - Virginie Aires
- University of Bourgogne-Franche Comté, Dijon, France.,INSERM U1231, Lipids, Nutrition Cancer, Dijon, France.,Research Team CADIR, Cancer and Adaptative Immune Response, Dijon, France
| | - Dominique Delmas
- University of Bourgogne-Franche Comté, Dijon, France.,INSERM U1231, Lipids, Nutrition Cancer, Dijon, France.,Research Team CADIR, Cancer and Adaptative Immune Response, Dijon, France
| | - Johanna Chluba
- INSERM U1231, Lipids, Nutrition Cancer, Dijon, France.,UFR SVTE-UFR Sciences de la Vie, de la Terre et de l'Environnement, Université de Bourgogne Franche-Comté, Dijon, France
| | - Pascale Winckler
- AgroSup Dijon, PAM UMR A 02.102, University Bourgogne Franche-Comté, Dijon, France.,Dimacell Imaging Facility, AgroSup Dijon, University Bourgogne Franche-Comté, Dijon, France
| | - Marie-Agnès Bringer
- AgroSup Dijon, CNRS, INRA, Centre des Sciences du Goût et de l'Alimentation, Université Bourgogne Franche-Comté, Dijon, France
| | - Jérémy Lamarche
- Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB-UMR CNRS 6302), Université of Bourgogne, Dijon, France
| | - Dominique Vervandier-Fasseur
- Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB-UMR CNRS 6302), Université of Bourgogne, Dijon, France
| | - Frédéric Dalle
- AgroSup Dijon, PAM UMR A 02.102, University Bourgogne Franche-Comté, Dijon, France
| | - Pierre Lapaquette
- AgroSup Dijon, PAM UMR A 02.102, University Bourgogne Franche-Comté, Dijon, France
| | - Jean Guzzo
- AgroSup Dijon, PAM UMR A 02.102, University Bourgogne Franche-Comté, Dijon, France
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20
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Zhao M, Chen Y, Wang C, Xiao W, Chen S, Zhang S, Yang L, Li Y. Systems Pharmacology Dissection of Multi-Scale Mechanisms of Action of Huo-Xiang-Zheng-Qi Formula for the Treatment of Gastrointestinal Diseases. Front Pharmacol 2019; 9:1448. [PMID: 30687082 PMCID: PMC6336928 DOI: 10.3389/fphar.2018.01448] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 11/26/2018] [Indexed: 12/19/2022] Open
Abstract
Multi-components Traditional Chinese Medicine (TCM) treats various complex diseases (multi-etiologies and multi-symptoms) via herbs interactions to exert curative efficacy with less adverse effects. However, the ancient Chinese compatibility theory of herbs formula still remains ambiguous. Presently, this combination principle is dissected through a systems pharmacology study on the mechanism of action of a representative TCM formula, Huo-xiang-zheng-qi (HXZQ) prescription, on the treatment of functional dyspepsia (FD), a chronic or recurrent clinical disorder of digestive system, as typical gastrointestinal (GI) diseases which burden human physical and mental health heavily and widely. In approach, a systems pharmacology platform which incorporates the pharmacokinetic and pharmaco-dynamics evaluation, target fishing and network pharmacological analyses is employed. As a result, 132 chemicals and 48 proteins are identified as active compounds and FD-related targets, and the mechanism of HXZQ formula for the treatment of GI diseases is based on its three function modules of anti-inflammation, immune protection and gastrointestinal motility regulation mainly through four, i.e., PIK-AKT, JAK-STAT, Toll-like as well as Calcium signaling pathways. In addition, HXZQ formula conforms to the ancient compatibility rule of "Jun-Chen-Zuo-Shi" due to the different, while cooperative roles that herbs possess, specifically, the direct FD curative effects of GHX (serving as Jun drug), the anti-bacterial efficacy and major accompanying symptoms-reliving bioactivities of ZS and BZ (as Chen), the detoxication and ADME regulation capacities of GC (as Shi), as well as the minor symptoms-treating efficacy of the rest 7 herbs (as Zuo). This work not only provides an insight of the therapeutic mechanism of TCMs on treating GI diseases from a multi-scale perspective, but also may offer an efficient way for drug discovery and development from herbal medicine as complementary drugs.
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Affiliation(s)
- Miaoqing Zhao
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China.,Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi, China
| | - Yangyang Chen
- Lab of Systems Pharmacology, Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling, China
| | - Chao Wang
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China
| | - Wei Xiao
- State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, China
| | - Shusheng Chen
- Systems Biology Laboratory, Department of Computer & Information Science & Engineering, University of Florida, Gainesville, FL, United States
| | - Shuwei Zhang
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China
| | - Ling Yang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Li
- Key Laboratory of Industrial Ecology and Environmental Engineering, Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian, China.,Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi, China
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21
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Zhang L, Liu B. Targeting Autophagy with Small-Molecule Modulators in Immune-Related Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1209:181-203. [PMID: 31728871 DOI: 10.1007/978-981-15-0606-2_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autophagy, a highly conserved and multistep lysosomal degradation process, plays a pivotal role in maintaining cellular and physiological homeostasis. Of note, autophagy controls intracellular homeostasis and cell responses to stresses by regulating the self-renewal, maturation, and survival of immune cells. And dysregulation of autophagy in immune cells may contribute to the inflammatory disorders and defect in immune responses against invasive pathogens. Accumulating evidence have indicated that dysregulated autophagy participates in the pathology of immune-related diseases. Therefore, targeting autophagy might represent a promising therapeutic strategy for treatment of immune-related diseases. In this chapter, we focus on discussing the link between autophagy and pathogenesis of immune-related diseases, as well as the dysregulation of autophagy-related signaling pathways, in different diseases. Moreover, we highlight the therapeutic potential of currently used small-molecule modulators of autophagy for treatment of immune-related diseases and illustrate the mechanisms of these small-molecule modulators.
