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Ikemoto M, Kotani T, Okada K, Matsuda S, Takeuchi T. A hybrid protein is a functional molecule to reduce the cytokine storm caused by excessively activated macrophages. Immunol Cell Biol 2025. [PMID: 39953927 DOI: 10.1111/imcb.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 06/16/2024] [Accepted: 01/23/2025] [Indexed: 02/17/2025]
Abstract
We recently developed a hybrid protein, tentatively named human MIKO-1 (hMIKO-1), based on the amino acid sequences of human S100A8 (hS100A8) and hS100A9. Human THP-1 macrophages (THP-1m), differentiated from THP-1 cells by phorbol 12-myristate 13-acetate, were used to investigate the immune function of hMIKO-1 as a drug for inflammatory diseases. Western blotting was conducted to confirm whether hMIKO-1 binds with β-actin and nuclear factor-kappa B to form complexes in THP-1m. A polymerase chain reaction (PCR) and quantitative PCR were performed to examine changes in the messenger RNA levels of proinflammatory cytokines in THP-1m. Fluorescent immunochemical staining was used to observe the intracellular localization of hMIKO-1 and hS100A8 or hS100A9 in THP-1m. As observed microscopically, the intracellular localization of hMIKO-1 in THP-1m was consistent with that of hS100A8, suggesting the close involvement of hS100A8 in the intracellular behavior of hMIKO-1 in THP-1m. Western blotting revealed that hMIKO-1 formed complexes with intracellular proteins, such as β-actin and nuclear factor-kappa B, to negatively regulate inflammatory signal transduction in THP-1m. Flow cytometry showed that the binding of hMIKO-1 to THP-1m significantly decreased when THP-1m were preliminarily treated with a sialidase (neuraminidases) cocktail. Therefore, the present results strongly suggest that the binding of hMIKO-1 to THP-1m closely involves the sugar chains of the surface proteins of cells. The messenger RNA expression of each proinflammatory cytokine was significantly suppressed in THP-1m preliminarily treated with hMIKO-1 despite a subsequent stimulation with lipopolysaccharide. In conclusion, hMIKO-1 is a functional molecule that significantly inhibits inflammatory signal transduction in THP-1m.
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Grants
- 21K08450 Ministry of Education, Science, Sports, and Culture of Japan
- 23K07914 Ministry of Education, Science, Sports, and Culture of Japan
- 24K11353 Ministry of Education, Science, Sports, and Culture of Japan
- C Ministry of Education, Science, Sports, and Culture of Japan
- 2646066 Ministry of Education, Science, Sports, and Culture of Japan
- 21K15422 Ministry of Education, Science, Sports, and Culture of Japan
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Affiliation(s)
- Masaki Ikemoto
- Division of Rheumatology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Takuya Kotani
- Division of Rheumatology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto, Japan
| | - Shogo Matsuda
- Division of Rheumatology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Tohru Takeuchi
- Division of Rheumatology, Department of Internal Medicine IV, Osaka Medical and Pharmaceutical University, Osaka, Japan
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2
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Zhang J, Yin YJ, Wang XW, Lu WQ, Chen ZY, Yu CH, Ren KF, Xu CF. Adhesive polyelectrolyte coating through UV-triggered polymerization on PLGA particles for enhanced drug delivery to inflammatory intestinal mucosa. J Nanobiotechnology 2025; 23:32. [PMID: 39844269 PMCID: PMC11753032 DOI: 10.1186/s12951-024-03066-3] [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: 07/10/2024] [Accepted: 12/09/2024] [Indexed: 01/24/2025] Open
Abstract
Administering medication precisely to the inflamed intestinal sites to treat ulcerative colitis (UC), with minimized side effects, is of urgent need. In UC, the inflammation damaged mucosa contains a large number of amino groups which are positively charged, providing new opportunities for drug delivery system design. Here, we report an oral drug delivery system utilizing the tacrolimus-loaded poly (lactic-co-glycolic acid) (TAC/PLGA) particles with an adhesion coating by in situ UV-triggered polymerization of polyacrylic acid and N-hydroxysuccinimide (PAA-NHS). The negatively charged carboxyl groups effectively interact with the positively charged focal mucosa, and the NHS ester groups form the covalent bonds with the amino groups, thereby synergically enhancing the adhesion of the PLGA particles to the focal mucosa. Our findings reveal that, compared to the naked particles, the PAA-NHS coating increases the adhesion of particles to the inflammatory intestine. In a dextran sulfate sodium-induced acute colitis mouse model, the TAC/PLGA particles with PAA-NHS coating exhibits substantial retention of TAC within the inflammatory intestine, enhancing drug delivery efficiency and therapeutic effects. This approach holds promise for UC management, minimizing systemic side effects and optimizing therapeutic outcomes.
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Affiliation(s)
- Jie Zhang
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yi-Jing Yin
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Xing-Wang Wang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Wei-Qi Lu
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Zhao-Yang Chen
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
- Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing, 312099, China
| | - Chao-Hui Yu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Ke-Feng Ren
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
| | - Cheng-Fu Xu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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3
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Matsuo K, Ikemoto M, Okada K. Intraperitoneal Administration of S100A8 Ameliorates Experimental Acute Colitis in Rats. BIOLOGY 2024; 13:916. [PMID: 39596871 PMCID: PMC11592024 DOI: 10.3390/biology13110916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/01/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024]
Abstract
S100A8 is a protein that is abundant in neutrophils and macrophages (MΦ), but its role in inflammation remains unclear. This study aimed to assess the immunological role(s) of S100A8 in acute intestinal inflammation in rats and its role in MΦ. Rat recombinant S100A8 (rr-S100A8, 1.0 mg/kg) was intraperitoneally administered daily to rats with 3% dextran sulfate sodium (DSS) (DSS + A8 group)-induced experimental acute colitis. The histological severity score (6.50 ± 0.51, p = 0.038) in the DSS + A8 group rats remained lower than that (9.75 ± 1.48) of the rats without S100A8 (DSS group) administration. The tumor necrosis factor-alpha (TNF-α) production in the colon tissues of the rats in the DSS + A8 group (4.76 ± 0.90 pg/mL/g, p = 0.042) was significantly suppressed, compared with that of the DSS group (10.45 ± 2.04 pg/mL/g). To stimulate rat peritoneal MΦ, rr-S100A8, the anti-rat S100A8 antibody, and a lipopolysaccharide (LPS) were used in the in vitro experiments. In the MΦ stimulated with rr-S100A8 for 2 h, the mRNA level of intracellular S100A8 (47.41 ± 24.44, p = 0.002) increased in an autocrine manner, whereas that of S100A9 (0.24 ± 0.43, p = 0.782) was not significant. The TNF-α mRNA level in the MΦ treated with LPS and the anti-rat S100A8 antibody significantly increased (102.26 ± 18.60, p = 0.001) compared to that with LPS alone (16.9 ± 8.56). These results indicate that S100A8 can serve as an anti-inflammatory protein in acute inflammation by negatively regulating S100A9 and TNF-α production through inflammatory signaling pathways in MΦ.
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Affiliation(s)
- Kano Matsuo
- Graduate School of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| | - Masaki Ikemoto
- Division of Clinical Immunology and Rheumatology, Department of Internal Medicine (IV), Faculty of Osaka Medical College, Osaka 569-8686, Japan
| | - Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
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4
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Ning S, Zhang Z, Zhou C, Wang B, Liu Z, Feng B. Cross-talk between macrophages and gut microbiota in inflammatory bowel disease: a dynamic interplay influencing pathogenesis and therapy. Front Med (Lausanne) 2024; 11:1457218. [PMID: 39355844 PMCID: PMC11443506 DOI: 10.3389/fmed.2024.1457218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 08/28/2024] [Indexed: 10/03/2024] Open
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic immune-mediated gastrointestinal disorders. The etiology of IBD is multifactorial, involving genetic susceptibility, environmental factors, and a complex interplay between the gut microbiota and the host's immune system. Intestinal resident macrophages play an important role in the pathogenesis and progress of IBD, as well as in maintaining intestinal homeostasis and facilitating tissue repair. This review delves into the intricate relationship between intestinal macrophages and gut microbiota, highlighting their pivotal roles in IBD pathogenesis. We discuss the impact of macrophage dysregulation and the consequent polarization of different phenotypes on intestinal inflammation. Furthermore, we explore the compositional and functional alterations in gut microbiota associated with IBD, including the emerging significance of fungal and viral components. This review also examines the effects of current therapeutic strategies, such as 5-aminosalicylic acid (5-ASA), antibiotics, steroids, immunomodulators, and biologics, on gut microbiota and macrophage function. We underscore the potential of fecal microbiota transplantation (FMT) and probiotics as innovative approaches to modulate the gut microbiome in IBD. The aim is to provide insights into the development of novel therapies targeting the gut microbiota and macrophages to improve IBD management.
