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Fakhari S, Moradzad M, Ahmadi A, Hekmatnia M, Jalili A, Nikkhoo B, Rahmani MR, Sheikhesmaeili F. Downregulation of MT2-MMP and MT5-MMP in ulcerative colitis serves a diagnostic predictor and potential therapeutic targets. Mol Biol Rep 2025; 52:359. [PMID: 40178713 DOI: 10.1007/s11033-025-10449-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/17/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by persistent inflammation and tissue remodeling. Matrix metalloproteinases (MMPs) play a key role in extracellular matrix degradation, and their dysregulation is implicated in IBD. However, the specific role of membrane-type MMPs (MT-MMPs) in UC remains underexplored. This study investigates the expression of MT-MMPs in UC patients, including new cases and treatment-resistant patients, and evaluates their expression patterns compared to healthy people. METHODS AND RESULTS Colon biopsy samples were collected from three groups: healthy controls (n = 20), newly diagnosed UC patients (n = 20), and UC patients resistant to standard treatments (n = 20). The mRNA expression levels of MT-MMPs were assessed using quantitative real-time PCR. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic utility of these MT-MMPs. Correlation analysis was also conducted to explore the relationship between MT-MMPs and inflammatory markers (CRP, ESR) and vitamin D levels. Out of 6 members of MT-MMPs, MT2-MMP, and MT5-MMP were significantly downregulated in new cases and resistant UC patients compared to controls (P < 0.0001). ROC analysis demonstrated high sensitivity and specificity for MT2-MMP and MT5-MMP in differentiating UC patients from healthy individuals. Additionally, MT2,5-MMP expression was negatively correlated with CRP, ESR, and vitamin D levels, indicating their possible modulation of systematic inflammation. CONCLUSION MT2-MMP and MT5-MMP are downregulated in UC and may serve as diagnostic biomarkers for disease severity. The findings highlight the need for further investigation into their therapeutic potential in modulating inflammation and tissue remodeling in UC.
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Affiliation(s)
- Shohreh Fakhari
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Moradzad
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Amjad Ahmadi
- Department of Microbiology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Melika Hekmatnia
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ali Jalili
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bahram Nikkhoo
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Reza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Farshad Sheikhesmaeili
- Liver& Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Zhu W, Xiong L, Oteiza PI. Structure-dependent capacity of procyanidin dimers to inhibit inflammation-induced barrier dysfunction in a cell model of intestinal epithelium. Redox Biol 2024; 75:103275. [PMID: 39059205 PMCID: PMC11327484 DOI: 10.1016/j.redox.2024.103275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Diet is of major importance in modulating intestinal inflammation, as the gastrointestinal tract is directly exposed to high concentrations of dietary components. Procyanidins are flavan-3-ol oligomers abundant in fruits and vegetables. Although with limited or no intestinal absorption, they can have GI health benefits which can promote overall health. We previously observed that epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) dimers inhibit in vitro colorectal cancer cell proliferation and invasiveness. Inflammation-mediated intestinal barrier permeabilization can result in a chronic inflammatory condition and promote colorectal cancer onset/progression. Thus, this study investigated the structure-dependent capacity of ECG, EGCG and (-)-epicatechin (EC) dimers to inhibit tumor necrosis factor alpha (TNFα)-induced inflammation, oxidative stress, and loss of barrier integrity in Caco-2 cells differentiated into an intestinal epithelial cell monolayer. Cells were incubated with TNFα (10 ng/ml), in the absence/presence of ECG, EGCG and EC dimers. The three dimers inhibited TNFα-mediated Caco-2 cell monolayer permeabilization, modulating events involved in the loss of barrier function and inflammation, i.e. decreased tight junction protein levels; increased matrix metalloproteinases expression and activity; increased NADPH oxidase expression and oxidant production; activation of the NF-κB and ERK1/2 pathways and downstream events leading to tight junction opening. For some of these mechanisms, the galloylated ECG and EGCG dimers had stronger protective potency than the non-galloylated EC dimer. These differences could be due to differential membrane interactions as pointed out by molecular dynamics simulation of procyanidin dimers-cell membrane interactions and/or by differential interactions with NOX1. Results show that dimeric procyanidins, although poorly absorbed, can promote health by alleviating intestinal inflammation, oxidative stress and barrier permeabilization.
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Affiliation(s)
- Wei Zhu
- Department of Nutrition, University of California, Davis, CA, 95618, USA
| | - Le Xiong
- Cleveland Clinic, Cleveland, OH, 44194, USA
| | - Patricia I Oteiza
- Department of Nutrition, University of California, Davis, CA, 95618, USA; Department of Environmental Toxicology, University of California, Davis, CA, 95618, USA.
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Han SH, Mo JS, Yun KJ, Chae SC. MicroRNA 429 regulates MMPs expression by modulating TIMP2 expression in colon cancer cells and inflammatory colitis. Genes Genomics 2024; 46:763-774. [PMID: 38733517 DOI: 10.1007/s13258-024-01520-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND In a previous study, we found that the expression of microRNA 429 (MIR429) was decreased in dextran sodium sulfate (DSS)-induced mouse colitis tissues. OBJECTIVE In this study, we aimed to investigate the interaction of MIR429 with TIMP metallopeptidase inhibitor 2 (TIMP2), one of its candidate target genes, in human colorectal cancer (CRC) cells and DSS-induced mouse colitis tissues. METHODS A luciferase reporter system was used to confirm the effect of MIR429 on TIMP2 expression. The expression levels of MIR429 and target genes in cells or tissues were evaluated through quantitative RT-PCR, western blotting, or immunohistochemistry. RESULTS We found that the expression level of MIR429 was downregulated in human CRC tissues, and also showed that TIMP2 is a direct target gene of MIR429 in CRC cell lines. Furthermore, MIR429 regulate TIMP2-mediated matrix metallopeptidases (MMPs) expression in CRC cells. We also generated cell lines stably expressing MIR429 in CRC cell lines and showed that MIR429 regulates the expression of MMPs by mediating TIMP2 expression. In addition to human CRC tissues, we found that TIMP2 was highly expressed in mouse colitis tissues and human ulcerative colitis (UC) tissues. CONCLUSIONS Our findings suggest that the expression of endogenous MIR429 was reduced in human CRC tissues and colitis, leading to upregulation of its target gene TIMP2. The upregulation of TIMP2 by decreased MIR429 expression in CRC tissues and inflamed tissues suggests that it may affect extracellular matrix (ECM) remodeling through downregulation of MMPs. Therefore, MIR429 may have therapeutic value for human CRC and colitis.
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Affiliation(s)
- Seol-Hee Han
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Ji-Su Mo
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Ki-Jung Yun
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea
| | - Soo-Cheon Chae
- Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea.
- Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk, 54538, Republic of Korea.
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Chen SY, Fang CY, Su BH, Chen HM, Huang SC, Wu PT, Shiau AL, Wu CL. Early Growth Response Protein 1 Exacerbates Murine Inflammatory Bowel Disease by Transcriptional Activation of Matrix Metalloproteinase 12. Biomedicines 2024; 12:780. [PMID: 38672136 PMCID: PMC11047900 DOI: 10.3390/biomedicines12040780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory condition affecting the colon and small intestine, with Crohn's disease and ulcerative colitis being the major types. Individuals with long-term IBD are at an increased risk of developing colorectal cancer. Early growth response protein 1 (Egr1) is a nuclear protein that functions as a transcriptional regulator. Egr1 is known to control the expression of numerous genes and play a role in cell growth, proliferation, and differentiation. While IBD has been associated with severe inflammation, the precise mechanisms underlying its pathogenesis remain unclear. This study aimed to investigate the role of Egr1 in the development of IBD. High levels of Egr1 expression were observed in a mouse model of colitis induced by dextran sulfate sodium (DSS), as determined by immunohistochemical (IHC) staining. Chronic DSS treatment showed that Egr1 knockout (KO) mice exhibited resistance to the development of IBD, as determined by changes in their body weight and disease scores. Additionally, enzyme-linked immunosorbent assay (ELISA) and IHC staining demonstrated decreased expression levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, as well as matrix metalloproteinase 12 (MMP12). Putative Egr1 binding sites were identified within the MMP12 promoter region. Through reporter assays and chromatin immunoprecipitation (ChIP) analysis, it was shown that Egr1 binds to the MMP12 promoter and regulates MMP12 expression. In conclusion, we found that Egr1 plays a role in the inflammation process of IBD through transcriptionally activating MMP12.
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Affiliation(s)
- Shih-Yao Chen
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan 717302, Taiwan;
| | - Chuan-Yin Fang
- Division of Colon and Rectal Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
| | - Bing-Hwa Su
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Hao-Ming Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Shih-Chi Huang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Po-Ting Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Orthopedics, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701401, Taiwan
- Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan 701401, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
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Salomão R, Assis V, de Sousa Neto IV, Petriz B, Babault N, Durigan JLQ, de Cássia Marqueti R. Involvement of Matrix Metalloproteinases in COVID-19: Molecular Targets, Mechanisms, and Insights for Therapeutic Interventions. BIOLOGY 2023; 12:843. [PMID: 37372128 PMCID: PMC10295079 DOI: 10.3390/biology12060843] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023]
Abstract
MMPs are enzymes involved in SARS-CoV-2 pathogenesis. Notably, the proteolytic activation of MMPs can occur through angiotensin II, immune cells, cytokines, and pro-oxidant agents. However, comprehensive information regarding the impact of MMPs in the different physiological systems with disease progression is not fully understood. In the current study, we review the recent biological advances in understanding the function of MMPs and examine time-course changes in MMPs during COVID-19. In addition, we explore the interplay between pre-existing comorbidities, disease severity, and MMPs. The reviewed studies showed increases in different MMP classes in the cerebrospinal fluid, lung, myocardium, peripheral blood cells, serum, and plasma in patients with COVID-19 compared to non-infected individuals. Individuals with arthritis, obesity, diabetes, hypertension, autoimmune diseases, and cancer had higher MMP levels when infected. Furthermore, this up-regulation may be associated with disease severity and the hospitalization period. Clarifying the molecular pathways and specific mechanisms that mediate MMP activity is important in developing optimized interventions to improve health and clinical outcomes during COVID-19. Furthermore, better knowledge of MMPs will likely provide possible pharmacological and non-pharmacological interventions. This relevant topic might add new concepts and implications for public health in the near future.
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Affiliation(s)
- Rebecca Salomão
- Laboratory of Molecular Analysis, Postgraduate Program in Health and Sciences and Technology, Faculty of Ceilândia, University of Brasilia, Brasilia 72220-275, DF, Brazil
| | - Victoria Assis
- Laboratory of Molecular Analysis, Postgraduate Program in Rehabilitation Sciences, Faculty of Ceilândia, University of Brasilia, Brasilia 72220-275, DF, Brazil; (V.A.); (J.L.Q.D.)
| | - Ivo Vieira de Sousa Neto
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-907, SP, Brazil;
| | - Bernardo Petriz
- Graduate Program in Genomic Sciences and Biotechnology, Catholic University of Brasilia, Brasilia 71966-700, DF, Brazil;
- Laboratory of Exercise Molecular Physiology, University Center UDF, Brasília 71966-900, DF, Brazil
| | - Nicolas Babault
- INSERM UMR1093-CAPS, UFR des Sciences du Sport, Université de Bourgogne, F-21000 Dijon, France;
- Centre d’Expertise de la Performance, UFR des Sciences du Sport, Université de Bourgogne, F-21000 Dijon, France
| | - João Luiz Quaglioti Durigan
- Laboratory of Molecular Analysis, Postgraduate Program in Rehabilitation Sciences, Faculty of Ceilândia, University of Brasilia, Brasilia 72220-275, DF, Brazil; (V.A.); (J.L.Q.D.)
| | - Rita de Cássia Marqueti
- Laboratory of Molecular Analysis, Postgraduate Program in Health and Sciences and Technology, Faculty of Ceilândia, University of Brasilia, Brasilia 72220-275, DF, Brazil
- Laboratory of Molecular Analysis, Postgraduate Program in Rehabilitation Sciences, Faculty of Ceilândia, University of Brasilia, Brasilia 72220-275, DF, Brazil; (V.A.); (J.L.Q.D.)