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Affiliation(s)
- Lan Zhang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
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22
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Han L, Maciejewski M, Brockel C, Afzelius L, Altman RB. Mendelian Disease Associations Reveal Novel Insights into Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:471-481. [PMID: 29462399 PMCID: PMC6037048 DOI: 10.1093/ibd/izx087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Indexed: 12/14/2022]
Abstract
Background Monogenic diseases have been shown to contribute to complex disease risk and may hold new insights into the underlying biological mechanism of Inflammatory Bowel Disease (IBD). Methods We analyzed Mendelian disease associations with IBD using over 55 million patients from the Optum's deidentified electronic health records dataset database. Using the significant Mendelian diseases, we performed pathway enrichment analysis and constructed a model using gene expression datasets to differentiate Crohn's disease (CD), ulcerative colitis (UC), and healthy patient samples. Results We found 50 Mendelian diseases were significantly associated with IBD, with 40 being significantly associated with both CD and UC. Our results for CD replicated those from previous studies. Pathways that were enriched consisted of mainly immune and metabolic processes with a focus on tolerance and oxidative stress. Our 3-way classifier for UC, CD, and healthy samples yielded an accuracy of 72%. Conclusions Mendelian diseases that are significantly associated with IBD may reveal novel insights into the genetic architecture of IBD.
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Affiliation(s)
- Lichy Han
- Biomedical Informatics Training Program, Stanford University, Stanford, CA
| | | | | | | | - Russ B Altman
- Biomedical Informatics Training Program, Stanford University, Stanford, CA
- Department of Genetics, Stanford University, Stanford, CA
- Department of Bioengineering, Stanford University, Stanford, CA
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23
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Dai YC, Zheng L, Zhang YL, Chen X, Chen DL, Wang LJ, Tang ZP. Jianpi Qingchang decoction regulates intestinal motility of dextran sulfate sodium-induced colitis through reducing autophagy of interstitial cells of Cajal. World J Gastroenterol 2017; 23:4724-4734. [PMID: 28765693 PMCID: PMC5514637 DOI: 10.3748/wjg.v23.i26.4724] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 04/30/2017] [Accepted: 06/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the underlying effect of Jianpi Qingchang decoction (JQD) regulating intestinal motility of dextran sulfate sodium (DSS)-induced colitis in mice. METHODS C57BL/6 mice were randomly divided into four groups: the control group, the DSS group, the JQD group, and the 5-aminosalicylic acid group. Except for the control group, colitis was induced in other groups by giving distilled water containing 5% DSS. Seven days after modeling, the mice were administered corresponding drugs intragastrically. The mice were sacrificed on the 15th day. The disease activity index, macroscopic and histopathologic lesions, and ultrastructure of colon interstitial cells of Cajal (ICC) were observed. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-10 and interferon gamma (IFN-γ), the expression of nuclear factor-kappa B (NF-κB) p65, c-kit, microtubule-associated protein 1 light chain 3 (LC3-II) and Beclin-l mRNA, and the colonic smooth muscle tension were assessed. RESULTS Acute inflammation occurred in the mice administered DSS. Compared with the control group, the levels of IL-1β, TNF-α, IL-10 and IFN-γ, the expression of LC3-II, Beclin-1 and NF-κB p65 mRNA, and the contractile frequency increased (P < 0.05), the expression of c-kit mRNA and the colonic smooth muscle contractile amplitude decreased in the DSS group (P < 0.05). Compared with the DSS group, the levels of IL-10 and IFN-γ, the expression of c-kit mRNA, and the colonic smooth muscle contractile amplitude increased (P < 0.05), the levels of TNF-α and IL-1β, the expression of LC3-II, Beclin-1 and NF-κB p65 mRNA, and the contractile frequency decreased in the JQD group (P < 0.05). CONCLUSION JQD can regulate the intestinal motility of DSS-induced colitis in mice through suppressing intestinal inflammatory cascade reaction, reducing autophagy of ICC, and regulating the network path of ICC/smooth muscle cells.
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24
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Schwerd T, Pandey S, Yang HT, Bagola K, Jameson E, Jung J, Lachmann RH, Shah N, Patel SY, Booth C, Runz H, Düker G, Bettels R, Rohrbach M, Kugathasan S, Chapel H, Keshav S, Elkadri A, Platt N, Muise AM, Koletzko S, Xavier RJ, Marquardt T, Powrie F, Wraith JE, Gyrd-Hansen M, Platt FM, Uhlig HH. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut 2017; 66:1060-1073. [PMID: 26953272 PMCID: PMC5532464 DOI: 10.1136/gutjnl-2015-310382] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 01/06/2016] [Accepted: 01/14/2016] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.
