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Ombasa L, Miller J, Ware L, Abbotts-Holmes H, Tang J, Gasser O, Fraser K, Bayer S, Kemp R, Costello R, Highton A, Evans J, Merry T, Schultz M, Frampton C, Gearry R, McNabb W, Roy N. Impact of Mānuka Honey on Symptoms and Quality of Life in Individuals With Functional Dyspepsia: Protocol for a Feasibility Randomized Controlled Trial. JMIR Res Protoc 2025; 14:e66417. [PMID: 40397937 DOI: 10.2196/66417] [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: 09/14/2024] [Revised: 03/28/2025] [Accepted: 04/04/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND Functional dyspepsia is a common gastrointestinal condition that reduces the quality of life and increases health care costs. The lack of well-defined causes limits effective treatments. Consumers report using mānuka honey to treat gastrointestinal symptoms, although clinical evidence supporting such use is limited. Preclinical studies suggest its unique bioactive compounds may reduce gastrointestinal inflammation. Recently, 3,6,7-trimethyllumazine (Lepteridine), a natural pteridine in mānuka honey, was shown to inhibit enzymes involved in gastrointestinal inflammation in in vitro studies. Therefore, Lepteridine-standardized mānuka honey may deliver digestive health benefits. OBJECTIVE The aim of this feasibility study is to gather the data required to estimate sample size and support study logistics to design future trials. The primary objective will be preliminary assessments of the impact of Lepteridine-standardized mānuka honey on symptom severity and the quality of life in participants with mild-to-moderate functional dyspepsia. Other feasibility objectives include assessing the biological responses to mānuka honey standardized to medium and high levels of Lepteridine and measuring mānuka honey-derived metabolites in blood and urine. METHODS This is a 3-arm, parallel, controlled, double-blind, randomized feasibility study. A total of 75 healthy adults with symptoms of functional dyspepsia (Rome IV criteria) and mild-to-moderate dyspepsia severity (Short Form Leeds Dyspepsia Questionnaire) were recruited between October 2022 and September 2023. Participants were randomized into one of three groups: (1) mānuka honey standardized to contain 10 mg/kg Lepteridine, (2) mānuka honey standardized to contain 40 mg/kg Lepteridine, or (3) honey maple flavored syrup control. After a 2-week lead-in period, participants consumed 10 g of allocated intervention twice daily for 6 weeks. Throughout the study, participants completed daily bowel movement diaries and validated weekly questionnaires about their gastrointestinal symptoms and quality of life. Stool samples and 3-day diet records were collected at baseline and the end of the intervention. Blood samples were collected at baseline, weeks 2 and 4, and at the end of the intervention. In addition, 6 healthy participants without symptoms of functional dyspepsia were recruited to undergo an acute 5-hour assessment for the appearance of Lepteridine and related metabolites in plasma and urine following consumption of Lepteridine-standardized mānuka honey. The study was approved by the Northern B Health and Disability Ethics Committee. RESULTS Initial analysis includes 68 participants, with laboratory and data analyses being undertaken as of March 2024. The results of the primary and secondary outcomes will be published in peer-reviewed journals. CONCLUSIONS This study will provide essential information on the potential efficacy and suitability of Lepteridine-standardized mānuka honey for designing future clinical trials investigating its effect in treating symptoms of functional dyspepsia. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12622001140741p; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384094. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/66417.
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Affiliation(s)
- Laura Ombasa
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
- Riddet Institute, Massey University, Palmerston North, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Jody Miller
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Lara Ware
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Holly Abbotts-Holmes
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Jeffry Tang
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Olivier Gasser
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Malaghan Institute of Medical Research, Wellington, New Zealand
| | | | - Simone Bayer
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Roslyn Kemp
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Rory Costello
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - Andrew Highton
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | | | - Troy Merry
- Comvita NZ Limited, Paengaroa, New Zealand
| | - Michael Schultz
- Department of Medicine, University of Otago, Dunedin, New Zealand
| | | | - Richard Gearry
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Warren McNabb
- Riddet Institute, Massey University, Palmerston North, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Nicole Roy
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
- Riddet Institute, Massey University, Palmerston North, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
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Luo Q, An M, Wu Y, Wang J, Mao Y, Zhang L, Wang C. Bioinformatics analysis reveals potential crosstalk genes and molecular mechanisms between ulcerative colitis and psoriasis. Arch Dermatol Res 2024; 317:118. [PMID: 39673621 DOI: 10.1007/s00403-024-03617-6] [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: 08/31/2024] [Revised: 09/07/2024] [Accepted: 11/26/2024] [Indexed: 12/16/2024]
Abstract
Ulcerative colitis (UC) and psoriasis are highly correlated clinically; however, it is unclear whether they have a common pathophysiological mechanism. The purpose of this study is to investigate the important molecules and pathways that mediate the coexistence of UC and psoriasis through quantitative bioinformatics analysis of public RNA-sequencing databases. The UC (GSE38713) and psoriasis (GSE30999) datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes were analysed using the "limma" package and their biological functions were investigated using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The Search Tool for the Retrieval of Interacting Genes database was used to create the protein-protein interaction (PPI) network, which was visualised by Cytoscape. The CytoHubba plugin was used to select the hub genes. The hub genes of psoriasis and UC were verified in GSE75214, GSE78097, GSE14905, and GSE87466. The predicted value of the hub gene was evaluated by the receiver operating characteristic curve (ROC). Gene Set Enrichment Analysis (GSEA) and immune infiltration were performed for the hub genes. Finally, we performed transcription factor (TF)-gene interaction network analysis, TF-miRNA co-regulation network analysis and candidate drug prediction. A total of 114 genes (89 ascending genes and 25 descending genes) with similar expression trends between UC and psoriasis were identified. Enrichment analysis revealed that the two signaling pathways were primarily related to immune and inflammatory responses. PPI network screened 13 hub genes (IL-1B, CXCL10, TLR2, CD274, CXCR2, CXCL9, MMP9, CXCL1, CASP1, IL-7R, IL-1RN, CCL18 and LCN2). Using NetworkAnalyst, we constructed a co-regulatory network diagram of TF-gene and TF-miRNA. Finally, diacerein was predicted to be effective in the treatment of UC and psoriasis. Our research revealed the common pathogenesis of UC and psoriasis, and examined the hub genes, TF and miRNA and potential therapeutic drugs (diacerein). These findings may provide new perspectives for further mechanism research and clinical treatment.
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Grants
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- 82260938,82374454, 82004374 National Natural Scientific Foundation of China
- YD202223 Clinical Medicine Leadership Project
- YD202223 Clinical Medicine Leadership Project
- YD202223 Clinical Medicine Leadership Project
- YD202223 Clinical Medicine Leadership Project
- YD202223 Clinical Medicine Leadership Project
- YD202223 Clinical Medicine Leadership Project
- YD202223 Clinical Medicine Leadership Project
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Affiliation(s)
- Qinghua Luo
- Clinical Medical College, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Mingwei An
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Yunxiang Wu
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Jiawen Wang
- Department of Anorectal Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanting Mao
- Clinical Medical College, Jiangxi University of Chinese Medicine, Nanchang, China
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Leichang Zhang
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China.
- Formula-Pattern Research Center, Jiangxi University of Chinese Medicine, Jiangxi, China.
| | - Chen Wang
- Department of Anorectal Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Wu Y, Shen J. Unraveling the intricacies of neutrophil extracellular traps in inflammatory bowel disease: Pathways, biomarkers, and promising therapies. Cytokine Growth Factor Rev 2024; 80:156-167. [PMID: 39438227 DOI: 10.1016/j.cytogfr.2024.10.003] [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: 09/21/2024] [Accepted: 10/06/2024] [Indexed: 10/25/2024]
Abstract
The development of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, involves various factors and is characterized by persistent inflammation of the mucosal lining. However, the role of neutrophils in this process remains controversial. Neutrophil extracellular traps (NETs), which consist of chromatin, antimicrobial proteins, and oxidative enzymes, are released by neutrophils to trap pathogens. They are also involved in various immune-mediated and vascular diseases. NETs act as a vital defense mechanisms at the gut-mucosal interface and are frequently exposed to bacterial, viral, and fungal threats. However, they can also contribute to inflammation and worsen imbalances in the gut bacteria. Recent studies have suggested that NETs have a significant impact on IBD development. Previous studies have shown increased levels of NETs in tissue and blood samples from patients with IBD, as well as in experimental colitis mouse models. Therefore, this review discusses how NETs are formed and their role in the pathophysiology of IBD. It discusses how NETs may lead to tissue damage and contribute to IBD-associated complications. Moreover, non-invasive biomarkers are needed to replace invasive procedures such as endoscopy to better evaluate the disease status. Given the crucial role of NETs in IBD progression, this review focuses on potential NET biomarkers that can help predict the evolution of IBD. Furthermore, this review identifies potential therapeutic targets for regulating NET production, which could expand the range of available treatment options for IBD.