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Yang FY, Chan WH, Gao CY, Zheng YT, Ke CH. Transabdominal ultrasound alleviates LPS-induced neuroinflammation by modulation of TLR4/NF-κB signaling and tight junction protein expression. Life Sci 2023; 325:121769. [PMID: 37178865 DOI: 10.1016/j.lfs.2023.121769] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/03/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023]
Abstract
AIM Inflammatory bowel disease (IBD) may be a risk factor in the development of brain inflammation. It has been demonstrated noninvasive neuromodulation through sub-organ ultrasound stimulation. The purpose of this study was to investigate whether abdominal low-intensity pulsed ultrasound (LIPUS) alleviates lipopolysaccharide (LPS)-induced cortical inflammation via inhibition of colonic inflammation. MATERIALS AND METHODS Colonic and cortical inflammation was induced in mice by LPS (0.75 mg/kg, i.p. injection) for 7 days, followed by application of LIPUS (0.5 and 1.0 W/cm2) to the abdominal area for 6 days. Biological samples were collected for Western blot analysis, gelatin zymography, colon length measurement, and histological evaluation. KEY FINDINGS LIPUS treatment significantly attenuated LPS-induced increases in IL-6, IL-1β, COX-2, and cleaved caspase-3 expression in the colon and cortex of mice. Moreover, LIPUS significantly increased the levels of tight junction proteins in the epithelial barrier in the mouse colon and cortex with LPS-induced inflammation. Compared to the group treated only with LPS, the LIPUS-treated groups showed decreased muscle thickness and increased crypt length and colon length. Furthermore, LIPUS treatment reduced inflammation by inhibiting the LPS-induced activation of TLR4/NF-κB inflammatory signaling in the brain. SIGNIFICANCE We found that LIPUS alleviated LPS-induced colonic and cortical inflammation through abdominal stimulation of mice. These results suggest that abdominal LIPUS stimulation may be a novel therapeutic strategy against neuroinflammation via enhancement of tight junction protein levels and inhibition of inflammatory responses in the colon.
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Affiliation(s)
- Feng-Yi Yang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Wan-Hsuan Chan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Cong-Yong Gao
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yin-Ting Zheng
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Hua Ke
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Sun S, Wang D, Dong D, Xu L, Xie M, Wang Y, Ni T, Jiang W, Zhu X, Ning N, Sun Q, Zhao S, Li M, Chen P, Yu M, Li J, Chen E, Zhao B, Peng Y, Mao E. Altered intestinal microbiome and metabolome correspond to the clinical outcome of sepsis. Crit Care 2023; 27:127. [PMID: 36978107 PMCID: PMC10044080 DOI: 10.1186/s13054-023-04412-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND The gut microbiome plays a pivotal role in the progression of sepsis. However, the specific mechanism of gut microbiota and its metabolites involved in the process of sepsis remains elusive, which limits its translational application. METHOD In this study, we used a combination of the microbiome and untargeted metabolomics to analyze stool samples from patients with sepsis enrolled at admission, then microbiota, metabolites, and potential signaling pathways that might play important roles in disease outcome were screened out. Finally, the above results were validated by the microbiome and transcriptomics analysis in an animal model of sepsis. RESULTS Patients with sepsis showed destruction of symbiotic flora and elevated abundance of Enterococcus, which were validated in animal experiments. Additionally, patients with a high burden of Bacteroides, especially B. vulgatus, had higher Acute Physiology and Chronic Health Evaluation II scores and longer stays in the intensive care unit. The intestinal transcriptome in CLP rats illustrated that Enterococcus and Bacteroides had divergent profiles of correlation with differentially expressed genes, indicating distinctly different roles for these bacteria in sepsis. Furthermore, patients with sepsis exhibited disturbances in gut amino acid metabolism compared with healthy controls; namely, tryptophan metabolism was tightly related to an altered microbiota and the severity of sepsis. CONCLUSION Alterations in microbial and metabolic features in the gut corresponded with the progression of sepsis. Our findings may help to predict the clinical outcome of patients in the early stage of sepsis and provide a translational basis for exploring new therapies.
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Affiliation(s)
- Silei Sun
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Daosheng Wang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Danfeng Dong
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Lili Xu
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Mengqi Xie
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Yihui Wang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Tongtian Ni
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Weisong Jiang
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Xiaojuan Zhu
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Ning Ning
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Qian Sun
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Shuyuan Zhao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Mengjiao Li
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Peili Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Meiling Yu
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Jian Li
- Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Erzhen Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China
| | - Bing Zhao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China.
| | - Yibing Peng
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China.
| | - Enqiang Mao
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin ER Road, Shanghai, 200025, China.
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Elbaz EM, Essam RM, Ahmed KA, Safwat MH. Donepezil halts acetic acid-induced experimental colitis in rats and its associated cognitive impairment through regulating inflammatory/oxidative/apoptotic cascades: An add-on to its anti-dementia activity. Int Immunopharmacol 2023; 116:109841. [PMID: 36764270 DOI: 10.1016/j.intimp.2023.109841] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/13/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
Ulcerative colitis (UC) is a persistent inflammatory bowel disease (IBD) that is regarded as a risk factor for cognitive impairment. Donepezil (DON), a centrally acting acetylcholinesterase inhibitor (AChEI), is approved for the management of Alzheimer's disease (AD). We aimed to scrutinize the impact of DON on acetic acid (AA)-induced UC in rats and to evaluate its ability to attenuate inflammatory response, oxidative strain, and apoptosis in this model and its associated cognitive deficits. Rats were categorized into: normal, DON, AA, and AA + DON groups. DON (5 mg/kg/day) was administered orally for 14 days either alone or beginning with the day of UC induction. Colitis was evoked by a single transrectal injection of 1 ml of 4 % acetic acid. Results revealed that DON significantly improved the behavioral abnormalities with the mitigation of inflammation, apoptosis, and histopathological changes in the hippocampi of the colitis group. Moreover, DON significantly alleviated the macroscopic and microscopic changes associated with colitis. Interestingly, DON inhibited pro-inflammatory cytokines via suppression of AA-induced activation of nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in the colon, along with serum IL-1β. DON inhibited colon lipid peroxidation, restored the antioxidants with a significant amelioration of the degree of neutrophil infiltration, and repressed colitis-induced matrix metalloproteinases-9 (MMP-9) production. Furthermore, DON decreased the Bax/Bcl-2 ratio and caspase-3 protein expressions. Eventually, in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells, DON suppressed nitric oxide (NO) release, demonstrating the ability of DON to significantly curtail inflammation in immune cells. Taken together, DON ameliorated experimental colitis and its linked cognitive dysfunction, possibly via its antioxidant effect and modulation of pro-inflammatory cytokines and apoptosis. Thereby, DON could be a therapeutic nominee for UC and associated neurological disorders.
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Affiliation(s)
- Eman M Elbaz
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Reham M Essam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Biology, School of Pharmacy, Newgiza University, First 6th of October, Giza 3296121, Egypt
| | - Kawkab A Ahmed
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
| | - Maheera H Safwat
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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9
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He L, Kang Q, Chan KI, Zhang Y, Zhong Z, Tan W. The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer. Front Immunol 2023; 13:1093990. [PMID: 36776395 PMCID: PMC9910179 DOI: 10.3389/fimmu.2022.1093990] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/07/2022] [Indexed: 01/22/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are an important class of enzymes in the body that function through the extracellular matrix (ECM). They are involved in diverse pathophysiological processes, such as tumor invasion and metastasis, cardiovascular diseases, arthritis, periodontal disease, osteogenesis imperfecta, and diseases of the central nervous system. MMPs participate in the occurrence and development of numerous cancers and are closely related to immunity. In the present study, we review the immunomodulatory role of MMPs in colitis-associated cancer (CAC) and discuss relevant clinical applications. We analyze more than 300 pharmacological studies retrieved from PubMed and the Web of Science, related to MMPs, cancer, colitis, CAC, and immunomodulation. Key MMPs that interfere with pathological processes in CAC such as MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13, as well as their corresponding mechanisms are elaborated. MMPs are involved in cell proliferation, cell differentiation, angiogenesis, ECM remodeling, and the inflammatory response in CAC. They also affect the immune system by modulating differentiation and immune activity of immune cells, recruitment of macrophages, and recruitment of neutrophils. Herein we describe the immunomodulatory role of MMPs in CAC to facilitate treatment of this special type of colon cancer, which is preceded by detectable inflammatory bowel disease in clinical populations.
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Affiliation(s)
- Luying He
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Qianming Kang
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Ka Iong Chan
- Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Macao SAR, China
| | - Yang Zhang
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Macao SAR, China,*Correspondence: Zhangfeng Zhong, ; Wen Tan,
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou, China,*Correspondence: Zhangfeng Zhong, ; Wen Tan,
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Ludwig EK, Hobbs KJ, McKinney-Aguirre CA, Gonzalez LM. Biomarkers of Intestinal Injury in Colic. Animals (Basel) 2023; 13:227. [PMID: 36670767 PMCID: PMC9854801 DOI: 10.3390/ani13020227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/03/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Biomarkers are typically proteins, enzymes, or other molecular changes that are elevated or decreased in body fluids during the course of inflammation or disease. Biomarkers pose an extremely attractive tool for establishing diagnoses and prognoses of equine gastrointestinal colic, one of the most prevalent causes of morbidity and mortality in horses. This topic has received increasing attention because early diagnosis of some forms of severe colic, such as intestinal ischemia, would create opportunities for rapid interventions that would likely improve case outcomes. This review explores biomarkers currently used in equine medicine for colic, including acute phase proteins, proinflammatory cytokines, markers of endotoxemia, and tissue injury metabolites. To date, no single biomarker has been identified that is perfectly sensitive and specific for intestinal ischemia; however, L-lactate has been proven to be a very functional and highly utilized diagnostic tool. However, further exploration of other biomarkers discussed in this review may provide the key to accelerated identification, intervention, and better outcomes for horses suffering from severe colic.
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Affiliation(s)
| | | | | | - Liara M. Gonzalez
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27606, USA
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11
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Domislovic V, Høg Mortensen J, Lindholm M, Kaarsdal MA, Brinar M, Barisic A, Manon-Jensen T, Krznaric Z. Inflammatory Biomarkers of Extracellular Matrix Remodeling and Disease Activity in Crohn’s Disease and Ulcerative Colitis. J Clin Med 2022; 11:jcm11195907. [PMID: 36233775 PMCID: PMC9572110 DOI: 10.3390/jcm11195907] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/24/2022] [Accepted: 09/30/2022] [Indexed: 11/16/2022] Open
Abstract
Extracellular matrix (ECM) homeostasis is highly affected in active inflammatory bowel disease (IBD). The aim of the study was to investigate serological biomarkers of type III, IV, and V collagen degradation and formation, and their association with disease activity in IBD. ECM remodeling serum biomarkers were measured in 162 IBD patients, 110 with Crohn’s disease (CD) and 52 with ulcerative colitis (UC), and in 29 healthy donors. Biomarkers of type III collagen degradation (C3M) and formation (PRO-C3), type IV collagen degradation (C4M) and formation (PRO-C4), and type V collagen formation (PRO-C5) were measured using ELISA. Inflammatory activity was assessed using endoscopic, clinical, and biochemical activity indices. The highest diagnostic value was identified in discriminating endoscopically moderate to severe disease in CD (PRO-C3, C3M/PRO-C3, and C4M with AUC of 0.70, 0.73, and 0.69, respectively) and UC (C3M, C3M/PRO-C3, and C4M with AUC of 0.86, 0.80, and 0.76, respectively). C4M and C3M/PRO-C3 in combination yielded AUC of 0.93 (0.66–0.90) in CD and 0.94 (0.65–0.99) in UC. This study confirmed that ECM remodeling reflected disease activity in CD and UC. A combination of C4M, C3M, and PRO-C3 biomarkers may potentially be considered as a biomarker differentiating moderate to severe endoscopic disease.