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Affiliation(s)
- Shiyang Ning
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhe Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chuan Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Binbin Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhanju Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Shanghai, China
| | - Baisui Feng
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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5
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van der Horst D, Kurmasheva N, Marqvorsen MHS, Assil S, Rahimic AHF, Kollmann CF, Silva da Costa L, Wu Q, Zhao J, Cesari E, Iversen MB, Ren F, Jensen TI, Narita R, Schack VR, Zhang BC, Bak RO, Sette C, Fenton RA, Mikkelsen JG, Paludan SR, Olagnier D. SAM68 directs STING signaling to apoptosis in macrophages. Commun Biol 2024; 7:283. [PMID: 38454028 PMCID: PMC10920828 DOI: 10.1038/s42003-024-05969-1] [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: 03/10/2023] [Accepted: 02/23/2024] [Indexed: 03/09/2024] Open
Abstract
DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.
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Affiliation(s)
- Demi van der Horst
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Naziia Kurmasheva
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Mikkel H S Marqvorsen
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Sonia Assil
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Anna H F Rahimic
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Christoph F Kollmann
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Leandro Silva da Costa
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Qi Wu
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Jian Zhao
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Eleonora Cesari
- GSTEP-Organoids Core Facility, IRCCS Fondazione Policlinico Agostino Gemelli, 00168, Rome, Italy
| | - Marie B Iversen
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Fanghui Ren
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Trine I Jensen
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Ryo Narita
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Vivien R Schack
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Bao-Cun Zhang
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Rasmus O Bak
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Claudio Sette
- GSTEP-Organoids Core Facility, IRCCS Fondazione Policlinico Agostino Gemelli, 00168, Rome, Italy
- Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Hearth, 00168, Rome, Italy
| | - Robert A Fenton
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Jacob G Mikkelsen
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark
| | - Søren R Paludan
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark.
| | - David Olagnier
- Department of Biomedicine, Aarhus University, Høegh Guldbergsgade 10, 8000, Aarhus C, Denmark.
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6
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Liu M, Liu J, Li K, Qiao L, Chen J, Lin Y, Shi Q. Evaluation of the effectiveness of using prednisolone, tacrolimus, and intravenous immunoglobulin combination therapy on immune-mediated necrotizing myopathy-A non-randomized, observational research. Int J Rheum Dis 2024; 27:e15124. [PMID: 38514893 DOI: 10.1111/1756-185x.15124] [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: 08/21/2023] [Revised: 02/05/2024] [Accepted: 03/05/2024] [Indexed: 03/23/2024]
Abstract
OBJECTIVE To recruit immune-mediated necrotizing myopathy (IMNM) patients with extramuscular manifestations who were refractory to initial therapy with either monotherapy with prednisolone or dual therapy with prednisolone and immunosuppressants. These patients subsequently received a combination of prednisolone, tacrolimus, and intravenous immunoglobulin (IVIG), and the efficacy of this treatment regimen was assessed in patients with IMNM. METHOD ①Clinical data and treatment measures are as follows: This study enrolled IMNM patients who were treated at the Neurology Department of the First Medical Center of PLA General Hospital from April 2020 to May 2023. These patients received a combination therapy of prednisolone, tacrolimus, and IVIG. ②Observational indicators included manual muscle test for 8 groups of muscles (MMT-8), muscle enzyme levels (creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and myositis disease activity assessment tool (MDAAT). RESULTS This study enrolled eight patients. All observational indicators declined after treatment compared to before treatment, and these changes were statistically significant. Moreover, extramuscular manifestations also ameliorated compared to before treatment. CONCLUSION The combination therapy of prednisolone, tacrolimus, and IVIG has demonstrated favorable efficacy in IMNM and broadened the treatment options for this disease. However, the results still require further validation by large-scale and randomized controlled studies.
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Affiliation(s)
- Mengyang Liu
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Jiaqi Liu
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Ke Li
- Department of Neurology, The Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Lingya Qiao
- Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China
| | - Juan Chen
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ying Lin
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Qiang Shi
- Department of Neurology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
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Bhat MA, Usman I, Dhaneshwar S. Application of Drug Repurposing Approach for Therapeutic Intervention of Inflammatory Bowel Disease. Curr Rev Clin Exp Pharmacol 2024; 19:234-249. [PMID: 37859409 DOI: 10.2174/0127724328245156231008154045] [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: 02/10/2023] [Revised: 07/07/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023]
Abstract
Inflammatory bowel disease (IBD), represented by Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract (GIT) characterized by chronic relapsing intestinal inflammation, abdominal pain, cramping, loss of appetite, fatigue, diarrhoea, and weight loss. Although the etiology of IBD remains unclear, it is believed to be an interaction between genes, and environmental factors, such as an imbalance of the intestinal microbiota, changing food habits, an ultra-hygiene environment, and an inappropriate immune system. The development of novel effective therapies is stymied by a lack of understanding of the aetiology of IBD. The current therapy involves the use of aminosalicylates, immunosuppressants, and corticosteroids that can effectively manage symptoms, induce and sustain remission, prevent complications, modify the course of the disease, provide diverse treatment options, showcase advancements in biologic therapies, and enhance the overall quality of life. However, the efficacy of current therapy is overshadowed by a plethora of adverse effects, such as loss of weight, mood swings, skin issues, loss of bone density, higher vulnerability to infections, and elevated blood pressure. Biologicals, like anti-tumour necrosis factor agents, can stimulate an autoimmune response in certain individuals that may diminish the effectiveness of the medication over time, necessitating a switch to alternative treatments. The response of IBD patients to current drug therapy is quite varied, which can lead to disease flares that underlines the urgent need to explore alternative treatment option to address the unmet need of developing new treatment strategies for IBD with high efficacy and fewer adverse effects. Drug repurposing is a novel strategy where existing drugs that have already been validated safe in patients for the management of certain diseases are redeployed to treat other, unindicated diseases. The present narrative review focuses on potential drug candidates that could be repurposed for the management of IBD using on-target and off-target strategies. It covers their preclinical, clinical assessment, mechanism of action, and safety profiles, and forecasts their appropriateness in the management of IBD. The review presents useful insights into the most promising candidates for repurposing, like anti-inflammatory and anti-apoptotic troxerutin, which has been found to improve the DSS-induced colitis in rats, an antiosteoarthritic drug diacetylrhein that has been found to have remarkable ameliorating effects on DSS-induced colitis via anti-oxidant and anti- inflammatory properties and by influencing both apoptosis and pyroptosis. Topiramate, an antiepileptic and anticonvulsant drug, has remarkably decreased overall pathophysiological and histopathological events in the experimental model of IBD in rodents by its cytokine inhibitory action.