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Affiliation(s)
- Yilin Wu
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Shanghai Institute of Digestive Disease, No.160 PuJian Road, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China; Shanghai Institute of Digestive Disease, No.160 PuJian Road, China.
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Wushouer X, Aximujiang K, Kadeer N, Aihemaiti A, Zhong L, Yunusi K. Effect of huankuile on colon injury in rats with ulcerative colitis by reducing TNF-α and MMP9. Eur J Med Res 2024; 29:102. [PMID: 38321559 PMCID: PMC10845565 DOI: 10.1186/s40001-024-01695-w] [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: 10/19/2022] [Accepted: 01/24/2024] [Indexed: 02/08/2024] Open
Abstract
OBJECTIVE To explore the mechanism of huankuile (HKL) in colon injury repair in rats with ulcerative colitis (UC). METHODS Fifty SPF Wistar male rats were divided randomly into a normal group, a negative control group, an HKL intervention group ('HKL group') and a 5-aminosalicylic acid intervention group ('5-ASA group'). After 14 days of intervention with corresponding drugs, pathological scores were obtained using the results of immunohistochemical staining; morphological changes were observed by hematoxylin-eosin staining, and the mRNA expression levels of tumour necrosis factor-α (TNF-α), matrix metalloproteinase 9 (MMP9) and interleukin-13 (IL-13) were detected by real-time quantitative PCR. RESULTS After the successful construction of the rat model, it was compared with the rats in the normal group. In the negative group, it was found that the expression of TNF-α and MMP9 was significantly increased in the colonic mucosal epithelia of the rats, the pathological score was significantly increased (P < 0.05), and the mRNA expression levels of TNF-α, MMP9 and IL-13 were increased (P < 0.05). After treatment with HKL, the colonic morphology of the rats returned to normal, the expression of TNF-α and MMP9 in the colonic mucosal epithelium of the rats returned to normal, the pathological score grade was significantly reduced (P < 0.05), and the mRNA expression levels of TNF-α, MMP9 and IL-13 were reduced; these results were largely consistent with those of the normal group, with no statistically significant difference. CONCLUSION HKL effectively improved the general symptoms and tissue injury in UC rats, and the therapeutic effect was better than that of 5-ASA group. Ulcerative colitis in rats increased the expression of TNF-α, MMP9 and IL-13. HKL repaired UC-induced colonic injury in rats by decreasing the expression of TNF-α, MMP9 and IL-13.
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Affiliation(s)
- Xilinguli Wushouer
- Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China
- Xinjiang key laboratory of Molecular Biology for endemic diseases, Urumqi , 830054, China
| | - Kasimujiang Aximujiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China
| | - Nafeisha Kadeer
- Department of Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China
| | - Abulaiti Aihemaiti
- The Functional Center, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China
| | - Li Zhong
- The Functional Center, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China
| | - Kurexi Yunusi
- UygurMedical College, Xinjiang Medical University, Urumqi, 830017, China.
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [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: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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Pasternak G, Chrzanowski G, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Sosna B, Cieślar G, Kawczyk-Krupka A, Filip R. Crohn's Disease: Basic Characteristics of the Disease, Diagnostic Methods, the Role of Biomarkers, and Analysis of Metalloproteinases: A Review. Life (Basel) 2023; 13:2062. [PMID: 37895443 PMCID: PMC10608618 DOI: 10.3390/life13102062] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/10/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Crohn's disease is a chronic inflammatory bowel disease that affects the ileum and/or large intestine. At the same time, it can also affect any other part of the human body, i.e., from the mouth to the anus. In Crohn's disease, the physiology and functioning of the epithelial barrier are inhibited due to the correlation of various factors, such as the environment, genetic susceptibility or intestinal microbiota. The symptoms are very troublesome and cause a significant reduction in quality of life, sometimes occurring with paralyzing permanent damage to the digestive tract, requiring enteral or parenteral nutrition throughout life. In order to make a proper and accurate diagnosis, an appropriately selected diagnostic path in a given clinical entity is necessary. Standard diagnostic methods are: laboratory examination, histopathological examination, endoscopic examination, X-ray, computed tomography, ultrasound examination and magnetic resonance imaging. Medical biology and the analysis of metalloproteinases have also proved helpful in diagnosing changes occurring as a result of Crohn's disease. Here we provide a thorough review of the latest reports on Crohn's disease and its genetic conditions, symptoms, morphology, diagnosis (including the analysis of Crohn's disease biomarkers, i.e., metalloproteinases) and treatment.
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Affiliation(s)
- Grzegorz Pasternak
- Department of General Surgery, Provincial Clinical Hospital No. 2 in Rzeszów, 35-301 Rzeszów, Poland;
| | - Grzegorz Chrzanowski
- Department of Biology, College of Natural Sciences, University of Rzeszów, 35-310 Rzeszów, Poland
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Rafał Filip
- Department of Internal Medicine, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland;
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Palandurkar GS, Kumar S. Biofilm's Impact on Inflammatory Bowel Diseases. Cureus 2023; 15:e45510. [PMID: 37868553 PMCID: PMC10585119 DOI: 10.7759/cureus.45510] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
The colon has a large surface area covered with a thick mucus coating. Colon's biomass consists of about 1,012 colony-forming units per gram of feces and 500-1,000 distinct bacterial species. The term inflammatory bowel disease (IBD) indicates the collection of intestinal illnesses in which the digestive system (esophagus, large intestine, mouth, stomach, and small intestine) experiences persistent inflammation. IBD development is influenced by environmental (infections, stress, and nutrition) and genetic factors. The microbes present in gut microbiota help maintain intestinal homeostasis and support immune and epithelial cell growth, differentiation, as well as proliferation. It has been discovered that a variety of variables and microorganisms are crucial for the development of biofilms and mucosal colonization during IBD. An extracellular matrix formed by bacteria supports biofilm production in our digestive system and harms the host's immunological response. Irritable bowel syndrome (IBS) and IBD considerably affect human socioeconomic well-being and the standard of living. IBD is a serious public health issue, affecting millions of people across the globe. The gut microbiome may significantly influence IBS pathogenesis, even though few diagnostic and treatment options are available. As a result, current research focuses more on disrupting biofilm in IBD patients and stresses primarily on drugs that help improve the quality of life for human well-being. We evaluate studies on IBD and bacterial biofilm to add fresh insights into the existing state of knowledge of biofilm formation in IBD, incidence of IBD patients, molecular level of investigations, bacteria that are involved in the formation of biofilm, and present and down the line regimens and probiotics. Planning advanced ways to control and eradicate bacteria in biofilms should be the primary goal to add fresh insights into generating innovative diagnostic and alternative therapy options for IBD.
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Affiliation(s)
- Gopal S Palandurkar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sunil Kumar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Magalhaes D, Peyrin-Biroulet L, Estevinho MM, Danese S, Magro F. Pursuing neutrophils: systematic scoping review on blood-based biomarkers as predictors of treatment outcomes in inflammatory bowel disease. Therap Adv Gastroenterol 2023; 16:17562848231155987. [PMID: 36923488 PMCID: PMC10009059 DOI: 10.1177/17562848231155987] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 01/23/2023] [Indexed: 03/14/2023] Open
Abstract
Background Long-term management of inflammatory bowel diseases (IBD) is challenging and the identification of reliable predictors for treatment outcomes is an unmet need. Neutrophil-related biomarkers have been mainly studied in the feces, but blood analyses have inherent advantages. Objective To review the recent learnings on the ability of blood-based neutrophil-expressed biomarkers to predict treatment outcomes in IBD. Design Systematic scoping review. Data sources and methods We performed a literature search in Pubmed, EMBASE, SCOPUS, Web of Science, ScienceDirect, and Cochrane Central Register of Controlled Trials from inception until May 2022 according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. All human studies associating blood-based neutrophil-related compounds with the prediction of disease progression, complication onset, or treatment outcomes were included. Results From 1032 retrieved entries, 34 studies were selected, 32 published in 2013 or later. In all, 17 biomarkers from granules, cytoplasm, plasmatic membrane, and plasma were explored. In total, 1850 Crohn's disease (CD) and 1122 ulcerative colitis non-duplicated patients were included. The most mentioned biomarkers were nCD64, serum calprotectin (SC), oncostatin M (OSM), neutrophil elastase-generated calprotectin fragment (CPa9-HNE), and triggering receptor expressed on myeloid cells 1 (TREM1). Six biomarkers showed promising results: OSM, SC, eNAMPT, nCD64, TREM1, and CPa9-HNE. Variable positive signals were found for human neutrophil peptide 1-3, LL-37, S100A12, and neutrophil gelatinase-associated lipocalin. No predictive ability was found for the remaining markers. Sharing a neutrophil compartment did not indicate similar behavior. Conclusion Advances in the last decade began to unveil the untapped potential of the readily accessible blood neutrophil-expressed biomarkers, especially nCD64, TREM1, and CPa9-HNE. Current evidence suggests that future research should focus on well-defined subpopulations instead of a one-size-fits-all biomarker. Registration https://osf.io/kes9a.