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Affiliation(s)
- Viktor Domislovic
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, 10000 Zagreb, Croatia
- Correspondence: ; Tel.: +385-992815000
| | | | - Majken Lindholm
- Biomarkers and Research, Nordic Bioscience A/S, 2730 Herlev, Denmark
| | | | - Marko Brinar
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ana Barisic
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, 10000 Zagreb, Croatia
| | - Tina Manon-Jensen
- Biomarkers and Research, Nordic Bioscience A/S, 2730 Herlev, Denmark
| | - Zeljko Krznaric
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Reicherz A, Eltit F, Almutairi K, Mojtahedzadeh B, Herout R, Chew B, Cox M, Lange D. Ureteral Obstruction Promotes Ureteral Inflammation and Fibrosis. Eur Urol Focus 2022; 9:371-380. [PMID: 36244955 DOI: 10.1016/j.euf.2022.09.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/23/2022] [Accepted: 09/27/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Hydronephrosis and renal impairment may persist even after relieving an obstruction, particularly in cases of chronic obstruction. Obstruction can cause fibrotic changes of the ureter, potentially contributing to long-term kidney damage. OBJECTIVE To characterise pathophysiological changes of obstructed ureters with focus on inflammatory responses triggering fibrosis and potential impairment of ureteral function. DESIGN, SETTING, AND PARTICIPANTS Eighty-eight mice were randomly assigned to unilateral ureteral obstruction (UUO) for 2 d, UUO for 7 d, and UUO for 7 d followed by 8 d of recovery, or a control group (no prior surgical intervention). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Peristaltic rate was determined over 2 min by direct visualisation with a microscope, while hydronephrosis was assessed by ultrasound. Obstructed and contralateral ureters were harvested, and underwent histopathological evaluation. We quantified 44 cytokines/chemokines, and five matrix metalloproteases using Luminex technology. Cell composition was characterised via immunofluorescence. Statistical significance was assessed using Welch analysis of variance, Kruskal-Wallis test, and Dunnett's T3 multiple comparison test. RESULTS AND LIMITATIONS Obstruction resulted in hydronephrosis and significantly impaired peristalsis. Marked fibrosis was observed in lamina propria, muscle layer, and adventitia. Connective tissue in obstructed ureters showed hyperaemia and leucocyte infiltration. Unsupervised hierarchical clustering demonstrated different cytokine/chemokine patterns between groups. Ureters obstructed for 7 d followed by recovery were notably different from other groups. Inflammatory cytokines, chemoattractants, and matrix metalloproteases increased significantly in obstructed ureters. Contralateral unobstructed ureters showed significantly increased levels of chemokines and matrix metalloproteases. Immunofluorescence confirmed activation of T cells, Th1 and Th2 cells, and M1 macrophages in obstructed and contralateral ureters, and a shift to M2 macrophages following prolonged obstruction. CONCLUSIONS Ureteral obstruction triggers severe inflammation and fibrosis, which may irreversibly impair ureteral functionality. Function of the unobstructed contralateral ureter may be regulated by a systemic immune response as a result of the obstruction. PATIENT SUMMARY Here, we studied in more detail the way the ureter responds to being blocked. We conclude that a strong immune response is activated by the blockage, leading to changes in the structure of the ureter possibly impacting function, which may not be reversible. This immune response also spreads to the opposite ureter, possibly allowing it to change its function to compensate for the reduced functionality of the blocked ureter.
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Eiro N, Barreiro-Alonso E, Fraile M, González LO, Altadill A, Vizoso FJ. Expression of MMP-2, MMP-7, MMP-9, and TIMP-1 by Inflamed Mucosa in the Initial Diagnosis of Ulcerative Colitis as a Response Marker for Conventional Medical Treatment. Pathobiology 2022; 90:81-93. [PMID: 35797965 DOI: 10.1159/000524978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/07/2022] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Experimental and clinical data involve matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) in the pathogenesis of inflammatory bowel diseases. However, the impact of MMPs/TIMPs expression by inflamed mucosa on medical response therapy has scarcely been investigated. METHODS The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 was determined by immunohistochemical analysis in inflamed mucosa samples at diagnosis in 82 patients with ulcerative colitis (UC; 22 never-treated with corticosteroids, 28 nonresponders, and 32 responders to corticosteroid therapy) and 15 patients with acute diverticulitis (AD). The global expression (score value) of each factor was analyzed by computer-generated image analysis. RESULTS UC samples showed higher MMP-2 and MMP-9 expression but lower TIMP-1 expression than the AD samples (p < 0.0001, for all). High MMP-9 and TIMP-1 scores were significantly associated with no need for corticosteroid treatment (p < 0.001 and p = 0.017, respectively); whereas higher score in the MMP-7 expression was significantly associated with nonresponse to corticosteroid therapy (p = 0.037). In addition, in this latter UC subgroup, MMP-7 correlated positively with the younger age of the patients and with the extension of the disease (p = 0.030 and p = 0.010, respectively). CONCLUSION Our results suggest the relevance of MMPs and TIMPs for predicting treatment response to both 5-aminosalicylates and corticosteroids in UC.
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Affiliation(s)
- Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
| | - Eva Barreiro-Alonso
- Department of Gastroenterology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Maria Fraile
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
| | - Luis O González
- Department of Anatomical Pathology, Fundación Hospital de Jove, Gijón, Spain
| | - Antonio Altadill
- Department of Internal Medicine, Fundación Hospital de Jove, Gijón, Spain
| | - Francisco J Vizoso
- Research Unit, Fundación Hospital de Jove, Gijón, Spain.,Department of Surgery, Fundación Hospital de Jove, Gijón, Spain
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Grape Pomace Extract Attenuates Inflammatory Response in Intestinal Epithelial and Endothelial Cells: Potential Health-Promoting Properties in Bowel Inflammation. Nutrients 2022; 14:nu14061175. [PMID: 35334833 PMCID: PMC8953566 DOI: 10.3390/nu14061175] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) implies the chronic inflammation of the gastrointestinal tract, combined with systemic vascular manifestations. In IBD, the incidence of cardiovascular disease appears to be related to an increase of oxidative stress and endothelial dysfunction. Grape pomace contains high levels of anti-oxidant polyphenols that are able to counteract chronic inflammatory symptoms. The aim of this study was to determine whether grape pomace polyphenolic extract (GPE) was able to mitigate the overwhelming inflammatory response in enterocyte-like cells and to improve vascular function. Intestinal epithelial Caco-2 cells, grown in monolayers or in co-culture with endothelial cells (Caco-2/HMEC-1), were treated with different concentrations of GPE (1, 5, 10 µg/mL gallic acid equivalents) for 2 h and then stimulated with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α for 16 h. Through multiple assays, the expression of intestinal and endothelial inflammatory mediators, intracellular reactive oxygen species (ROS) levels and NF-κB activation, as well as endothelial-leukocyte adhesion, were evaluated. The results showed that GPE supplementation prevented, in a concentration-dependent manner, the intestinal expression and release of interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinases (MMP)-9 and MMP-2. In Caco-2 cells, GPE also suppressed the gene expression of several pro-inflammatory markers, such as IL-1β, TNF-α, macrophage colony-stimulating factor (M-CSF), C-X-C motif ligand (CXCL)-10, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and cyclooxygenase (COX)-2. The GPE anti-inflammatory effect was mediated by the inhibition of NF-κB activity and reduced intracellular ROS levels. Furthermore, transepithelial GPE suppressed the endothelial expression of IL-6, MCP-1, VCAM-1, and ICAM-1 and the subsequent adhesion of leukocytes to the endothelial cells under pro-inflammatory conditions. In conclusion, our findings suggest grape pomace as a natural source of polyphenols with multiple health-promoting properties that could contribute to the mitigation of gut chronic inflammatory diseases and improve vascular endothelial function.
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Joung EJ, Cao L, Gwon WG, Kwon MS, Lim KT, Kim HR. Meroterpenoid-Rich Ethanoic Extract of Sargassum macrocarpum Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice. Foods 2022; 11:foods11030329. [PMID: 35159480 PMCID: PMC8834051 DOI: 10.3390/foods11030329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/18/2022] [Accepted: 01/21/2022] [Indexed: 11/28/2022] Open
Abstract
Colitis is a colon mucosal disorder characterized by intestinal damage and inflammation. This current study aimed to evaluate the effect of meroterpenoid-rich ethanoic extract of a brown algae, Sargassum macrocarpum (MES) on dextran sulfate sodium (DSS)-induced colitis in mice and explore the possible mechanisms. Mice were given 4% DSS in drinking water for 7 days to induce colitis, followed by 3 days of regular water. MES (12 mg/kg body weight) or celecoxib (10 mg/kg body weight) was administrated orally to mice on a daily basis during these 10 days. Both MES and celecoxib supplementations significantly attenuated DSS-induced weight loss, shortening of colon length, elevated myeloperoxidase activity as well as histomorphological changes of colon. MES and celecoxib reduced the inflammation level of colon tissue, as indicated by its suppression on a panel of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-17, tumor necrosis factor α, and interferon γ, and a group of inflammatory proteins, including intracellular adhesion molecule 1, vascular adhesion molecule 1, matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, and inducible nitric oxidase. In addition, their administration down-regulated pro-inflammatory cytokines in serum. Moreover, the supplementation of MES suppressed the DSS-induced hyperactivation of Akt, JNK, and NF-κB signaling pathways. Taken together, our results demonstrate that MES ameliorates DSS-induced colitis in mice, suggesting that MES may have therapeutic implications for the treatment of colitis.
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Affiliation(s)
- Eun-Ji Joung
- Department of Food Science and Nutrition, Pukyong National University, Busan 608737, Korea; (E.-J.J.); (W.-G.G.); (M.-S.K.)
| | - Lei Cao
- Institute of Marine Sciences, Pukyong National University, Busan 608737, Korea;
| | - Wi-Gyeong Gwon
- Department of Food Science and Nutrition, Pukyong National University, Busan 608737, Korea; (E.-J.J.); (W.-G.G.); (M.-S.K.)
| | - Mi-Sung Kwon
- Department of Food Science and Nutrition, Pukyong National University, Busan 608737, Korea; (E.-J.J.); (W.-G.G.); (M.-S.K.)
| | - Kwon Taek Lim
- Department of Display Engineering, Pukyong National University, Busan 608737, Korea;
- Department of Smart Green Technology Engineering, Pukyong National University, Busan 608737, Korea
| | - Hyeung-Rak Kim
- Department of Food Science and Nutrition, Pukyong National University, Busan 608737, Korea; (E.-J.J.); (W.-G.G.); (M.-S.K.)