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Affiliation(s)
- Tobias Schwerd
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Sumeet Pandey
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Huei-Ting Yang
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Katrin Bagola
- Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
| | - Elisabeth Jameson
- Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK
| | - Jonathan Jung
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | | | - Neil Shah
- Great Ormond Street Hospital, London, UK
| | - Smita Y Patel
- NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Claire Booth
- Department of Clinical Immunology, Great Ormond Street Hospital, London, UK
| | - Heiko Runz
- University of Heidelberg, Heidelberg, Germany
| | - Gesche Düker
- University Children's Hospital Bonn, Bonn, Germany
| | | | - Marianne Rohrbach
- Children's Research Centre Zurich, University Children's Hospital, Zurich, Switzerland
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Helen Chapel
- NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Satish Keshav
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Abdul Elkadri
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada,Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Nick Platt
- Department of Pharmacology, University of Oxford, Oxford, UK
| | - Alexio M Muise
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada,Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Sibylle Koletzko
- Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
| | - Ramnik J Xavier
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | | | - Fiona Powrie
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK,Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - James E Wraith
- Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester, UK
| | - Mads Gyrd-Hansen
- Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK
| | - Frances M Platt
- Department of Pharmacology, University of Oxford, Oxford, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK,Department of Pediatrics, University of Oxford, Oxford, UK
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Pelissier-Rota M, Chartier NT, Bonaz B, Jacquier-Sarlin MR. A crosstalk between muscarinic and CRF2 receptors regulates cellular adhesion properties of human colon cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017; 1864:1246-1259. [PMID: 28432022 DOI: 10.1016/j.bbamcr.2017.04.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 04/04/2017] [Accepted: 04/14/2017] [Indexed: 12/24/2022]
Abstract
Patients with inflammatory bowel disease often suffer from chronic and relapsing intestinal inflammation that favor the development of colitis associated cancer. An alteration of the epithelial intestinal barrier function observed in IBD is supposed to be a consequence of stress. It has been proposed that corticotrophin-releasing factor receptor (CRF2), one of the two receptors of CRF, the principal neuromediator of stress, acts on cholinergic nerves to induce stress-mediated epithelial barrier dysfunction. Non-neuronal acetylcholine (Ach) and muscarinic receptors (mAchR) also contribute to alterations of epithelial cell functions. In this study, we investigated the mechanisms through which stress and Ach modulate epithelial cell adhesive properties. We show that Ach-induced activation of mAchR in HT-29 cells results in cell dissociation together with changes in cell-matrix contacts, which correlates with the acquisition of invasive potential consistent with a matrix metalloproteinase (MMP) mode of invasion. These processes result from mAchR subsequent stimulation of the cascade of src/Erk and FAK activation. Ach-induced secretion of laminin 332 leads to α3β1 integrin activation and RhoA-dependent reorganization of the actin cytoskeleton. We show that Ach-mediated effects on cell adhesion are blocked by astressin 2b, a CRF2 antagonist, suggesting that Ach action depends partly on CRF2 signaling. This is reinforced by the fact that Ach-mediated activation of mAchR stimulates both the synthesis and the release of CRF2 ligands in HT-29 cells (effects blocked by atropine). In summary, our data provides evidence for a novel intracellular circuit involving mAchR acting on CRF2-signaling that could mediate colonic mucosal barrier dysfunction and exacerbate mucosal inflammation.
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Affiliation(s)
- M Pelissier-Rota
- Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France; INSERM U1216, F-38000 Grenoble, France
| | - N T Chartier
- Biotechnology Center, Technical University Dresden, 01307 Dresden, Germany
| | - B Bonaz
- Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France; INSERM U1216, F-38000 Grenoble, France; CHU, Grenoble, F-38000 Grenoble, France
| | - M R Jacquier-Sarlin
- Université Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France; INSERM U1216, F-38000 Grenoble, France.
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Iida T, Onodera K, Nakase H. Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2017; 23:1944-1953. [PMID: 28373760 PMCID: PMC5360635 DOI: 10.3748/wjg.v23.i11.1944] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/07/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. Recently, some studies provided strong evidence that the process of autophagy affects several aspects of mucosal immune responses. Autophagy is a cellular stress response that plays key roles in physiological processes, such as innate and adaptive immunity, adaptation to starvation, degradation of aberrant proteins or organelles, antimicrobial defense, and protein secretion. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including IBD. Autophagy plays multiple roles in IBD pathogenesis by altering processes that include intracellular bacterial killing, antimicrobial peptide secretion by Paneth cells, goblet cell function, proinflammatory cytokine production by macrophages, antigen presentation by dendritic cells, and the endoplasmic reticulum stress response in enterocytes. Recent studies have identified susceptibility genes involved in autophagy, such as NOD2, ATG16L1, and IRGM, and active research is ongoing all over the world. The aim of this review is a systematic appraisal of the current literature to provide a better understanding of the role of autophagy in the pathogenesis of IBD. Understanding these mechanisms will bring about new strategies for the treatment and prevention of IBD.
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Abstract
Inflammatory bowel disease [IBD] is characterized by chronic inflammation of the gastrointestinal tract. Medications such as corticosteroids, thiopurines, immunomodulators and biologic agents are used to induce and maintain remission; however, response to these drugs is variable and can diminish over time. Defective autophagy has been strongly linked to IBD pathogenesis, with evidence showing that enhancing autophagy may be therapeutically beneficial by regulating inflammation and clearing intestinal pathogens. It is plausible that the therapeutic effects of some IBD drugs are mediated in part through modulation of the autophagy pathway, with studies investigating a wide range of diseases and cell types demonstrating autophagy pathway regulation by these agents. This review will highlight the current evidence, both in vitro and in vivo, for the modulation of autophagy by drugs routinely used in IBD. A clearer understanding of their mechanisms of action will be invaluable to utilize these drugs in a more targeted and personalized manner in this diverse and often complex group of patients.