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Affiliation(s)
- Diogo Magalhaes
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Maria Manuela Estevinho
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IBD center, Humanitas Research Hospital, IRCCS, Rozzano, Milan, Italy
| | - Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Rua Dr. Plácido Costa, 3, Porto, 4200-450, Portugal
- Department of Gastroenterology, São João Hospital University Centre, Porto, Portugal
- Center for Health Technology and Services Research (CINTESIS), Porto, Portugal
- Unidade de Farmacologia Clínica, São João Hospital University Centre, Porto, Portugal
- Portuguese Inflammatory Bowel Disease group (GEDII)
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Yin L, Li X, Hou J. Macrophages in periodontitis: A dynamic shift between tissue destruction and repair. JAPANESE DENTAL SCIENCE REVIEW 2022; 58:336-347. [DOI: 10.1016/j.jdsr.2022.10.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 09/14/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022] Open
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10
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Varol A, Sezen S, Evcimen D, Zarepour A, Ulus G, Zarrabi A, Badr G, Daştan SD, Orbayoğlu AG, Selamoğlu Z, Varol M. Cellular targets and molecular activity mechanisms of bee venom in cancer: recent trends and developments. TOXIN REV 2022; 41:1382-1395. [DOI: 10.1080/15569543.2021.2024576] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Ayşegül Varol
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Serap Sezen
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Istanbul, Turkey
- Faculty of Engineering and Natural Science, Sabanci University, Istanbul, Turkey
| | - Dilhan Evcimen
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey
| | - Atefeh Zarepour
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Gönül Ulus
- Department of Biology, Faculty of Science, Ege University, Izmir, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Turkey
| | - Gamal Badr
- Department of Zoology, Faculty of Science, Laboratory of Immunology, Assiut University, Assiut, Egypt
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, Sivas, Turkey
| | - Asya Gülistan Orbayoğlu
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey
| | - Zeliha Selamoğlu
- Department Medical Biology, Faculty of Medicine, Nigde Ömer Halisdemir University, Nigde, Turkey
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla, Turkey
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Czajkowska A, Guzinska-Ustymowicz K, Pryczynicz A, Lebensztejn D, Daniluk U. Are Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Useful as Markers in Diagnostic Management of Children with Newly Diagnosed Ulcerative Colitis? J Clin Med 2022; 11:jcm11092655. [PMID: 35566780 PMCID: PMC9103541 DOI: 10.3390/jcm11092655] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/28/2022] [Accepted: 05/06/2022] [Indexed: 02/06/2023] Open
Abstract
Matrix Metaloproteinase-9 (MMP-9) and Tissue Inhibitor of Metaloproteinase-1 (TIMP-1), enzymes involved in tissue remodelling, have been previously reported to be overexpressed in the colonic mucosa of patients with Ulcerative colitis (UC). The aim of this study was to determine the relation of MMP-9 and TIMP-1 with UC phenotypes, the disease activity index and routinely tested inflammatory markers in newly diagnosed paediatric patients. The study group comprised 35 children diagnosed with UC and 20 control groups. Serum and faecal concentrations of MMP-9 and TIMP-1 were estimated using enzyme-like immunosorbent assay kits and correlated to the disease activity index (Paediatric Ulcerative Colitis Activity Index, PUCAI), UC phenotype (Paris Classification), inflammatory markers and endoscopic score (Mayo score). Children with UC presented with significantly higher serum and faecal concentrations of studied markers compared to the control group. Both serums, MMP-9 and TIMP-1, were higher in children with more extended and severe lesions in the colon. Furthermore, serum MMP-9 correlated with the Mayo score, Paris classification and C-reactive protein (CRP) levels. Serum TIMP-1 showed correlation with PUCAI, Paris Classification, CRP levels and the erythrocyte sedimentation rate. Serum and faecal levels of MMP-9 and TIMP-1 are useful in discriminating UC patients and non-invasive assessments of disease phenotypes. It seemed that simultaneous measurement of these proteins in combination with other common markers of inflammation could be applied in clinical practice.
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Affiliation(s)
- Aleksandra Czajkowska
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, 17 Waszyngtona Street, 15-274 Bialystok, Poland; (D.L.); (U.D.)
- Correspondence: or
| | | | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.G.-U.); (A.P.)
| | - Dariusz Lebensztejn
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, 17 Waszyngtona Street, 15-274 Bialystok, Poland; (D.L.); (U.D.)
| | - Urszula Daniluk
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, 17 Waszyngtona Street, 15-274 Bialystok, Poland; (D.L.); (U.D.)
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12
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Serum matrix metalloproteinase-9 concentration as a marker of disease activity in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2021; 33:e803-e809. [PMID: 34678857 DOI: 10.1097/meg.0000000000002264] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIM Diagnosing inflammatory bowel disease (IBD), determining the appropriate treatment and follow-up of patients rely mainly on endoscopy and biopsy. Finding a sensitive, specific, cost-effective and less-invasive biomarker is the focus of much of the current research in this field. The aim was to investigate the relation between serum matrix metalloproteinase-9 (MMP-9) levels and disease activity in patients with IBD, correlating with clinical and endoscopic indices of disease activity and with treatment received. PATIENTS AND METHODS Sixty patients (30 with ulcerative colitis, 30 with Crohn's disease) and 20 controls were included. Serum MMP-9 levels were measured for all patients and controls by ELISA. Clinical activity was determined by partial Mayo score for patients with ulcerative colitis and Crohn's Disease Activity Index for patients with Crohn's disease, and endoscopic activity was assessed using Ulcerative Colitis Endoscopic Index of Severity for patients with ulcerative colitis and Simple Endoscopic Score of Crohn's disease for patients with Crohn's disease. RESULTS Serum MMP-9 was higher in patients with active ulcerative colitis than in patients with inactive disease and the control group. Serum MMP-9 was also higher in patients with active Crohn's disease than in patients with inactive disease and the control group. In both ulcerative colitis and Crohn's disease groups, there was a significant difference between serum MMP-9 levels in patients receiving conventional treatment and those on biological treatment, with lower levels of the marker detected in the sera of patients subgroups receiving biologics. CONCLUSION Serum MMP-9 can be used to differentiate between active and inactive IBD (including both ulcerative colitis and Crohn's disease).
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Santos MI, Lima A, Mota J, Rebelo P, Ferreira RB, Pedroso L, Ferreira MA, Sousa I. Extended Cheese Whey Fermentation Produces a Novel Casein-Derived Antibacterial Polypeptide That Also Inhibits Gelatinases MMP-2 and MMP-9. Int J Mol Sci 2021; 22:ijms222011130. [PMID: 34681790 PMCID: PMC8541382 DOI: 10.3390/ijms222011130] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/06/2021] [Accepted: 10/09/2021] [Indexed: 01/18/2023] Open
Abstract
Our previous works produced a whey fermentation methodology that yielded antibacterial activity and potential inhibition of matrix metalloproteases (MMP)-2 and -9. Here, we evaluated if these activities were due to fermentation-produced peptides. Prolonged fermentation was carried out in the presence of our specific lactic acid bacteria (LAB) consortium. LAB fermentation yielded a total of 11 polypeptides, which were predominantly produced after 6 days of fermentation. One which was derived from beat casein presented a particularly high antibacterial activity against food pathogenic bacteria and was more effective than standard food disinfectants. This polypeptide was further studied and was also found to be active against several strains of pathogenic bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), in a dose-dependent manner. It also inhibited MMP-2 and MMP-9 whilst reducing HT29 cancer cell migration in vitro. Overall, this novel whey-derived polypeptide presents dual antibacterial and anti-inflammatory activity, revealing a strong potential to be used in functional foods or as a nutraceutical. Its identification and further characterization can open novel perspectives in the field of preventive/curative diets related to gut microbiota, gut inflammation, and cancer prevention, particularly if used in in vivo studies.