- Correspondence: ; Tel.: +82-051-629-5847
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16
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Nighot M, Ganapathy AS, Saha K, Suchanec E, Castillo EF, Gregory A, Shapiro S, Ma T, Nighot P. Matrix Metalloproteinase MMP-12 Promotes Macrophage Transmigration Across Intestinal Epithelial Tight Junctions and Increases Severity of Experimental Colitis. J Crohns Colitis 2021; 15:1751-1765. [PMID: 33836047 PMCID: PMC8495490 DOI: 10.1093/ecco-jcc/jjab064] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Matrix metalloproteinases [MMPs] play an important role in extracellular matrix regulation during cell growth and wound healing. Increased expression of MMP-12 [human macrophage elastase] has been reported in inflammatory bowel disease [IBD] which is characterised by the loss of epithelial tight junction [TJ] barrier function and an excessive inflammatory response. The aim of this study was to investigate the role of MMP-12 in intestinal TJ barrier function and inflammation. METHODS Wild type [WT] and MMP-12-/- mice were subjected to experimental acute or chronic dextran sodium sulphate [DSS] colitis. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon and ex vivo by Ussing chamber studies. RESULTS DSS administration increased colonic permeability through modulation of TJ proteins and also increased MMP-12 expression in the colonic mucosa of WT mice. The acute as well as chronic DSS-induced increase in colonic TJ permeability and the severity of DSS colitis was found to be markedly attenuated in MMP-12-/- mice. The resistance of MMP-12-/- mice to DSS colitis was characterised by reduced macrophage infiltration and transmigration, and reduced basement membrane laminin degradation. Further in vitro and in vivo studies show that macrophage transmigration across the epithelial layer is MMP-12 dependent and the epithelial TJ barrier is compromised during macrophage transmigration. Conclusions: Together, these data demonstrate that MMP-12 mediated degradation of basement membrane laminin, macrophage transmigration, and associated loss of intestinal TJ barrier are key pathogenic factors for intestinal inflammation.
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Affiliation(s)
- Meghali Nighot
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | | | - Kushal Saha
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | - Eric Suchanec
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | - Eliseo F Castillo
- University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
| | - Alyssa Gregory
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven Shapiro
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Thomas Ma
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
| | - Prashant Nighot
- Department of Medicine, College of Medicine, Penn State University, Hershey, PA, USA
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Abstract
BACKGROUND Ulcerative colitis (UC) was a type of inflammatory bowel diseases, which was difficult to cure and even would malignant turn into colon cancer. The specific etiology and molecular mechanism of UC were unclear to date. The purpose of this study was to search for new targets for the diagnosis and treatment of UC. METHODS Firstly, we downloaded the gene expression data of UC from the gene expression omnibus database database (GSE107499), and used multiple bioinformatics methods to find differently expressed genes (DEGs) in UC. Subsequently, we evaluated the lymphocyte infiltration in UC inflamed colon tissue by using the cell type identification by estimating relative subset of known RNA transcripts method. RESULTS We obtained 1175 DEGs and 8 hub genes (IL6, TNF, PTPRC, CXCL8, FN1, CD44, IL1B, and MMP9) in this study. Among them, 903 DEGs were up-regulated and 272 DEGs were down-regulated. Compared with non-inflamed colon tissues, the inflamed colon tissues had higher levels of memory B cells, activated memory CD4 T cells, follicular helper T cells, M1 macrophages, resting dendritic cells, activated dendritic cells, activated mast cells, and neutrophils, whereas the proportions of plasma cells, resting memory CD4 T cells, gamma delta T cells, activated NK cells, M2 macrophages and resting mast cells were relatively lower. CONCLUSIONS The DEGs, hub genes and different lymphatic infiltration conditions can provide new targets for diagnosis and treatment of UC. However, these were just predictions through some theoretical methods, and more basic experiments will be needed to prove in the future.
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Affiliation(s)
- Junhui Zhang
- Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital of Xiamen University, Xiamen
- Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guixiu Shi
- Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital of Xiamen University, Xiamen
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18
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Khare T, Palakurthi SS, Shah BM, Palakurthi S, Khare S. Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:E3956. [PMID: 32486445 PMCID: PMC7312938 DOI: 10.3390/ijms21113956] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.
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Affiliation(s)
- Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
| | - Sushesh Srivatsa Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Brijesh M. Shah
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Srinath Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
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19
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Luzardo-Ocampo I, Campos-Vega R, Gonzalez de Mejia E, Loarca-Piña G. Consumption of a baked corn and bean snack reduced chronic colitis inflammation in CD-1 mice via downregulation of IL-1 receptor, TLR, and TNF-α associated pathways. Food Res Int 2020; 132:109097. [PMID: 32331643 DOI: 10.1016/j.foodres.2020.109097] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/06/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) is a condition that has been rising in the number of cases around the world. Food products made from natural ingredients such as corn and common bean might serve as alternatives for the treatment of UC. This study aimed to assess the anti-inflammatory effect of the consumption of a baked corn and bean snack (CBS) in an in vivo model of UC using 2% dextran sodium sulfate (DSS) as inductor of colitis. CD-1 mice (45, n = 9/group) were randomly separated into 5 groups, treated for 6-weeks as follows: G1 (basal diet, BD), G2 (2% DSS), G3 (20 g CBS/body weight BW/day + BD), G4 (40 g CBS/BW/day + BD) and G5 (60 g CBS/BW/day + BD). BW, Disease Activity Index (DAI), and feces were collected throughout the treatment. After euthanasia, organs (spleen, liver, and colon) were excised and weighed. Feces were analyzed for β-glucuronidase (β-GLUC) activity and gas-chromatography. The colons were analyzed for histopathology, myeloperoxidase (MPO) activity, and gene analysis. At the end of treatments, among the DSS-induced groups, G3 exhibited the lowest BW losses (11.5%), MPO activity (10.4%) and β-GLUC (8.6%). G4 presented the lowest DAI (0.88), relative spleen weight, and histological inflammation score (p < 0.05). Compared to G2, CBS consumption significantly (p < 0.05) reduced serum TNF-α, IL-10, and MCP-1 levels. The fecal metabolome analysis ranked 9-decenoic acid, decane, and butyric acid as the main contributors of pathways associated with the β-oxidation of fatty acids. G4 showed the highest fecal/cecal contents of short-chain fatty acids among all the DSS-induced groups. For the gene expression, G4 was clustered with G1, showing a differential inhibition of the pro-inflammatory genes Il1r1, Il1a, Tlr4, Tlr2, and Tnfrsf1b. In conclusion, CBS consumption decreased the inflammatory state and reduced the expression of the IL-1 receptor, TLR, and TNF-α-associated pathways in DSS-induced UC in CD-1 mice.
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Affiliation(s)
- Ivan Luzardo-Ocampo
- Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Program in Food Science, School of Chemistry, Universidad Autónoma de Querétaro, 76010 Queretaro, Mexico; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 228-230 ERML, 1201 W. Gregory Dr., Urbana, IL 61801, United States.
| | - Rocio Campos-Vega
- Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Program in Food Science, School of Chemistry, Universidad Autónoma de Querétaro, 76010 Queretaro, Mexico.
| | - Elvira Gonzalez de Mejia
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 228-230 ERML, 1201 W. Gregory Dr., Urbana, IL 61801, United States.
| | - Guadalupe Loarca-Piña
- Programa de Posgrado en Alimentos del Centro de la República (PROPAC), Research and Graduate Program in Food Science, School of Chemistry, Universidad Autónoma de Querétaro, 76010 Queretaro, Mexico.
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20
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Li H, Fan C, Feng C, Wu Y, Lu H, He P, Yang X, Zhu F, Qi Q, Gao Y, Zuo J, Tang W. Inhibition of phosphodiesterase-4 attenuates murine ulcerative colitis through interference with mucosal immunity. Br J Pharmacol 2019; 176:2209-2226. [PMID: 30883697 DOI: 10.1111/bph.14667] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase-4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill-defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium-induced murine UC. EXPERIMENTAL APPROACH Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4-mediated pathways in colon and macrophages were determined using quantitative real-time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry. KEY RESULTS Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA-CREB and Epac-Rap1 pathways and subsequently suppressed MAPK, NF-κB, PI3K-mTOR, and JAK-STAT-SOCS3 activation. CONCLUSION AND IMPLICATIONS Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation.
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Affiliation(s)
- Heng Li
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| | - Chen Fan
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Chunlan Feng
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yanwei Wu
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Huimin Lu
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| | - Peilan He
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoqian Yang
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Fenghua Zhu
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Qing Qi
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yuanzhuo Gao
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
| | - Jianping Zuo
- School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.,Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Wei Tang
- Laboratory of Anti-inflammation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China
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Saad RE, Shobar R, Mutlu EA. Collagenous colitis development occurs after long standing mucosal healing in IBD with TNF-α inhibitors, and could be due to exaggerated healing response from excess TNF-α inhibition. Med Hypotheses 2019; 123:90-94. [PMID: 30696605 DOI: 10.1016/j.mehy.2019.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 01/06/2019] [Indexed: 12/16/2022]
Abstract
Collagenous colitis is a relatively rare disorder affecting mainly middle-aged women where they present with chronic non-bloody diarrhea. Both with lymphocytic colitis they compose microscopic colitis. The exact cause of collagenous colitis is still unknown however; many potential pathophysiologic mechanisms have been proposed but no convincing mechanism has been identified. Collagenous colitis has been linked to medications mainly NSAIDs, SSRIs, and PPIs. It is also believed that collagenous colitis is autoimmune disease and there are weak believe it could have some genetic inheritance. We reported before two cases of collagenous colitis developed in patients with Crohn's disease and ulcerative colitis while they were in complete mucosal remission after being treated with tumor necrosis factors-α inhibitors. In this article we will try to explain how collagenous colitis can develop in patients with inflammatory bowel disease especially those on tumor necrosis factors-α inhibitors.
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Affiliation(s)
- Rahoma E Saad
- Section of Gastroenterology, Hepatology & Nutrition, Rush University Medical Center, Chicago, IL, United States
| | - Rima Shobar
- Section of Gastroenterology, Hepatology & Nutrition, Rush University Medical Center, Chicago, IL, United States
| | - Ece A Mutlu
- Section of Gastroenterology, Hepatology & Nutrition, Rush University Medical Center, Chicago, IL, United States.
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22
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Schreiber S, Siegel CA, Friedenberg KA, Younes ZH, Seidler U, Bhandari BR, Wang K, Wendt E, McKevitt M, Zhao S, Sundy JS, Lee SD, Loftus EV. A Phase 2, Randomized, Placebo-Controlled Study Evaluating Matrix Metalloproteinase-9 Inhibitor, Andecaliximab, in Patients With Moderately to Severely Active Crohn's Disease. J Crohns Colitis 2018; 12:1014-1020. [PMID: 29846530 PMCID: PMC6113705 DOI: 10.1093/ecco-jcc/jjy070] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 04/23/2018] [Accepted: 05/27/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of Crohn's disease and may serve as a potential biomarker. A phase 2 trial was conducted to examine the efficacy and safety of the anti-MMP9 antibody andecaliximab [GS-5745] in patients with moderately to severely active Crohn's disease. METHODS Patients were randomized 1:2:2:2 to receive subcutaneous injections of placebo weekly [QW], andecaliximab 150 mg every 2 weeks [Q2W], andecaliximab 150 mg QW, or andecaliximab 300 mg QW.The co-primary study efficacy endpoints were evaluation of a clinical response, defined as liquid or very soft stool frequency and abdominal pain composite [from Patient-Reported Outcome 2] score ≤ 8 at week 8, and an endoscopic response, defined as a ≥ 50% reduction from baseline in the Simple Endoscopic Score for Crohn's Disease, following 8 weeks of treatment. RESULTS A total of 187 participants were randomized to treatment; 53 participants were randomized to each andecaliximab treatment group and 28 participants were randomized to placebo. Proportions of patients receiving andecaliximab were not different from proportions of patients receiving placebo based on clinical and endoscopic response and Crohn's disease activity index-defined remission at week 8. Rates of adverse events were comparable among the andecaliximab and placebo groups. CONCLUSIONS Eight weeks of induction treatment with 150 mg andecaliximab Q2W, 150 mg andecaliximab QW, or 300 mg andecaliximab QW in patients with Crohn's disease did not induce a clinically meaningful symptomatic or endoscopic response. Andecaliximab was well tolerated. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT02405442.
