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Warrick KA, Vallez CN, Meibers HE, Pasare C. Bidirectional Communication Between the Innate and Adaptive Immune Systems. Annu Rev Immunol 2025; 43:489-514. [PMID: 40279312 DOI: 10.1146/annurev-immunol-083122-040624] [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] [Indexed: 04/27/2025]
Abstract
Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.
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Affiliation(s)
- Kathrynne A Warrick
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA ;
| | - Charles N Vallez
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA ;
| | - Hannah E Meibers
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA ;
| | - Chandrashekhar Pasare
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA ;
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Lee HH, Solitano V, Singh S, Ananthakrishnan AN, Jairath V, Syal G, Boland BS, Ghosh P, Chang JT, Singh S. Differential Efficacy of Advanced Therapies in Inducing Remission in Ulcerative Colitis Based on Prior Exposure to TNF Antagonists. Clin Gastroenterol Hepatol 2024:S1542-3565(24)01132-7. [PMID: 39732355 DOI: 10.1016/j.cgh.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/15/2024] [Accepted: 12/10/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND AND AIMS We sought to ascertain how prior exposure to tumor necrosis factor (TNF) antagonists impacts treatment response with various classes of advanced therapies in patients with ulcerative colitis (UC), through a systematic review and meta-analysis. METHODS Through a systematic review of multiple databases through June 30, 2024, we identified 17 randomized controlled trials in 8871 adults with moderate-severe UC who were treated with different advanced therapies vs placebo, and reported efficacy in induction of clinical remission, stratified by prior exposure to TNF antagonists. We calculated the ratio of odds ratio of achieving remission with active drug vs placebo, in TNF antagonist-naïve vs TNF antagonist-exposed patients. We grouped advanced therapies based on primary mechanism of action: lymphocyte trafficking inhibitors (anti-integrins and sphingosine-1 phosphate [S1P] receptor modulators), anti-interleukins (interleukin-12/23 antagonist and selective interleukin-23 antagonists) and Janus kinase inhibitors. RESULTS Lymphocyte trafficking inhibitors were more efficacious in TNF antagonist-naïve vs exposed patients (5 trials; odds ratio [OR], 1.88; 95% confidence interval [CI], 1.02-3.49), whereas JAK inhibitors were less efficacious in TNF antagonist-naïve vs exposed patients (6 trials; ratio of OR, 0.47; 95% CI, 0.22-1.01). No significant difference was observed in efficacy of selective interleukin-23 antagonists vs placebo in TNF antagonist-naïve vs exposed patients (6 trials; ratio of OR, 1.07; 95% CI, 0.64-1.80). There was minimal heterogeneity across analyses. CONCLUSION There is significant heterogeneity of treatment efficacy with different advanced therapies in inducing remission in patients with UC based on prior exposure to TNF antagonists, with plausible potentiation of JAK inhibitors and attenuation of lymphocyte trafficking inhibitors. Future studies on the mechanistic basis for these observations are warranted.
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Affiliation(s)
- Han Hee Lee
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Division of Gastroenterology, Department of Internal Medicine, Yeouido St. Mary's Hospital College of Medicine, Catholic University of Korea, Seoul, South Korea
| | - Virginia Solitano
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Division of Gastroenterology and Gastrointestinal Endoscopy, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy
| | - Sujay Singh
- College of Human Medicine, Michigan State University, East Lansing, Michigan
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Gaurav Syal
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California
| | - Brigid S Boland
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California
| | - Pradipta Ghosh
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California
| | - John T Chang
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Siddharth Singh
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, California.
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Jeong YJ, Lee HR, Park SA, Lee JW, Kim LK, Kim HJ, Seo JH, Heo TH. A derivative of 3-(1,3-diarylallylidene)oxindoles inhibits dextran sulfate sodium-induced colitis in mice. Pharmacol Rep 2024; 76:851-862. [PMID: 38916850 PMCID: PMC11294400 DOI: 10.1007/s43440-024-00616-2] [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: 02/12/2024] [Revised: 06/15/2024] [Accepted: 06/17/2024] [Indexed: 06/26/2024]
Abstract
BACKGROUND IA-0130 is a derivative of 3-(1,3-diarylallylidene)oxindoles, which is a selective estrogen receptor modulator (SERM). A previous study demonstrated that SERM exhibits anti-inflammatory effects on colitis by promoting the anti-inflammatory phenotype of monocytes in murine colitis. However, the therapeutic effects of oxindole on colitis remain unknown. Therefore, we evaluated the efficacy of IA-0130 on dextran sulfate sodium (DSS)-induced mouse colitis. METHODS The DSS-induced colitis mouse model was established by administration of 2.5% DSS for 5 days. Mice were orally administered with IA-0130 (0.01 mg/kg or 0.1 mg/kg) or cyclosporin A (CsA; 30 mg/kg). Body weight, disease activity index score and colon length of mice were calculated and histological features of mouse colonic tissues were analyzed using hematoxylin and eosin staining. The expression of inflammatory cytokines and tight junction (TJ) proteins were analyzed using quantitative real-time PCR and enzyme-linked immunosorbent assay. The expression of interleukin-6 (IL-6) signaling molecules in colonic tissues were investigated using Western blotting and immunohistochemistry (IHC). RESULTS IA-0130 (0.1 mg/kg) and CsA (30 mg/kg) prevented colitis symptom, including weight loss, bleeding, colon shortening, and expression of pro-inflammatory cytokines in colon tissues. IA-0130 treatment regulated the mouse intestinal barrier permeability and inhibited abnormal TJ protein expression. IA-0130 down-regulated IL-6 expression and prevented the phosphorylation of signaling molecules in colonic tissues. CONCLUSIONS This study demonstrated that IA-0130 suppressed colitis progression by inhibiting the gp130 signaling pathway and expression of pro-inflammatory cytokines, and maintaining TJ integrity.
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Affiliation(s)
- Young-Jin Jeong
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea
| | - Hae-Ri Lee
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea
| | - Sun-Ae Park
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea
| | - Joong-Woon Lee
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea
| | - Lee Kyung Kim
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea
| | - Hee Jung Kim
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea
| | - Jae Hong Seo
- Laboratory of Pharmaceutical Manufacturing Chemistry, Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-Ro, Bucheon‑si, Gyeonggi‑do, 14662, Republic of Korea
| | - Tae-Hwe Heo
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences, BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, NP512, Hall of Cardinal Jin-Suk Cheong, 43 Jibong-Ro, Bucheon-Si, Gyeonggi‑do, 14662, Republic of Korea.
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Jing R, Zhang L, Li R, Yang Z, Song J, Wang Q, Cao N, Han G, Yin H. Milk-derived extracellular vesicles functionalized with anti-tumour necrosis factor-α nanobody and anti-microbial peptide alleviate ulcerative colitis in mice. J Extracell Vesicles 2024; 13:e12462. [PMID: 38840457 PMCID: PMC11154809 DOI: 10.1002/jev2.12462] [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: 01/08/2024] [Revised: 04/16/2024] [Accepted: 05/22/2024] [Indexed: 06/07/2024] Open
Abstract
Ulcerative colitis (UC) manifests clinically with chronic intestinal inflammation and microflora dysbiosis. Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk-derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell-penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti-tumour necrosis factor-α (TNF-α) nanobody (VHHm3F) (EVVHH) via TAT significantly reduced tissue TNF-α levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EVLV), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC-induced depression and anxiety. Collectively, we demonstrated that oral delivery of EVLV effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug-loaded orally-administrable EV treatment for other diseases.
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Affiliation(s)
- Renwei Jing
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Leijie Zhang
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Ruibin Li
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Zhongqiu Yang
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Jun Song
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Qian Wang
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Nan Cao
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - Gang Han
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
| | - HaiFang Yin
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co‐sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Basic Medical Sciences & School of Medical TechnologyTianjin Medical UniversityTianjinChina
- Department of Clinical LaboratoryTianjin Medical University General HospitalTianjinChina
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Sciurti E, Signore MA, Velardi L, Di Corato R, Blasi L, Campa A, Martucci MC, Siciliano PA, Francioso L. Label-free electrochemical biosensor for direct detection of Oncostatin M (OSM) inflammatory bowel diseases (IBD) biomarker in human serum. Talanta 2024; 271:125726. [PMID: 38316076 DOI: 10.1016/j.talanta.2024.125726] [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: 11/24/2023] [Revised: 12/22/2023] [Accepted: 01/26/2024] [Indexed: 02/07/2024]
Abstract
Oncostatin M (OSM) is an interleukin-6 (IL-6) member family cytokine implicated in the pathogenesis of chronic diseases including inflammatory bowel disease (IBD). OSM is a novel diagnostic biomarker over-expressed in the serum of IBD patients. This paper reports on the first electrochemical OSM immunosensor, developed using a multistep fabrication process aimed at covalently immobilizing OSM antibodies on a mixed self-assembled monolayer coated gold working electrode. Cyclic voltammetry, atomic force microscopy (AFM), IR spectroscopy and optical characterizations were used to validate the sensor functionalization protocol. Electrochemical impedance spectroscopy (EIS) measurements were performed to assess the reliability of the immunosensor preparation and to verify the antibody-antigen complexes formation. The label-free immunosensor showed high sensitivity identifying OSM at clinically relevant concentrations (37-1000 pg mL-1) with low detection limit of 2.86 pg mL-1. Both sensitivity and selectivity of the proposed immunosensor were also demonstrated in human serum in the presence of interfering biomarkers, making it an innovative potential platform for the OSM biomarker detection in IBD patients' serum.
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Affiliation(s)
- E Sciurti
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy.
| | - M A Signore
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - L Velardi
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - R Di Corato
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - L Blasi
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - A Campa
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - M C Martucci
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - P A Siciliano
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
| | - L Francioso
- Institute for Microelectronics and Microsystems - National Research Council (IMM - CNR), Via Monteroni, 73100 Lecce, Italy
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Bonovas S, Tsantes AG, Sokou R, Tsantes AE, Nikolopoulos GK, Piovani D. Racial Disparities in Infliximab Efficacy for Ulcerative Colitis: Evidence Synthesis and Effect Modification Assessment. J Clin Med 2024; 13:319. [PMID: 38256453 PMCID: PMC10816873 DOI: 10.3390/jcm13020319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/21/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
An increasing amount of research explores the role of race in clinical phenotypes and outcomes in ulcerative colitis (UC). We aimed to investigate racial differences in infliximab (IFX) treatment efficacy in UC. We used aggregate data from IFX trials and evidence synthesis methods to generate race-specific efficacy estimates. Then, we tested the effect modification by race by comparing the race-specific estimates derived from independent evidence syntheses. We computed ratios of relative risks (RRRs) and performed tests of statistical interaction. We analyzed data from five randomized, placebo-controlled trials evaluating IFX as induction and maintenance therapy for adults with moderate-to-severe UC (875 participants; 45% Asians). We found no substantial evidence of racial differences concerning the efficacy of IFX in inducing clinical response (RRR = 0.89, 95% CI: 0.66-1.20; p = 0.44), clinical remission (RRR = 0.58, 95% CI: 0.24-1.44; p = 0.24), and mucosal healing (RRR = 0.99, 95% CI: 0.69-1.41; p = 0.95), or maintaining clinical remission (RRR = 0.81, 95% CI: 0.46-1.42; p = 0.45) and mucosal healing (RRR = 0.84, 95% CI: 0.48-1.46; p = 0.53), between Asian and Caucasian populations. Future clinical studies should expand the participation of racial minorities to comprehensively assess potential racial differences in the effectiveness of advanced therapies, including IFX, in the context of treating UC.