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Affiliation(s)
- Maria Isabel Santos
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
- Faculty of Veterinary Medicine, Universidade Lusófona de Humanidades e Tecnologias, Campo Grande, 376, 1749-024 Lisboa, Portugal
- Correspondence:
| | - Ana Lima
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
- Faculty of Veterinary Medicine, Universidade Lusófona de Humanidades e Tecnologias, Campo Grande, 376, 1749-024 Lisboa, Portugal
| | - Joana Mota
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
- Faculty of Veterinary Medicine, Universidade Lusófona de Humanidades e Tecnologias, Campo Grande, 376, 1749-024 Lisboa, Portugal
| | - Patrícia Rebelo
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
| | - Ricardo Boavida Ferreira
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
| | - Laurentina Pedroso
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
- Faculty of Veterinary Medicine, Universidade Lusófona de Humanidades e Tecnologias, Campo Grande, 376, 1749-024 Lisboa, Portugal
| | - Maria Adélia Ferreira
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
| | - Isabel Sousa
- Linking Landscape, Environment, Agriculture and Food (LEAF), Instituto Superior de Agronomia, University of Lisbon, Tapada da Ajuda, 1349-017 Lisboa, Portugal; (A.L.); (J.M.); (P.R.); (R.B.F.); (L.P.); (M.A.F.); (I.S.)
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Extracellular Matrix Components as Diagnostic Tools in Inflammatory Bowel Disease. BIOLOGY 2021; 10:biology10101024. [PMID: 34681123 PMCID: PMC8533508 DOI: 10.3390/biology10101024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/14/2021] [Accepted: 09/30/2021] [Indexed: 12/20/2022]
Abstract
Simple Summary For decades, the extracellular matrix (ECM) has been defined as a structure component playing a rather neglected role in the human body. In recent years, research has shed light on the role of ECM within cellular processes, including proliferation, migration and differentiation, as well as in inflammation. In inflammation, ECM composition is constantly being remodeled and undergoes dynamic and rapid changes. Tracking these changes could serve as a novel diagnostic tool. Inflammatory bowel disease is accompanied by complications such as fibrosis, stenosis and fistulas. All of these structural complications involve excessive synthesis or degradation of ECM. With this review, we explored whether the analysis of ECM composition can be of support in diagnosing inflammatory bowel disease and whether changes within ECM can help to predict a complicated disease course early on. Abstract Work from the last years indicates that the extracellular matrix (ECM) plays a direct role in various cellular processes, including proliferation, migration and differentiation. Besides homeostatic processes, its regulatory function in inflammation becomes more and more evident. In inflammation, such as inflammatory bowel disease, the ECM composition is constantly remodeled, and this can result in a structuring of fistulizing disease course. Thus, tracking early ECM changes might bear the potential to predict the disease course. In this review, we provide an overview of relevant diagnostic methods, focusing on ECM changes.
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Derkacz A, Olczyk P, Olczyk K, Komosinska-Vassev K. The Role of Extracellular Matrix Components in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10051122. [PMID: 33800267 PMCID: PMC7962650 DOI: 10.3390/jcm10051122] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
The remodeling of extracellular matrix (ECM) within the intestine tissues, which simultaneously involves an increased degradation of ECM components and excessive intestinal fibrosis, is a defining trait of the progression of inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn's disease (CD). The increased activity of proteases, especially matrix metalloproteinases (MMPs), leads to excessive degradation of the extracellular matrix and the release of protein and glycoprotein fragments, previously joined with the extracellular matrix, into the circulation. MMPs participate in regulating the functions of the epithelial barrier, the immunological response, and the process of wound healing or intestinal fibrosis. At a later stage of fibrosis during IBD, excessive formation and deposition of the matrix is observed. To assess changes in the extracellular matrix, quantitative measurement of the concentration in the blood of markers dependent on the activity of proteases, involved in the breakdown of extracellular matrix proteins as well as markers indicating the formation of a new ECM, has recently been proposed. This paper describes attempts to use the quantification of ECM components as markers to predict intestinal fibrosis and evaluate the healing process of the gut. The markers which reflect increased ECM degradation, together with the ones which show the process of creating a new matrix during IBD, allow the attainment of important information regarding the changes in the intestinal tissue, epithelial integrity and extracellular matrix remodeling. This paper contains evidence confirming that ECM remodeling is an integral part of directional cell signaling in the progression of IBD, and not only a basis for the ongoing processes.
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Affiliation(s)
- Alicja Derkacz
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.D.); (K.O.)
| | - Paweł Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland;
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.D.); (K.O.)
| | - Katarzyna Komosinska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.D.); (K.O.)
- Correspondence: ; Tel.: +48-32364-1150
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Early Electroacupuncture Extends the rtPA Time Window to 6 h in a Male Rat Model of Embolic Stroke via the ERK1/2-MMP9 Pathway. Neural Plast 2020. [DOI: 10.1155/2020/8851089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background. Recombinant tissue plasminogen activator (rtPA) is the only recommended pharmacological treatment for acute ischemic stroke, but it has a restricted therapeutic time window. When administered at time points greater than 4.5 h after stroke onset, rtPA disrupts the blood-brain barrier (BBB), which leads to serious brain edema and hemorrhagic transformation. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; however, researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. Objective. The present study was conducted to test the hypothesis that EA extends the therapeutic time window of rtPA for ischemic stroke in a male rat model of embolic stroke. Methods. SD rats were randomly divided into the sham operation group, model group, rtPA group, EA+rtPA group, and rtPA+MEK1/2 inhibitor group. An injection of rtPA was administered 6 h after ischemia. Rats were treated with EA at the Shuigou (GV26) and Neiguan (PC6) acupoints at 2 h after ischemia. Neurological function, infarct volume, BBB permeability, brain edema, and hemorrhagic transformation were assessed at 24 h after ischemia. Western blotting and immunofluorescence staining were performed to detect the levels of proteins involved in the ERK1/2 signaling pathway (MEK1/2 and ERK1/2), tight junction proteins (Claudin5 and ZO-1), and MMP9 in the ischemic penumbra at 24 h after stroke. Results. Delayed rtPA treatment aggravated hemorrhagic transformation and brain edema. However, treatment with EA plus rtPA significantly improved neurological function and reduced the infarct volume, hemorrhagic transformation, brain edema, and EB leakage in rats compared with rtPA alone. EA increased the levels of tight junction proteins, inhibited the activation of the ERK1/2 signaling pathway, and reduced MMP9 overexpression induced by delayed rtPA thrombolysis. Conclusions. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB.
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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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Lin WW, Lu YC, Chuang CH, Cheng TL. Ab locks for improving the selectivity and safety of antibody drugs. J Biomed Sci 2020; 27:76. [PMID: 32586313 PMCID: PMC7318374 DOI: 10.1186/s12929-020-00652-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023] Open
Abstract
Monoclonal antibodies (mAbs) are a major targeted therapy for malignancies, infectious diseases, autoimmune diseases, transplant rejection and chronic inflammatory diseases due to their antigen specificity and longer half-life than conventional drugs. However, long-term systemic antigen neutralization by mAbs may cause severe adverse events. Improving the selectivity of mAbs to distinguish target antigens at the disease site from normal healthy tissue and reducing severe adverse events caused by the mechanisms-of-action of mAbs is still a pressing need. Development of pro-antibodies (pro-Abs) by installing a protease-cleavable Ab lock is a novel and advanced recombinant Ab-based strategy that efficiently masks the antigen binding ability of mAbs in the normal state and selectively "turns on" the mAb activity when the pro-Ab reaches the proteolytic protease-overexpressed diseased tissue. In this review, we discuss the design and advantages/disadvantages of different Ab lock strategies, focusing particularly on spatial-hindrance-based and affinity peptide-based approaches. We expect that the development of different masking strategies for mAbs will benefit the local reactivity of mAbs at the disease site, increase the therapeutic efficacy and safety of long-term treatment with mAbs in chronic diseases and even permit scientists to develop Ab drugs for formerly undruggable targets and satisfy the unmet medical needs of mAb therapy.
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Affiliation(s)
- Wen-Wei Lin
- Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yun-Chi Lu
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan
| | - Chih-Hung Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tian-Lu Cheng
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, 80708, Taiwan.