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Affiliation(s)
- Kirsty M Hooper
- School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Peter G Barlow
- School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Craig Stevens
- School of Life, Sport & Social Sciences, Edinburgh Napier University, Edinburgh, UK
| | - Paul Henderson
- Child Life and Health, University of Edinburgh, Edinburgh, UK
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK
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28
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Wang Q, Xu KQ, Qin XR, Wen-Lu, Yan-Liu, Wang XY. Association between physical activity and inflammatory bowel disease risk: A meta-analysis. Dig Liver Dis 2016; 48:1425-1431. [PMID: 27671622 DOI: 10.1016/j.dld.2016.08.129] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/17/2016] [Accepted: 08/27/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous studies of an association between physical activity and inflammatory bowel disease have yielded conflicting results. AIM This meta-analysis was conducted to clarify whether there is an association between physical activity and inflammatory bowel disease. METHODS The PubMed and Web of Science databases were searched for relevant studies published up to October 2015. Data were extracted and the summary relative risks (RRs) were calculated using a random effects or a fixed-effects model, according to heterogeneity. RESULTS Seven studies were included in the analysis. Relative to individuals with low physical activity, those who participated in high physical activity had an RR of 0.63 (95% CI, 0.50-0.79) for developing Crohn's disease. In stratified analyses, a significantly lower risk for Crohn's disease was associated with high physical activity in Europeans only (RR, 0.62; 95% CI, 0.43-0.91); population-based control studies (RR, 0.56; 95% CI, 0.41-0.76); and case-control studies (RR, 0.56; 95% CI, 0.41-0.75). The data of 6 studies were pooled to analyze the effect of physical activity on the risk of ulcerative colitis, and no significant association was found (RR, 0.82; 95% CI, 0.68-1.00). CONCLUSIONS The pooled results of observational studies support that physical activity has a protective effect against Crohn's disease.
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Affiliation(s)
- Qiang Wang
- Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China
| | - Ke-Qun Xu
- Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China
| | - Xiang-Rong Qin
- Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China
| | - Wen-Lu
- Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China
| | - Yan-Liu
- Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China
| | - Xiao-Yong Wang
- Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China.
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Synthesis and biological evaluation of matrine derivatives containing benzo-α-pyrone structure as potent anti-lung cancer agents. Sci Rep 2016; 6:35918. [PMID: 27786281 PMCID: PMC5081519 DOI: 10.1038/srep35918] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 10/05/2016] [Indexed: 01/29/2023] Open
Abstract
Matrine, an active component of root extracts from Sophora flavescens Ait, is the main chemical ingredient of Fufang Kushen injection which was approved by Chinese FDA (CFDA) in 1995 as an anticancer drug to treat non-small cell lung cancer and liver cancer in combination with other anticancer drugs. Owning to its druggable potential, matrine is considered as an ideal lead compound for modification. We delineate herein the synthesis and anticancer effects of 17 matrine derivatives bearing benzo-α-pyrone structures. The results of cell viability assays indicated that most of the target compounds showed improved anticancer effects. Further studies showed that compound 5i could potently inhibit lung cancer cell proliferation in vitro and in vivo with no obvious side effects. Moreover, compound 5i could induce G1 cell cycle arrest and autophagy in lung cancer cells through up-regulating P27, down-regulating CDK4 and cyclinD1 and attenuating PI3K/Akt/mTOR pathway. Suppression of autophagy attenuated 5i induced proliferation inhibition. Collectively, our results infer that matrine derivative 5i bears therapeutic potentials for lung cancer.
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30
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Salem M, Ammitzboell M, Nys K, Seidelin JB, Nielsen OH. ATG16L1: A multifunctional susceptibility factor in Crohn disease. Autophagy 2016; 11:585-94. [PMID: 25906181 DOI: 10.1080/15548627.2015.1017187] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease.
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Key Words
- ATG16L1
- ATG16L1, autophagy-related 16-like 1 (S. cerevisiae)
- BCL2, B-cell CLL/lymphoma 2
- Crohn disease
- DCs, dendritic cells
- ER, endoplasmic reticulum
- GWAS, genome-wide association studies
- IBD, inflammatory bowel disease
- MDP, muramyl dipeptide
- MTOR, mechanistic target of rapamycin
- NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells
- NOD2
- NOD2, nucleotide-binding oligomerization domain containing 2
- RIPK2, receptor-interacting serine-threonine kinase 2
- SNP, single-nucleotide polymorphism
- T300A, threonine-to-alanine substitution at amino acid position 300
- TNF/TNF-α, tumor necrosis factor
- UC, ulcerative colitis
- ULK1, unc-51 like autophagy-activating kinase 1
- XBP1, X-box binding protein 1
- autophagy
- bacterial clearance
- endoplasmic reticulum stress
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Affiliation(s)
- Mohammad Salem
- a Department of Gastroenterology ; Medical Section; Herlev Hospital; University of Copenhagen ; Copenhagen , Denmark
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Vanhove W, Nys K, Vermeire S. Therapeutic innovations in inflammatory bowel diseases. Clin Pharmacol Ther 2015; 99:49-58. [PMID: 26509246 DOI: 10.1002/cpt.286] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 10/22/2015] [Accepted: 10/23/2015] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel disease (IBD) is a spectrum of complex multifactorial immune disorders characterized by chronic inflammation of the gut. Significant advances have been made in unraveling the pathogenesis of this disease spectrum, which have spurred the discovery of new therapeutic targets and strategies. In this review, we highlight the emerging new classes of IBD therapeutics under clinical evaluation and their method of action, including JAK inhibitors, anti-SMAD7 oligonucleotides, and cell-based therapies. Moreover, we discuss how an approach based on unique molecular insights in a given patient will, in the future, lead to a truly individualized/tailored disease management, starting at diagnosis, aiding in prognosis, and resulting in a personalized therapeutic approach.