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Affiliation(s)
- Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Andreas G. Tsantes
- Microbiology Department, “Saint Savvas” Oncology Hospital, 11522 Athens, Greece;
| | - Rozeta Sokou
- Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikea, 18454 Piraeus, Greece;
| | - Argirios E. Tsantes
- Laboratory of Haematology and Blood Bank Unit, “Attiko” Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | | | - Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy;
- IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
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Cantorna MT, Arora J. Vitamin D, microbiota, and inflammatory bowel disease. FELDMAN AND PIKE'S VITAMIN D 2024:1057-1073. [DOI: 10.1016/b978-0-323-91338-6.00047-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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8
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Yang J, Guan X, He S, Ge L, Gao Q, Wu X. FTY720 attenuates acute colitis via colonic T cells reduction and inhibition of M1 macrophages polarization independent of CCR2-mediated monocytes input. Int Immunopharmacol 2023; 123:110731. [PMID: 37541109 DOI: 10.1016/j.intimp.2023.110731] [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: 05/20/2023] [Revised: 07/11/2023] [Accepted: 07/27/2023] [Indexed: 08/06/2023]
Abstract
Ulcerative colitis (UC) is a complex multifactorial disease, of which the exact etiology is not fully understood. The inappropriate aggressive inflammatory response is closely related to the disease progression of UC. FTY720 is a sphingosine-1-phosphate receptor agonist and acts as a key immunomodulator in inflammation. This study aims to investigate the protective influence of FTY720 on inflammation in the DSS-induced colitis model. In the present study, the C57BL/6 mice and the CCR2-/- mice were exposed to 5% Dextran Sodium Sulfate (DSS) drinking water for 6 days followed by an injection of FTY720 (1 mg/kg/d) or vehicle (PBS) 6 times starting on the next day. The body weight, stool consistency, and occult blood were assessed daily. The inflammatory cytokines level in colon tissues and serum were assessed. Leukocyte subsets of bone marrow (BM), spleen, and colon were analyzed by flow cytometry. Our results demonstrated that FTY720 ameliorated the aberrant immune responses by trapping T cells and inhibiting the polarization of M1 macrophages in colitis mice. The effect of FTY720 on the increased number of colonic macrophages did not dependent on CCR2-mediated monocyte influx, despite most monocytes being reduced after DSS administration in the inflamed colon of CCR2-/- mice. Rather, depletion of CCR2 did not impact the protective influence of FTY720 on colonic injury in acute colitis. All these findings unravel a beneficial function of FTY720 in the inflammatory response to DSS-induced acute colitis, provided further insights into monocyte migration and might provide potential opportunities for UC therapeutic intervention.
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Affiliation(s)
- Jing Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Nankai University Affiliated Nankai Hospital, Tianjin, China.
| | - Xin Guan
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Nankai University Affiliated Nankai Hospital, Tianjin, China
| | - Simeng He
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, China
| | - Lixiu Ge
- Department of Clinical Laboratory, Nankai University Affiliated Nankai Hospital, Tianjin, China
| | - Qiaoying Gao
- Department of Clinical Laboratory, Nankai University Affiliated Nankai Hospital, Tianjin, China
| | - Xiaoyang Wu
- Department of Anesthesiology and Critical Care Medicine, Nankai University Affiliated Nankai Hospital, Tianjin, China
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9
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Xiao Y, Powell DW, Liu X, Li Q. Cardiovascular manifestations of inflammatory bowel diseases and the underlying pathogenic mechanisms. Am J Physiol Regul Integr Comp Physiol 2023; 325:R193-R211. [PMID: 37335014 PMCID: PMC10979804 DOI: 10.1152/ajpregu.00300.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 06/01/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023]
Abstract
Inflammatory bowel disease (IBD), consisting of ulcerative colitis and Crohn's disease, mainly affects the gastrointestinal tract but is also known to have extraintestinal manifestations because of long-standing systemic inflammation. Several national cohort studies have found that IBD is an independent risk factor for the development of cardiovascular disorders. However, the molecular mechanisms by which IBD impairs the cardiovascular system are not fully understood. Although the gut-heart axis is attracting more attention in recent years, our knowledge of the organ-to-organ communication between the gut and the heart remains limited. In patients with IBD, upregulated inflammatory factors, altered microRNAs and lipid profiles, as well as dysbiotic gut microbiota, may induce adverse cardiac remodeling. In addition, patients with IBD have a three- to four times higher risk of developing thrombosis than people without IBD, and it is believed that the increased risk of thrombosis is largely due to increased procoagulant factors, platelet count/activity, and fibrinogen concentration, in addition to decreased anticoagulant factors. The predisposing factors for atherosclerosis are present in IBD and the possible mechanisms may involve oxidative stress system, overexpression of matrix metalloproteinases, and changes in vascular smooth muscle phenotype. This review focuses mainly on 1) the prevalence of cardiovascular diseases associated with IBD, 2) the potential pathogenic mechanisms of cardiovascular diseases in patients with IBD, and 3) adverse effects of IBD drugs on the cardiovascular system. Also, we introduce here a new paradigm for the gut-heart axis that includes exosomal microRNA and the gut microbiota as a cause for cardiac remodeling and fibrosis.
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Affiliation(s)
- Ying Xiao
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
| | - Don W Powell
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
| | - Qingjie Li
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
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10
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Mohan LJ, Daly JS, Ryan BM, Ramtoola Z. Oral infliximab nanomedicines for targeted treatment of inflammatory bowel diseases. Eur J Pharm Sci 2023; 183:106379. [PMID: 36646154 DOI: 10.1016/j.ejps.2023.106379] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND AIMS Anti-TNF biological therapies such as infliximab (INF) have revolutionised the treatment of inflammatory bowel diseases (IBD). However, serious adverse effects due to systemic administration can significantly impact patient quality of life, limiting their success. Oral nanomedicines propose an innovative solution to provide local delivery to inflamed gastrointestinal tissues, thereby limiting systemic exposure and enhancing therapeutic efficacy. This study aimed to examine the potential of INF nanomedicines for IBD treatment with a focus on nanoparticle (NP) size to modulate the targeting of INF to the epithelial barrier. METHODS Healthy and inflamed in vitro models of the intestinal epithelial barrier were established to examine the cell interaction of PLGA-PEGNPs of varying particle sizes and polydispersities. INF-loaded NPs were prepared by electrostatic interaction of INF with NPs and examined for their therapeutic efficacy in the inflamed epithelial cell barrier model. RESULTS NP interaction was significantly enhanced in the inflamed cell barrier model, with increased transport observed for 130 - 300 nm NPs and accumulation of larger NPs (∼600 nm) at the barrier. Delivery of INF directly to the inflamed barrier by ∼600 nm NPs accelerated recovery of barrier integrity and reduced inflammatory cytokine secretion and cytotoxicity in comparison to treatment with INF alone. CONCLUSIONS Results from this study show that NP particle size can be used to differentially target and treat the inflamed intestinal barrier. Oral INF nanomedicines of modulated size present a novel strategy for the local, targeted treatment of IBD.
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Affiliation(s)
- Lauren J Mohan
- Division of Biology, Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, 2, Dublin, Ireland; School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 2, Dublin, Ireland
| | - Jacqueline S Daly
- Division of Biology, Department of Anatomy and Regenerative Medicine, RCSI University of Medicine and Health Sciences, 2, Dublin, Ireland
| | - Barbara M Ryan
- Department of Gastroenterology and Clinical Medicine, Tallaght Hospital and Trinity College, Dublin, Ireland
| | - Zebunnissa Ramtoola
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, 2, Dublin, Ireland.
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11
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Monteleone G, Stolfi C, Marafini I, Atreya R, Neurath MF. Smad7 Antisense Oligonucleotide-Based Therapy in Crohn's Disease: Is it Time to Re-Evaluate? Mol Diagn Ther 2022; 26:477-481. [PMID: 35841457 PMCID: PMC9411088 DOI: 10.1007/s40291-022-00606-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2022] [Indexed: 11/30/2022]
Abstract
Abundant preclinical work showed that in Crohn’s disease (CD), the defective activity of the immunosuppressive cytokine tumor necrosis factor (TGF)-β1 due to high levels of the intracellular inhibitor Smad7 contributes to amplify the tissue-damaging inflammatory response. Consistently, phase I and II studies documented clinical and endoscopic benefit in active CD patients treated with mongersen, an oral antisense oligonucleotide targeting Smad7. However, a multicenter, randomized, double-blind, placebo-controlled, phase III study was prematurely discontinued as a futility analysis showed that mongersen was not effective in CD patients. The reasons why the phase III study failed despite the fact that previous clinical trials documented the efficacy of the drug remain unknown. The primary objective of this Viewpoint was to provide clues about the factors explaining discrepancies among the clinical trials. We illustrate the recent data indicating that the various batches of mongersen, used during the phase III program, are chemically different, with some of them being unable to downregulate Smad7 expression. Overall, these findings suggest the necessity of new clinical studies to further evaluate the efficacy of chemically homogenous batches of mongersen in patients with inflammatory bowel diseases (IBDs), and, at the same time, they can help understand the failure of other clinical trials with antisense oligonucleotides in IBD (i.e. alicaforsen).
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Affiliation(s)
- Giovanni Monteleone
- Department of Systems Medicine, University of Rome "TOR VERGATA", Via Montpellier, 1, 00133, Rome, Italy.
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome "TOR VERGATA", Via Montpellier, 1, 00133, Rome, Italy
| | - Irene Marafini
- Department of Systems Medicine, University of Rome "TOR VERGATA", Via Montpellier, 1, 00133, Rome, Italy
| | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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Tadesse R, Ewnte B, Tesfaye K. Perforated ileum as the initial presentation of Crohn's disease, a case report. Int J Surg Case Rep 2022; 97:107305. [PMID: 35907295 PMCID: PMC9403019 DOI: 10.1016/j.ijscr.2022.107305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/09/2022] [Accepted: 06/11/2022] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION The perforation of the bowel as the first presentation of inflammatory bowel disease is a rare occurrence reported in about 0.15-3 % of the literature and is especially unusual in young patients <30 years of age. It is a serious event with most of the perforations occurring on the ileum. This article describes a unique case of a 20-year-old female patient who presented with perforated ileum due to Crohn's disease as an initial presentation operated at a private surgical center. CASE PRESENTATION We present a case of a previously asymptomatic 21-year-old female presenting with intestinal perforation secondary to Crohn's disease for the first time. The patient presented with crampy abdominal pain and frequent bilious vomiting of 3 days duration. She also had a high-grade fever and abdominal distension. WBC was 24,000 and an abdominal CT scan showed perforation of the bowel consistent with Crohn's Disease. Ruling out other etiologies perforated viscous secondary to query Crohn's Disease was entertained and laparotomy revealed 2 × 2 cm perforation on the anti-mesenteric border of the terminal ileum. The perforated segment was resected primary anastomosis was performed. Following surgery, the patient was discharged symptom-free and linked to the Gastroenterology unit after a biopsy confirmed Crohn's disease. She was started on Prednisolone and Azathioprine exactly a month after her surgery. Her 6-month follow-up is smooth. CONCLUSION Presentation of bowel perforation as an initial feature of Crohn's Disease is a rare phenomenon. Adequate resuscitation followed by emergency laparotomy with primary resection and anastomosis could be life-saving for a hemodynamically stable patient.