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He JS, Tan JY, Li XZ, Feng R, Xiong SS, Lin SN, Qiu Y, Mao R. Serum biomarkers of fibrostenotic Crohn's disease: Where are we now? J Dig Dis 2020; 21:336-341. [PMID: 32496631 DOI: 10.1111/1751-2980.12913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/01/2020] [Accepted: 06/02/2020] [Indexed: 12/11/2022]
Abstract
Intestinal fibrosis and subsequent stricture formation are major clinical challenges in inflammatory bowel disease, resulting in an increased rate of operation and poor prognosis compared with those without. With the changing perception that intestinal fibrosis is irreversible to the point of view that it is reversible in recent years, various candidate serum biomarkers have been studied over the past decades, which may stratify patients based on their risks of developing stenosis and enable the detection of early stages of fibrosis. However, reliable and accurate biomarkers are still unavailable due to conflicting results and the lack of high-quality evidence. In this review we summarized the serum biomarkers that have been proposed for intestinal fibrosis in recent years, which includes gene polymorphisms or variants, epigenetic markers, extracellular matrix components, growth factors, and antibodies, aiming to provide clues for future research.
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Affiliation(s)
- Jin Shen He
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jin Yu Tan
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao Zhi Li
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Rui Feng
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shan Shan Xiong
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Si Nan Lin
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yun Qiu
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Ren Mao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
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Chen P, Zhou G, Lin J, Li L, Zeng Z, Chen M, Zhang S. Serum Biomarkers for Inflammatory Bowel Disease. Front Med (Lausanne) 2020; 7:123. [PMID: 32391365 PMCID: PMC7188783 DOI: 10.3389/fmed.2020.00123] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic, inflammatory disorder of the gastrointestinal tract. As the novel therapeutic goal and biologicals are widely recognized, accurate assessment of disease and prediction of therapeutic response have become a crucial challenge in clinical practice. Also, because of the continuously rising incidence, convenient and economical methods of diagnosis and clinical assessment are urgently needed. Recently, serum biomarkers have made a great progress and become a focus in IBD study because they are non-invasive, convenient, and relatively inexpensive than are markers in biopsy tissue, stool, breath, and other body fluids. Aims: To review the available data on serological biomarkers for IBD. Methods: We searched PubMed using predefined key words on relevant literatures of serum biomarkers regarding diagnosis, evaluation of therapeutic efficacy, surveillance of disease activity, and assessment of prognosis for IBD. Results: We reviewed serological biomarkers that are well-established and widely used (e.g., C-reactive protein), newly discovered biomarkers (e.g., cytokines, antibodies, and non-coding RNAs), and also recently advancements in serological biomarkers (e.g., metabolomics and proteomics) that are used in different aspects of IBD management. Conclusions: With such a wealth of researches, to date, there are still no ideal serum biomarkers for IBD. Serum profiling and non-coding RNAs are just starting to blossom but reveal great promise for future clinical practice. Combining different biomarkers can be valuable in improving performance of disease evaluation.
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Affiliation(s)
- Peng Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jingxia Lin
- Division of Blood Transfusion, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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21
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Lucafò M, Pugnetti L, Bramuzzo M, Curci D, Di Silvestre A, Marcuzzi A, Bergamo A, Martelossi S, Villanacci V, Bozzola A, Cadei M, De Iudicibus S, Decorti G, Stocco G. Long Non-Coding RNA GAS5 and Intestinal MMP2 and MMP9 Expression: A Translational Study in Pediatric Patients with IBD. Int J Mol Sci 2019; 20:5280. [PMID: 31652976 PMCID: PMC6862115 DOI: 10.3390/ijms20215280] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/16/2019] [Accepted: 10/21/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. METHODS In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. RESULTS Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. CONCLUSION These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.
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Affiliation(s)
- Marianna Lucafò
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Letizia Pugnetti
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Debora Curci
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Alessia Di Silvestre
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Annalisa Marcuzzi
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | | | | | | | - Anna Bozzola
- Pathology Section, Spedali Civili, 25123 Brescia, Italy.
| | - Moris Cadei
- Pathology Section, Spedali Civili, 25123 Brescia, Italy.
| | - Sara De Iudicibus
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Giuliana Decorti
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
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22
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Kourkoulis P, Kapizioni C, Michalopoulos G, Andreou NP, Papaconstantinou I, Karamanolis G, Gazouli M. Novel potential biomarkers for the diagnosis and monitoring of patients with ulcerative colitis. Eur J Gastroenterol Hepatol 2019; 31:1173-1183. [PMID: 31498278 DOI: 10.1097/meg.0000000000001490] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Unambiguously, great progress has been achieved in the unraveling of more pathological pathways implicated in the development and progression of ulcerative colitis during the last decades. Novel effective drugs that have augmented the management armamentarium have been developed alongside this growing comprehension of the disease, rendering mucosal healing not only a feasible but the optimal goal of every therapy. Clinical evaluation, colonoscopy and biomarkers are the tools used by practitioners for the diagnosis and assessment of the status of the disease in order to achieve clinical remission and mucosal healing for their patients. Among these tools, colonoscopy is the gold method for the cause but is still an invasive, high-cost procedure with possible adverse events such as perforation. While clinical evaluation entails much subjectivity, biomarkers are objective, easily reproducible, non-invasive, cheap and potent surrogate tools of mucosal inflammation. Unfortunately, the well-established, currently in use serum biomarkers, such as C-reactive protein, erythrocyte sedimentation rate and others, do not display sufficiently acceptable sensitivity and specificity rates for the diagnosis of ulcerative colitis and, most importantly, do not represent precisely the mucosal inflammation status of the disease. Therefore, the discovery of new serum biomarkers has been the cause of several studies attempting to discover an "optimal" serum biomarker during the recent years. After thorough research, collection and examination of current data, this review focuses on and selectively presents promising, potential, novel serum biomarkers of ulcerative colitis as they are indicated by studies on the patient over the last years.
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Affiliation(s)
- P Kourkoulis
- Gastroenterology Department, Tzaneion General Hospital of Piraeus, Piraeus
| | - C Kapizioni
- Gastroenterology Department, Tzaneion General Hospital of Piraeus, Piraeus
| | - G Michalopoulos
- Gastroenterology Department, Tzaneion General Hospital of Piraeus, Piraeus
| | - N P Andreou
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens
| | - I Papaconstantinou
- 2nd Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - G Karamanolis
- 2nd Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - M Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens
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23
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Ostrowski J, Dabrowska M, Lazowska I, Paziewska A, Balabas A, Kluska A, Kulecka M, Karczmarski J, Ambrozkiewicz F, Piatkowska M, Goryca K, Zeber-Lubecka N, Kierkus J, Socha P, Lodyga M, Klopocka M, Iwanczak B, Bak-Drabik K, Walkowiak J, Radwan P, Grzybowska-Chlebowczyk U, Korczowski B, Starzynska T, Mikula M. Redefining the Practical Utility of Blood Transcriptome Biomarkers in Inflammatory Bowel Diseases. J Crohns Colitis 2019; 13:626-633. [PMID: 30541017 PMCID: PMC6486489 DOI: 10.1093/ecco-jcc/jjy205] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The study investigates the practical utility of whole-blood gene expression profiling to diagnose inflammatory bowel diseases [IBDs]. METHODS The discovery cohorts included 102 and 51 paediatric IBD patients and controls, and 95 and 46 adult IBD patients and controls, respectively. The replication cohorts included 447 and 76 paediatric IBD patients and controls, and 271 and 108 adult IBD patients and controls, respectively. In the discovery phase, RNA samples extracted from whole peripheral blood were analysed using RNA-Seq, and the predictive values of selected biomarkers were validated using quantitative polymerase chain reaction [qPCR]. RESULTS In all, 15 differentially expressed transcripts [adjusted p ≤0.05] were selected from the discovery sequencing datasets. The receiver operating characteristic curves and area under the curve [ROC-AUC] in replication analyses showed high discriminative power [AUC range, 0.91-0.98] for 11 mRNAs in paediatric patients with active IBD. By contrast, the AUC-ROC values ranged from 0.63 to 0.75 in comparison among inactive paediatric IBDs and active/inactive adult IBDs, indicating a lack of discriminative power. The best multi-mRNA diagnostic classifier showed moderate discriminative power [AUC = 0.81] for paediatric inactive IBD, but was not able to discriminate active or inactive adult IBD patients from controls. The AUC-ROC values did not confirm an ability of the mRNAs abundances to discriminate between active ulcerative colitis and active Crohn's disease in paediatric or adult populations. CONCLUSIONS This study identifies and validates blood transcriptional biomarkers that could be used in clinical settings as diagnostic predictors of IBD clinical activity in paediatric, but not adult, IBD patients.