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Affiliation(s)
- W Vanhove
- Department of Clinical and Experimental Medicine, University Hospitals Leuven, Leuven, Belgium
| | - K Nys
- Department of Clinical and Experimental Medicine, University Hospitals Leuven, Leuven, Belgium
| | - S Vermeire
- Department of Clinical and Experimental Medicine, University Hospitals Leuven, Leuven, Belgium
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Salem M, Nielsen OH, Nys K, Yazdanyar S, Seidelin JB. Impact of T300A Variant of ATG16L1 on Antibacterial Response, Risk of Culture Positive Infections, and Clinical Course of Crohn's Disease. Clin Transl Gastroenterol 2015; 6:e122. [PMID: 26673830 PMCID: PMC4816087 DOI: 10.1038/ctg.2015.47] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES: Autophagy-related 16-like 1 (ATG16L1) deficiency leads to impaired cellular autophagy and bacterial degradation as well as an altered cytokine production. The single-nucleotide polymorphism rs2241880 (T300A) is associated with an increased risk for Crohn's disease (CD). ATG16L1 polymorphisms could therefore have an impact on the risk of infectious complications and disease course in CD. We examined the impact of the T300A genotype on the antibacterial response toward a panel of pathogenic bacteria in vitro, as well as clinical infectious complications in vivo and the disease course in a Danish cohort of patients with CD. METHODS: A total of 236 CD patients were genotyped for ATG16L1T300A; their clinical records were reviewed, and microbial, radiological, and surgical data were scrutinized. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and CD patients carrying the different ATG16L1 genotypes, and the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β was measured by enzyme-linked immunosorbent assay after stimulation with a panel of pathogenic bacteria of clinical relevance for the gastrointestinal tract, e.g., enteroinvasive Escherichia coli (EIEC), Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, or Mycobacterium avium paratuberculosis. RESULTS: Fifty-seven healthy controls (15, 29, 13) and 236 patients with CD (50, 108, 78) were genotyped for the T300A ATG16L1 polymorphism (AA homozygous, GG homozygous risk variant, AG heterozygous variant, respectively). The median duration of disease was 128 months (range, 30–175). The cumulative follow-up of this cohort was 2,366 patient-years. ATG16L1 gene variations interfered with the production of IL-1β, which was significantly increased in PBMCs from GG patients in response to all tested bacteria, whereas the TNF-α production was decreased in PBMCs from GG patients stimulated with EIEC, L. monocytogenes, and S. typhimurium, but unaffected by the other bacteria tested. Moreover, the GG variant showed a nonsignificant increase in the risk of bowel resections (P=0.07) and postsurgical infections (P=0.08), whereas the risk of non-disease-related infections was unaffected by genotype in the observation period. In addition, patients with AA and AG variants had a higher frequency of complicated fistulizing disease (P=0.03) with an overall more aggravated disease course with an increased number of surgical procedures for fistulous disease from a median 6.5 operations (2.0 in GG patients; P=0.002). This risk was independent on disease phenotype (penetrating vs. non-penetrating) and immunomodulating medication. CONCLUSIONS: The T300A variant in patients with CD strongly increases the risk for complicated fistulizing disease, and significantly affects antibacterial responses in vitro, but the latter effect seems to have a minor role for the infectious risk in CD.
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Affiliation(s)
- Mohammad Salem
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Kris Nys
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, Catholic University of Leuven, Leuven, Belgium
| | - Shiva Yazdanyar
- Department of Clinical Biochemistry, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Jakob Benedict Seidelin
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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Zhao J, Dong JN, Wang HG, Zhao M, Sun J, Zhu WM, Zuo LG, Gong JF, Li Y, Gu LL, Li N, Li JS. Docosahexaenoic Acid Attenuated Experimental Chronic Colitis in Interleukin 10-Deficient Mice by Enhancing Autophagy Through Inhibition of the mTOR Pathway. JPEN J Parenter Enteral Nutr 2015; 41:824-829. [PMID: 26407598 DOI: 10.1177/0148607115609308] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND In the battle against Crohn's disease, autophagy stimulation is a promising therapeutic option-one both new and newly rediscovered. In experimental models, docosahexaenoic acid (DHA)-a long-chain polyunsaturated fatty acid-has been demonstrated to be useful in the treatment of inflammatory bowel disease through inhibition of the nuclear factor-κB pathway. However, the impact of DHA on autophagy in the colon remains unclear. METHODS Mice were divided into 3 groups: wild type (placebo), the interleukin 10 knockout group (IL-10-/-, placebo), and the DHA group (IL-10-/-, DHA). DHA was administered to IL-10-/- mice by gavage at a dosage of 35.5 mg/kg/d for 2 weeks. The severity of colitis, expression of proinflammatory cytokines, expression/distribution of LC3B, and mTOR signaling pathway were evaluated in the proximal colon tissues collected from all mice at the end of the experiment. RESULTS DHA administration ameliorated experimental colitis in the IL-10-/- mice, as demonstrated by decreased proinflammatory cytokines (TNF-α and IFN-γ), reduced infiltration of inflammatory cells, and lowered histologic scores of the proximal colon mucosa. Moreover, in the DHA-treated mice, enhanced autophagy was observed to be associated with (1) increased expression and restoration of the distribution integrity of LC3B in the colon and (2) inhibition of the mTOR signaling pathway. CONCLUSION This study showed that DHA therapy could attenuate experimental chronic colitis in IL-10-/- mice by triggering autophagy via inhibition of the mTOR pathway.