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Kamoi K, Watanabe T, Uchimaru K, Okayama A, Kato S, Kawamata T, Kurozumi-Karube H, Horiguchi N, Zong Y, Yamano Y, Hamaguchi I, Nannya Y, Tojo A, Ohno-Matsui K. Updates on HTLV-1 Uveitis. Viruses 2022; 14:v14040794. [PMID: 35458524 PMCID: PMC9030471 DOI: 10.3390/v14040794] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed several long-standing uncertainties about HU. HTLV-1-related diseases are known to be caused mainly through vertical transmission (mother-to-child transmission), but emerging HTLV-1 infection by horizontal transmission (such as sexual transmission) has become a major problem in metropolitan areas, such as Tokyo, Japan. Investigation in Tokyo showed that horizontal transmission of HTLV-1 was responsible for HU with severe and persistent ocular inflammation. The development of ATL and HAM is known to be related to a high provirus load and hence involves a long latency period. On the other hand, factors contributing to the development of HU are poorly understood. Recent investigations revealed that severe HU occurs against a background of Graves’ disease despite a low provirus load and short latency period. This review highlights the recent knowledge on HU and provides an update on the topic of HU in consideration of a recent nationwide survey.
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Affiliation(s)
- Koju Kamoi
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; (H.K.-K.); (N.H.); (Y.Z.); (K.O.-M.)
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
- Correspondence: ; Tel.: +81-3-5803-5302
| | - Toshiki Watanabe
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
- Department of Practical Management of Medical Information, St. Marianna University School of Medicine, Kanagawa 216-8512, Japan
| | - Kaoru Uchimaru
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
- Department of Medical Computational Biology and Genome Sciences, Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan
| | - Akihiko Okayama
- Department of Rheumatology, Infectious Diseases and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan;
| | - Seiko Kato
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
| | - Toyotaka Kawamata
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
| | - Hisako Kurozumi-Karube
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; (H.K.-K.); (N.H.); (Y.Z.); (K.O.-M.)
| | - Noe Horiguchi
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; (H.K.-K.); (N.H.); (Y.Z.); (K.O.-M.)
| | - Yuan Zong
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; (H.K.-K.); (N.H.); (Y.Z.); (K.O.-M.)
| | - Yoshihisa Yamano
- Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan;
| | - Isao Hamaguchi
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo 208-0011, Japan;
| | - Yasuhito Nannya
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
| | - Arinobu Tojo
- Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; (T.W.); (K.U.); (S.K.); (T.K.); (Y.N.); (A.T.)
- Institute of Innovation Advancement, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Kyoko Ohno-Matsui
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; (H.K.-K.); (N.H.); (Y.Z.); (K.O.-M.)
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14
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Shivaleela B, Srushti SC, Shreedevi SJ, Babu RL. Thalidomide-based inhibitor for TNF-α: designing and Insilico evaluation. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2022. [DOI: 10.1186/s43094-021-00393-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Inflammatory diseases are the vast array of disorders caused by inflammation. During most inflammatory events, many cytokines expressions were modulated, and one such cytokine is tumor necrosis factor-alpha (TNF-α). TNF-α is mainly secreted by monocytes and macrophages. Notably, it has been proposed as a therapeutic target for several diseases. The anti-TNF biology approach is mainly based on monoclonal antibodies. The fusion protein and biosimilars are prevalent in treating inflammation for decades. Only a few small molecule inhibitors are available to inhibit the expression of TNF-α, and one such promising drug was thalidomide. Therefore, the study was carried out to design thalidomide-based small molecule inhibitors for TNF-α. The main objective of our study is to design thalidomide analogs to inhibit TNF-α using the insilico approach.
Results
Several thalidomide analogs were designed using chemsketch. After filtration of compounds through ‘Lipinski rule of 5’ by Molinspiration tool, as a result, five compounds were selected. All these compounds were subjected to molecular docking, and the study showed that all five compounds had good binding energy. However, based on ADMET predictions, two compounds (S3 and S5) were eliminated.
Conclusions
Our preliminary results suggest that S1, S2, S4 compounds showed potential ligand binding capacity with TNF-α and, interestingly, with limited or no toxicity. Our preliminary investigation and obtained results have fashioned more interest for further in vitro studies.
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15
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Tripodi A, Spina L, Pisani LF, Padovan L, Cavallaro F, Chantarangkul V, Valsecchi C, Peyvandi F, Vecchi M. Anti-TNF-α Treatment Reduces the Baseline Procoagulant Imbalance of Patients With Inflammatory Bowel Diseases. Inflamm Bowel Dis 2021; 27:1901-1908. [PMID: 33393637 DOI: 10.1093/ibd/izaa351] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are characterized by an increased thrombosis risk of uncertain etiology. Coagulation derangement arising from inflammation may be a triggering factor. We hypothesized that strong inflammation inhibitors (eg, anti-tumor necrosis factor-α drugs) may affect coagulation. METHODS Forty patients with IBD were compared with 57 control patients for coagulation factors and endogenous thrombin potential (ETP), the latter being the most sensitive marker of in vivo pro- and anticoagulation balance. We measured ETP in the presence and absence of thrombomodulin (the physiologic protein C [PC] activator). Coagulation at different timepoints was also assessed for 28 of these patients during infliximab treatment. RESULTS The median ETP (nM thrombin × minutes) and range (minimum-maximum) were each higher in patients at baseline than in control patients in both the absence (2120 [1611-3041] vs 1865 [1270-2337]) and the presence (1453 [464-2522] vs 831 [104-1741]) of thrombomodulin. The ETP ratio (with/without thrombomodulin) was high at baseline (0.73 [0.21-0.90] vs 0.45 [0.07-0.85]). The ETP and ETP ratio declined during treatment and were significantly lower at the end than at baseline. Factor (F) VIII and fibrinogen, which were high at baseline, decreased during treatment and at the end were significantly lower than at baseline. The FVIII/PC ratio, which was high in patients at baseline, declined during treatment and at the end was lower than at baseline. C-reactive protein recorded at the end of treatment was lower than at baseline. CONCLUSIONS Patients with IBD have a procoagulant imbalance as shown by increased ETP at baseline. The ETP decreases during treatment with infliximab, which is related to decreased FVIII and FVIII/PC ratio. This effect is also related to the improvement of inflammation as shown by decreased fibrinogen and C-reactive protein.
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Affiliation(s)
- Armando Tripodi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Luisa Spina
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Laura Francesca Pisani
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Lidia Padovan
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Flaminia Cavallaro
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Veena Chantarangkul
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Carla Valsecchi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Flora Peyvandi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy.,Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi, Milano, Italy
| | - Maurizio Vecchi
- Department of Pathophysiology and Transplantation, Università degli Studi, Milano, Italy.,Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
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16
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Ba H, Jiang R, Zhang M, Yin B, Wang J, Li Z, Li B, Zhou X. Suppression of Transmembrane Tumor Necrosis Factor Alpha Processing by a Specific Antibody Protects Against Colitis-Associated Cancer. Front Immunol 2021; 12:687874. [PMID: 34675913 PMCID: PMC8524043 DOI: 10.3389/fimmu.2021.687874] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/16/2021] [Indexed: 12/26/2022] Open
Abstract
Soluble tumor necrosis factor-α (sTNF-α) plays an important role in colitis-associated cancer (CAC); however, little is known about transmembrane TNF-α (tmTNF-α). Here, we observed an increase in sTNF-α mainly in colitis tissues from an azoxymethane/dextran sodium sulfate (DSS)-induced CAC mouse model whereas tmTNF-α levels were chiefly increased on epithelial cells at the tumor stage. The ratio of intracolonic tmTNF-α/sTNF-α was negatively correlated with the levels of pro-inflammatory mediators (IL-1β, IL-6, and NO) and M1 macrophages but positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and the level of the anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory effect of tmTNF-α. This effect of tmTNF-α was confirmed again by the induction of resistance to LPS in colonic epithelial cell lines NCM460 and HCoEpiC through the addition of exogenous tmTNF-α or transfection of the tmTNF-α leading sequence that lacks the extracellular segment but retains the intracellular domain of tmTNF-α. A tmTNF-α antibody was used to block tmTNF-α shedding after the first or second round of inflammation induction by DSS drinking to shift the time window of tmTNF-α expression ahead to the inflammation stage. Antibody treatment significantly alleviated inflammation and suppressed subsequent adenoma formation, accompanied by increased apoptosis. An antitumor effect was also observed when the antibody was administered at the malignant phase of CAC. Our results reveal tmTNF-α as a novel molecular marker for malignant transformation in CAC and provide a new insight into blocking the pathological process by targeting tmTNF-α processing.
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Affiliation(s)
- Hongping Ba
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Jiang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Zhang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bingjiao Yin
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuoya Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baihua Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxi Zhou
- Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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Kim J, Noh SW, Park C, Lee JH, Cho HY, Min J, Lee T. Fabrication of electrochemical biosensor composed of multi-functional DNA 4 way junction for TNF-α detection in human serum. Bioelectrochemistry 2021; 142:107939. [PMID: 34474207 DOI: 10.1016/j.bioelechem.2021.107939] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 01/08/2023]
Abstract
Tumor necrosis factor (TNF-α) is a representative cytokine family known to induce multiple signaling cascades leading to various cellular responses, such as cell death, survival, and differentiation. It has been reported that blocking the action of TNF-α in various diseases can improve disease prognosis. Therefore, it is important to monitor TNF-α in patient plasma and properly regulate its action. In this study, we report a label-free electrochemical biosensor consisting of a multifunctional DNA 4-way junction (MF-4WJ) for TNF-α detection in human serum. MF-4WJ does not require additional labeling and signal amplification processes. The electrochemical properties of functionalized MF-4WJ were evaluated by cyclic voltammetry (CV) in the presence of Ag+ intercalated between the mismatched sequences of MF-aptamers as redox-active species. Afterward, CV was carried out to evaluate the performance of the fabricated biosensor. The proposed label-free electrochemical biosensor was able to effectively detect TNF-α in a dynamic range of 0.15 pg/ml to 150 ng/ml. Limit of detection (LOD) was at 0.07 pg/ml in HEPES. Moreover, it was confirmed that even in 10% diluted human serum, TNF-α could be detected in an excellent dynamic range of 0.15 pg/ml to ∼ 15 ng/ml and LOD was at 0.14 pg/ml in 10% diluted human serum.