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Affiliation(s)
- Mohammad Aadil Bhat
- Department of Pharmacology, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, UP, Noida, India
| | - Iqra Usman
- Department of Pharmacology, Amity Institute of Pharmacy, Lucknow, Amity University Uttar Pradesh, UP, Noida, India
| | - Suneela Dhaneshwar
- Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Maharashtra, Mumbai, Maharashtra, India
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Lackner K, Ebner S, Watschinger K, Maglione M. Multiple Shades of Gray-Macrophages in Acute Allograft Rejection. Int J Mol Sci 2023; 24:8257. [PMID: 37175964 PMCID: PMC10179242 DOI: 10.3390/ijms24098257] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Long-term results following solid organ transplantation do not mirror the excellent short-term results achieved in recent decades. It is therefore clear that current immunosuppressive maintenance protocols primarily addressing the adaptive immune system no longer meet the required clinical need. Identification of novel targets addressing this shortcoming is urgently needed. There is a growing interest in better understanding the role of the innate immune system in this context. In this review, we focus on macrophages, which are known to prominently infiltrate allografts and, during allograft rejection, to be involved in the surge of the adaptive immune response by expression of pro-inflammatory cytokines and direct cytotoxicity. However, this active participation is janus-faced and unspecific targeting of macrophages may not consider the different subtypes involved. Under this premise, we give an overview on macrophages, including their origins, plasticity, and important markers. We then briefly describe their role in acute allograft rejection, which ranges from sustaining injury to promoting tolerance, as well as the impact of maintenance immunosuppressants on macrophages. Finally, we discuss the observed immunosuppressive role of the vitamin-like compound tetrahydrobiopterin and the recent findings that suggest the innate immune system, particularly macrophages, as its target.
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Affiliation(s)
- Katharina Lackner
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.L.); (S.E.)
| | - Susanne Ebner
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.L.); (S.E.)
| | - Katrin Watschinger
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Manuel Maglione
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.L.); (S.E.)
- Department of Visceral, Transplant, and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
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9
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Nicotine Exerts a Stronger Immunosuppressive Effect than Its Structural Analogs and Regulates Experimental Colitis in Rats. Biomedicines 2023; 11:biomedicines11030922. [PMID: 36979901 PMCID: PMC10046003 DOI: 10.3390/biomedicines11030922] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. To achieve this objective, we compared the effects of nicotine with those of structural nicotine analogs in a UC rodent model (Slc: Wistar rats, male, 9-week-old, and 220–250 g/rat). Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis. Examining the colon tissues of model rats, we compared disease severity, cytokine secretion, and α7 nicotine acetylcholine receptor (nAChR7) expression. We observed that nicotine administration induced weight loss at 2.35% in 10 days. Notably, the reduction in histological severity (score) of UC was more pronounced in rats treated with nicotine (score = 4.83, p = 0.042) than in untreated rats (score = 8.17). Nicotine administration increased nAChR7 expression 6.88-fold (p = 0.022) in inflammatory sites of the colon, mainly by suppressing the production of interleukin (IL)-1β and IL-6. Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ.
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10
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Lv W, Zhang D, He T, Liu Y, Shao L, Lv Z, Pu X, Wang Y, Liu L. Combination of Lactobacillus plantarum improves the effects of tacrolimus on colitis in a mouse model. Front Cell Infect Microbiol 2023; 13:1130820. [PMID: 36992690 PMCID: PMC10040537 DOI: 10.3389/fcimb.2023.1130820] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/06/2023] [Indexed: 03/14/2023] Open
Abstract
The gut microbiome has been considered to play an important role in inflammatory bowel disease (IBD). Our previous study reported that tacrolimus-altered gut microbiota elicited immunoregulatory effects in both colonic mucosa and circulation, contributing to an increased allograft survival rate in mice. Here, we aimed to observe the changes in the tacrolimus-induced microbiome in a dextran sulfate sodium (DSS)-induced colitis mouse model and explore the possibility and efficacy of combination therapy with tacrolimus and the microbiome on colitis. Mice were divided into the control, DSS, tacrolimus monotherapy and tacrolimus plus Lactobacillus plantarum 550 (Lacto)-treated groups. The body weight, stool consistency, hematochezia and survival of mice were observed daily. Total RNA from colonic mucosa was extracted and subjected to transcriptome sequencing. Cecal contents were collected and the 16S rRNA sequencing was performed to characterize the gut microbiome and the ultrahigh- performance liquid chromatography-MS/MS (UHPLC-MS/MS) was used for targeted quantification of bile acids. The results confirmed that tacrolimus significantly ameliorated DSS-induced colitis in mice. Beneficial alterations of the gut microbiome characterized by a remarkable expansion of the genus Lactobacillus were induced by tacrolimus treatment. Oral supplementation with Lacto further improved the tacrolimus-mediated suppression of body weight loss in colitis, while the survival time of mice was further prolonged and the inflammation of colonic mucosa was obviously relieved. The immune and inflammation-related signaling pathways, including IFN-γ and IFN-α response, allograft rejection, IL2 STAT5 signaling and the inflammatory response pathways, were further downregulated in the tacrolimus plus Lacto cotreatment group. Cotreatment also improved the diversity of the gut microbiome and rescued the concentration of taurochenodeoxycholic acid (TCDCA) in colitis. The latter was positively correlated with the abundance of Lactobacillus but negatively related to the disease activity index score. Overall, our results indicated that Lactobacillus plantarum promoted the therapeutic effect of tacrolimus in experimental colitis, offering a promising strategy to combine tacrolimus and Lactobacillus in the treatment of colitis patients.
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Affiliation(s)
- Wei Lv
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Di Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Tian He
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingying Liu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Limei Shao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhongping Lv
- Technology Research Institute of Shuxi Condiments of Sichuan Cuisine Co. LTD, Chengdu, Sichuan, China
| | - Xiaoping Pu
- Technology Research Institute of Shuxi Condiments of Sichuan Cuisine Co. LTD, Chengdu, Sichuan, China
| | - Yufang Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- *Correspondence: Yufang Wang, ; Ling Liu,
| | - Ling Liu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- *Correspondence: Yufang Wang, ; Ling Liu,
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11
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Wang Y, Yan Z, Liu W, Liu C, Xu N, Wu Y, Sun F, Wang X, Qian Y, Jiang L, Sun X. Biomechanically-Adapted Immunohydrogels Reconstructing Myelin Sheath for Peripheral Nerve Regeneration. Adv Healthc Mater 2022; 11:e2201596. [PMID: 35920510 DOI: 10.1002/adhm.202201596] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/28/2022] [Indexed: 01/28/2023]
Abstract
Myelin sheath reconstruction plays an important role in peripheral nerve regeneration. But the hindered reconstruction of myelin sheath, due to the inadequate repair phenotypes of macrophages and Schwann cells after peripheral nerve injury, often causes poor functional nerve recovery. Here, biomechanically-adapted immunohydrogels are prepared as the FK506-loaded platforms and nerve tissue engineering scaffolds to reconstruct myelin sheath for peripheral nerve regeneration. By immunofluorescent staining, an increase in the proportion of F4/80+ markers reveals that the biomechanically-adapted scaffolds facilitate recruitment of macrophages. Furthermore, the high Interleukin 10 (IL-10) mRNA expression level suggests the anti-inflammation learning effects of FK506 in vitro, which is further confirmed by a high CD206/TNF-α ratio in the FK506 Gel group in vivo. The immune learning effects are positively related to the increase in compactness and thickness of myelin sheath, indicating the synergy of structural reconstruction of myelin sheath and M2 phenotype polarization of macrophages. All these data indicate that the biomechanically-adapted immunohydrogels enhance recruitment of macrophages, educate M2 polarization of macrophages and promote a neuroprotective environment, which in consequence reconstructs myelin sheath for peripheral nerve regeneration.
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Affiliation(s)
- Yifan Wang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Zhiwen Yan
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, P. R. China.,Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, 200233, P. R. China
| | - Wenjun Liu
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, P. R. China.,Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, 200233, P. R. China
| | - Chunlin Liu
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Nan Xu
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Yixian Wu
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Fengbo Sun
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Xiumei Wang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Yun Qian
- Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, P. R. China.,Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, 200233, P. R. China
| | - Le Jiang
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
| | - Xiaodan Sun
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China.,Key Laboratory of Advanced Materials of Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, P. R. China
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12
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Shimada T, Higashida-Konishi M, Akiyama M, Hama S, Izumi K, Matsubara S, Oshima H, Okano Y. Immune-mediated necrotizing myopathy which showed deposition of C5b-9 in the necrotic muscle fibers and was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins. Immunol Med 2022; 45:175-179. [PMID: 35389818 DOI: 10.1080/25785826.2022.2060169] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Currently, no standard treatment strategy has been established for immune-mediated necrotizing myopathy (IMNM). Here we present a case of IMNM which was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins. Her muscle weakness was rapidly progressive and severe so that she became bedridden one week after admission. She was complicated with dysphagia and had serum myogenic enzymes elevation, ventricular diastolic dysfunction, and interstitial lung disease. Serum anti-SRP antibody was positive and her muscle biopsy revealed many necrotic fibers with minimal inflammation. Further histological analysis demonstrated infiltration of phagocytic macrophages with deposition of membrane attack complex (C5b-9) in the necrotic muscle fibers, suggesting activation of complement pathway and macrophages as a pathomechanism of this disease. She was diagnosed as IMNM and was immediately initiated a combination therapy described above, which led to dramatic clinical improvements. Recent studies suggest that intravenous immunoglobulins and tacrolimus can inhibit the activation of complement pathway and macrophages. Our present case suggests that early initiation of intensive combined therapy including intravenous immunoglobulins and tacrolimus might be effective for preventing irreversible muscle damages by disrupting a pathogenic activation of complement and macrophages in IMNM.