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Affiliation(s)
- Jerzy Ostrowski
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland,Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland,Corresponding author: Jerzy Ostrowski, MD, PhD; Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland. Tel.: +48 225462575; e-mail:
| | - Michalina Dabrowska
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Izabella Lazowska
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Paziewska
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland
| | - Aneta Balabas
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Anna Kluska
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Maria Kulecka
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland
| | - Jakub Karczmarski
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Filip Ambrozkiewicz
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Magdalena Piatkowska
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Krzysztof Goryca
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Natalia Zeber-Lubecka
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland
| | - Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute, Warsaw, Poland
| | - Piotr Socha
- Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute, Warsaw, Poland
| | - Michal Lodyga
- Department of Internal Medicine and Gastroenterology with IBD Subdivision, Central Clinical Hospital of the Ministry of the Interior, Warsaw, Poland
| | - Maria Klopocka
- Vascular Diseases and Internal Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum, Bydgoszcz, Poland
| | - Barbara Iwanczak
- Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
| | - Katarzyna Bak-Drabik
- Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Jaroslaw Walkowiak
- Department of Pediatric Gastroenterology & Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Radwan
- Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
| | | | | | - Teresa Starzynska
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
| | - Michal Mikula
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
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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: 21] [Impact Index Per Article: 3.0] [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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25
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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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Lin X, Li J, Zhao Q, Feng JR, Gao Q, Nie JY. WGCNA Reveals Key Roles of IL8 and MMP-9 in Progression of Involvement Area in Colon of Patients with Ulcerative Colitis. Curr Med Sci 2018; 38:252-258. [PMID: 30074183 DOI: 10.1007/s11596-018-1873-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 01/15/2018] [Indexed: 12/21/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease and its involvement area in colon is influenced by a complex network of gene interactions. We analyzed the weighted gene co-expression networks in microarray dataset from colonic mucosa of patients with UC and identified one gene co-expression module that was highly associated with the progression of involved area in UC colon (Pearson coefficient=0.81, P<0.0001). In total, 523 hub genes in this module were found to be involved in immune system process after enrichment analysis in Gene Ontology. By the STRING and Cytoscape analysis, we observed that interleukin-8 (IL-8) and matrix metalloproteinase-9 (MMP-9) were centered in the network of hub genes. We then detected the expression of IL-8 and MMP-9 in mucosa from left-sided colon of patients using quantitative PCR and immunofluorescence assay respectively. Both quantitative PCR and immunofluorescence assay revealed the expression levels of IL-8 and MMP-9 were significantly different among the healthy controls, left-sided colitis group and pancolitis group (P<0.05). IL-8 and MMP-9 were detected with an enhanced expression in pancolitis as compared with leftsided colitis and healthy controls, respectively (P<0.05). This study demonstrates that immune system process is indispensable in the progression of disease in colon, and identifies that IL-8 and MMP-9 play potential critical roles for the progression.
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Affiliation(s)
- Xue Lin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jin Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jue-Rong Feng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Qian Gao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China
| | - Jia-Yan Nie
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan, 430071, China.
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Srivastava A, Gupta J, Kumar S, Kumar A. Gut biofilm forming bacteria in inflammatory bowel disease. Microb Pathog 2017; 112:5-14. [PMID: 28942174 DOI: 10.1016/j.micpath.2017.09.041] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/15/2017] [Accepted: 09/18/2017] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease (IBD) symbolizes a group of intestinal disorders in which prolonged inflammation occur in the digestive tract (esophagus, large intestine, small intestine mouth, stomach). Both genetic and environmental factors (infections, stress, diet) are involved in the development of IBD. As we know that bacteria are found in the intestinal mucosa of human and clinical observations revealed bacterial biofilms associated with patients of IBD. Various factors and microbes are found to play an essential role in biofilm formation and mucosal colonization during IBD. Biofilm formation in the digestive tract is dependent on an extracellular matrix synthesized by the bacteria and it has an adverse effect on the immune response of the host. There is no satisfactory and safe treatment option for IBD. Therefore, the current research aims to disrupt biofilm in IBD and concentrates predominantly on improving the drug. Here, we review the literature on bacterial biofilm and IBD to gather new knowledge on the current understanding of biofilm formation in IBD, host immune deregulation and dysbiosis in IBD, molecular mechanism, bacteria involved in biofilm formation, current and future regimen. It is urgently required to plan new ways to control and eradicate bacteria in biofilms that will open up novel diagnostic and therapeutic avenues for IBD. This article includes the mechanism of signaling molecules with respect to the biofilm-related genes as well as the diagnostic methods and new technologies involved in the treatment of IBD.
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Affiliation(s)
- Ankita Srivastava
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Lucknow-Deva Road, Vill: Hadauri, Post: Tindola, Dist: Barabanki 225003, Uttar Pradesh, India
| | - Jaya Gupta
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Lucknow-Deva Road, Vill: Hadauri, Post: Tindola, Dist: Barabanki 225003, Uttar Pradesh, India
| | - Sunil Kumar
- Faculty of Biotechnology, Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Lucknow-Deva Road, Vill: Hadauri, Post: Tindola, Dist: Barabanki 225003, Uttar Pradesh, India.
| | - Awanish Kumar
- Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India.
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de Sousa Moraes LF, Sun X, Peluzio MDCG, Zhu MJ. Anthocyanins/anthocyanidins and colorectal cancer: What is behind the scenes? Crit Rev Food Sci Nutr 2017; 59:59-71. [PMID: 28799785 DOI: 10.1080/10408398.2017.1357533] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cause of cancer death. Phytochemicals, especially anthocyanins/anthocyanidins (A/A), have gathered attention of the scientific community owing to their anti-inflammatory, antioxidant, and cancer-inhibitory properties. In this review, we discussed the possible mechanisms whereby A/A exhibit intestinal anticarcinogenic characteristics. Anthocyanins/anthocyanidins inhibit the pro-inflammatory NF-κB pathway, attenuate Wnt signaling and suppress abnormal epithelial cell proliferation. In addition, A/A induce mitochondrial-mediated apoptosis and downregulate Akt/mTOR (mammalian target of rapamycin) pathway. Furthermore, activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) also contributes to the anti-carcinogenic effects of A/A. Finally, downregulation of metalloproteinases (MMPs) by A/A inhibits tumor invasion and metastasis. In conclusion, A/A exert their anti-tumor effects against colorectal carcinogenesis via multiple mechanisms, providing insights into the use of A/A as a natural chemopreventive intervention on major colorectal carcinogenesis.
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Affiliation(s)
- Luís Fernando de Sousa Moraes
- a School of Food Science , Washington State University , Pullman , WA , USA.,b Department of Nutrition and Health , Universidade Federal de Viçosa , Viçosa - Minas Gerais , Brazil
| | - Xiaofei Sun
- a School of Food Science , Washington State University , Pullman , WA , USA
| | | | - Mei-Jun Zhu
- a School of Food Science , Washington State University , Pullman , WA , USA
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Gawrońska B, Matowicka-Karna J, Kralisz M, Kemona H. Markers of inflammation and influence of nitric oxide on platelet activation in the course of ulcerative colitis. Oncotarget 2017; 8:68108-68114. [PMID: 28978100 PMCID: PMC5620240 DOI: 10.18632/oncotarget.19202] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 06/19/2017] [Indexed: 12/15/2022] Open
Abstract
Ulcerative colitis is a non-specific inflammatory bowel disease of unknown etiology. We investigated whether severe form of ulcerative colitis may lead to increased number of platelets, changes in platelet parameters and their activation. To address our objectives, we measured concentrations of nitric oxide and markers of inflammation. We found increased number of low-volume platelets in a group of affected patients. However, their activity was not as high as expected. In addition to that we observed eight times higher concentration of nitric oxide in patients suffering from ulcerative colitis than in healthy individuals. Besides, severe form of the disease manifested itself with increased concentrations of interleukine 6, matrix metalloproteinase-9 and neopterin. Based on the results we propose that high amounts of nitric oxide inhibit platelet activation in severe form of ulcerative colitis. Moreover, our observations regarding interleukine 6, matrix metalloproteinase-9 and neopterin suggest that they may become useful markers of active form of ulcerative colitis.