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Affiliation(s)
| | | | | | | | | | | | - Ke Wang
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | - Sally Zhao
- Gilead Sciences, Inc., Foster City, CA, USA
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23
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Sandborn WJ, Bhandari BR, Randall C, Younes ZH, Romanczyk T, Xin Y, Wendt E, Chai H, McKevitt M, Zhao S, Sundy JS, Keshav S, Danese S. Andecaliximab [Anti-matrix Metalloproteinase-9] Induction Therapy for Ulcerative Colitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2/3 Study in Patients With Moderate to Severe Disease. J Crohns Colitis 2018; 12:1021-1029. [PMID: 29767728 PMCID: PMC6113706 DOI: 10.1093/ecco-jcc/jjy049] [Citation(s) in RCA: 23] [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: 01/10/2018] [Revised: 03/09/2018] [Accepted: 05/13/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND AIMS Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. METHODS Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. RESULTS Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. CONCLUSIONS Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.
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Affiliation(s)
- William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,Corresponding author: William J. Sandborn, Professor of Medicine and Adjunct Professor of Surgery; Chief, Division of Gastroenterology; Vice Chair for Clinical Operations, Department of Medicine; Director, UCSD IBD Center, 9500 Gilman Drive, MC 0956, La Jolla, CA 92093, USA. Tel.: [858] 657-5331; fax [858] 657-5022;
| | | | - Charles Randall
- Gastroenterology Research America and University of Texas, San Antonio, TX, USA
| | | | | | - Yan Xin
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - Hao Chai
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - Sally Zhao
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | - Satish Keshav
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Silvio Danese
- Inflammatory Bowel Diseases Center, Humanitas Research Hospital, Rozzano, Italy
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24
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Chongwe G, Michelo C, Sinkala E, Kayamba V, Nzayisenga JB, Drobniewski F, Kelly P. Mycobacterium avium lysate induces matrix metalloproteinase-1 in intestinal tissue and peripheral blood: Observations from selected hospital based Zambian adults. Int J Infect Dis 2018; 71:73-81. [PMID: 29680481 PMCID: PMC5985370 DOI: 10.1016/j.ijid.2018.03.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 03/16/2018] [Accepted: 03/30/2018] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVES Environmental enteropathy is prevalent in low-income countries, although its aetiology is unknown. We investigated if Mycobacterium avium antigens, which are commonly found in the environment, could contribute to its pathogenesis in a population known to have widespread environmental enteropathy. METHODS Routine endoscopy patients at the University Teaching Hospital, Lusaka whose endoscopy results were normal submitted duodenal biopsies and whole blood samples. Samples were stimulated with M. avium lysate over 24h while unstimulated samples served as negative controls. Matrix metalloproteinase (MMP) and cytokine response in supernatants were quantified using ELISA and cytometric bead array. RESULTS Samples from 48 patients (56% women) were analysed, with a median age of 35 years (IQR 27.5, 50.5). M. avium induced the secretion of a wide-range of Th1, Th2 and Th17 cytokines in blood but only IL-1β and IL-6 in duodenal tissue. However it differentially induced the secretion of MMP-1 in duodenal tissue compared to negative controls (p=0.004). A similar MMP-1 response but with lower concentrations was observed in blood. CONCLUSION The induction of MMP-1 and cytokines by M. avium in duodenal tissue suggests that environmental mycobacteria could contribute to the epithelial disruption seen in environmental enteropathy, and a need to further explore possible biomarkers that may predict this exposure in at-risk populations.
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Affiliation(s)
- Gershom Chongwe
- Department of Epidemiology & Biostatistics, University of Zambia School of Public Health, Lusaka, Zambia.
| | - Charles Michelo
- Department of Epidemiology & Biostatistics, University of Zambia School of Public Health, Lusaka, Zambia; University of Zambia, Strategic Centre for Health Systems Metrics & Evaluations (SCHEME), School of Public Health, Lusaka, Zambia.
| | - Edford Sinkala
- Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia.
| | - Violet Kayamba
- Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia.
| | | | - Francis Drobniewski
- Infectious Diseases and Immunity, Department of Medicine, Imperial College, London, UK.
| | - Paul Kelly
- Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia; Blizard Institute, Barts & The London School of Medicine, Queen Mary University of London, London, UK.
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Chami B, Martin NJJ, Dennis JM, Witting PK. Myeloperoxidase in the inflamed colon: A novel target for treating inflammatory bowel disease. Arch Biochem Biophys 2018; 645:61-71. [PMID: 29548776 DOI: 10.1016/j.abb.2018.03.012] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 03/08/2018] [Accepted: 03/12/2018] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a debilitating disorder involving inflammation of the gastrointestinal tract. The incidence of IBD is increasing worldwide. Immunological responses in the gastrointestinal (GI) tract to altered gut microbiota, mucosal injury and loss of intestinal epithelial cell function all contribute to a complex mechanism underlying IBD pathogenesis. Immune cell infiltration, particularly neutrophils, is a histological feature of IBD. This innate immune response is aimed at resolving intestinal damage however, neutrophils and monocytes that are recruited and accumulate in the GI wall, participate in IBD pathogenesis by producing inflammatory cytokines and soluble mediators such as reactive oxygen species (ROS; one- and two-electron oxidants). Unregulated ROS production in host tissue is linked to oxidative damage and inflammation and may potentiate mucosal injury. Neutrophil-myeloperoxidase (MPO) is an abundant granule enzyme that catalyses production of potent ROS; biomarkers of oxidative damage (and MPO protein) are increased in the mucosa of patients with IBD. Targeting MPO may mitigate oxidative damage to host tissue and ensuing inflammation. Here we identify mechanisms by which MPO activity perpetuates inflammation and contributes to host-tissue injury in patients with IBD and discuss MPO as a potential therapeutic target to protect the colon from inflammatory injury.
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Affiliation(s)
- Belal Chami
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Nathan J J Martin
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Joanne M Dennis
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Paul K Witting
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia.
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Hanifeh M, Rajamäki MM, Syrjä P, Mäkitalo L, Kilpinen S, Spillmann T. Identification of matrix metalloproteinase-2 and -9 activities within the intestinal mucosa of dogs with chronic enteropathies. Acta Vet Scand 2018. [PMID: 29530095 PMCID: PMC5848456 DOI: 10.1186/s13028-018-0371-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) 2 and 9 are zinc- and calcium-dependent endopeptidases involved in the breakdown and reconstitution of extracellular matrix under both physiological and pathological conditions. Mucosal MMP-2 and -9 activities have been reported to be upregulated in the intestine of humans with inflammatory bowel disease (IBD), and in animal models of IBD. However, their involvement in the pathogenesis of canine chronic enteropathies (CE) is unknown. This study investigated mucosal pro- and active MMP-2 and -9 activities in dogs with CE and healthy dogs using gelatin zymography, and also to determine the association of their activities in dogs with CE with the canine IBD activity index (CIBDAI), histopathologic findings, the clinical outcome, and hypoalbuminemia. Intestinal mucosal samples from duodenum, ileum, colon, and cecum were collected from 40 dogs with CE and 18 healthy Beagle dogs. RESULTS In dogs with CE, the number of samples positive for mucosal pro- and active MMP-2 was significantly higher in the duodenum (P < 0.0001 and P = 0.011, respectively), ileum (P = 0.002 and P = 0.018, respectively), and colon (P < 0.0001 and P = 0.002, respectively), compared with healthy controls. Mucosal pro-MMP-9-positive samples in the duodenum and colon were significantly more frequent in dogs with CE than in healthy dogs (P = 0.0004 and P = 0.001, respectively). Despite the presence of mucosal samples positive for active MMP-9 in the intestinal segments of dogs with CE, the difference compared to healthy controls did not reach statistical significance. None of the intestinal mucosal samples in healthy dogs showed gelatinolytic activity corresponding to the control bands of active MMP-2 and -9. Mucosal active MMP-9 activities displayed a significant positive association with the severity of neutrophil infiltration in the duodenum (P = 00.040), eosinophils in the cecum (P = 00.037), and the CIBDAI score for ileum samples (P = 0.023). There was no significant association of pro- and active MMP-2 and -9 levels with the clinical outcome or hypoalbuminemia. CONCLUSIONS This study is the first to demonstrate upregulation of mucosal pro- and active MMP-2 and pro-MMP-9 in the intestine of dogs with CE compared to healthy dogs. The results provide supporting evidence for the possible involvement of MMP-2 and -9 in the pathogenesis of canine CE.
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Rebamipide ameliorates radiation-induced intestinal injury in a mouse model. Toxicol Appl Pharmacol 2017; 329:40-47. [PMID: 28526636 DOI: 10.1016/j.taap.2017.05.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/10/2017] [Accepted: 05/15/2017] [Indexed: 12/31/2022]
Abstract
Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis.
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Ruan H, Liang X, Zhao W, Ma L, Zhao Y. The effects of microRNA-183 promots cell proliferation and invasion by targeting MMP-9 in endometrial cancer. Biomed Pharmacother 2017; 89:812-818. [PMID: 28273643 DOI: 10.1016/j.biopha.2017.02.091] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/23/2017] [Accepted: 02/23/2017] [Indexed: 01/12/2023] Open
Abstract
MiRNAs are known to play important roles in cancer cell development. However, the pattern and biological role of miR-183 in endometrial cancer (EC) have not been completely unexplored. Here, we found that miR-183 was upregulated in endometrial cancer cells. The purpose of the study was to evaluate the function of miR-183 in the endometrial cancer cell line and the mechanisms regulating its direct target protein in these processes. The mRNA and protein expressions were analyzed by quantitative RT-PCR and western blotting, respectively. The experiments about MTT assay, colony formation assay and transwell assay showed that miR-183 can positively regulate cell proliferation, migration and invasion in vitro. Furthermore, the in vivo experiments indicated that knockdown of miR-183 significantly attenuated EC cells growth. Mechanistically, luciferase reporter assay and western blotting assay was conducted to confirm target associations. The data analysis revealed that MMP-9 as a direct target of miR-183 in EC and there was a negatively relationship between miR-183 and MMP-9 expression in EC cells. Taken together, our results demonstrated that miR-183 plays a critical role in EC tumorigenesis and metastasis by suppressing MMP-9 expression, which may be an attractive therapeutic target for the treatment of endometrial cancer.
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Affiliation(s)
- Hongjie Ruan
- Department of Gynecology, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210000, China
| | - Xin Liang
- Department of Clinical Laboratory, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210000, China
| | - Wei Zhao
- Department of Clinical Laboratory, Nanjing Maternity and Child Health Care Hospital, Nanjing 210000, China
| | - Li Ma
- Department of Clinical Laboratory, Huai'an Hospital, Xuzhou Medical University, Huai'an 223002, China.
| | - Yibing Zhao
- Department of Gynecology, Jiangsu Cancer Hospital, Nanjing 210000, China.