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Affiliation(s)
- Jinmyeong Kim
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro,Nowon-Gu, Seoul 01897, Republic of Korea
| | - Seung Woo Noh
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro,Nowon-Gu, Seoul 01897, Republic of Korea
| | - Chulhwan Park
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro,Nowon-Gu, Seoul 01897, Republic of Korea
| | - Jin-Ho Lee
- Pusan National University, School of Biomedical Convergence Engineering, 49, Busandaehak-ro, Yangsan 50612, Republic of Korea
| | - Hyeon-Yeol Cho
- Department of Bio & Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-Ro, Seongbuk-Gu, Seoul 02707, Republic of Korea
| | - Junhong Min
- School of Integrative Engineering, Chung-Ang University, Heukseok-dong, Dongjak-gu, Seoul 06910, Republic of Korea.
| | - Taek Lee
- Department of Chemical Engineering, Kwangwoon University, 20 Kwangwoon-Ro,Nowon-Gu, Seoul 01897, Republic of Korea.
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Protective Effect of the Abelmoschus manihot Flower Extract on DSS-Induced Ulcerative Colitis in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:7422792. [PMID: 34408782 PMCID: PMC8367538 DOI: 10.1155/2021/7422792] [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: 04/12/2021] [Revised: 06/24/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Background The flower of Abelmoschus manihot (AM) has been widely used in the treatment of chronic inflammatory diseases, including ulcerative colitis. This paper aimed to confirm the therapeutic effect of AM on ulcerative colitis (UC) and explore its mechanism. Methods Mouse models were induced by 2.5% dextran sulfate sodium (DSS) and treated with AM. UC signs, symptoms, colon macroscopic lesion scores, and disease activity index (DAI) scores were observed. Colon levels of interleukin- (IL-) 6, IL-1β, IL-18, IL-17, tumor necrosis factor- (TNF-) α, and IL-10 were quantified by ELISA. The colon protein expression levels of NLRP3, ASC, caspase 1 p10, β-arrestin1, ZO-1, occludin-1, and claudin-1 were examined by immunohistochemistry and western blotting. The mRNA levels of IL-1β, IL-18, NLRP3, ASC, and caspase 1 p10 in the colon were determined by real-time quantitative polymerase chain reaction (qPCR). Results After treatment with AM, the mortality of mice, pathological damage to the colon, splenomegaly, and the spleen coefficient were decreased. AM reduced the levels of proinflammatory cytokines (IL-6, IL-1β, IL-18, IL-17, and TNF-α) and increased the level of IL-10. The mRNA expression levels of NLRP3, ASC, and caspase 1 in colon tissue were decreased by AM in a dose-dependent manner. In addition, AM also reduced the protein expression of NLRP3, ASC, caspase 1 p10, IL-1β, IL-18, and β-arrestin1 in the colon tissue of model mice. Western blot analysis confirmed that AM increased the expression of occludin-1, claudin-1, and ZO-1 in a dose-dependent manner. Conclusion This study shows that AM has a significant therapeutic effect on mice with UC, and the mechanism may be related to the inhibition of the β-arrestin1/NLRP3 inflammasome signaling pathway and the protection of intestinal barrier function.
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Bosman-Schluep D, de Pril R, Verbaken B, Legent A, Stallen J, de Jong EC, Janssen RAJ. siRNA-based identification of IBD-related targets in human monocyte-derived dendritic cells. J Immunol Methods 2021; 494:113058. [PMID: 33891922 DOI: 10.1016/j.jim.2021.113058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/31/2021] [Accepted: 04/16/2021] [Indexed: 01/09/2023]
Abstract
Inflammatory bowel disease (IBD) is thought to be caused by an aberrant host response to the commensal enteric flora in genetically susceptible individuals. Dendritic cells (DCs) play a key role in the regulation of this response as they sample gut commensals. In healthy individuals DCs actively contribute to tolerance upon recognition of these resident bacteria, whereas in individuals with IBD, DCs will initiate an inflammatory response. To mimic the disease response in vitro, human monocyte-derived DCs were matured with E. coli causing the cells to produce high levels of the pro-inflammatory cytokine IL-12/IL-23p40 (p40) and low levels of the anti-inflammatory cytokine IL-10. A siRNA-based screening assay was developed and screened to identify potential therapeutic targets that shift this balance towards an immunosuppressive state with lower levels of p40 and higher levels of IL-10. The screening assay was optimized and quality controlled using non-targeting controls and positive control siRNAs targeting IL12B and TLR4 transcripts. In the primary screen, smartpool siRNAs were screened for reduction in p40 expression, induction of IL-10 levels, or increase in IL-10:p40 ratios without affecting cell viability. All potential targets were taken forward into a confirmation screen in a different DC donor in which four individual siRNAs per target were screened. At least two siRNAs per target should have an effect to be considered a valid target. This screen resulted in a concise list of ten genes, of which their role in DC maturation is currently being investigated.
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Affiliation(s)
| | | | | | | | | | - Esther C de Jong
- Department of Experimental Immunology, Amsterdam UMC, the Netherlands
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20
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Mercogliano MF, Bruni S, Mauro F, Elizalde PV, Schillaci R. Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy. Cancers (Basel) 2021; 13:cancers13030564. [PMID: 33540543 PMCID: PMC7985780 DOI: 10.3390/cancers13030564] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/17/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects.
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Affiliation(s)
- María Florencia Mercogliano
- Laboratorio de Biofisicoquímica de Proteínas, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales-Consejo Nacional de Investigaciones Científicas y Técnicas (IQUIBICEN-CONICET), Buenos Aires 1428, Argentina;
| | - Sofía Bruni
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Florencia Mauro
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Patricia Virginia Elizalde
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Roxana Schillaci
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
- Correspondence: ; Tel.: +54-11-4783-2869; Fax: +54-11-4786-2564
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21
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Kurozumi-Karube H, Kamoi K, Ando N, Uchida M, Hamaguchi I, Ohno-Matsui K. In vitro Evaluation of the Safety of Adalimumab for the Eye Under HTLV-1 Infection Status: A Preliminary Study. Front Microbiol 2020; 11:522579. [PMID: 33424777 PMCID: PMC7785715 DOI: 10.3389/fmicb.2020.522579] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 12/07/2020] [Indexed: 01/29/2023] Open
Abstract
Adalimumab (ADA), a fully human monoclonal tumor necrosis factor (TNF)-α antibody, is one of the most widely used biologics in the treatment of inflammatory diseases. However, ADA can exacerbate infectious conditions, induce paradoxical reactions such as inflammation, and cause neoplasia. Human T-cell leukemia virus type 1 (HTLV-1) is an infectious agent that induces inflammation and neoplastic infiltration in the eye. To date, numerous HTLV-1 carriers have been treated with adalimumab to suppress inflammation out of necessity, when standard anti-inflammatory drugs such as steroids and immunosuppressive agents have proven inadequate to control the inflammation. Here, we clarify the safety of adalimumab for the eye under HTLV-1 infectious conditions in vitro. We used the adult retinal pigment epithelial cell line (ARPE)-19 cell line as ocular resident cells, and used MT2 and TL-Om1 as HTLV-1-infected cells. ARPE-19 and MT2/TL-Om1 were co-cultured, and then adalimumab was administered. Production of cytokines and chemokines, TNF-α receptor (TNF-R), HTLV-1 proviral load (PVL), and apoptosis were measured to assess the effects of adalimumab. Contact between ARPE-19 and MT2/TL-Om1 produced inflammatory cytokines such as TNF, interleukin (IL)-6, IL-8 and IL-10, and transduced chemokines such as interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), monokine induced by interferon-γ (MIG), and regulated on activation, normal T cell expressed and secreted (RANTES). No inflammatory cytokines and chemokines were exacerbated by adalimumab. Expression of TNF-R on ARPE-19 and MT2/TL-Om1 cells, HTLV-1 PVLs of MT2/TL-Om1 cells, and cell growth rate and apoptotic rate of ARPE-19 were unaffected by adalimumab. In conclusion, adalimumab does not appear to exacerbate HTLV-1-associated inflammatory conditions in the eye or increase PVL in HTLV-1-infected T cells. These data suggest that adalimumab could be used safely for the eye under HTLV-1 infectious conditions from the perspective of in vitro assessment.
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Affiliation(s)
- Hisako Kurozumi-Karube
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Koju Kamoi
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Naoko Ando
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Minami Uchida
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Isao Hamaguchi
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kyoko Ohno-Matsui
- Department of Ophthalmology & Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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22
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Nam J, Kim KJ, Park G, Kim BG, Jeong GH, Jeon JE, Hurh BS, Kim JY. Anti-Inflammatory Properties of Mineral-Balanced Deep Sea Water in In-Vitro and In-Vivo Models of Inflamed Intestinal Epithelium. APPLIED SCIENCES 2020; 10:5183. [DOI: 10.3390/app10155183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
This study aimed to determine the effect of deep-sea water (DSW)-derived mineral waters on intestinal health, using a cell model and a dextran sulfate sodium (DSS)-induced enteritis mouse model. DSW was desalted and minerals were added to generate mineral waters that were classified as trace mineral (TM), high magnesium (HM), high magnesium low salt (HMLS), and high magnesium high calcium (HMHC), using a tabletop electrodialysis device. Caco-2 cells cocultured with Raw264.7 cells were either pre-treated or not with the four water groups, and inflammation was induced by treatment with lipopolysaccharide (LPS). Compared to LPS-treated Caco-2 cells, HMLS-cotreated cells maintained high transepithelial electrical resistance, similar to control cells. FITC-dextran permeability was lower in HMLS-treated than in other cells. In vivo, in comparison to DSS-treated mice, colon shortening was inhibited, and disease activity and colon injury were suppressed in HMLS-cotreated mice. RNA-seq of colonic tissues revealed that inflammatory gene expression was similar among the control and HMLS mice, and DSS-induced expression of inflammation-related genes such as TNF-α and NOS2 and inflammatory chemokine genes was suppressed. Our findings suggest that DSW-derived mineral water intake can help reduce colitis symptoms, and the effects may be partially regulated by magnesium and other minerals.
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Affiliation(s)
- Jain Nam
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Korea
| | - Kyeong Jin Kim
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Korea
| | - Geonhee Park
- Sempio Fermentation Research Center, 183, Osongsaengmyeong 4-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28156, Korea
| | - Byeong Goo Kim
- Sempio Fermentation Research Center, 183, Osongsaengmyeong 4-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28156, Korea
| | - Gwi-Hwa Jeong
- Sempio Fermentation Research Center, 183, Osongsaengmyeong 4-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28156, Korea
| | - Jong-eun Jeon
- Sempio Fermentation Research Center, 183, Osongsaengmyeong 4-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28156, Korea
| | - Byung Serk Hurh
- Sempio Fermentation Research Center, 183, Osongsaengmyeong 4-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28156, Korea
| | - Ji Yeon Kim
- Department of Food Science and Technology, Seoul National University of Science and Technology, Seoul 01811, Korea
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23
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Rossi G, Cerquetella M, Gavazza A, Galosi L, Berardi S, Mangiaterra S, Mari S, Suchodolski JS, Lidbury JA, Steiner JM, Pengo G. Rapid Resolution of Large Bowel Diarrhea after the Administration of a Combination of a High-Fiber Diet and a Probiotic Mixture in 30 Dogs. Vet Sci 2020; 7:vetsci7010021. [PMID: 32050688 PMCID: PMC7158687 DOI: 10.3390/vetsci7010021] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/06/2020] [Accepted: 02/07/2020] [Indexed: 12/13/2022] Open
Abstract
Canine fiber responsive diarrhea is a form of chronic colitis that improves clinically after adding fiber to the diet. In the present study, we investigated the effect of a combination of a high-fiber, highly digestible, hypoallergenic diet with a probiotic mixture in 30 dogs with chronic colitis that were unresponsive to various dietary and/or pharmacological interventions. Fecal scores, canine chronic enteropathy clinical activity index (CCECAI) scores, the dysbiosis index (DI), and histologic images of colonic biopsies were evaluated. At baseline (day 0; T0) and after 30 days of treatment (T1), all variables evaluated in our patients (i.e., fecal and CCECAI scores and histopathology) improved significantly at T1, with the exception of DI. However, there was a numerical shift from a state of dysbiosis to one of normobiosis. The combination of the diet and the probiotic used in the present study induced the resolution of clinical signs in a mean of 8.5 days (maximum 15 days) and did not necessitate any other treatments or the further addition of alimentary fiber.