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Affiliation(s)
- Tatsuya Shimada
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.,Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Misako Higashida-Konishi
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Mitsuhiro Akiyama
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.,Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Satoshi Hama
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Keisuke Izumi
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.,Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Shiro Matsubara
- Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
| | - Hisaji Oshima
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Yutaka Okano
- Department of Medicine, Division of Rheumatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
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13
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Okada K, Ikemoto M. Carbonic Anhydrase III Has Potential as a Biomarker for Experimental Colitis and Functions as an Immune Regulator by Inhibiting Inflammatory Cytokine Secretion. BIOLOGY 2022; 11:biology11040494. [PMID: 35453694 PMCID: PMC9029778 DOI: 10.3390/biology11040494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/19/2022] [Accepted: 03/21/2022] [Indexed: 11/22/2022]
Abstract
Simple Summary The mechanism underlying the onset of ulcerative colitis (UC) has not yet been elucidated in detail. Unknown components in colorectal tissue may be important risk factors to elucidate the cause of UC; however, they have not been highlighted as targets. To identify key factors, rats with dextran sulfate sodium-induced experimental colitis were used. The level of carbonic anhydrase III was significantly decreased in both the serum and colon tissues of these UC rats. Upon stimulation of peritoneal macrophages (MΦ) with lipopolysaccharide, the intracellular concentration of carbonic anhydrase III significantly decreased, while the secretion of pro-inflammatory cytokines from MΦ treated with an anti-carbonic anhydrase III antibody was negatively regulated. In conclusion, carbonic anhydrase III may be a novel regulator of experimental colitis in rats. Abstract Ulcerative colitis (UC) is characterized by chronic inflammation of the large intestine, repeated remissions, and symptom relapses. Although unknown components in colonic regions are deeply involved in the pathogenesis of UC, the causes of UC development and aggravation have not yet been elucidated in detail. To identify key factors, we investigated the changes in protein components in the large intestine of rats with dextran sulfate sodium-induced experimental colitis (UCR). The components that differed in their concentration between normal rats (WT) and UCR were carefully investigated by electrophoretic separation and mass spectrometry. Based on these results, seven proteins with different expression levels between the WT and UCR were observed. Among them, we focused on carbonic anhydrase III (CA-III) in the pathogenesis of UC. CA-III concentrations in the colon tissue and serum were quantitatively measured using an enzyme-linked immunosorbent assay (ELISA) and real-time PCR, and the levels significantly decreased in both the colon tissue and serum of UCR with the aggravation of experimental UC. In an in vitro assay, CA-III function in peritoneal macrophages (MΦ) from rats was investigated. Upon stimulation of MΦ with lipopolysaccharide (LPS), the CA-III concentration significantly decreased in the cytoplasm of these cells. MΦ treated with an anti-CAIII antibody followed by stimulation with LPS actively secreted inflammatory cytokines, particularly interleukin-6 and tumor necrosis factor-α. Therefore, CA-III in MΦ appears to be an immune regulator that suppresses the secretion of inflammatory cytokines.
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Affiliation(s)
- Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
- Correspondence:
| | - Masaki Ikemoto
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan;
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14
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Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne) 2021; 8:765474. [PMID: 34988090 PMCID: PMC8720971 DOI: 10.3389/fmed.2021.765474] [Citation(s) in RCA: 212] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/29/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD), as a global disease, has attracted much research interest. Constant research has led to a better understanding of the disease condition and further promoted its management. We here reviewed the conventional and the novel drugs and therapies, as well as the potential ones, which have shown promise in preclinical studies and are likely to be effective future therapies. The conventional treatments aim at controlling symptoms through pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, with other general measures and/or surgical resection if necessary. However, a considerable fraction of patients do not respond to available treatments or lose response, which calls for new therapeutic strategies. Diverse therapeutic options are emerging, involving small molecules, apheresis therapy, improved intestinal microecology, cell therapy, and exosome therapy. In addition, patient education partly upgrades the efficacy of IBD treatment. Recent advances in the management of IBD have led to a paradigm shift in the treatment goals, from targeting symptom-free daily life to shooting for mucosal healing. In this review, the latest progress in IBD treatment is summarized to understand the advantages, pitfalls, and research prospects of different drugs and therapies and to provide a basis for the clinical decision and further research of IBD.
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Affiliation(s)
- Zhaobei Cai
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
- Department of Gastroenterology and Hepatology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Shu Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
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15
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Alberca RW, Benard G, Alberca GGF, Sato MN. SARS-CoV-2 infection in liver transplant recipients: A complex relationship. World J Gastroenterol 2021; 27:7734-7738. [PMID: 34908810 PMCID: PMC8641049 DOI: 10.3748/wjg.v27.i44.7734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/14/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023] Open
Abstract
The recent manuscript reviewed investigations involving liver damage in coronavirus disease 2019 (COVID-19) patients, and COVID-19 in patients with previous chronic hepatological diseases, such as patients with liver graft. The literature presents several conflicting results concerning the anti-SARS-CoV-2 response in patients with solid organ transplants, in liver transplant recipients. Therefore, we would like to humbly state a few points for consideration involving liver transplant recipients and COVID-19, such as the time since transplantation, comorbidities, and immunosuppressive regimens.
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Affiliation(s)
- Ricardo Wesley Alberca
- Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia e Institute de Medicina Tropical, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
| | - Gil Benard
- Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
| | - Gabriela Gama Freire Alberca
- Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
| | - Maria Notomi Sato
- Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
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16
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Okada K, Ikemoto M. A New Hybrid Protein Is a Novel Regulator for Experimental Colitis in Rats. Inflammation 2021; 45:180-195. [PMID: 34628574 PMCID: PMC8502114 DOI: 10.1007/s10753-021-01537-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 08/06/2021] [Indexed: 11/26/2022]
Abstract
We newly developed a hybrid protein, tentatively named rMIKO-1, using gene technology. We herein investigated the effects of rMIKO-1 on activated macrophages and discussed its potential as a suppressor of experimental colitis. Fluorescent microscopy was used to observe the dynamic mobility of rMIKO-1 in macrophages. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, fluorescent immunochemical staining, flow cytometry, enzyme-linked immunosorbent assays, a polymerase chain reaction/quantitative polymerase chain reaction, and hematoxylin and eosin staining were conducted to assess the potential activity of rMIKO-1. A large amount of bleeding was observed in rats treated with 5% dextran sulfate sodium (DSS) alone on day 8 after treatment initiation, but not in those treated with 5% DSS plus rMIKO-1. In the in vitro assay, rMIKO-1 rapidly bound to macrophages, immediately entered cells by an unknown mechanism, and then migrated inside the nucleus. This result suggests that rMIKO-1 plays important immunological roles in the nucleus. Despite the activation of macrophages by lipopolysaccharide, the mRNA expression of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, was significantly suppressed in macrophages preliminarily treated with rMIKO-1 for 1 h. Complexes of rMIKO-1 with nuclear factor-kappa B (NF-κB)/p65 and β-actin formed in activated macrophages, which attenuated experimental colitis in rats. These results strongly suggest that rMIKO-1 negatively regulates excessively activated macrophages through the NF-κB/p65 signaling pathway. Therefore, rMIKO-1 is a novel suppressor of experimental colitis in rats through the negative regulation of activated macrophages.