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Affiliation(s)
- Beata Gawrońska
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland
| | - Joanna Matowicka-Karna
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland
| | - Maciej Kralisz
- Department of Internal Diseases and Gastroenterology, The Sniadecki Regional Hospital in Bialystok, Białystok, Poland
| | - Halina Kemona
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Białystok, Poland
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Serum Cyclophilin A Correlates with Increased Tissue MMP-9 in Patients with Ulcerative Colitis, but Not with Crohn's Disease. Dig Dis Sci 2017; 62:1511-1517. [PMID: 28391416 DOI: 10.1007/s10620-017-4568-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 04/01/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND Cyclophilin A (CyPA) is an immunomodulatory protein, high expression of which correlates with poor outcome of patients with inflammatory diseases. However, its role in inflammatory bowel disease (IBD) has not been studied. AIM This study analyzes the correlation between cyclophilin A, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP (TIMP)/MMP-9 complexes in the inflamed and non-inflamed colon mucosa of UC and CD patients. METHODS Serum and biopsy specimens from inflamed and non-inflamed colonic mucosa of 38 patients with IBD (19 with UC and 19 with CD) and 16 controls were included in our study. We measured serum and tissue level of CyPA, and tissue level of TNF-α, MMP-9, TIMP-1/MMP-9, and TIMP-2/MMP-9 using ELISA method. RESULTS Our results indicated that serum, but not tissue CyPA is increased in UC, rather than in CD patients, compared to the control. The increase correlated with higher tissue concentration of MMP-9 and TNF-α, especially in the UC group. Moreover, we observed significantly higher level of TIMP-1/MMP-9 in UC and CD group, which overlapped with the change in MMP-9. There was no change in TIMP-2/MMP-9 in the analyzed groups. CONCLUSION The current study suggests that serum CyPA may be an independent additional marker of IBD, especially of UC. Higher CyPA level may be followed by increased MMP-9 in those patients. However, further studies are necessary to verify the role of CyPA in IBD development.
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Abstract
Various therapeutic advances have led to a paradigm shift in the clinical management of patients with IBD. The introduction of immunosuppressive (such as azathioprine) and biologic agents (such as TNF blockers) has markedly reduced the need to use corticosteroids for therapy. Furthermore, the α4β7 integrin blocker vedolizumab has been introduced for clinical IBD therapy. Moreover, various new inhibitors of cytokines (for example, IL-6-IL-6R and IL-12-IL-23 blockers or apremilast), modulators of cytokine signalling events (for example, JAK inhibitors or SMAD7 blocker), inhibitors of transcription factors (for example, GATA3 or RORγt) and new anti-adhesion and anti-T-cell-activation and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors and MAdCAM1 inhibitors, regulatory T-cell therapy and stem cells) are currently being evaluated in controlled clinical trials. This Review aims to provide a comprehensive overview about current and future therapeutic approaches for IBD therapy. Furthermore, potential mechanisms of action of these therapeutic approaches and their implications for clinical therapy in IBD are discussed.
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Affiliation(s)
- Markus F Neurath
- Department of Medicine 1, Kussmaul Campus for Medical Research, Ludwig Demling Endoscopy Center of Excellence, Ulmenweg 18, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
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Wu MY, Wu Y, Zhang Y, Liu CY, Deng CY, Peng L, Zhou L. Associations between matrix metalloproteinase gene polymorphisms and glaucoma susceptibility: a meta-analysis. BMC Ophthalmol 2017; 17:48. [PMID: 28431514 PMCID: PMC5401566 DOI: 10.1186/s12886-017-0442-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 04/14/2017] [Indexed: 11/10/2022] Open
Abstract
Background Matrix metalloproteinases (MMPs) polymorphisms have been implicated in the pathogenesis of glaucoma risk. However, the results were controversial. We performed a meta-analysis to evaluate the precise associations between MMPs polymorphisms and glaucoma risk. Methods Related studies were reviewed by searching electronic databases within four databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between the most common polymorphisms of MMPs and glaucoma risk. Heterogeneity, publication bias and sensitivity analysis were conducted to guarantee the statistical power. Results Overall, 11 selected articles involving 2,388 cases and 2,319 controls were included in this meta-analysis. Significant associations were only found between MMP-9 rs17576 G > A polymorphism (GA vs. GG: OR = 0.80, 95%CI = 0.67-0.97, P = 0.02, I2 = 0%), MMP-9 rs3918249 C > T polymorphism (TT vs. CC + CT: OR = 0.71, 95%CI = 0.51-0.98, P = 0.04, I2 = 0%) and glaucoma risk in the general population. Subgroup analysis also suggested that MMP-9 rs17576 G > A was related to glaucoma in the Caucasian population (GA vs. GG: OR = 0.67, 95%CI = 0.45-1.00, P = 0.05; GA + AA vs. GG: OR = 0.66, 95%CI = 0.45-0.97, P = 0.03, I2 = 0%). Conclusions Our meta-analysis demonstrates that MMP-9 rs17576 G > A polymorphism might be a protective factor against the development of glaucoma in Caucasian population.
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Affiliation(s)
- Ming-Yue Wu
- Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, 230032, China.,Department of Neurology, Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, 442000, China
| | - Yang Wu
- Department of Oral and Maxillofacial Surgery, State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yong Zhang
- Department of Ophthalmology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Cai-Yun Liu
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, 442000, China
| | - Chun-Yan Deng
- Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Le Peng
- Department of Neurology, Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, 442000, China
| | - Lan Zhou
- Department of Neurology, Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, 442000, China.
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Muthas D, Reznichenko A, Balendran CA, Böttcher G, Clausen IG, Kärrman Mårdh C, Ottosson T, Uddin M, MacDonald TT, Danese S, Berner Hansen M. Neutrophils in ulcerative colitis: a review of selected biomarkers and their potential therapeutic implications. Scand J Gastroenterol 2017; 52:125-135. [PMID: 27610713 DOI: 10.1080/00365521.2016.1235224] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. MATERIAL We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. RESULTS Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. CONCLUSION We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.
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Affiliation(s)
- Daniel Muthas
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Anna Reznichenko
- b Department of Cardiovascular and Metabolic Diseases , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Clare A Balendran
- c Department of Personalised HealthCare & Biomarkers , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Gerhard Böttcher
- d Department of Drug Safety and Metabolism , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Ib Groth Clausen
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Carina Kärrman Mårdh
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Tomas Ottosson
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Mohib Uddin
- c Department of Personalised HealthCare & Biomarkers , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Thomas T MacDonald
- e Blizard Institute, Barts and the London School of Medicine and Dentistry, QMUL , London , UK
| | - Silvio Danese
- f Department of Gastroenterology , IBD Center, Humanitas Research Hospital , Milan , Italy
| | - Mark Berner Hansen
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden.,g Digestive Disease Center K, Bispebjerg Hospital, University of Copenhagen , Copenhagen , Denmark
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Fonseca FLA, da Costa Aguiar Alves B, Azzalis LA, Belardo TMG. Matrix Metalloproteases as Biomarkers of Disease. Methods Mol Biol 2017; 1579:299-311. [PMID: 28299745 DOI: 10.1007/978-1-4939-6863-3_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Matrix metalloprotease play a vital role in many cellular processes. Dysfunction in activity of these enzymes has been implicated in the pathogenesis of a number of diseases. Factors that affect the balanced interaction between MMPs and their inhibitors, such as genetic mutations of extracellular matrix components or dysregulation of MMP expression, can lead to various diseases. Due to their essential role in ECM remodeling, MMPs have become targets of interest as biomarkers for the diagnosis and prognosis of diseases associated with alterations of the ECM.
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Affiliation(s)
- Fernando Luiz Affonso Fonseca
- Departamento de Ciências Biológicas, Instituto de Ciências Químicas, Ambientais e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil. .,Laboratório de Análises Clínicas-Anexo 3, Faculdade de Medicina do ABC, Vila Principe de Gales, n.821, Santo André, SP, 09060-650, Brazil.
| | - Beatriz da Costa Aguiar Alves
- Laboratório de Análises Clínicas-Anexo 3, Faculdade de Medicina do ABC, Vila Principe de Gales, n.821, Santo André, SP, 09060-650, Brazil
| | - Ligia Ajaime Azzalis
- Departamento de Ciências Biológicas, Instituto de Ciências Químicas, Ambientais e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil
| | - Thaís Moura Gáscon Belardo
- Laboratório de Análises Clínicas-Anexo 3, Faculdade de Medicina do ABC, Vila Principe de Gales, n.821, Santo André, SP, 09060-650, Brazil
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Paściak M, Górska S, Jawiarczyk N, Gamian A. Lactobacillus johnsonii glycolipids, their structure and immunoreactivity with sera from inflammatory bowel disease patients. Microb Biotechnol 2016; 10:456-468. [PMID: 27766756 PMCID: PMC5328823 DOI: 10.1111/1751-7915.12424] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 07/19/2016] [Accepted: 08/20/2016] [Indexed: 12/19/2022] Open
Abstract
Structural studies of the major glycolipids produced by two Lactobacillus johnsonii (LJ) strains, LJ 151 isolated from intestinal tract of healthy mice and LJ 142 isolated from mice with experimentally induced inflammatory bowel disease (IBD), were performed. Two major glycolipids, GL1 and GL2, were present in lipid extracts from L. johnsonii 142 and 151 strains. Glycolipid GL1 has been identified as β-D-Glcp-(1→6)-α-D-Galp-(1→2)-α-D-Glcp-diglyceride and GL2 as α-D-Galp-(1→2)-α-D-Glcp-diglyceride. The main fatty acid residues identified by gas-liquid chromatography-mass spectrometry were palmitic, stearic and lactobacillic acids. Besides structural elucidation of the major glycolipids, the aim of this study was to determine the immunochemical properties of these glycolipids and to compare their immunoreactivity to that of polysaccharides obtained from the same strains. Sera from rabbits immunized with bacterial cells possessed much higher serological reactivity with polysaccharides than with glycolipids. Inversely, reactivity of the glycolipids with human sera from patients with IBD was much higher than that determined for the polysaccharides, while reactivity of glycolipids with human sera from healthy individuals was much lower than one measured for the polysaccharides. Results indicate that glycoconjugates from Lactobacillus cell wall act as antigens and may represent new IBD diagnostic biomarkers.