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Affiliation(s)
- Giacomo Rossi
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
| | - Matteo Cerquetella
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
| | - Alessandra Gavazza
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
- Correspondence: ; Tel.: +39-0737-403-458
| | - Livio Galosi
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
| | - Sara Berardi
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
| | - Sara Mangiaterra
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
| | - Subeide Mari
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica (MC), Italy; (G.R.); (M.C.); (L.G.); (S.B.); (S.M.); (S.M.)
| | - Jan S. Suchodolski
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX 77843, USA; (J.S.S.); (J.A.L.); (J.M.S.)
| | - Jonathan A. Lidbury
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX 77843, USA; (J.S.S.); (J.A.L.); (J.M.S.)
| | - Joerg M. Steiner
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX 77843, USA; (J.S.S.); (J.A.L.); (J.M.S.)
| | - Graziano Pengo
- St. Antonio Veterinary Clinic, S.S. 415 Paullese 6, 26020 Madignano (CR), Italy;
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24
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Khoury T, Ilan Y. Introducing Patterns of Variability for Overcoming Compensatory Adaptation of the Immune System to Immunomodulatory Agents: A Novel Method for Improving Clinical Response to Anti-TNF Therapies. Front Immunol 2019; 10:2726. [PMID: 31824506 PMCID: PMC6879658 DOI: 10.3389/fimmu.2019.02726] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/06/2019] [Indexed: 12/18/2022] Open
Abstract
Primary lack of response and secondary loss of response (LOR) are major obstacles to the use of anti-tumor necrosis factor (TNF)-based therapies in patients with rheumatoid arthritis or inflammatory bowel disease. Here, we review the mechanisms and methods for predicting LOR and the currently used methods for overcoming the ineffectiveness of anti-TNFs. The complex functions of TNF and anti-TNF antibodies, which can promote both pro- or anti-inflammatory actions, and the factors that affect the induction of immune tolerance to their effects are presented. The lack of rules and the continuous dynamics of the immune processes partly underlie the unpredictability of the response to anti-TNFs. Variability is inherent to biological systems, including immune processes, and intra/inter-patient variability has been described in the response to drugs. This variability is viewed as a compensatory adaptation mechanism of the immune system in response to drugs and may contribute to treatment LOR. Dose reductions and drug holidays have been tested in patients treated with anti-TNFs. Regular dose-based regimens may be incompatible with physiological variability, further contributing to treatment inefficacy. We present the concept of overcoming immune system adaptation to anti-TNFs by introducing patient-tailored patterns of variability to treatment regimens.
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Affiliation(s)
- Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
| | - Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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25
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Bertani L, Antonioli L, Fornai M, Tapete G, Baiano Svizzero G, Marchi S, Blandizzi C, Costa F. Evaluation of cytokine levels as putative biomarkers to predict the pharmacological response to biologic therapy in inflammatory bowel diseases. MINERVA GASTROENTERO 2019; 65:298-308. [PMID: 31646851 DOI: 10.23736/s1121-421x.19.02621-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cytokines play a central role in the pathogenesis of inflammatory bowel diseases. For this reason, the vast majority of biological therapies are aimed to block pro-inflammatory cytokines or their receptors. Although these drugs have modified the course of the disease due to their efficacy, a high rate of non-response or loss of response over time is still an important issue for clinicians. In this perspective, many studies have been conducted in recent years to individuate a reliable biomarker of therapeutic response. In this review, we discuss the role of cytokines involved in the pathogenesis and in the therapy of inflammatory bowel diseases, and their putative use as pharmacological biomarkers of therapy responsiveness.
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Affiliation(s)
- Lorenzo Bertani
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy -
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gherardo Tapete
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy
| | - Giovanni Baiano Svizzero
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy
| | - Santino Marchi
- Unit of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa University Hospital, Pisa, Italy
| | - Corrado Blandizzi
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Costa
- Unit of Inflammatory Bowel Diseases, Department of General Surgery and Gastroenterology, Pisa University Hospital, Pisa, Italy
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26
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Flavonoid VI-16 protects against DSS-induced colitis by inhibiting Txnip-dependent NLRP3 inflammasome activation in macrophages via reducing oxidative stress. Mucosal Immunol 2019; 12:1150-1163. [PMID: 31152156 DOI: 10.1038/s41385-019-0177-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 05/13/2019] [Accepted: 05/16/2019] [Indexed: 02/04/2023]
Abstract
Emerging evidence suggests that NLRP3 inflammasome was associated with various kinds of immunological diseases including colitis. However, there are few drugs targeting inflammasomes in the treatment of colitis. Several flavonoids have been found to affect the inflammasome pathway, but the mechanism is still confusing. Here we report that VI-16, a synthetic flavonoid compound, exerts potent anti-inflammatory effects on macrophages in DSS-induced colitis mice, which intervened in the activation of NLRP3 inflammasome without affecting intestinal epithelial cells. However, the protection of VI-16 against DSS-induced colitis was dependent on NLRP3 expression in hematopoietic cells. Furthermore, this inhibitory effect of VI-16 was found to be at least partially achieved by decreasing the mitochondrial ROS generation without affecting autophagy. Further studies confirm that VI-16 inhibits the binding of Txnip to NLRP3 by reducing oxidative stress and ultimately inhibits NLRP3 inflammasome. This demonstrates the ability of VI-16 to inhibit the NLRP3 inflammasome activation and its potential use in the treatment of inflammatory bowel disease.
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27
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Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, Herbst RH, Rogel N, Slyper M, Waldman J, Sud M, Andrews E, Velonias G, Haber AL, Jagadeesh K, Vickovic S, Yao J, Stevens C, Dionne D, Nguyen LT, Villani AC, Hofree M, Creasey EA, Huang H, Rozenblatt-Rosen O, Garber JJ, Khalili H, Desch AN, Daly MJ, Ananthakrishnan AN, Shalek AK, Xavier RJ, Regev A. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 2019; 178:714-730.e22. [PMID: 31348891 PMCID: PMC6662628 DOI: 10.1016/j.cell.2019.06.029] [Citation(s) in RCA: 826] [Impact Index Per Article: 137.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/25/2019] [Accepted: 06/18/2019] [Indexed: 11/29/2022]
Abstract
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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Affiliation(s)
| | - Moshe Biton
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Molecular Biology, MGH, Boston, MA, USA
| | - Jose Ordovas-Montanes
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Division of Infectious Diseases and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA
| | - Keri M Sullivan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Grace Burgin
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Daniel B Graham
- Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA
| | - Rebecca H Herbst
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Noga Rogel
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Michal Slyper
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Julia Waldman
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Malika Sud
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Elizabeth Andrews
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Gabriella Velonias
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Adam L Haber
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | | | - Sanja Vickovic
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Junmei Yao
- Center for Computational and Integrative Biology, MGH, Boston, MA, USA
| | | | - Danielle Dionne
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Lan T Nguyen
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Alexandra-Chloé Villani
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
| | - Matan Hofree
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | | | - Hailiang Huang
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA
| | | | - John J Garber
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Hamed Khalili
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - A Nicole Desch
- Broad Institute, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA
| | - Mark J Daly
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Ashwin N Ananthakrishnan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA.
| | - Alex K Shalek
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
| | - Ramnik J Xavier
- Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA.
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA.
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28
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Chen Y, Le TH, Du Q, Zhao Z, Liu Y, Zou J, Hua W, Liu C, Zhu Y. Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling. Int Immunopharmacol 2019; 71:144-154. [PMID: 30901677 DOI: 10.1016/j.intimp.2019.01.021] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 01/13/2019] [Accepted: 01/14/2019] [Indexed: 12/17/2022]
Abstract
NLRP3 inflammasome has been reported to be associated with inflammatory bowel disease including colitis due to its potential ability to induce IL-1β secretion. Emerging studies have demonstrated that Genistein, a major isoflavone, has potential anti-inflammatory effects in murine model colitis. However, its anti-inflammatory mechanism remains unclear. The effects of Genistein in dextran sulfate sodium (DSS)-induced murine colitis via targeting NLRP3 inflammasome was investigated in this study. Also, the mechanisms of protective action of Genistein in DSS-induced colitis may relate to TGR5 signaling. Genistein treatment not only remarkably attenuated loss of body weight and shortening of colon length but also significantly reduced inflammatory cells infiltration and pro-inflammatory mediator production in serum and colon. Moreover, Genistein treatment down-regulated production of caspase-1 and IL-1β and increased intracellular cAMP level, which were similar to the treatment for INT-777, a semi-synthetic TGR5 agonist, in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells and U937 cells. These protective effects of Genistein might be attributed by ubiquination of NLRP3 which was induced due to interaction of cAMP with NLRP3. Furthermore, the effects of Genistein on NLRP3 inflammasome disappeared in TGR5-silenced U937 cells. In conclusion, our study unveils that Genistein was able to inhibit NLRP3 inflammasome via TGR5-cAMP signaling in macrophages. It therefore might be a potential effective drug for inflammatory bowel diseases.
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Affiliation(s)
- Yu Chen
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Thi Ha Le
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Qianming Du
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, PR China
| | - Zheng Zhao
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China
| | - Yunxin Liu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China
| | - Jianjun Zou
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China
| | - Weiwei Hua
- Department of Clinical Pharmacy, School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China
| | - Chao Liu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
| | - Yubing Zhu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
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29
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Payne SC, Furness JB, Burns O, Sedo A, Hyakumura T, Shepherd RK, Fallon JB. Anti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation. Front Neurosci 2019; 13:418. [PMID: 31133776 PMCID: PMC6517481 DOI: 10.3389/fnins.2019.00418] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 04/11/2019] [Indexed: 12/11/2022] Open
Abstract
Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation. Specifically, we aimed to: (i) compare off-target effects during abdominal and cervical VNS; (ii) verify that VNS levels were suprathreshold; and (iii) determine whether abdominal VNS reduces chemically-induced intestinal inflammation in rats. An electrode array was developed in-house to stimulate and record vagal neural responses. In a non-recovery experiment, stimulation-induced off-target effects were measured by implanting the cervical and abdominal vagus nerves of anaesthetized rats (n = 5) and recording changes to heart rate, respiration and blood pressure during stimulation (10 Hz; symmetric biphasic current pulse; 320 nC per phase). In a chronic experiment, the efficacy of VNS treatment was assessed by implanting an electrode array onto the abdominal vagus nerve and recording in vivo electrically-evoked neural responses during the implantation period. After 14 days, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid) and rats received therapeutic VNS (n = 7; 10 Hz; 320 nC per phase; 3 h/day) or no stimulation (n = 8) for 4.5 days. Stool quality, plasma C-reactive protein and histology of the inflamed intestine were assessed. Data show that abdominal VNS had no effect (two-way RM-ANOVA: P ≥ 0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute (P ≥ 0.05), respiration was inhibited and blood pressure decreased. Data addressing efficacy of VNS treatment show that electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: P ≥ 0.05) and therapeutic stimulation remained above threshold. Chronically stimulated rats, compared to unstimulated rats, had improved stool quality (two-way RM ANOVA: P < 0.0001), no blood in feces (P < 0.0001), reduced plasma C-reactive protein (two-way RM ANOVA: P < 0.05) and a reduction in resident inflammatory cell populations within the intestine (Kruskal–Wallis: P < 0.05). In conclusion, abdominal VNS did not evoke off-target effects, is an effective treatment of TNBS-induced inflammation, and may be an effective treatment of IBD in humans.