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Affiliation(s)
- Jie Zhao
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jian-Ning Dong
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hong-Gang Wang
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Mingli Zhao
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jing Sun
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wei-Ming Zhu
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lu-Gen Zuo
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jian-Feng Gong
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yi Li
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Li-Li Gu
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ning Li
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jie-Shou Li
- 1 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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Nicotine-induced cellular stresses and autophagy in human cancer colon cells: A supportive effect on cell homeostasis via up-regulation of Cox-2 and PGE(2) production. Int J Biochem Cell Biol 2015; 65:239-56. [PMID: 26100595 DOI: 10.1016/j.biocel.2015.06.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 05/28/2015] [Accepted: 06/12/2015] [Indexed: 12/12/2022]
Abstract
Nicotine, one of the active components in cigarette smoke, has been described to contribute to the protective effect of smoking in ulcerative colitis (UC) patients. Furthermore, the nicotinic acetylcholine receptor α7 subunit (α7nAChR) expressed on immune cells, is an essential regulator of inflammation. As intestinal epithelial cells also express α7nAChR, we investigated how nicotine could participate in the homeostasis of intestinal epithelial cells. First, using the human adenocarcinoma cell line HT-29, we revealed that nicotine, which triggers an influx of extracellular Ca(2+) following α7nAChR stimulation, induces mitochondrial reactive oxygen species (ROS) production associated with a disruption of the mitochondrial membrane potential and endoplasmic reticulum stress. This results in caspase-3 activation, which in turn induces apoptosis. Additionally, we have shown that nicotine induces a PI3-K dependent up-regulation of cyclooxygenase-2 (Cox-2) expression and prostaglandin E2 (PGE2) production. In this context, we suggest that this key mediator participates in the cytoprotective effects of nicotine against apoptosis by stimulating autophagy in colon cancer cells. Our results provide new insight into one potential mechanism by which nicotine could protect from UC and suggest an anti-inflammatory role for the cholinergic pathway at the epithelial cell level.
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Chinnadurai R, Copland IB, Ng S, Garcia M, Prasad M, Arafat D, Gibson G, Kugathasan S, Galipeau J. Mesenchymal Stromal Cells Derived From Crohn's Patients Deploy Indoleamine 2,3-dioxygenase-mediated Immune Suppression, Independent of Autophagy. Mol Ther 2015; 23:1248-1261. [PMID: 25899824 DOI: 10.1038/mt.2015.67] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 04/10/2015] [Indexed: 02/06/2023] Open
Abstract
Autologous bone marrow-derived mesenchymal stromal cells (MSCs) for adoptive cell therapy of luminal Crohn's disease (CD) are being tested in clinical trials. However, CD is associated with dysregulation of autophagy and its effect on MSC's immunobiology is unknown. Here, we demonstrate no quantitative difference in phenotype, in vitro growth kinetics and molecular signatures to IFNγ between MSCs derived from CD and healthy individuals. CD MSCs were indistinguishable from those derived from healthy controls at inhibiting T-cell proliferation through an indoleamine 2,3-dioxygenase (IDO)-dependent mechanism. Upon IFNγ prelicensing, both MSC populations inhibit T-cell effector functions. Neither a single-nucleotide polymorphism (SNP) rs7820268 in the IDO gene, nor a widely reported CD predisposing SNP ATG16L1rs2241880 modulated the suppressive function of MSCs carrying these haplotypes. IFNγ stimulation or coculture with activated T cells upregulated the expression of autophagy genes and/or vacuoles on MSCs. Pharmacological blockade of autophagy pathway did not reverse the immunosuppressive properties and IFNγ responsiveness of MSCs confirming the absence of a functional link between these two cell biochemical properties. We conclude that autophagy, but not IDO and IFNγ responsiveness, is dispensable for MSC's immunosuppressive properties. MSCs from CD subjects are functionally analogous to those of healthy individuals.
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Affiliation(s)
- Raghavan Chinnadurai
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Ian B Copland
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Spencer Ng
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | | | - Mahadev Prasad
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Dalia Arafat
- School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Greg Gibson
- School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Subra Kugathasan
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Jacques Galipeau
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA; Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
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Zhao J, Sun Y, Shi P, Dong JN, Zuo LG, Wang HG, Gong JF, Li Y, Gu LL, Li N, Li JS, Zhu WM. Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy. Int Immunopharmacol 2015; 26:221-8. [PMID: 25858875 DOI: 10.1016/j.intimp.2015.03.033] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/12/2015] [Accepted: 03/25/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Celastrol had been proved effective in the treatment for IBD, probably with the modulation of oxidative stress, inflammatory cytokines and intestinal homeostasis. This study was aimed to investigate whether celastrol could ameliorate the inflammation of IL-10 deficient mice, a murine model of Crohn's disease (CD) with the induction of autophagy. MATERIAL AND METHODS The mice included were divided into four groups, ##WT group, IL-10(-/-) group, Cel group and Control group (celastrol+3-Methyladenine). Celastrol (2 mg/kg) treatment by gavage was administered to mice daily over one week. 3-Methyladenine (autophagy inhibitors) was administered at a dose of 30 mg/kg by intraperitoneal injection. The histological evaluation of the colon, tissue myeloperoxidase (MPO), and colon inflammation of mice in the four groups was evaluated and compared. Furthermore, the PI3K/Akt/mTOR pathway and the status of autophagy in intestine affected by celastrol were also assessed. RESULTS The one-week administration of celastrol ameliorated established colitis in IL-10 deficient mice, associated with a reduction of marked histological inflammation, a decreased colon MPO concentration and suppression of colonic proinflammatory cytokine. Furthermore, the decreased neutrophil infiltration in proximal colon and improvement of inflammation in the Cel group was much more obvious than that in the Control group. The Western blotting analysis of the PI3K/Akt/mTOR pathway and autophagy showed that celastrol treatment up-regulated the autophagy of colon tissue by suppressing the PI3K/Akt/mTOR signaling pathway. CONCLUSIONS Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy by suppressing the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Jie Zhao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Ye Sun
- The Center of Diagnosis and Treatment for Joint Disease, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, China.
| | - Peiliang Shi
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, China.
| | - Jian-Ning Dong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Lu-Gen Zuo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Hong-Gang Wang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Jian-Feng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Li-Li Gu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Ning Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Jie-Shou Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, 210002 Jiangsu, China.