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Affiliation(s)
- Mariola Paściak
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wrocław, Poland
| | - Sabina Górska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wrocław, Poland
| | - Natalia Jawiarczyk
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wrocław, Poland
| | - Andrzej Gamian
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wrocław, Poland
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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: 63] [Impact Index Per Article: 7.0] [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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Sandborn WJ, Bhandari BR, Fogel R, Onken J, Yen E, Zhao X, Jiang Z, Ge D, Xin Y, Ye Z, French D, Silverman JA, Kanwar B, Subramanian GM, McHutchison JG, Lee SD, Shackelton LM, Pai RK, Levesque BG, Feagan BG. Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis. Aliment Pharmacol Ther 2016; 44:157-69. [PMID: 27218676 PMCID: PMC5089609 DOI: 10.1111/apt.13653] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 03/26/2016] [Accepted: 04/16/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. METHODS We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. RESULTS Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.
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Affiliation(s)
- W. J. Sandborn
- Robarts Clinical TrialsUniversity of Western OntarioLondonONCanada,University of CaliforniaSan DiegoCAUSA
| | | | - R. Fogel
- Clinical Research Institute of MichiganLLCChesterfieldMIUSA
| | - J. Onken
- Duke University Medical CenterDurhamNCUSA
| | - E. Yen
- Gilead Sciences, Inc.Foster CityCAUSA
| | - X. Zhao
- Gilead Sciences, Inc.Foster CityCAUSA
| | - Z. Jiang
- Gilead Sciences, Inc.Foster CityCAUSA
| | - D. Ge
- Gilead Sciences, Inc.Foster CityCAUSA
| | - Y. Xin
- Gilead Sciences, Inc.Foster CityCAUSA
| | - Z. Ye
- Gilead Sciences, Inc.Foster CityCAUSA
| | - D. French
- Gilead Sciences, Inc.Foster CityCAUSA
| | | | - B. Kanwar
- Gilead Sciences, Inc.Foster CityCAUSA
| | | | | | - S. D. Lee
- University of WashingtonSeattleWAUSA
| | - L. M. Shackelton
- Robarts Clinical TrialsUniversity of Western OntarioLondonONCanada
| | | | - B. G. Levesque
- Robarts Clinical TrialsUniversity of Western OntarioLondonONCanada
| | - B. G. Feagan
- Robarts Clinical TrialsUniversity of Western OntarioLondonONCanada,Department of MedicineUniversity of Western OntarioLondonONCanada,Department of Epidemiology and BiostatisticsUniversity of Western OntarioLondonONCanada
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YOSHIMOTO T, NIIMI K, TAKAHASHI E. Serum matrix metalloproteinase 9 (MMP9) as a biochemical marker for wasting marmoset syndrome. J Vet Med Sci 2016; 78:837-43. [PMID: 26876041 PMCID: PMC4905840 DOI: 10.1292/jvms.15-0675] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 01/27/2016] [Indexed: 01/11/2023] Open
Abstract
Use of the common marmoset (Callithrix jacchus) as a non-human primate experimental animal has increased in recent years. Although wasting marmoset syndrome (WMS) is one of the biggest problems in captive marmoset colonies, the molecular mechanisms, biochemical markers for accurate diagnosis and a reliable treatment remain unknown. In this study, as a first step to finding biochemical marker(s) for the accurate diagnosis of WMS, we conducted blood cell counts, including hematocrit, hemoglobin and platelets, and examined serum chemistry values, including albumin, calcium and levels of serum matrix metalloproteinase 9 (MMP9), using a colony of marmosets with and without weight loss. MMP9 is thought to be an enzyme responsible for the degradation of extracellular matrix components and participates in the pathogenesis of inflammatory conditions, such as human and murine inflammatory bowel disease, which, like WMS, are characterized histologically by inflammatory cell infiltrations in the intestines. The values of hematocrit and hemoglobin and levels of serum albumin and calcium in the WMS group were significantly decreased versus the control group. The platelet values and serum MMP9 concentrations were increased significantly in the WMS group compared with the control group. MMP9 could be a new and useful marker for the diagnosis of WMS in addition to hematocrit, hemoglobin, serum albumin and calcium. Our results also indicate that MMP9 could be a useful molecular candidate for treatment.
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Affiliation(s)
- Takuro YOSHIMOTO
- Research Resources Center, RIKEN Brain Science Institute,
2–1 Hirosawa, Wako, Saitama 351–0198, Japan
| | - Kimie NIIMI
- Research Resources Center, RIKEN Brain Science Institute,
2–1 Hirosawa, Wako, Saitama 351–0198, Japan
| | - Eiki TAKAHASHI
- Research Resources Center, RIKEN Brain Science Institute,
2–1 Hirosawa, Wako, Saitama 351–0198, Japan
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Giuffrida P, Pinzani M, Corazza GR, Di Sabatino A. Biomarkers of intestinal fibrosis - one step towards clinical trials for stricturing inflammatory bowel disease. United European Gastroenterol J 2016; 4:523-30. [PMID: 27536362 DOI: 10.1177/2050640616640160] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 02/20/2016] [Indexed: 01/14/2023] Open
Abstract
Intestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-19, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors (i.e. basic fibroblast growth factor, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease.
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Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Massimo Pinzani
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Gino R Corazza
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy; Institute for Liver and Digestive Health, University College London, London, UK
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Matrix metalloproteinases in inflammatory bowel disease: an update. Mediators Inflamm 2015; 2015:964131. [PMID: 25948887 PMCID: PMC4408746 DOI: 10.1155/2015/964131] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 09/07/2014] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are known to be upregulated in inflammatory bowel disease (IBD) and other inflammatory conditions, but while their involvement is clear, their role in many settings has yet to be determined. Studies of the involvement of MMPs in IBD since 2006 have revealed an array of immune and stromal cells which release the proteases in response to inflammatory cytokines and growth factors. Through digestion of the extracellular matrix and cleavage of bioactive proteins, a huge diversity of roles have been revealed for the MMPs in IBD, where they have been shown to regulate epithelial barrier function, immune response, angiogenesis, fibrosis, and wound healing. For this reason, MMPs have been recognised as potential biomarkers for disease activity in IBD and inhibition remains a huge area of interest. This review describes new roles of MMPs in the pathophysiology of IBD and suggests future directions for the development of treatment strategies in this condition.
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Papanikolaou I, Kagouridis K, Papiris SA. Patterns of airway involvement in inflammatory bowel diseases. World J Gastrointest Pathophysiol 2014; 5:560-569. [PMID: 25400999 PMCID: PMC4231520 DOI: 10.4291/wjgp.v5.i4.560] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Revised: 08/03/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Extraintestinal manifestations occur commonly in inflammatory bowel diseases (IBD). Pulmonary manifestations (PM) of IBD may be divided in airway disorders, interstitial lung disorders, serositis, pulmonary vasculitis, necrobiotic nodules, drug-induced lung disease, thromboembolic lung disease and enteropulmonary fistulas. Pulmonary involvement may often be asymptomatic and detected solely on the basis of abnormal screening tests. The common embryonic origin of the intestine and the lungs from the primitive foregut, the co-existence of mucosa associated lymphoid tissue in both organs, autoimmunity, smoking and bacterial translocation from the colon to the lungs may all be involved in the pathogenesis of PM in IBD. PM are mainly detected by pulmonary function tests and high-resolution computed tomography. This review will focus on the involvement of the airways in the context of IBD, especially stenoses of the large airways, tracheobronchitis, bronchiectasis, bronchitis, mucoid impaction, bronchial granulomas, bronchiolitis, bronchiolitis obliterans syndrome and the co-existence of IBD with asthma, chronic obstructive pulmonary disease, sarcoidosis and a1-antitrypsin deficiency.
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