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Affiliation(s)
- Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, 34 Yamada-cho Oyake Yamashina-ku, Kyoto, 607-8175 Japan
| | - Masaki Ikemoto
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama-shi, Shiga, Tamuracho 1266526-0829 Japan
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17
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Okada K, Itoh H, Ikemoto M. Serum complement C3 and α 2-macroglobulin are potentially useful biomarkers for inflammatory bowel disease patients. Heliyon 2021; 7:e06554. [PMID: 33851052 PMCID: PMC8022144 DOI: 10.1016/j.heliyon.2021.e06554] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 01/10/2021] [Accepted: 03/16/2021] [Indexed: 10/25/2022] Open
Abstract
Aims Ulcerative colitis (UC), characterized by chronic inflammation and its recurrence in the large intestine, is well known as inflammatory bowel disease (IBD). Suitable biomarkers specific for UC are poorly understood till date. We aimed to discover novel serum biomarkers for UC and identify good indicators that reflected the severity of UC. Main methods Serum samples were obtained from out-patients with IBD (n = 101) and healthy volunteers (HVs, n = 101). Serum proteins were subjected to high performance liquid chromatography (HPLC) and sodium dodecyl sulfate-electrophoresis (SDS-PAGE) analysis. After electrophoresis, proteins in the gel were identified by mass spectrometry. Further, the protein concentration was measured by enzyme-linked immunosorbent assays (ELISAs). Based on the results, correlations between the serum levels of these proteins and the disease activity index scores for UC were statistically evaluated. Principal findings HPLC showed that chromatograms of serum proteins from HVs apparently differed from those of patients with IBD. Eleven protein bands, which were different in their protein concentrations from those in HVs, were separated by SDS-PAGE accordingly. Among them, complement C3 (c-C3) and α2-macroglobulin (α2-MG), with high protein scores, were identified by mass spectrometry. The serum concentration of c-C3 in patients with IBD was higher than that in HVs. However, the level of α2-MG in patients with IBD was significantly lower than that in HVs. Hence, the serum levels of c-C3 and α2-MG could be good indicators of the severity of UC. Conclusion Serum c-C3 and α2-MG are suitable biomarkers for monitoring the condition of patients with UC.
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Affiliation(s)
- Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto 607-8175, Japan
| | - Hiroshi Itoh
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Shiga 526-0829, Japan
| | - Masaki Ikemoto
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Shiga 526-0829, Japan
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18
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Salem G, Ding K, Sakuraba A, Cohen R. Role of topical tacrolimus in the management of proctitis, perianal manifestations in Crohn's disease, and chronic pouchitis: a systematic review. J Investig Med 2021; 69:jim-2020-001699. [PMID: 33622709 DOI: 10.1136/jim-2020-001699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2021] [Indexed: 11/04/2022]
Abstract
Several published studies have evaluated the safety and effectiveness of oral and intravenous tacrolimus for the management of patients with inflammatory bowel disease (IBD). However, little is known about the effectiveness of topical tacrolimus in this patient population. The aim of this systematic review was to evaluate the current state of literature to evaluate the safety and effectiveness of rectal administration of topical tacrolimus, in the form of suppository, ointment, and/or enema in patients with ulcerative proctitis, perianal Crohn's disease (CD), and chronic refractory pouchitis. Electronic database searches were conducted in international databases since their inception until February 2020. Study subjects were categorized into three groups: topical tacrolimus for patients with proctitis, perianal CD, and chronic refractory pouchitis. The primary end point of this study was the remission rate. Secondary end points were response rate and the incidence of AEs. Eleven studies were included in the final assessment in this systematic review. This provided information from 188 patients. Tacrolimus was administered topically as suppositories, ointment, or enema. Clinical remission was achieved in 57.1%, 57.14%, and 70.0% in patients with proctitis, fistulizing perianal CD, and chronic pouchitis. The most commonly reported side effect was perianal itching and burning. Reversible nephrotoxicity occurred in a single patient. No clear correlation was found between blood levels and clinical outcomes. Topical tacrolimus is effective for a subset of patients with IBD. The adverse effects were minimal and tolerable. Well-designed randomized clinical trials are warranted to establish the appropriate dose and administration method.
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Affiliation(s)
- George Salem
- Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Kai Ding
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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19
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Ueda H, Dozono N, Tanaka K, Kaneko S, Neyama H, Uchida H. Allodynia by Splenocytes From Mice With Acid-Induced Fibromyalgia-Like Generalized Pain and Its Sexual Dimorphic Regulation by Brain Microglia. Front Neurosci 2021; 14:600166. [PMID: 33424538 PMCID: PMC7785978 DOI: 10.3389/fnins.2020.600166] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/24/2020] [Indexed: 12/23/2022] Open
Abstract
Fibromyalgia (FM), a disease of unknown etiology characterized by chronic generalized pain, is partly recapitulated in an animal model induced by repeated acid saline injections into the gastrocnemius muscle. Here, we attempted to investigate the sex difference in pain hypersensitivity (mechanical allodynia and hypersensitivity to electrical stimulation) in the repeated acid saline-induced FM-like generalized pain (AcGP) model. The first unilateral acid injection into gastrocnemius muscle at day 0/D0 and second injection at D5 (post day 0, P0) induced transient and long-lasting mechanical allodynia, respectively, on both sides of male and female mice. The pretreatment with gonadectomy did not affect the first injection-induced allodynia in both sexes, but gradually reversed the second injection-induced allodynia in male but not female mice. Moreover, the AcGP in male mice was abolished by intracerebroventricular minocycline treatments during D4–P4 or P5–P11, but not by early treatments during D0–D5 in male but not female mice, suggesting that brain microglia are required for AcGP in late-onset and sex-dependent manners. We also found that the intravenous treatments of splenocytes derived from male but not female mice treated with AcGP caused allodynia in naive mice. In addition, the purified CD4+ T cells derived from splenocytes of acid-treated male mice retained the ability to cause allodynia in naive mice. These findings suggest that FM-like AcGP has multiple sexual dimorphic mechanisms.
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Affiliation(s)
- Hiroshi Ueda
- Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan.,Department of Molecular Pharmacology, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan
| | - Naoki Dozono
- Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan.,Department of Molecular Pharmacology, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan
| | - Keigo Tanaka
- Department of Molecular Pharmacology, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan
| | - Hiroyuki Neyama
- Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan.,RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Hitoshi Uchida
- Department of Pharmacology and Therapeutic Innovation, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan.,Department of Cellular Neuropathology, Brain Research Institute, Niigata University, Niigata, Japan
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20
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Murakami Y, Fujiya M, Konishi H, Isozaki S, Sugiyama Y, Kobayashi Y, Sasaki T, Kunogi T, Takahashi K, Ando K, Ueno N, Kashima S, Moriichi K, Tanabe H, Okumura T. The Optimal Dose of Tacrolimus in Combination Therapy with an Anti-TNFα Antibody in a Mouse Colitis Model. Biol Pharm Bull 2021; 44:564-570. [PMID: 33790106 DOI: 10.1248/bpb.b20-00916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC + anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC + anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC + anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC + anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC + anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.