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Pulmonary Remodeling in Equine Asthma: What Do We Know about Mediators of Inflammation in the Horse? Mediators Inflamm 2016; 2016:5693205. [PMID: 28053371 PMCID: PMC5174180 DOI: 10.1155/2016/5693205] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 10/05/2016] [Accepted: 10/12/2016] [Indexed: 12/31/2022] Open
Abstract
Equine inflammatory airway disease (IAD) and recurrent airway obstruction (RAO) represent a spectrum of chronic inflammatory disease of the airways in horses resembling human asthma in many aspects. Therefore, both are now described as severity grades of equine asthma. Increasing evidence in horses and humans suggests that local pulmonary inflammation is influenced by systemic inflammatory processes and the other way around. Inflammation, coagulation, and fibrinolysis as well as extracellular remodeling show close interactions. Cytology of bronchoalveolar lavage fluid and tracheal wash is commonly used to evaluate the severity of local inflammation in the lung. Other mediators of inflammation, like interleukins involved in the chemotaxis of neutrophils, have been studied. Chronic obstructive pneumopathies lead to remodeling of bronchial walls and lung parenchyma, ultimately causing fibrosis. Matrix metalloproteinases (MMPs) are discussed as the most important proteolytic enzymes during remodeling in human medicine and increasing evidence exists for the horse as well. A systemic involvement has been shown for severe equine asthma by increased acute phase proteins like serum amyloid A and haptoglobin in peripheral blood during exacerbation. Studies focusing on these and further possible inflammatory markers for chronic respiratory disease in the horse are discussed in this review of the literature.
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Cazarin CBB, Rodriguez-Nogales A, Algieri F, Utrilla MP, Rodríguez-Cabezas ME, Garrido-Mesa J, Guerra-Hernández E, Braga PADC, Reyes FGR, Maróstica MR, Gálvez J. Intestinal anti-inflammatory effects of Passiflora edulis peel in the dextran sodium sulphate model of mouse colitis. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.08.020] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Anti-MMP-9 Antibody: A Promising Therapeutic Strategy for Treatment of Inflammatory Bowel Disease Complications with Fibrosis. Inflamm Bowel Dis 2016; 22:2041-57. [PMID: 27542125 DOI: 10.1097/mib.0000000000000863] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Despite medical treatments or surgical options, more than one-third of patients with Crohn's disease suffer from recurring fistulae. Matrix metalloprotease 9 (MMP-9), a type IV collagenase that cleaves components of the extracellular matrix leading to tissue remodeling, is upregulated in crypt abscesses and around fistulae suggesting an important role for this enzyme in fistula formation. Our aims were (1) to correlate serum levels of MMP-9 degradation products in patients with CD with the presence of fistulae and (2) to investigate the impact of selective MMP-9 inhibition in a mouse model of intestinal fibrosis. METHODS Serum MMP-9 degradation products were quantified in subjects affected with nonstricturing and nonpenetrating CD (n = 50), stricturing CD (n = 41), penetrating CD (n = 22), CD with perianal fistula (n = 29), and healthy controls (n = 10). Therapeutic efficacy of anti-MMP-9 monoclonal antibodies was assessed in a heterotopic xenograft model of intestinal fibrosis. RESULTS C3M, an MMP-9 degradation product of collagen III, demonstrated the highest serum levels in patients with penetrating CD and differentiated penetrating CD from other CD subgroups and healthy controls, P = 0.0005. Anti-MMP-9 treatments reduced collagen deposition and hydroxyproline content in day-14 intestinal grafts indicating reduced fibrosis. CONCLUSIONS The serologic biomarker C3M can discriminate penetrating CD from other CD subgroups and could serve as marker for the development of penetrating CD. Anti-MMP-9 antibody has therapeutic potential to prevent intestinal fibrosis in CD complications.
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Zádori ZS, Tóth VE, Fehér Á, Al-Khrasani M, Puskár Z, Kozsurek M, Timár J, Tábi T, Helyes Z, Hein L, Holzer P, Gyires K. Inhibition of α2A-Adrenoceptors Ameliorates Dextran Sulfate Sodium-Induced Acute Intestinal Inflammation in Mice. J Pharmacol Exp Ther 2016; 358:483-91. [PMID: 27418171 DOI: 10.1124/jpet.116.235101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 07/08/2016] [Indexed: 12/19/2022] Open
Abstract
It has been hypothesized that α2-adrenoceptors (α2-ARs) may be involved in the pathomechanism of colitis; however, the results are conflicting because both aggravation and amelioration of colonic inflammation have been described in response to α2-AR agonists. Therefore, we aimed to analyze the role of α2-ARs in acute murine colitis. The experiments were carried out in wild-type, α2A-, α2B-, and α2C-AR knockout (KO) C57BL/6 mice. Colitis was induced by dextran sulfate sodium (DSS, 2%); alpha2-AR ligands were injected i.p. The severity of colitis was determined both macroscopically and histologically. Colonic myeloperoxidase (MPO) and cytokine levels were measured by enzyme-linked immunosorbent assay and proteome profiler array, respectively. The nonselective α2-AR agonist clonidine induced a modest aggravation of DSS-induced colitis. It accelerated the disease development and markedly enhanced the weight loss of animals, but did not influence the colon shortening, tissue MPO levels, or histologic score. Clonidine induced similar changes in α2B- and α2C-AR KO mice, whereas it failed to affect the disease activity index scores and caused only minor weight loss in α2A-AR KO animals. In contrast, selective inhibition of α2A-ARs by BRL 44408 significantly delayed the development of colitis; reduced the colonic levels of MPO and chemokine (C-C motif) ligand 3, chemokine (C-X-C motif) ligand 2 (CXCL2), CXCL13, and granulocyte-colony stimulating factor; and elevated that of tissue inhibitor of metalloproteinases-1. In this work, we report that activation of α2-ARs aggravates murine colitis, an effect mediated by the α2A-AR subtype, and selective inhibition of these receptors reduces the severity of gut inflammation.
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Affiliation(s)
- Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Viktória E Tóth
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Ágnes Fehér
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Zita Puskár
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Márk Kozsurek
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Júlia Timár
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Tamás Tábi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Lutz Hein
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Peter Holzer
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine (Z.S.Z., V.E.T., Á.F., M.A.-K., J.T., K.G.), Department of Anatomy, Histology, and Embryology, János Szentágothai Laboratory (Z.P., M.K.), and Department of Pharmacodynamics (T.T.), Semmelweis University, Budapest, Hungary; Department of Pharmacology and Pharmacotherapy, Szentagothai Research Centre and MTA-NAP B Chronic Pain Research Group, University of Pécs, Pécs, Hungary (Z.H.); Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine and BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany (L.H.); and Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria (P.H.)
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Matrix Metalloproteinases in Non-Neoplastic Disorders. Int J Mol Sci 2016; 17:ijms17071178. [PMID: 27455234 PMCID: PMC4964549 DOI: 10.3390/ijms17071178] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/16/2016] [Accepted: 07/04/2016] [Indexed: 12/23/2022] Open
Abstract
The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action.
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Brauer R, Tureckova J, Kanchev I, Khoylou M, Skarda J, Prochazka J, Spoutil F, Beck IM, Zbodakova O, Kasparek P, Korinek V, Chalupsky K, Karhu T, Herzig KH, Hajduch M, Gregor M, Sedlacek R. MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function. Mucosal Immunol 2016; 9:974-85. [PMID: 26555704 DOI: 10.1038/mi.2015.117] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 09/29/2015] [Indexed: 02/04/2023]
Abstract
Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of pro-inflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-) mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.
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Affiliation(s)
- R Brauer
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.,Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, USA
| | - J Tureckova
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - I Kanchev
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - M Khoylou
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic
| | - J Skarda
- Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic
| | - J Prochazka
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - F Spoutil
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - I M Beck
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - O Zbodakova
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - P Kasparek
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.,Faculty of Sciences, Charles University in Prague, Prague, Czech Republic
| | - V Korinek
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - K Chalupsky
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
| | - T Karhu
- Institute of Biomedicine and Biocenter of Oulu, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
| | - K-H Herzig
- Institute of Biomedicine and Biocenter of Oulu, Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
| | - M Hajduch
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic
| | - M Gregor
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic.,Institute of Molecular Genetics of the ASCR, Laboratory of Integrative Biology, Prague, Czech Republic
| | - R Sedlacek
- Institute of Molecular Genetics of the ASCR, Laboratory of Transgenic Models of Diseases, Prague, Czech Republic
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Angelica acutiloba Kitagawa Extract Attenuates DSS-Induced Murine Colitis. Mediators Inflamm 2016; 2016:9275083. [PMID: 27293323 PMCID: PMC4886075 DOI: 10.1155/2016/9275083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/27/2016] [Indexed: 12/13/2022] Open
Abstract
We examined the protective effects of Angelica acutiloba Kitagawa (AAK) extract on a murine model of acute experimental colitis. Colitis was induced by 4% dextran sulfate sodium (DSS) in the drinking water of male C57BL/6 mice, for 7 consecutive days. Oral administration of AAK extract (500 mg/kg/day) significantly alleviated DSS-induced symptoms such as anorexia, weight loss, events of diarrhea or bloody stools, and colon shortening. Histological damage was also ameliorated, as evidenced by the architectural preservation and suppression of inflammatory cell infiltration in colonic samples. Treatment improved the colonic mRNA expression of different inflammatory markers: cytokines, inducible enzymes, matrix metalloproteinases, and tight junction-related proteins. In the isolated serum, IgE levels were downregulated. Collectively, these findings indicate the therapeutic potentials of AAK as an effective complementary or alternative modality for the treatment of ulcerative colitis.
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Gren ST, Janciauskiene S, Sandeep S, Jonigk D, Kvist PH, Gerwien JG, Håkansson K, Grip O. The protease inhibitor cystatin C down-regulates the release of IL-β and TNF-α in lipopolysaccharide activated monocytes. J Leukoc Biol 2016; 100:811-822. [DOI: 10.1189/jlb.5a0415-174r] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 05/04/2016] [Indexed: 01/14/2023] Open
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Nighot P, Al-Sadi R, Rawat M, Guo S, Watterson DM, Ma T. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis. Am J Physiol Gastrointest Liver Physiol 2015; 309:G988-G997. [PMID: 26514773 PMCID: PMC4683300 DOI: 10.1152/ajpgi.00256.2015] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 10/07/2015] [Indexed: 01/31/2023]
Abstract
Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9(-/-) mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9(-/-) mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9(-/-) mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK(-/-) mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9(-/-) mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK.
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Affiliation(s)
- Prashant Nighot
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Rana Al-Sadi
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Manmeet Rawat
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico;
| | - Shuhong Guo
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - D Martin Watterson
- Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Thomas Ma
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Veterans Affairs Medical Center, Albuquerque, New Mexico
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Wang Z, Wang L, Fan R, Zhou J, Zhong J. Molecular design and structural optimization of potent peptide hydroxamate inhibitors to selectively target human ADAM metallopeptidase domain 17. Comput Biol Chem 2015; 61:15-22. [PMID: 26709988 DOI: 10.1016/j.compbiolchem.2015.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 10/07/2015] [Accepted: 12/06/2015] [Indexed: 11/29/2022]
Abstract
Human ADAMs (a disintegrin and metalloproteinases) have been established as an attractive therapeutic target of inflammatory disorders such as inflammatory bowel disease (IBD). The ADAM metallopeptidase domain 17 (ADAM17 or TACE) and its close relative ADAM10 are two of the most important ADAM members that share high conservation in sequence, structure and function, but exhibit subtle difference in regulation of downstream cell signaling events. Here, we described a systematic protocol that combined computational modeling and experimental assay to discover novel peptide hydroxamate derivatives as potent and selective inhibitors for ADAM17 over ADAM10. In the procedure, a virtual combinatorial library of peptide hydroxamate compounds was generated by exploiting intermolecular interactions involved in crystal and modeled structures. The library was examined in detail to identify few promising candidates with both high affinity to ADAM17 and low affinity to ADAM10, which were then tested in vitro with enzyme inhibition assay. Consequently, two peptide hydroxamates Hxm-Phe-Ser-Asn and Hxm-Phe-Arg-Gln were found to exhibit potent inhibition against ADAM17 (Ki=92 and 47nM, respectively) and strong selectivity for ADAM17 over ADAM10 (∼7-fold and ∼5-fold, S=0.86 and 0.71, respectively). The structural basis and energetic property of ADAM17 and ADAM10 interactions with the designed inhibitors were also investigated systematically. It is found that the exquisite network of nonbonded interactions involving the side chains of peptide hydroxamates is primarily responsible for inhibitor selectivity, while the coordination interactions and hydrogen bonds formed by the hydroxamate moiety and backbone of peptide hydroxamates confer high affinity to inhibitor binding.