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Salem M, Ammitzboell M, Nys K, Seidelin JB, Nielsen OH. ATG16L1: A multifunctional susceptibility factor in Crohn disease. Autophagy 2015. [PMID: 25906181 DOI: 10.1080/+15548627.2015.1017187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022] Open
Abstract
Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease.
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Key Words
- ATG16L1
- ATG16L1, autophagy-related 16-like 1 (S. cerevisiae)
- BCL2, B-cell CLL/lymphoma 2
- Crohn disease
- DCs, dendritic cells
- ER, endoplasmic reticulum
- GWAS, genome-wide association studies
- IBD, inflammatory bowel disease
- MDP, muramyl dipeptide
- MTOR, mechanistic target of rapamycin
- NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells
- NOD2
- NOD2, nucleotide-binding oligomerization domain containing 2
- RIPK2, receptor-interacting serine-threonine kinase 2
- SNP, single-nucleotide polymorphism
- T300A, threonine-to-alanine substitution at amino acid position 300
- TNF/TNF-α, tumor necrosis factor
- UC, ulcerative colitis
- ULK1, unc-51 like autophagy-activating kinase 1
- XBP1, X-box binding protein 1
- autophagy
- bacterial clearance
- endoplasmic reticulum stress
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Affiliation(s)
- Mohammad Salem
- a Department of Gastroenterology ; Medical Section; Herlev Hospital; University of Copenhagen ; Copenhagen , Denmark
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Gerster R, Eloranta JJ, Hausmann M, Ruiz PA, Cosin-Roger J, Terhalle A, Ziegler U, Kullak-Ublick GA, von Eckardstein A, Rogler G. Anti-inflammatory Function of High-Density Lipoproteins via Autophagy of IκB Kinase. Cell Mol Gastroenterol Hepatol 2014; 1:171-187.e1. [PMID: 28247863 PMCID: PMC5301135 DOI: 10.1016/j.jcmgh.2014.12.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 12/12/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Plasma levels of high-density lipoprotein (HDL) cholesterol are frequently found decreased in patients with inflammatory bowel disease (IBD). Therefore, and because HDL exerts anti-inflammatory activities, we investigated whether HDL and its major protein component apolipoprotein A-I (apoA-I) modulate mucosal inflammatory responses in vitro and in vivo. METHODS The human intestinal epithelial cell line T84 was used as the in vitro model for measuring the effects of HDL on the expression and secretion of tumor necrosis factor (TNF), interleukin-8 (IL-8), and intracellular adhesion molecule (ICAM). Nuclear factor-κB (NF-κB)-responsive promoter activity was studied by dual luciferase reporter assays. Mucosal damage from colitis induced by dextran sodium sulphate (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) was scored by colonoscopy and histology in apoA-I transgenic (Tg) and apoA-I knockout (KO) and wild-type (WT) mice. Myeloperoxidase (MPO) activity and TNF and ICAM expression were determined in intestinal tissue samples. Autophagy was studied by Western blot analysis, immunofluorescence, and electron microscopy. RESULTS HDL and apoA-I down-regulated TNF-induced mRNA expression of TNF, IL-8, and ICAM, as well as TNF-induced NF-κB-responsive promoter activity. DSS/TNBS-treated apoA-I KO mice displayed increased mucosal damage upon both colonoscopy and histology, increased intestinal MPO activity and mRNA expression of TNF and ICAM as compared with WT and apoA-I Tg mice. In contrast, apoA-I Tg mice showed less severe symptoms monitored by colonoscopy and MPO activity in both the DSS and TNBS colitis models. In addition, HDL induced autophagy, leading to recruitment of phosphorylated IκB kinase to the autophagosome compartment, thereby preventing NF-κB activation and induction of cytokine expression. CONCLUSIONS Taken together, the in vitro and in vivo findings suggest that HDL and apoA-I suppress intestinal inflammation via autophagy and are potential therapeutic targets for the treatment of IBD.
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Key Words
- 3-MA, 3-methyl adenine
- ApoA-I, apolipoprotein A-I
- Apolipoprotein A-I
- Autophagy
- CD, Crohn’s disease
- DAPI, 4′,6-diamidino-2-phenylindole
- DSS, dextran sodium sulphate
- EMSA, electrophoretic mobility shift assay
- HDL, high-density lipoprotein
- IBD, inflammatory bowel disease
- ICAM, intracellular adhesion molecule
- IL, interleukin
- Inflammatory Bowel Disease
- KO, knockout
- LC3II, light chain 3 II
- MEICS, murine endoscopic index of colitis severity
- MPO, myeloperoxidase
- NF-κB
- NF-κB, nuclear factor κB
- PBS, phosphate-buffered saline
- PFA, paraformaldehyde
- PI-3, phosphatidylinositol-3
- RT-PCR, real-time polymerase chain reaction
- TNBS, 2,4,6-trinitrobenzenesulfonic acid
- TNF, tumor necrosis factor
- Tg, transgenic
- WT, wild type
- mTOR, the mammalian target of rapamycin
- p-IKK, phosphorylated IκB kinase
- siRNA, small interfering RNA
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Affiliation(s)
- Ragam Gerster
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Schlieren, Switzerland
- Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Jyrki J. Eloranta
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Schlieren, Switzerland
| | - Martin Hausmann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Pedro A. Ruiz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jesus Cosin-Roger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Anne Terhalle
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Urs Ziegler
- Centre for Microscopy and Image Analysis, University Hospital Zurich, Zurich, Switzerland
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Schlieren, Switzerland
- Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Arnold von Eckardstein
- Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Zurich Center of Integrative Human Physiology, University of Zurich, Zurich, Switzerland
- Correspondence Address correspondence to: Gerhard Rogler, MD, PhD, Division of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. fax: +41-0-44-255-9497.