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Affiliation(s)
- Yuki Murakami
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University
| | - Hiroaki Konishi
- Department of Gastroenterology and Advanced Medical Sciences, Asahikawa Medical University
| | - Shotaro Isozaki
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Yuya Sugiyama
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Yu Kobayashi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Takahiro Sasaki
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Takehito Kunogi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Keitaro Takahashi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Katsuyoshi Ando
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Nobuhiro Ueno
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Shin Kashima
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Kentaro Moriichi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Hiroki Tanabe
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University
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21
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Seoane-Viaño I, Gómez-Lado N, Lázare-Iglesias H, García-Otero X, Antúnez-López JR, Ruibal Á, Varela-Correa JJ, Aguiar P, Basit AW, Otero-Espinar FJ, González-Barcia M, Goyanes A, Luzardo-Álvarez A, Fernández-Ferreiro A. 3D Printed Tacrolimus Rectal Formulations Ameliorate Colitis in an Experimental Animal Model of Inflammatory Bowel Disease. Biomedicines 2020; 8:E563. [PMID: 33276641 PMCID: PMC7761558 DOI: 10.3390/biomedicines8120563] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
The aim of this study was to fabricate novel self-supporting tacrolimus suppositories using semisolid extrusion 3-dimensional printing (3DP) and to investigate their efficacy in an experimental model of inflammatory bowel disease. Blends of Gelucire 44/14 and coconut oil were employed as lipid excipients to obtain suppository formulations with self-emulsifying properties, which were then tested in a TNBS (2,4,6-trinitrobenzenesulfonic acid) induced rat colitis model. Disease activity was monitored using PET/CT medical imaging; maximum standardized uptake values (SUVmax), a measure of tissue radiotracer accumulation rate, together with body weight changes and histological assessments, were used as inflammatory indices to monitor treatment efficacy. Following tacrolimus treatment, a significant reduction in SUVmax was observed on days 7 and 10 in the rat colon sections compared to non-treated animals. Histological analysis using Nancy index confirmed disease remission. Moreover, statistical analysis showed a positive correlation (R2 = 71.48%) between SUVmax values and weight changes over time. Overall, this study demonstrates the effectiveness of 3D printed tacrolimus suppositories to ameliorate colitis and highlights the utility of non-invasive PET/CT imaging to evaluate new therapies in the preclinical area.
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Affiliation(s)
- Iria Seoane-Viaño
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; (I.S.-V.); (X.G.-O.); (F.J.O.-E.)
- Paraquasil Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Noemí Gómez-Lado
- Nuclear Medicine Department and Molecular Imaging Group, University Clinical Hospital (CHUS) and Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (N.G.-L.); (Á.R.); (P.A.)
| | - Héctor Lázare-Iglesias
- Pathology Department, University Clinical Hospital Santiago de Compostela (SERGAS) (CHUS), 15706 Santiago de Compostela, Spain; (H.L.-I.); (J.R.A.-L.)
| | - Xurxo García-Otero
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; (I.S.-V.); (X.G.-O.); (F.J.O.-E.)
- Nuclear Medicine Department and Molecular Imaging Group, University Clinical Hospital (CHUS) and Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (N.G.-L.); (Á.R.); (P.A.)
| | - José Ramón Antúnez-López
- Pathology Department, University Clinical Hospital Santiago de Compostela (SERGAS) (CHUS), 15706 Santiago de Compostela, Spain; (H.L.-I.); (J.R.A.-L.)
| | - Álvaro Ruibal
- Nuclear Medicine Department and Molecular Imaging Group, University Clinical Hospital (CHUS) and Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (N.G.-L.); (Á.R.); (P.A.)
- Tejerina Foundation, José Abascal 40, 28003 Madrid, Spain
| | - Juan Jesús Varela-Correa
- Pharmacy Department, University Hospital Ourense (SERGAS), Calle Ramón Puga Noguerol 54, 32005 Ourense, Spain;
| | - Pablo Aguiar
- Nuclear Medicine Department and Molecular Imaging Group, University Clinical Hospital (CHUS) and Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (N.G.-L.); (Á.R.); (P.A.)
| | - Abdul W. Basit
- FabRx Ltd., 3 Romney Road, Ashford, Kent TN24 0RW, UK;
- Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
| | - Francisco J. Otero-Espinar
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; (I.S.-V.); (X.G.-O.); (F.J.O.-E.)
- Paraquasil Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Miguel González-Barcia
- Pharmacy Department, University Clinical Hospital Santiago de Compostela (SERGAS) (CHUS), 15706 Santiago de Compostela, Spain;
| | - Alvaro Goyanes
- FabRx Ltd., 3 Romney Road, Ashford, Kent TN24 0RW, UK;
- Department of Pharmaceutics, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Asteria Luzardo-Álvarez
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; (I.S.-V.); (X.G.-O.); (F.J.O.-E.)
- Paraquasil Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Anxo Fernández-Ferreiro
- Pharmacy Department, University Clinical Hospital Santiago de Compostela (SERGAS) (CHUS), 15706 Santiago de Compostela, Spain;
- Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
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22
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Mårtensson T, Szakos A, Mellgren K, Toporski J, Arvidson J, Mattsson J, Gustafsson B, Casswall TH. Diagnostic disagreement between clinical standard histopathological- and retrospective assessment of histopathology-based gastrointestinal graft-versus-host disease in children. Pediatr Transplant 2020; 24:e13824. [PMID: 33085820 DOI: 10.1111/petr.13824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/20/2020] [Accepted: 07/23/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND No previous paediatric study has evaluated the frequency of diagnostic disagreement between clinical standard histopathological assessment (CSHA) and retrospective, independent, histopathological assessment (RIHA) of gastrointestinal Graft-Versus-Host Disease (GI-GVHD) METHODS: In a retrospective cohort study, based on gastrointestinal biopsies collected from allogeneic HSCT-treated children (<18 years) with symptom-based GI-GVHD, we evaluated; disagreement of histopathology-based GI-GVHD diagnosis in CSHA vs RIHA, and potential clinical consequences of differences between the assessments. The CSHA-based diagnoses were retrieved from histopathology reports. The RIHA was performed by one pathologist, blinded to the CSHA outcomes and based on the minimal criteria for histopathology-based GI-GVHD diagnosis by the NIH 2014. RESULTS Seventy children with 92 endoscopic occasions (including 22 re-endoscopies) were enrolled. GI-GVHD was observed in 73% (67/92) of the endoscopies in the RIHA and in 54% (50/92) in the CSHA (P = .014). The RIHA confirmed 94% (47/50) with GI-GVHD and 52% (22/42) with non-GI-GVHD diagnoses, established in the CSHA. Disagreement, that is endoscopic occasions with GI-GVHD solely detected in RIHA or detection of GI-GVHD in CSHA but not in RIHA, was observed in 20/42 (48%) and 3/50 (6%), respectively (McNemar's test, P = .0008). The risk of a subsequent re-endoscopy was higher in endoscopic occasions with GI-GVHD detected in RIHA but not in CSHA vs if non-GI-GVHD were detected in both readings (P = .005). CONCLUSION Our results suggest that in children with symptom-based GI-GVHD without histopathological confirmation in CSHA, a second, NIH 2014 based histopathological assessment should be considered before performing a re-endoscopy.
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Affiliation(s)
- Thomas Mårtensson
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Attila Szakos
- Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Karin Mellgren
- Department of Pediatric Oncology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jacek Toporski
- Department of Pediatrics, Skåne University Hospital, Lund, Sweden
| | - Johan Arvidson
- Department of Women´s and Children´s Health, Uppsala University Children´s Hospital, Uppsala, Sweden
| | - Jonas Mattsson
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Britt Gustafsson
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Thomas H Casswall
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
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23
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Nakase H. Optimizing the Use of Current Treatments and Emerging Therapeutic Approaches to Achieve Therapeutic Success in Patients with Inflammatory Bowel Disease. Gut Liver 2020; 14:7-19. [PMID: 30919602 PMCID: PMC6974326 DOI: 10.5009/gnl18203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 10/06/2018] [Accepted: 10/12/2018] [Indexed: 12/18/2022] Open
Abstract
The current goal of inflammatory bowel disease (IBD) treatment is a symptom-free everyday life accompanied by mucosal healing with minimal use of corticosteroids. Recent therapeutic advances, particularly, the emergence of anti-tumor necrosis factor (anti-TNF) antibodies, have changed the natural history of IBD. Additionally, these advances also led to the emergence of the therapeutic concept of the “treat to target” strategy. With the development of new drugs and clinical trials, not only biologics but also small molecules have been applied to clinical practice to better individualize and optimize therapy. However, if newer drugs, including anti-TNF therapies, are recommended for all patients diagnosed with IBD, a significant number of patients will be overtreated. The basic goal of IBD treatment is still to make the best use of conventional treatments based on IBD pathophysiology. Thus, physicians should be familiar with the modes of action of the available drugs. In this review, the author discusses the existing data for many approved drugs and provide insights for optimizing current treatments for the management of patients with IBD in the era of biologics.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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24
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Pulmonary surfactant and drug delivery: Vehiculization, release and targeting of surfactant/tacrolimus formulations. J Control Release 2020; 329:205-222. [PMID: 33245954 DOI: 10.1016/j.jconrel.2020.11.042] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/19/2020] [Accepted: 11/22/2020] [Indexed: 12/19/2022]
Abstract
This work explores the potential for strategizing pulmonary surfactant (PS) for drug delivery over the respiratory air-liquid interface: the interfacial delivery. The efficacy of PS- and interface-assisted drug vehiculization was determined both in vitro and in vivo using a native purified porcine PS combined with the hydrophobic anti-inflammatory drug Tacrolimus (TAC), a calcineurin inhibitor. In vitro assays were conducted in a novel double surface balance setup designed to emulate compression-expansion dynamics applied to interfacially connected drug donor and recipient compartments. In this setup, PS transported TAC efficiently over air-liquid interfaces, with compression/expansion breathing-like dynamics enhancing rapid interface-assisted diffusion and drug release. The efficacy of PS-assisted TAC vehiculization was also evaluated in vivo in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In anesthetized mice, TAC combined with PS was intra-nasally (i.n) instilled prior administering i.n. LPS. PS/TAC pre-treatment caused greater TAC internalization into a higher number of lung cells obtained from bronchoalveolar lavages (BAL) than TAC pre-treatment alone. Additionally, the PS/TAC combination but not TAC or PS alone attenuated the LPS-induced pro-inflammatory effects reducing cells and proteins in BAL fluid. These findings indicated that PS-mediated increase in TAC uptake blunted the pro-injurious effects of LPS, suggesting a synergistic anti-inflammatory effect of PS/drug formulations. These in vitro and in vivo results establish the potential utility of PS to open novel effective delivery strategies for inhaled drugs.