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Affiliation(s)
- Sophie C Payne
- Bionics Institute, Fitzroy, VIC, Australia.,Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia.,Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia
| | - Owen Burns
- Bionics Institute, Fitzroy, VIC, Australia
| | - Alicia Sedo
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Tomoko Hyakumura
- Bionics Institute, Fitzroy, VIC, Australia.,Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Robert K Shepherd
- Bionics Institute, Fitzroy, VIC, Australia.,Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - James B Fallon
- Bionics Institute, Fitzroy, VIC, Australia.,Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia.,Department of Otolaryngology, University of Melbourne, Parkville, VIC, Australia
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30
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Meddens CA, van der List ACJ, Nieuwenhuis EES, Mokry M. Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential. Gut 2019; 68:928-941. [PMID: 30692146 DOI: 10.1136/gutjnl-2018-317516] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/28/2018] [Accepted: 12/04/2018] [Indexed: 12/13/2022]
Abstract
Genome-wide association studies have identified over 200 loci associated with IBD. We and others have recently shown that, in addition to variants in protein-coding genes, the majority of the associated loci are related to DNA regulatory elements (DREs). These findings add a dimension to the already complex genetic background of IBD. In this review we summarise the existing evidence on the role of DREs in IBD. We discuss how epigenetic research can be used in candidate gene approaches that take non-coding variants into account and can help to pinpoint the essential pathways and cell types in the pathogenesis of IBD. Despite the increased level of genetic complexity, these findings can contribute to novel therapeutic options that target transcription factor binding and enhancer activity. Finally, we summarise the future directions and challenges of this emerging field.
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Affiliation(s)
- Claartje Aleid Meddens
- Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | | | - Michal Mokry
- Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
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31
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Park YE, Kim TO. Sexual Dysfunction and Fertility Problems in Men with Inflammatory Bowel Disease. World J Mens Health 2019; 38:285-297. [PMID: 30929327 PMCID: PMC7308231 DOI: 10.5534/wjmh.190007] [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] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 01/29/2019] [Accepted: 02/10/2019] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is usually diagnosed in young individuals. Crohn's disease and ulcerative colitis are the 2 principal forms of IBD. Patients with IBD demonstrate varying degrees of disease activity and sometimes need to undergo bowel surgery such as proctocolectomy with ileal pouch-anal anastomosis that involves removal of the entire colon and rectum with consequent sexual dysfunction. Several studies have shown that sulfasalazine, affects male fertility. Additionally, many men with IBD are unable to control their smoking, drinking, and eating habits, which can cause worsening of disease activity and fertility. Therefore, infertility and sexual dysfunction are important issues in young patients diagnosed with IBD because they are related to optimal management of the disease and patients' quality of life. Only a few studies have reported sexual dysfunction and infertility in men with IBD. Therefore, this study reviewed the current literature describing male sexual dysfunction scales and evaluated the causes of sexual dysfunction and infertility in men with IBD.
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Affiliation(s)
- Yong Eun Park
- Division of Gastroenterology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Tae Oh Kim
- Division of Gastroenterology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.
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32
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Matsuoka K, Hamada S, Shimizu M, Nanki K, Mizuno S, Kiyohara H, Arai M, Sugimoto S, Iwao Y, Ogata H, Hisamatsu T, Naganuma M, Kanai T, Mochizuki M, Hashiguchi M. Factors predicting the therapeutic response to infliximab during maintenance therapy in Japanese patients with Crohn's disease. PLoS One 2018; 13:e0204632. [PMID: 30286108 PMCID: PMC6171861 DOI: 10.1371/journal.pone.0204632] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 09/11/2018] [Indexed: 12/18/2022] Open
Abstract
Since anti-tumor necrosis factor (TNF)-α agents (TNF-α inhibitors) induce both clinical response and remission in patients with moderate to severe inflammatory bowel disease (IBD), the use of anti-TNF therapies has fundamentally changed the approach to treatment for patients with IBD. Infliximab (IFX) is a TNF-α inhibitor approved for the induction and remission of Crohn’s disease (CD). However, even among patients who initially demonstrate a clinical response to IFX therapy, secondary loss of response occurs, although the reason remains unknown. We therefore investigated predictive factors associated with the response to IFX in long-term maintenance treatment in Japanese CD patients. Eight types of single-nucleotide polymorphisms (SNPs) were investigated using the real-time PCR method, and patient characteristics were collected from the electronic medical records. The Crohn’s Disease Activity Index criteria were used as the response to IFX therapy. The observation period was 1 year after IFX had been administered for more than 1 year. Associations between the IFX response and patient characteristics were evaluated using the multivariate logistic regression model. We studied 121 unrelated adult Japanese with CD treated for more than 1 year with IFX as outpatients at Keio University Hospital from November 1, 2014 to November 30, 2015. Among them, 71 were classified as in remisson. In multivariate analysis, patients with the TNF-α 857C>T C/C genotype, shorter disease duration, without double dosing, and combination treatment with an immunomodulator had higher remisson rates than those with the C/T or T/T genotype, longer disease duration, with double dosing, and no combination treatment with an immunomodulator. The response to IFX in Japanese CD patients may therefore be predicted by these 4 characteristics in actual clinical practice.
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Affiliation(s)
- Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Shunsuke Hamada
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Shibakoen, Minato-ku, Tokyo, Japan
| | - Mikiko Shimizu
- Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, Shibakoen, Minato-ku, Tokyo, Japan
| | - Kosaku Nanki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Shinta Mizuno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Mari Arai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Shinya Sugimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Yasushi Iwao
- Center for Preventive Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Tadakazu Hisamatsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Mayumi Mochizuki
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Shibakoen, Minato-ku, Tokyo, Japan
| | - Masayuki Hashiguchi
- Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Shibakoen, Minato-ku, Tokyo, Japan
- * E-mail:
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Rufino MN, Aleixo GFP, Trombine-Batista IE, Giuffrida R, Keller R, Bremer-Neto H. Systematic review and meta-analysis of preclinical trials demonstrate robust beneficial effects of prebiotics in induced inflammatory bowel disease. J Nutr Biochem 2018; 62:1-8. [PMID: 30053633 DOI: 10.1016/j.jnutbio.2018.05.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 05/10/2018] [Accepted: 05/16/2018] [Indexed: 02/07/2023]
Affiliation(s)
| | | | | | | | | | - Hermann Bremer-Neto
- Department of Functional Sciences, Faculty of Medicine, University of West Paulista.
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Gray MA, Chao CY, Staudacher HM, Kolosky NA, Talley NJ, Holtmann G. Anti-TNFα therapy in IBD alters brain activity reflecting visceral sensory function and cognitive-affective biases. PLoS One 2018. [PMID: 29518097 PMCID: PMC5843226 DOI: 10.1371/journal.pone.0193542] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background In inflammatory bowel disease (IBD), immune activation with increased circulating TNF-α is linked to the intensity of gastrointestinal symptoms and depression or anxiety. A central feature of depression is cognitive biases linked to negative attributions about self, the world and the future. We aimed to assess the effects of anti-TNFα therapy on the central processing of self-attribution biases and visceral afferent information in patients with Crohn’s disease. Methods We examined 9 patients with Crohn’s disease (age 26.1±10.6. yrs, 5 female, 5 ileocolonic, 2 colonic and 2 ileal disease) during chronic anti-TNFα therapy (5 adalimumab, 4 infliximab). Patients were studied twice in randomized order before and after anti-TNFα administration. On each occasion patients underwent functional magnetic resonance imaging (fMRI) of the brain during a test of implicit attribution biases regarding sickness/health and undertook a standardized nutrient challenge. Results Following anti-TNFα treatment, ratings of ‘fullness’ following nutrient challenge reduced compared to pre-treatment ratings (p<0.05). Reaction times revealed improved processing of self-related and positive health words, consistent with improved implicit sense of wellbeing that correlated with improvements in sensory function after treatment (r = 0.67, p<0.05). Treatment-associated improvements in implicit processing were mirrored by alterations of prefrontal, amygdala, posterior cingulate and visual regions. Between patients, the degree of functional amygdala change was additionally explained by individual differences in attention regulation and body awareness rankings. Conclusion In patients with Crohn’s disease, anti-TNFα administration reduces visceral sensitivity and improves implicit cognitive-affective biases linked to alterations in limbic (amygdala) function.