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Affiliation(s)
- Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Lei Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Rong Fan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jie Zhou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jie Zhong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
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Myrelid P, Salim SY, Darby T, Almer S, Melgar S, Andersson P, Söderholm JD. Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis. Scand J Gastroenterol 2015; 50:991-1001. [PMID: 25861827 DOI: 10.3109/00365521.2014.964760] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to examine the effect of colitis and anti-inflammatory therapies on the healing of colonic anastomoses in mice. METHODS Female C57BL/6 mice were randomized into eight groups; four groups receiving plain tap-water and four groups receiving dextran sulfate sodium. Intra-peritoneal treatment was given therapeutically for 14 days with placebo, prednisolone, azathioprine, or infliximab (IFX). Colonic anastomoses were performed and bursting pressure (BP) measurements were recorded and the inflammation evaluated with histology and zymography. RESULTS The mice with colitis had a more active inflammation based on histology and bowel weight compared with the tap water group, 8.3 (7.6-9.5) mg/mm and 5.5 (4.8-6.2) mg/mm respectively (p < 0.0001). Similarly mice with colitis receiving placebo had a more active inflammation, 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms among the colitic mice; prednisolone 8.1 (7.5-9.1) mg/mm (p = 0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p = 0.0046), IFX 6.7 (6.4-7.9) mg/mm (p = 0.0055). BP for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from azathioprine or IFX groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast BP for the prednisolone group was significantly decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p = 0.0004). CONCLUSIONS All therapies had a beneficial effect on the colitis. An impaired BP of colonic anastomoses was noted after preoperative steroids but not after azathioprine or IFX in this model.
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Affiliation(s)
- Pär Myrelid
- Department of Surgery and Department of Clinical and Experimental Medicine, Linköping University , Linköping , Sweden
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Eum SY, Jaraki D, András IE, Toborek M. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2. Toxicol Appl Pharmacol 2015; 287:258-66. [PMID: 26080028 DOI: 10.1016/j.taap.2015.06.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 05/20/2015] [Accepted: 06/11/2015] [Indexed: 01/30/2023]
Abstract
Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs.
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Affiliation(s)
- Sung Yong Eum
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Dima Jaraki
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Ibolya E András
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Michal Toborek
- Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Marshall DC, Lyman SK, McCauley S, Kovalenko M, Spangler R, Liu C, Lee M, O’Sullivan C, Barry-Hamilton V, Ghermazien H, Mikels-Vigdal A, Garcia CA, Jorgensen B, Velayo AC, Wang R, Adamkewicz JI, Smith V. Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer. PLoS One 2015; 10:e0127063. [PMID: 25961845 PMCID: PMC4427291 DOI: 10.1371/journal.pone.0127063] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 04/11/2015] [Indexed: 12/20/2022] Open
Abstract
Expression of matrix metalloproteinase 9 (MMP9) is elevated in a variety of inflammatory and oncology indications, including ulcerative colitis and colorectal cancer. MMP9 is a downstream effector and an upstream mediator of pathways involved in growth and inflammation, and has long been viewed as a promising therapeutic target. However, previous efforts to target matrix metalloproteinases (MMPs), including MMP9, have utilized broad-spectrum or semi-selective inhibitors. While some of these drugs showed signs of efficacy in patients, all MMP-targeted inhibitors have been hampered by dose-limiting toxicity or insufficient clinical benefit, likely due to their lack of specificity. Here, we show that selective inhibition of MMP9 did not induce musculoskeletal syndrome (a characteristic toxicity of pan-MMP inhibitors) in a rat model, but did reduce disease severity in a dextran sodium sulfate-induced mouse model of ulcerative colitis. We also found that MMP9 inhibition decreased tumor growth and metastases incidence in a surgical orthotopic xenograft model of colorectal carcinoma, and that inhibition of either tumor- or stroma-derived MMP9 was sufficient to reduce primary tumor growth. Collectively, these data suggest that selective MMP9 inhibition is a promising therapeutic strategy for treatment of inflammatory and oncology indications in which MMP9 is upregulated and is associated with disease pathology, such as ulcerative colitis and colorectal cancer. In addition, we report the development of a potent and highly selective allosteric MMP9 inhibitor, the humanized monoclonal antibody GS-5745, which can be used to evaluate the therapeutic potential of MMP9 inhibition in patients.
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MESH Headings
- Allosteric Regulation
- Animals
- Antibodies, Monoclonal, Humanized/biosynthesis
- Antibodies, Monoclonal, Humanized/isolation & purification
- Antibodies, Monoclonal, Humanized/pharmacology
- Antineoplastic Agents/isolation & purification
- Antineoplastic Agents/metabolism
- Antineoplastic Agents/pharmacology
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/enzymology
- Colitis, Ulcerative/genetics
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/enzymology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/pathology
- Dextran Sulfate
- Disease Models, Animal
- Drug Evaluation, Preclinical
- Epitope Mapping
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Hybridomas/immunology
- Male
- Matrix Metalloproteinase 9/administration & dosage
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Matrix Metalloproteinase Inhibitors/isolation & purification
- Matrix Metalloproteinase Inhibitors/metabolism
- Matrix Metalloproteinase Inhibitors/pharmacology
- Mice
- Mice, Nude
- Rats
- Rats, Inbred Lew
- Recombinant Proteins/administration & dosage
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Signal Transduction
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Derek C. Marshall
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Susan K. Lyman
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Scott McCauley
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Maria Kovalenko
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Rhyannon Spangler
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Chian Liu
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Michael Lee
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Christopher O’Sullivan
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Vivian Barry-Hamilton
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Haben Ghermazien
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Amanda Mikels-Vigdal
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Carlos A. Garcia
- Department of Process Development, Gilead Sciences, Inc., Oceanside, California, United States of America
| | - Brett Jorgensen
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Arleene C. Velayo
- Department of Process Development, Gilead Sciences, Inc., Oceanside, California, United States of America
| | - Ruth Wang
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Joanne I. Adamkewicz
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
| | - Victoria Smith
- Department of Biology, Gilead Sciences, Inc., Foster City, California, United States of America
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The anti-inflammatory activity of a novel fused-cyclopentenone phosphonate and its potential in the local treatment of experimental colitis. Gastroenterol Res Pract 2015; 2015:939483. [PMID: 25949237 PMCID: PMC4408640 DOI: 10.1155/2015/939483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 03/15/2015] [Accepted: 03/23/2015] [Indexed: 11/17/2022] Open
Abstract
A novel fused-cyclopentenone phosphonate compound, namely, diethyl 3-nonyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (P-5), was prepared and tested in vitro (LPS-activated macrophages) for its cytotoxicity and anti-inflammatory activity and in vivo (DNBS induced rat model) for its potential to ameliorate induced colitis. Specifically, the competence of P-5 to reduce TNFα, IL-6, INFγ, MCP-1, IL-1α, MIP-1α, and RANTES in LPS-activated macrophages was measured. Experimental colitis was quantified in the rat model, macroscopically and by measuring the activity of tissue MPO and iNOS and levels of TNFα and IL-1β. It was found that P-5 decreased the levels of TNFα and the tested proinflammatory cytokines and chemokines in LPS-activated macrophages. In the colitis-induced rat model, P-5 was effective locally in reducing mucosal inflammation. This activity was equal to the activity of local treatment with 5-aminosalicylic acid. It is speculated that P-5 may be used for the local treatment of IBD (e.g., with the aid of colon-specific drug platforms). Its mode of action involves inhibition of the phosphorylation of MAPK ERK but not of p38 and had no effect on IκBα.
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43
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Utrilla MP, Peinado MJ, Ruiz R, Rodriguez-Nogales A, Algieri F, Rodriguez-Cabezas ME, Clemente A, Galvez J, Rubio LA. Pea (Pisum sativum L.) seed albumin extracts show anti-inflammatory effect in the DSS model of mouse colitis. Mol Nutr Food Res 2015; 59:807-19. [PMID: 25626675 DOI: 10.1002/mnfr.201400630] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 01/15/2015] [Accepted: 01/16/2015] [Indexed: 01/10/2023]
Abstract
SCOPE This study investigates the preventive effects of two pea (Pisum sativum) seed albumin extracts, either in the presence (pea seed extract [PSE]) or absence (albumin fraction from PSE [AF-PSE]) of soluble polysaccharides, in the dextran sodium sulfate (DSS) induced colitis in mice. METHODS AND RESULTS Male C57BL/6J mice were assigned to five groups: one noncolitic and four colitic. Colitis was induced by incorporating DSS (3.5%) in the drinking water for 4 days, after which DSS was removed. Treated groups received orally PSE (15 g/kg⋅day), or AF-PSE (1.5 g/kg⋅day), or pure soy Bowman-Birk inhibitor (BBI; 50 mg/kg⋅day), starting 2 wk before colitis induction, and maintained for 9 days after. All treated groups showed intestinal anti-inflammatory effect, evidenced by reduced microscopic histological damage in comparison with untreated colitic mice. The treatments ameliorated the colonic mRNA expression of different proinflammatory markers: cytokines, inducible enzymes, metalloproteinases, adhesion molecules, and toll-like receptors, as well as proteins involved in maintaining the epithelial barrier function. Furthermore, the administration of PSE, AF-PSE, or soy BBI restored bacterial counts, partially or totally, to values in healthy mice. CONCLUSION PSE and AF-PSE ameliorated DSS-induced damage to mice, their effects being due, at least partially, to the presence of active BBI.
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Affiliation(s)
- Ma Pilar Utrilla
- CIBER-EHD, Department of Pharmacology, ibs. GRANADA, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain
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44
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Sprung CN, Forrester HB, Siva S, Martin OA. Immunological markers that predict radiation toxicity. Cancer Lett 2015; 368:191-7. [PMID: 25681035 DOI: 10.1016/j.canlet.2015.01.045] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/30/2015] [Accepted: 01/31/2015] [Indexed: 12/31/2022]
Abstract
Radiotherapy is a major modality of cancer treatment responsible for a large proportion of cancer that is cured. Radiation exposure induces an inflammatory response which can be influenced by genetic, epigenetic, tumour, health and other factors which can lead to very different treatment outcomes between individuals. Molecules involved in the immunological response provide excellent potential biomarkers for the prediction of radiation-induced toxicity. The known molecular and cellular immunological responses in relation to radiation and the potential to improve cancer treatment are presented in this review. In particular, immunological biomarkers of radiation-induced fibrosis and pneumonitis in cancer radiotherapy patients are discussed.