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25
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Du SY, Huang HF, Li XQ, Zhai LX, Zhu QC, Zheng K, Song X, Xu CS, Li CY, Li Y, He ZD, Xiao HT. Anti-inflammatory properties of uvaol on DSS-induced colitis and LPS-stimulated macrophages. Chin Med 2020; 15:43. [PMID: 32411289 PMCID: PMC7206718 DOI: 10.1186/s13020-020-00322-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/23/2020] [Indexed: 01/01/2023] Open
Abstract
Background Apocynum venetum leaves are used as a kind of phytomedicine and the main ingredient in some traditional Chinese medicine products for the relief of colitis. To understand the bioactive constituents of A. venetum L., we did a phytochemistry study and investigated anti-Inflammatory effects of compounds and explored the underlying mechanisms. Methods We isolated compounds from ethanol extract of A. venetum L. leaf and detected the most effective compound by NO inhibition assay. We investigated anti-Inflammatory effects on dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The disease activity index was determined by scores of body weight loss, diarrhea and rectal bleeding; histological damage was analyzed by H&E staining; macrophages change in the colon were analyzed by immunohistochemistry (IHC); myeloperoxidase activity was measured by myeloperoxidase assay kits; levels of proinflammatory cytokines were determined by qPCR and ELISA; protein production such as COX-2, iNOS, STAT3 and ERK1/2 were determined by western blotting. Results We isolated uvaol from ethanol extract of A. venetum L. leaf and found uvaol has excellent potential of inhibiting NO production. We further found uvaol could attenuate disease activity index (DAI), colon shortening, colon injury, and colonic myeloperoxidase activity in DSS-induced colitis mice. Moreover, uvaol significantly reduces mRNA expression and production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1) and infiltration of macrophages in colonic tissues of colitis mice. Studies on LPS challenged murine macrophage RAW246.7 cells also revealed that uvaol reduces mRNA expression and production of pro-inflammatory cytokines and mediators. Mechanically, uvaol inhibits the pro-inflammatory ERK/STAT3 axis in both inflamed colonic tissues and macrophages. Conclusions A. venetum leaf contains uvaol and uvaol has potent anti-inflammatory effects on DSS-induced experimental colitis and LPS-stimulated RAW264.7 macrophage cells. These results suggest uvaol is a prospective anti-inflammatory agent for colonic inflammation.
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Affiliation(s)
- Shi-Yun Du
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Hai-Feng Huang
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China.,2The Key Laboratory of Pharmacology and Druggability for Natural Medicines, Department of Education, Guizhou Medical University, Guiyang, 550025 Guizhou China
| | - Xian-Qian Li
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China.,3School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China
| | - Li-Xiang Zhai
- 3School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong, China
| | - Qin-Chang Zhu
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Kai Zheng
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Xun Song
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Chen-Shu Xu
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Chen-Yang Li
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Ying Li
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Zhen-Dan He
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China
| | - Hai-Tao Xiao
- 1School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen Key Laboratory of Novel Natural Health Care Products, Innovation Platform for Natural Small Molecule Drugs, Engineering Laboratory of Shenzhen Natural Small Molecule Innovative Drugs, Health Science Center, Shenzhen University, Shenzhen, 518060 China.,2The Key Laboratory of Pharmacology and Druggability for Natural Medicines, Department of Education, Guizhou Medical University, Guiyang, 550025 Guizhou China
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26
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Zhang Y, Yang J, Zhang J, Li S, Zheng L, Zhang Y, Meng H, Zhang X, Wu Z. A bio-inspired injectable hydrogel as a cell platform for real-time glycaemic regulation. J Mater Chem B 2020; 8:4627-4641. [PMID: 32373901 DOI: 10.1039/d0tb00561d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Frequent subcutaneous insulin injection and islet transplantation are promising therapeutic options for type 1 diabetes mellitus. However, poor patient compliance, insufficient appropriate islet β cell donors and body immune rejection limit their clinical applications. The design of a platform capable of encapsulating insulin-secreting cells and achieving real-time blood glucose regulation, is a so far unmet need. Herein, inspired by the natural processes of regulating blood glucose in pancreatic islet β cells, we developed a poly(N-isopropylacrylamide-co-dextran-maleic acid-co-3-acrylamidophenylboronic acid) (P(AAPBA-Dex-NIPAM)) hydrogel as a cell platform with glucose responsiveness and thermo-responsiveness for the therapy of diabetes. This platform showed good biocompatibility against insulin-secreting cells and presented glucose-dependent insulin release behaviour. The bioinspired P(AAPBA6-Dex-NIPAM64) hydrogel had a positive effect on real-time glycaemic regulation, as observed by intraperitoneal glucose tolerance tests. The non-fasting blood glucose of diabetic rats was restored to a normal level during the period of treatment. Additionally, the inflammatory response did not occur after administration of the platform. Collectively, we expected that the bio-mimetic platform combined with an insulin-secreting capability could be a new diabetic treatment strategy.
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Affiliation(s)
- Yu Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
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27
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Nakase H. Treatment of inflammatory bowel disease from the immunological perspective. Immunol Med 2020; 43:79-86. [DOI: 10.1080/25785826.2020.1751934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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28
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Veys KRP, Elmonem MA, Van Dyck M, Janssen MC, Cornelissen EAM, Hohenfellner K, Prencipe G, van den Heuvel LP, Levtchenko E. Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis. J Am Soc Nephrol 2020; 31:1092-1106. [PMID: 32273301 DOI: 10.1681/asn.2019080774] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 02/16/2020] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis. METHODS We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1β, IL-6, IL-18, and chitotriosidase enzyme activity. RESULTS A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications. CONCLUSIONS Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.