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Affiliation(s)
- Marcus A. Gray
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital Brisbane, Queensland, Australia
- Translational Research Institute, Brisbane, Queensland, Australia
- Faculty of Health and Behavioral Science, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
- * E-mail:
| | - Che-yung Chao
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital Brisbane, Queensland, Australia
| | - Heidi M. Staudacher
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital Brisbane, Queensland, Australia
- Translational Research Institute, Brisbane, Queensland, Australia
| | - Natasha A. Kolosky
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital Brisbane, Queensland, Australia
- Translational Research Institute, Brisbane, Queensland, Australia
- Faculty of Medicine, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia
| | - Nicholas J. Talley
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia
| | - Gerald Holtmann
- Department of Gastroenterology & Hepatology, Princess Alexandra Hospital Brisbane, Queensland, Australia
- Translational Research Institute, Brisbane, Queensland, Australia
- Faculty of Health and Behavioral Science, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
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35
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Argollo M, Fiorino G, Peyrin-Biroulet L, Danese S. Vedolizumab for the treatment of Crohn’s disease. Expert Rev Clin Immunol 2018; 14:179-189. [DOI: 10.1080/1744666x.2018.1438189] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Marjorie Argollo
- Department of Gastroenterology, Universidade Federal de São Paulo - UNIFESP, São Paulo, Brazil
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy
| | - Gionata Fiorino
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre, France
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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36
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Momen S, Kirkham B, Barker J, Smith C. Tumour necrosis factor antagonist-induced lupus: a Critically Appraised Topic. Br J Dermatol 2017; 177:1519-1526. [DOI: 10.1111/bjd.15866] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- S.E. Momen
- St John's Institute of Dermatology; Guy's and St Thomas’ NHS Foundation Trust; London U.K
| | - B. Kirkham
- Department of Rheumatology; Guy's and St Thomas’ NHS Foundation Trust; London U.K
| | - J.N. Barker
- St John's Institute of Dermatology; Guy's and St Thomas’ NHS Foundation Trust; London U.K
| | - C.H. Smith
- St John's Institute of Dermatology; Guy's and St Thomas’ NHS Foundation Trust; London U.K
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Hwang DY, Kim S, Hong HS. Substance-P Ameliorates Dextran Sodium Sulfate-Induced Intestinal Damage by Preserving Tissue Barrier Function. Tissue Eng Regen Med 2017; 15:63-73. [PMID: 30603535 DOI: 10.1007/s13770-017-0085-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 08/30/2017] [Accepted: 09/11/2017] [Indexed: 02/07/2023] Open
Abstract
Intestinal inflammation alters immune responses in the mucosa and destroys colon architecture, leading to serious diseases such as inflammatory bowel disease. Thus, the modulation of intestinal integrity and immune responses in IBD can be the critical factor to be considered to reduce the severity of damages. Substance-P (SP), endogenous peptide to be involved in cell proliferation, migration and immune modulation, can exert the therapeutic effect on diverse diseases including cornea damage, rheumatoid arthritis and diabetic complications. SP was found to elevate expression of junctional molecule. Considering the function of SP reported previously, it was inferred that SP is capable of exert the beneficial effect of SP on intestinal diseases by controlling intestinal structure as well as immune responses. In this study, we explored the therapeutic effect of SP on dextran sodium sulfate-induced intestine damage by injecting SP. The effects of SP were evaluated by analyzing crypt structures, proliferating cell pool and infiltration of immune cells. DSS treatment provoked abnormal immune response and disruption of intestine epithelial barrier. However, co-treatment of SP obviously blocked the development of intestinal damages by declining inflammatory responses and sustaining intestinal structure more intact. The treatment of SP to chronic damages also promoted intestinal regeneration by preserving the integrity of colon tissue. Moreover, DSS-induced reduction of epithelial junctional molecule was obviously inhibited by SP treatment in vitro. Taken together, our data indicate that SP can reduce intestinal damages, possibly by modulating barrier structure and immune response. Our results propose SP as candidate therapeutics in intestinal damages.
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Affiliation(s)
- Dae Yeon Hwang
- 1Department of Medicine, Graduate School, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447 Republic of Korea
| | - Suna Kim
- 2Graduate School of Biotechnology and Department of Genetic Engineering, College of Life Science, Kyung Hee University Global Campus, 1732 Deogyeong-daero, Giheung-gu, Yongin-si, Gyeonggi-do 17104 Republic of Korea
| | - Hyun Sook Hong
- 3College of Medicine/East-West Medical Research Institute, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447 Republic of Korea
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Ono K, Nimura S, Hideshima Y, Nabeshima K, Nakashima M. Orally administered sodium 4-phenylbutyrate suppresses the development of dextran sulfate sodium-induced colitis in mice. Exp Ther Med 2017; 14:5485-5490. [PMID: 29285080 DOI: 10.3892/etm.2017.5251] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 03/23/2017] [Indexed: 12/14/2022] Open
Abstract
Sodium 4-phenylbutyrate (PBA) exerts therapeutic effects in a wide range of pathologies. A previous study by the present authors revealed that intraperitoneal administration of PBA suppresses the onset of dextran sulfate sodium (DSS)-induced colitis in mice. In the present study, the effects of orally administered PBA are investigated, as this route of administration is more clinically relevant. The therapeutic efficacy of PBA (10 mg/12 h) in mice with experimental colitis was assessed based on the disease activity index, production of inflammatory cytokines, colon length and histopathological investigations. The results of the present study demonstrated a significantly higher survival rate in the PBA-treated group compared with the PBA-untreated (DSS control) group (P=0.0156). PBA treatment improved pathological indices of experimental colitis (P<0.05). Furthermore, the oral administration of PBA significantly inhibited the DSS-induced shortening of the colon (P<0.05) and overproduction of interleukin (IL)-1β and IL-6 (both P<0.05) as measured in colonic lavage fluids. A marked attenuation of the DSS-induced overproduction of tumor necrosis factor was also observed. For histopathological analysis, a marked decrease in mature goblet cells and increase in enlarged nuclei of the absorptive cells was observed in colon lesions of DSS control mice as compared with normal untreated mice. However, in the PBA-treated mice, no such lesions were observed and the mucosa resembled that of DSS-untreated mice. The results of the present study, combined with those results of a previous study, suggest that oral and intraperitoneal administration of PBA have similar preventative effects on DSS-induced colitis, achieved by suppressing its pathogenesis.
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Affiliation(s)
- Kazuhiko Ono
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
| | - Satoshi Nimura
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
| | - Yuko Hideshima
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
| | - Kazuki Nabeshima
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
| | - Manabu Nakashima
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka 814-0180, Japan
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Holleran G, Lopetuso L, Petito V, Graziani C, Ianiro G, McNamara D, Gasbarrini A, Scaldaferri F. The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease. Int J Mol Sci 2017; 18:E2020. [PMID: 28934123 PMCID: PMC5666702 DOI: 10.3390/ijms18102020] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 09/10/2017] [Accepted: 09/14/2017] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-α directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date.
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Affiliation(s)
- Grainne Holleran
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
- Gastroenterology Department, Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
| | - Loris Lopetuso
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
| | - Valentina Petito
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
| | - Cristina Graziani
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
| | - Gianluca Ianiro
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
| | - Deirdre McNamara
- Gastroenterology Department, Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
| | - Franco Scaldaferri
- Internal Medicine, Gastroenterology and Liver Unit, Gastroenterology Area, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
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Discovery and structure-activity relationship studies of 2-benzylidene-2,3-dihydro-1 H -inden-1-one and benzofuran-3(2 H )-one derivatives as a novel class of potential therapeutics for inflammatory bowel disease. Eur J Med Chem 2017. [DOI: 10.1016/j.ejmech.2017.06.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups. The annual incidence of CD in North America is reported to be 3.1-20.2 per 100,000 with a prevalence of 201 per 100,000 population. Based on the epidemiological, genetic and immunological data, CD is considered to be a heterogeneous disorder with multifactorial etiology in which genetics and environment interact to manifest the disease. Several genes have been studied so for with respect to CD, but thus far the strong and replicated associations have been identified with NOD2, IL23R and ATG16L1 genes. The risk factors implicated with CD include smoking, low fiber- high carbohydrate diet, altered microbiome and medications such as non-steroidal anti-inflammatory drugs. CD is typically characterized by transmural inflammation of the intestine and could affect any part of the gastrointestinal tract from mouth to perianal area. In terms of distribution of the disease 25% of the patients have colitis only, 25% is ileitis only and 50% have ileocolitis. The Montreal classification is based on the age at diagnosis (<16, 17-40, > 40), disease location (Ileal, colonic, Ileocolonic) and the disease behavior (nonstricturing/nonpenetrating, stricturing, penetrating). The key features for diagnosing CD comprises a combination of radiographic, endoscopic and pathological findings demonstrating focal, asymmetric, transmural or granulomatous features. Abdominal Computed tomography (CT) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score. Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or "induction therapy", followed by maintenance of adequate response or remission, i.e. "maintenance therapy". The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence in postoperative CD patients, as defined by Rutgeers score i2-i4 occur in 30-90% of the patients at the neoterminal ileum within 12 months of surgery and almost universally by 5 years. Treating CD requires a comprehensive care team including the patient, primary care provider, and gastroenterologist. In summary CD is a chronic inflammatory condition with a remitting and relapsing course primarily affecting relatively younger population with significant socioeconomic effects.
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Affiliation(s)
- Mahesh Gajendran
- Department of Internal Medicine, Texas Tech University Health Science Center El Paso, 2000B Transmountain Road, El Paso, TX 79911, United States.
| | - Priyadarshini Loganathan
- Department of Internal Medicine, Texas Tech University Health Science Center El Paso, 2000B Transmountain Road, El Paso, TX 79911, United States
| | - Anthony P Catinella
- Department of Family Medicine, Texas Tech University Health Science Center El Paso, 2000B Transmountain Road, El Paso, TX 79911, United States
| | - Jana G Hashash
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, M2, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, United States
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Choi SY, Kang B, Lee JH, Choe YH. Clinical Use of Measuring Trough Levels and Antibodies against Infliximab in Patients with Pediatric Inflammatory Bowel Disease. Gut Liver 2017; 11:55-61. [PMID: 27609485 PMCID: PMC5221861 DOI: 10.5009/gnl16041] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 03/28/2016] [Accepted: 04/04/2016] [Indexed: 12/23/2022] Open
Abstract
Background/Aims The clinical use of measuring infliximab (IFX) trough levels (TLs) and antibodies against IFX (ATIs) in patients with pediatric inflammatory bowel disease (IBD) remains unclear. We propose measuring these variables to create individual IFX treatment strategies for patients with pediatric IBD. Methods This retrospective study was conducted in pediatric patients with IBD who received IFX from July 2009 to June 2014. Results Samples were available from 39 patients with pediatric IBD. A significant difference was observed in IFX TLs in 16 patients who were in clinical remission (group A) after IFX therapy (median, 3.99 μg/mL; interquartile range [IQR], 0.30 to 21.96) compared to 23 patients who had a poor response to treatment (group B) (median, 0.88 μg/mL; IQR, 0.00 to 6.80, p=0.002). In group B, 21 patients underwent empiric intensification of IFX treatment. After dose intensification, 17 patients had an improved response to treatment. Four patients still had no response to dose intensification. Therefore, these patients were switched to other biologics. Conclusions Patients who had poor responses and subtherapeutic IFX TLs had an improved response to dose intensification. Patients who had ATIs were likely to continue to have no response after dose intensification. Therefore, tailoring individual IFX treatments based on IFX TLs, ATIs, and the clinical response should be considered.
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Affiliation(s)
- So Yoon Choi
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ben Kang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jee Hyun Lee
- Department of Pediatrics, Korea University Ansan Hospital, Korea University School of Medicine, Ansan, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Rufini S, Ciccacci C, Novelli G, Borgiani P. Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease. Pharmacogenomics 2017; 18:1095-1114. [PMID: 28686143 DOI: 10.2217/pgs-2017-0068] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.