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Ke PY, Chen SSL. Autophagy in hepatitis C virus-host interactions: potential roles and therapeutic targets for liver-associated diseases. World J Gastroenterol 2014; 20:5773-93. [PMID: 24914338 PMCID: PMC4024787 DOI: 10.3748/wjg.v20.i19.5773] [Citation(s) in RCA: 28] [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: 10/08/2013] [Revised: 01/14/2014] [Accepted: 03/04/2014] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a lysosome-associated, degradative process that catabolizes cytosolic components to recycle nutrients for further use and maintain cell homeostasis. Hepatitis C virus (HCV) is a major cause of chronic hepatitis, which often leads to end-stage liver-associated diseases and is a significant burden on worldwide public health. Emerging lines of evidence indicate that autophagy plays an important role in promoting the HCV life cycle in host cells. Moreover, the diverse impacts of autophagy on a variety of signaling pathways in HCV-infected cells suggest that the autophagic process is required for balancing HCV-host cell interactions and involved in the pathogenesis of HCV-related liver diseases. However, the detailed molecular mechanism underlying how HCV activates autophagy to benefit viral growth is still enigmatic. Additionally, how the autophagic response contributes to disease progression in HCV-infected cells remains largely unknown. Hence, in this review, we overview the interplay between autophagy and the HCV life cycle and propose possible mechanisms by which autophagy may promote the pathogenesis of HCV-associated chronic liver diseases. Moreover, we outline the related studies on how autophagy interplays with HCV replication and discuss the possible implications of autophagy and viral replication in the progression of HCV-induced liver diseases, e.g., steatosis and hepatocellular carcinoma. Finally, we explore the potential therapeutics that target autophagy to cure HCV infection and its related liver diseases.
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Cravo M, Ferreira P, Sousa P, Moura-Santos P, Velho S, Tavares L, Deus JR, Ministro P, da Silva JP, Correia L, Velosa J, Maio R, Brito M. Clinical and genetic factors predicting response to therapy in patients with Crohn's disease. United European Gastroenterol J 2014; 2:47-56. [PMID: 24918007 PMCID: PMC4040806 DOI: 10.1177/2050640613519626] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 12/14/2013] [Indexed: 12/18/2022] Open
Abstract
AIM To identify clinical and/or genetic predictors of response to several therapies in Crohn's disease (CD) patients. METHODS We included 242 patients with CD (133 females) aged (mean ± standard deviation) 39 ± 12 years and a disease duration of 12 ± 8 years. The single-nucleotide polymorphisms (SNPs) studied were ABCB1 C3435T and G2677T/A, IL23R G1142A, C2370A, and G9T, CASP9 C93T, Fas G670A and LgC844T, and ATG16L1 A898G. Genotyping was performed with real-time PCR with Taqman probes. RESULTS Older patients responded better to 5-aminosalicylic acid (5-ASA) and to azathioprine (OR 1.07, p = 0.003 and OR 1.03, p = 0.01, respectively) while younger ones responded better to biologicals (OR 0.95, p = 0.06). Previous surgery negatively influenced response to 5-ASA compounds (OR 0.25, p = 0.05), but favoured response to azathioprine (OR 2.1, p = 0.04). In respect to genetic predictors, we observed that heterozygotes for ATGL16L1 SNP had a significantly higher chance of responding to corticosteroids (OR 2.51, p = 0.04), while homozygotes for Casp9 C93T SNP had a lower chance of responding both to corticosteroids and to azathioprine (OR 0.23, p = 0.03 and OR 0.08, p = 0.02,). TT carriers of ABCB1 C3435T SNP had a higher chance of responding to azathioprine (OR 2.38, p = 0.01), while carriers of ABCB1 G2677T/A SNP, as well as responding better to azathioprine (OR 1.89, p = 0.07), had a lower chance of responding to biologicals (OR 0.31, p = 0.07), which became significant after adjusting for gender (OR 0.75, p = 0.005). CONCLUSIONS In the present study, we were able to identify a number of clinical and genetic predictors of response to several therapies which may become of potential utility in clinical practice. These are preliminary results that need to be replicated in future pharmacogenomic studies.
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Affiliation(s)
- Marilia Cravo
- Hospital Beatriz Angelo, Loures, Portugal
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - Paula Ferreira
- Escola Superior de Tecnologias da Saude, Lisbon, Portugal
| | | | - Paula Moura-Santos
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Hospital Santa Maria, Lisboa, Portugal
| | | | | | | | | | | | - Luis Correia
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Hospital Santa Maria, Lisboa, Portugal
| | - Jose Velosa
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Hospital Santa Maria, Lisboa, Portugal
| | - Rui Maio
- Hospital Beatriz Angelo, Loures, Portugal
| | - Miguel Brito
- Escola Superior de Tecnologias da Saude, Lisbon, Portugal
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