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Affiliation(s)
- Carl N Sprung
- Centre for Innate Immunology and Infectious Disease, MIMR-PHI Institute of Medical Research, 27-31 Wright Street, Clayton, Vic. 3168, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, Vic., Australia.
| | - Helen B Forrester
- Centre for Innate Immunology and Infectious Disease, MIMR-PHI Institute of Medical Research, 27-31 Wright Street, Clayton, Vic. 3168, Australia; Department of Molecular and Translational Sciences, Monash University, Clayton, Vic., Australia
| | - Shankar Siva
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia
| | - Olga A Martin
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Vic., Australia; Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, Vic., Australia
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45
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Puig KL, Lutz BM, Urquhart SA, Rebel AA, Zhou X, Manocha GD, Sens M, Tuteja AK, Foster NL, Combs CK. Overexpression of mutant amyloid-β protein precursor and presenilin 1 modulates enteric nervous system. J Alzheimers Dis 2015; 44:1263-78. [PMID: 25408221 PMCID: PMC6295343 DOI: 10.3233/jad-142259] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder histologically characterized by amyloid-β (Aβ) protein accumulation and activation of associated microglia. Although these features are well described in the central nervous system, the process and consequences of Aβ accumulation in the enteric nervous system have not been extensively studied. We hypothesized that Aβ also may accumulate in the enteric nervous system and lead to immune cell activation and neuronal dysfunction in the digestive tract not unlike that observed in diseased brain. To test this hypothesis, ileums of the small intestine of thirteen month old AβPP/PS1 and C57BL/6 (wild type) mice were collected and analyzed using immunohistochemistry, western blot analysis, cytokine arrays, and ELISA. AβPP/PS1 mice demonstrated no differences in intestinal motility or water absorption but elevated luminal IgA levels compared to wild type mice. They also had increased protein levels of AβPP and the proteolytic enzyme, BACE, corresponding to an increase in Aβ1-40 in the intestinal lysate as well as an increase in both Aβ1-40 and Aβ1-42 in the stool. This correlated with increased protein markers of proinflammatory and immune cell activation. Histologic analysis localized AβPP within enteric neurons but also intestinal epithelial cells with elevated Aβ immunoreactivity in the AβPP/PS1 mice. The presence of AβPP, Aβ, and CD68 immunoreactivity in the intestines of some patients with neuropathologically-confirmed AD are consistent with the findings in this mouse model. These data support the hypothesis that in AD the intestine, much like the brain, may develop proinflammatory and immune changes related to AβPP and Aβ.
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Affiliation(s)
- Kendra L. Puig
- Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Brianna M. Lutz
- Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Siri A. Urquhart
- Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Andrew A. Rebel
- Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Xudong Zhou
- Department of Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Gunjan D. Manocha
- Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - MaryAnn Sens
- Department of Pathology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Ashok K. Tuteja
- Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA
| | - Norman L. Foster
- Center for Alzheimer’s Care, Imaging and Research, Department of Neurology, University of Utah, Salt Lake City, UT, USA
| | - Colin K. Combs
- Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
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46
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Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases. Hepatobiliary Pancreat Dis Int 2014; 13:570-9. [PMID: 25475858 DOI: 10.1016/s1499-3872(14)60261-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is a growing evidence that matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinases) play an important role in the pathogenesis of numerous disorders, especially with inflammatory etiology and extracellular matrix (ECM) remodeling. Despite the fact that gelatinases involve in liver cirrhosis is provided in the literature, their role in the pathogenesis of chronic pancreatitis and non-specific inflammatory bowel diseases is still under investigation. DATA SOURCES We carried out a PubMed search of English-language articles relevant to the involvement of gelatinases in the pathogenesis of liver fibrosis, pancreatitis, and non-specific inflammatory bowel diseases. RESULTS The decreased activity of gelatinases, especially MMP-2, is related to the development of liver fibrosis, probably due to the decrease of capability for ECM remodeling. Similar situation can be found in chronic pancreatitis; however, reports on this matter are rare. The presence of non-specific inflammatory bowel diseases results in MMP-9 activity elevation. CONCLUSION The fluctuation of gelatinases activity during liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases is observed, but the exact role of these enzymes demands further studies.
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47
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Siva S, MacManus M, Kron T, Best N, Smith J, Lobachevsky P, Ball D, Martin O. A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer. PLoS One 2014; 9:e109560. [PMID: 25289758 PMCID: PMC4188745 DOI: 10.1371/journal.pone.0109560] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 08/29/2014] [Indexed: 12/25/2022] Open
Abstract
Purpose Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity. Experimental Design In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0. Results Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity. Conclusions Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies.
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Affiliation(s)
- Shankar Siva
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- * E-mail:
| | - Michael MacManus
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia
| | - Tomas Kron
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia
- Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Nickala Best
- Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia
| | - Jai Smith
- Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia
| | - Pavel Lobachevsky
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia
- Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia
| | - David Ball
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia
| | - Olga Martin
- Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, the University of Melbourne, Melbourne, VIC, Australia
- Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, VIC, Australia
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Martinesi M, Ambrosini S, Treves C, Zuegel U, Steinmeyer A, Vito A, Milla M, Bonanomi AG, Stio M. Role of vitamin D derivatives in intestinal tissue of patients with inflammatory bowel diseases. J Crohns Colitis 2014; 8:1062-1071. [PMID: 24630484 DOI: 10.1016/j.crohns.2014.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 02/07/2014] [Accepted: 02/07/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM The adhesion molecule expression and matrix metalloproteinases (MMPs) are proposed to be major factors for intestinal injury mediated by T cells in (IBD) and are up-regulated in intestinal mucosa of IBD patients. To investigate the effect of vitamin D derivatives on adhesion molecules and MMPs in colonic biopsies of IBD patients. METHODS Biopsies from inflamed and non-inflamed tract of terminal ileum and colon and PBMC from the same IBD patients were cultured with or without vitamin D derivatives. MMP activity and adhesion molecule levels were determined. RESULTS 1,25(OH)2D3 and ZK 191784 significantly decrease ICAM-1 protein levels in the biopsies obtained only from the inflamed region of intestine of UC patients, while MAdCAM-1 levels decrease in the presence of 1,25(OH)2D3 in the non-inflamed region, and, in the presence of ZK, in the inflamed one. In CD patients 1,25(OH)2D3 and ZK decrease ICAM-1 and MAdCAM-1 in the biopsies obtained from the non-inflamed and inflamed regions, with the exception of ICAM-1 in the inflamed region in the presence of 1,25(OH)2D3. The expression of MMP-9, MMP-2, and MMP-3 decreases in the presence of vitamin D derivatives in UC and CD with the exception of 1,25(OH)2D3 that does not affect the levels of MMP-9 and MMP-2 in CD. Vitamin D derivatives always affect MMP-9, MMP-2 and ICAM-1 in PBMC of UC and CD patients. CONCLUSIONS Based on the increased expression of ICAM-1, MAdCAM-1 and MMP-2,-9,-3 in IBD, our study suggests that vitamin D derivatives may be effective in the management of these diseases.
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Affiliation(s)
- Maria Martinesi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Stefano Ambrosini
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Cristina Treves
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Ulrich Zuegel
- Clinical Sciences, Global Biomarker, Global Discovery, Bayer Healthcare, Bayer, 10178 Berlin, Germany
| | - Andreas Steinmeyer
- Medicinal Chemistry, Global Drug Discovery, Bayer Healthcare, Bayer, 10178 Berlin, Germany
| | - Annese Vito
- Division of Gastroenterology 2, Careggi Hospital, 50134 Florence, Italy
| | - Monica Milla
- Regional Referral Center for IBD, Careggi Hospital, 50134 Florence, Italy
| | - Andrea G Bonanomi
- Division of Gastroenterology 2, Careggi Hospital, 50134 Florence, Italy
| | - Maria Stio
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
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49
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Eum SY, Jaraki D, Bertrand L, András IE, Toborek M. Disruption of epithelial barrier by quorum-sensing N-3-(oxododecanoyl)-homoserine lactone is mediated by matrix metalloproteinases. Am J Physiol Gastrointest Liver Physiol 2014; 306:G992-G1001. [PMID: 24742991 PMCID: PMC4042118 DOI: 10.1152/ajpgi.00016.2014] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The intestinal epithelium forms a selective barrier maintained by tight junctions (TJs) and separating the luminal environment from the submucosal tissues. N-acylhomoserine lactone (AHL) quorum-sensing molecules produced by gram-negative bacteria in the gut can influence homeostasis of the host intestinal epithelium. In the present study, we evaluated the regulatory mechanisms affecting the impact of two representative long- and short-chain AHLs, N-3-(oxododecanoyl)-homoserine lactone (C12-HSL) and N-butyryl homoserine lactone (C4-HSL), on barrier function of human intestinal epithelial Caco-2 cells. Treatment with C12-HSL, but not with C4-HSL, perturbed Caco-2 barrier function; the effect was associated with decreased levels of the TJ proteins occludin and tricellulin and their delocalization from the TJs. C12-HSL also induced matrix metalloprotease (MMP)-2 and MMP-3 activation via lipid raft- and protease-activated receptor (PAR)-dependent signaling. Pretreatment with lipid raft disruptors, PAR antagonists, or MMP inhibitors restored the C12-HSL-induced loss of the TJ proteins and increased permeability of Caco-2 cell monolayers. These results indicate that PAR/lipid raft-dependent MMP-2 and -3 activation followed by degradation of occludin and tricellulin are involved in C12-HSL-induced alterations of epithelial paracellular barrier functions.
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Affiliation(s)
- Sung Yong Eum
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Dima Jaraki
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Luc Bertrand
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Ibolya E. András
- 1Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida; and Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
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50
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Oliveira LGD, Cunha ALD, Duarte AC, Castañon MCMN, Chebli JMF, Aguiar JAKD. Positive correlation between disease activity index and matrix metalloproteinases activity in a rat model of colitis. ARQUIVOS DE GASTROENTEROLOGIA 2014; 51:107-112. [PMID: 25003261 DOI: 10.1590/s0004-28032014000200007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 12/10/2013] [Indexed: 01/01/2023]
Abstract
CONTEXT Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, comprising a broad spectrum of diseases those have in common chronic inflammation of the gastrointestinal tract, histological alterations and an increased activity levels of certain enzymes, such as, metalloproteinases. OBJECTIVES Evaluate a possible correlation of disease activity index with the severity of colonic mucosal damage and increased activity of metalloproteinases in a model of ulcerative colitis induced by dextran sulfate sodium. METHODS Colitis was induced by oral administration of 5% dextran sulfate sodium for seven days in this group (n=10), whereas control group (n=16) received water. Effects were analyzed daily by disease activity index. In the seventh day, animals were euthanized and hematological measurements, histological changes (hematoxylin and eosin and Alcian Blue staining), myeloperoxidase and metalloproteinase activities (MMP-2 and MMP-9) were determined. RESULTS Dextran sulfate sodium group showed elevated disease activity index and reduced hematological parameters. Induction of colitis caused tissue injury with loss of mucin and increased myeloperoxidase (P<0.001) and MMP-9 activities (45 fold) compared to the control group. CONCLUSIONS In this study, we observed a disease activity index correlation with the degree of histopathological changes after induction of colitis, and this result may be related mainly to the increased activity of MMP-9 and mieloperoxidase.
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Affiliation(s)
- Luiz Gustavo de Oliveira
- Laboratório de Análise de Glicoconjugados, Departamento de Bioquímica, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora - UFJF, Juiz de Fora, MG, Brasil
| | - André Luiz da Cunha
- Laboratório de Análise de Glicoconjugados, Departamento de Bioquímica, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora - UFJF, Juiz de Fora, MG, Brasil
| | - Amaury Caiafa Duarte
- Laboratório de Análise de Glicoconjugados, Departamento de Bioquímica, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora - UFJF, Juiz de Fora, MG, Brasil
| | | | | | - Jair Adriano Kopke de Aguiar
- Laboratório de Análise de Glicoconjugados, Departamento de Bioquímica, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora - UFJF, Juiz de Fora, MG, Brasil
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