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Affiliation(s)
- Sara Rufini
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
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Varga G, Ugocsai M, Hartmann P, Lajkó N, Molnár R, Szűcs S, Jász DK, Érces D, Ghyczy M, Tóth G, Boros M. Acetylsalicylic acid-tris-hydroxymethyl-aminomethane reduces colon mucosal damage without causing gastric side effects in a rat model of colitis. Inflammopharmacology 2017; 26:261-271. [PMID: 28451776 DOI: 10.1007/s10787-017-0354-z] [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] [Received: 01/30/2017] [Accepted: 04/21/2017] [Indexed: 01/17/2023]
Abstract
BACKGROUND We have developed a novel compound from acetylsalicylic acid (ASA) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors with ASA-like anti-inflammatory efficacy and reduced the mucosa-damaging side-effects. Our aim was to examine local and remote consequences of ASA-Tris administration in 2-,4-,6-trinitrobenzene-sulfonic acid (TNBS)-induced colitis as compared to ASA or mesalamine (5-aminosalicylate) treatment. METHODS Sprague-Dawley rats were randomized to five groups (n = 6, each), and TNBS enemas were performed. Group 1 was the negative control; group 2 was the untreated colitis group. 12 hour after colitis induction repeated doses of ASA, ASA-Tris (both 0.55 mmol/kg) and mesalamine (0.77 mmol/kg) were given 3 times daily for 3 days to groups 3-5. On day 3 of colitis, the in vivo histology of the colon and stomach was investigated. Tissue xanthine-oxidoreductase, myeloperoxidase, nitrite/nitrate changes, and circulating TNF-alpha levels were measured. In addition, liver mitochondria were examined with high-resolution respirometry to analyze alterations in the electron transport chain. RESULTS TNBS enema significantly elevated inflammatory enzyme activities, NO production, TNF-alpha concentration, and induced morphological damage in the colon. ASA-treatment reduced the inflammatory marker levels and mucosal injury in the colon, but gastric tissue damage was present. ASA-Tris- and mesalamine-treatments significantly reduced the cytokine levels, inflammatory enzyme activities, and colonic mucosal damage without inducing gastric injury. Also, ASA significantly reduced the Complex IV-linked respiration of liver mitochondria, which was not observed after ASA-Tris-treatment. CONCLUSION As compared to ASA, ASA-Tris conjugation provides significant protection against the colonic injury and cytokine-mediated progression of inflammatory events in experimental colitis without influencing the gastric epithelial structure.
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Affiliation(s)
- Gabriella Varga
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Melinda Ugocsai
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Petra Hartmann
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Norbert Lajkó
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Réka Molnár
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Szilárd Szűcs
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Dávid Kurszán Jász
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Dániel Érces
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Miklós Ghyczy
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary
| | - Gábor Tóth
- Department of Medical Chemistry, Faculty of Medicine, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary
| | - Mihály Boros
- Institute of Surgical Research, Faculty of Medicine, University of Szeged, Szőkefalvi-Nagy Béla u. 6, Szeged, 6720, Hungary.
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Cheon JH. Understanding the complications of anti-tumor necrosis factor therapy in East Asian patients with inflammatory bowel disease. J Gastroenterol Hepatol 2017; 32:769-777. [PMID: 27723166 DOI: 10.1111/jgh.13612] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2016] [Indexed: 02/06/2023]
Abstract
Remarkable advances have been made in the treatment of inflammatory bowel disease since the introduction of anti-tumor necrosis factor-α agents, especially for patients who are refractory to or cannot tolerate conventional therapies. Currently, infliximab, adalimumab, and golimumab are available in the East Asian medical market, and these agents have been shown to be effective for inducing and maintaining long-term remission of inflammatory bowel disease. Despite their clinical benefits, anti-tumor necrosis factor therapy can also lead to increased vulnerability to infections, development of autoimmune diseases and malignancy, and decreased immunogenicity of vaccinations. Because infectious diseases, such as tuberculosis, hepatitis, and influenza, remain major health problems in East Asia, more cautious use of biologics is needed. To further improve treatment efficacy and safety, close monitoring of inflammation, regular surveillance for malignancy, and regularly scheduled vaccinations are needed. Treatment strategies for biologics should be customized to meet the needs of different patients.
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Affiliation(s)
- Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Clinical role, optimal timing and frequency of serum infliximab and anti-infliximab antibody level measurements in patients with inflammatory bowel disease. PLoS One 2017; 12:e0172916. [PMID: 28362851 PMCID: PMC5376081 DOI: 10.1371/journal.pone.0172916] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/06/2017] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Serum infliximab (IFX) and antibody-to-infliximab (ATI) levels are objective parameters, that may have a great role in the therapeutic decisions during maintenance biological therapy. RESEARCH DESIGN AND METHODS 48 inflammatory bowel disease patients receiving maintenance IFX therapy were prospectively enrolled and divided into adequate (complete remission N = 20) and inadequate responder (partial response, loss of response, dose escalation; N = 28) groups. Blood samples were collected just before (trough level, TL) and two (W2aTL) and six weeks (W6aTL) after the administration of IFX. RESULTS Single measurement of ATI titer was insufficient for predicting therapeutic response due to transient expression of ATI, however, using the three points' measurements, significant difference has been detected between the adequate and inadequate responder group (5.0% vs 35.7%; p = 0.016). The mean value of TL was significantly higher in the adequate responder group (3.11±1.64 vs.1.19±1.11; p<0.001) without further difference on the second and sixth week. Sensitivity and specificity for predicting the therapeutic response were 85.0% and 71.4% based on the cut-off value of TL 2.0 μg/ml. CONCLUSION Simultaneous measurement of serum IFX level prior to administration of regular IFX infusion and ATI titers significantly increase the diagnostic accuracy for the therapeutic decision in patients uncertainly responding to the therapy. The measurement of W2aTL and W6aTL levels did not result in further improvement in the prediction of therapeutic response.
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Graney PL, Lurier EB, Spiller KL. Biomaterials and Bioactive Factor Delivery Systems for the Control of Macrophage Activation in Regenerative Medicine. ACS Biomater Sci Eng 2017; 4:1137-1148. [PMID: 33418652 DOI: 10.1021/acsbiomaterials.6b00747] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Macrophages play an important role in tissue repair, regeneration, and the ability of biomaterials to mediate these processes. Macrophages are highly plastic cells that exhibit altered behavior in response to changes in the microenvironment. With the growing knowledge of the roles that different macrophage phenotypes play in specific pathologies and/or injuries, researchers are now focusing on designing biomaterials to actively control macrophage behavior and promote healing outcomes. In this review, we highlight a variety of biomaterial strategies for controlling macrophage phenotype in chronic wounds, tissue defects, and inflammatory conditions, although these strategies can be applied to many other applications. In particular, we highlight the different situations in which biomaterials should inhibit or promote M1 or M2 activation, or both, for therapeutic outcomes.
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Affiliation(s)
- Pamela L Graney
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, United States
| | - Emily B Lurier
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, United States
| | - Kara L Spiller
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, United States
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48
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Knyazev OV, Parfenov AI, Kagramanova AV, Ruchkina IN, Shcherbakov PL, Shakhpazyan NK, Noskova KK, Ivkina TI, Khomeriki SG. [Long-term infliximab therapy for ulcerative colitis in real clinical practice]. TERAPEVT ARKH 2017; 88:46-52. [PMID: 27636927 DOI: 10.17116/terarkh201688846-52] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIM to retrospectively evaluate the efficiency of long-term infliximab (INF) therapy in patients with refractory ulcerative colitis (UC). SUBJECTS AND METHODS The investigation enrolled 48 patients with refractory UC who had taken IFL in 2008 to 2014. Steroid-dependent or steroid-refractory UC was established in 40 (83.3%) patients; 8 (16.7%) were noted to be refractory to therapy with azathioprine or 6-mercaptopurine. Cytomegalovirus DNA was identified in the biopsy specimens of the large intestinal mucosa (LIM) from 7 patients. One patient received antiviral therapy. Induction therapy with IFL was in its administration in a dose of 5 mg/kg at 0, 2, and 6 weeks, then maintenance therapy was continued every 8 weeks. RESULTS After an IFL induction cycle, 3 (6.3%) patients were unresponsive to therapy and were excluded from the investigation. At present, 25 (55.5%) of the 45 patients who have responded to the therapy continue to take IFL 5 mg/kg every 8 weeks and are in clinical remission; 4 (8.8%) patients receive intensified IFL therapy. Initially 23 patients received combined therapy with IFL + an immunosuppressive drug; 22 had IFL monotherapy. Escape from the effect of the performed therapy was observed in 5 (11.1%) patients, which required its intensification. The intensified therapy resulted in sustained remission in 4 (8.8%) patients; colectomy was carried out in one (2.2%) case. Secondary loss of response to IFL, its intolerance, development of severe infectious complications, which did not allow for further maintenance therapy with IFL, were seen in 11 (24.4%) patients; 5 (11.1%) stopped the therapy because they had been excluded from the additional drug subsidy list. Maintenance therapy with IFL proved successful during 64 months in 29 (64.4%) of the 45 patients and during 64 months if its intensity, when the occasion required, was enhanced. CONCLUSION The long-term use of IFL in UC confirmed its high efficacy in achieving clinical response, in inducing a clinical remission and its capacity to heal LIM, and in sustaining remission.
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Affiliation(s)
- O V Knyazev
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - A I Parfenov
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - A V Kagramanova
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - I N Ruchkina
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - P L Shcherbakov
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | | | - K K Noskova
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - T I Ivkina
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
| | - S G Khomeriki
- Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow, Russia
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MacDonald TT, Di Sabatino A, DiSabatino A, Gordon JN. Immunopathogenesis of Crohn's Disease. JPEN J Parenter Enteral Nutr 2016; 29:S118-24; discussion S124-5, S184-8. [PMID: 15980273 DOI: 10.1177/01486071050290s4s118] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This review highlights the huge advances made in the understanding of Crohn's disease in the last 15 years. The pathogenic immune response in the gut wall is a highly polarised T helper cell type 1 response, probably directed against antigens of the commensal flora. There is marked over-expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and increased production of matrix degrading enzymes by fibroblasts and macrophages, which are probably responsible for ulceration and fistula formation. Crohn's disease runs in families and the susceptibility genes identified so far are associated with innate recognition of microbial products (Nod2) or epithelial barrier function (OCTN cation transporter genes and DLG5). Endogenous healing pathways mediated by transforming growth factor (TGF)-beta1 are inhibited because mucosal inflammatory cells express Smad7, the endogenous intracellular inhibitor of TGF-beta signalling. This makes it unlikely that enteral feeds containing TFG-beta are therapeutic by means of direct anti-inflammatory effects, however TGF-beta may still be involved because it is a well known epithelial motogen and may promote mucosal healing, in synergy with changes in mucosal bacterial populations as a result of the change in the diet.
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Affiliation(s)
- Thomas T MacDonald
- Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton, United Kingdom.
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50
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Baird AC, Mallon D, Radford-Smith G, Boyer J, Piche T, Prescott SL, Lawrance IC, Tulic MK. Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy. World J Gastroenterol 2016; 22:9104-9116. [PMID: 27895398 PMCID: PMC5107592 DOI: 10.3748/wjg.v22.i41.9104] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 08/25/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders" (n = 12) and "non-responders" (n = 12) and compared to healthy controls (n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. RESULTS Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders (P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls (P < 0.01) and diminished TNF (P < 0.001) and IL-1β (P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) (P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) (P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation (P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.
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MESH Headings
- Adolescent
- Adult
- Anti-Inflammatory Agents/therapeutic use
- Biological Products/therapeutic use
- Cells, Cultured
- Child
- Colitis, Ulcerative/blood
- Colitis, Ulcerative/diagnosis
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/immunology
- Dendritic Cells/drug effects
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Female
- Gastrointestinal Agents/therapeutic use
- Humans
- Immunity, Innate/drug effects
- Interleukin-1 Receptor-Associated Kinases/immunology
- Interleukin-1 Receptor-Associated Kinases/metabolism
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Male
- Middle Aged
- Prospective Studies
- Retrospective Studies
- Signal Transduction/drug effects
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Toll-Like Receptors/immunology
- Toll-Like Receptors/metabolism
- Treatment Failure
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/blood
- Tumor Necrosis Factor-alpha/immunology
- Young Adult
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