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Affiliation(s)
- Koenraad R P Veys
- Division of Pediatric Nephrology, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.,Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Mohamed A Elmonem
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Maria Van Dyck
- Division of Pediatric Nephrology, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Mirian C Janssen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | | - Giusi Prencipe
- Division of Rheumatology and Immuno-Rheumatology Research Laboratories, Bambino Gesù Children's Hospital, Rome, Italy
| | - Lambertus P van den Heuvel
- Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium.,Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Elena Levtchenko
- Division of Pediatric Nephrology, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium .,Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium
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Okada K, Itoh H, Ikemoto M. Circulating S100A8/A9 is potentially a biomarker that could reflect the severity of experimental colitis in rats. Heliyon 2020; 6:e03470. [PMID: 32140589 PMCID: PMC7052069 DOI: 10.1016/j.heliyon.2020.e03470] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/17/2019] [Accepted: 02/11/2020] [Indexed: 01/14/2023] Open
Abstract
Aims The clinical significance of circulating S100A8/A9 (calprotectin) in patients with ulcerative colitis (UC) is poorly understood. We examined whether serum S100A8/A9 is a good biomarker for UC, and whether the serum level is a useful index for the severity of the disease. Main methods Experimental animal (rats) were used to verify clinical significance of serum S100A8/A9 as a biomarker. Rats treated with 5% dextran sulfate sodium (DSS) alone (UCR) or with 5%DSS plus tacrolimus (TMR) were subjected to the experiment. The serum concentrations of rat S100A8/A9 (r-S100A8/A9) and other inflammatory biomarkers, such as C-reactive protein (CRP) and inflammatory cytokines, in the both groups were measured using enzyme-linked immunosorbent assays (ELISAs). The tissue damage in the large intestinal tract was visualized by hematoxylin-eosin staining. The relationship between the serum concetrations of these inflammatory biomarkers and the histological scores of the rectal tissue was statistically analyzed. Principle findings As determined by the ELISAs, the serum concentration of r-S100A8/A9 in the UCR hardly correlated with those of not only CRP but also some inflammatory cytokines. The deterioration of the rectal tissue, mainly epithelium structure of a large intestine, in the UCR was clearly observed, but was not so severe as that in the TMR. The histological scores of the rectal tissue in the UCR significantly correlated with the serum level of r-S100A8/A9, but not with other inflammatory biomarkers. Furthermore, macrophages actively produced r-S100A8/A9 in response to stimulation with lipopolysaccharide and quickly secreted it in circulation. Therefore, the serum level of r-S100A8/A9 suggestively changes in accordance with the severity of experimental UC. Conclusion Circulating r-S100A8/A9 is a useful biomarker for experimental UC, and its serum level correlates with the disease severity as judged by histological score.
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Affiliation(s)
- Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto, 607-8175, Japan
- Corresponding author.
| | - Hiroshi Itoh
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Shiga, 526-0829, Japan
| | - Masaki Ikemoto
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Shiga, 526-0829, Japan
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Okada K, Okabe M, Kimura Y, Itoh H, Ikemoto M. Serum S100A8/A9 as a Potentially Sensitive Biomarker for Inflammatory Bowel Disease. Lab Med 2020; 50:370-380. [PMID: 30994906 DOI: 10.1093/labmed/lmz003] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The clinical significance of human S100A8/A9 (h-S100A8/A9) in patients with inflammatory bowel disease (IBD) is poorly understood. OBJECTIVE To clarify whether serum S100A8/A9 is a sensitive biomarker for IBD. METHODS Serum specimens from outpatients with IBD (n = 101) and healthy volunteers (HVs) (n = 101) were used in this study. Enzyme-linked immunosorbent assays for h-S100A8/A9 and inflammatory cytokines were performed using these specimens. Further, correlation analysis was performed to investigate the significance of h-S100A8/A9 fluctuation in patients with IBD. RESULTS The average of serum h-S100A8/A9 concentration in outpatients with IBD was significantly higher than that in HVs. The concentration of h-S100A8/A9 in patients with IBD was barely correlated with that of CRP and inflammatory cytokines. Despite that finding, the serum level of h-S100A8/A9 in patients with ulcerative colitis (UC) was correlated with the severity of IBD, compared with other inflammatory proteins. CONCLUSION Serum h-S100A8/A9 is superior to CRP as a sensitive biomarker for IBD.
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Affiliation(s)
- Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto, Japan.,Department of Clinical Laboratory Science, Faculty of Health Care, Tenri Health Care University, Tenri, Japan
| | - Makoto Okabe
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuto Kimura
- Department of Gastroenterology, Tenri Hospital, Tenri, Japan
| | - Hiroshi Itoh
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
| | - Masaki Ikemoto
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
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Iida T, Nojima M, Nakase H. Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis. Dig Dis Sci 2019; 64:2945-2954. [PMID: 30982208 DOI: 10.1007/s10620-019-05619-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 04/08/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. METHODS We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. RESULTS The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. CONCLUSION This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.
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Affiliation(s)
- Tomoya Iida
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Masanori Nojima
- Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
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Abstract
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that presents as a late sequela from traumatic brain injury (TBI). TBI is a growing and under-recognized public health concern with a high degree of morbidity and large associated global costs. While the immune response to TBI is complex, its contribution to the development of CTE remains largely unknown. In this review, we summarize the current understanding of the link between CTE and the resident innate immune system of the brain-microglia. We discuss the neuropathology underlying CTE including the creation and aggregation of phosphorylated tau protein into neurofibrillary tangles and the formation of amyloid beta deposits. We also present how microglia, the resident innate immune cells of the brain, drive the continuous low-level inflammation associated with the insidious onset of CTE. In this review, we conclude that the latency period between the index brain injury and the long-term development of CTE presents an opportunity for therapeutic intervention. Encouraging advances with microtubule stabilizers, cis p-tau antibodies, and the ability to therapeutically alter the inflammatory state of microglia have shown positive results in both animal and human trials. Looking forward, recent advancements in next-generation sequencing technology for the study of genomic, transcriptomic, and epigenetic information will provide an opportunity for significant advancement in our understanding of prorepair and pro-injury gene signatures allowing for targeted intervention in this highly morbid injury process.
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Mencarelli A, Vacca M, Khameneh HJ, Acerbi E, Tay A, Zolezzi F, Poidinger M, Mortellaro A. Calcineurin B in CD4 + T Cells Prevents Autoimmune Colitis by Negatively Regulating the JAK/STAT Pathway. Front Immunol 2018. [PMID: 29515579 PMCID: PMC5826051 DOI: 10.3389/fimmu.2018.00261] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Calcineurin (Cn) is a protein phosphatase that regulates the activation of the nuclear factor of activated T-cells (NFAT) family of transcription factors, which are key regulators of T-cell development and function. Here, we generated a conditional Cnb1 mouse model in which Cnb1 was specifically deleted in CD4+ T cells (Cnb1CD4 mice) to delineate the role of the Cn–NFAT pathway in immune homeostasis of the intestine. The Cnb1CD4 mice developed severe, spontaneous colitis characterized at the molecular level by an increased T helper-1-cell response but an unaltered regulatory T-cell compartment. Antibiotic treatment ameliorated the intestinal inflammation observed in Cnb1CD4 mice, suggesting that the microbiota contributes to the onset of colitis. CD4+ T cells isolated from Cnb1CD4 mice produced high levels of IFNγ due to increased activation of the JAK2/STAT4 pathway induced by IL-12. Our data highlight that Cn signaling in CD4+ T cells is critical for intestinal immune homeostasis in part by inhibiting IL-12 responsiveness of CD4+ T cells.
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Affiliation(s)
- Andrea Mencarelli
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Maurizio Vacca
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Hanif Javanmard Khameneh
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Enzo Acerbi
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Alicia Tay
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Francesca Zolezzi
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Michael Poidinger
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Alessandra Mortellaro
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Okada K, Itoh H, Kamikubo Y, Adachi S, Ikemoto M. Establishment of S100A8 Transgenic Rats to Understand Innate Property of S100A8 and Its Immunological Role. Inflammation 2017; 41:59-72. [DOI: 10.1007/s10753-017-0664-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Hu Y, Yang B, Xu Y, Jiang L, Tsui CK, Liang X. FK506 suppresses hypoxia‑induced inflammation and protects tight junction function via the CaN‑NFATc1 signaling pathway in retinal microvascular epithelial cells. Mol Med Rep 2017; 16:6974-6980. [PMID: 28901449 DOI: 10.3892/mmr.2017.7475] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 05/24/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to identify whether FK506 suppresses hypoxia‑induced inflammation and protects tight junction function via the calcineurin‑nuclear factor of activated T‑cells 1 (CaN‑NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans‑epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions. The concentrations of inflammatory cytokines were measured using reverse transcription‑quantitative polymerase chain reaction analysis and enzyme‑linked immunosorbent assays. The protein expression levels of zonula occludens‑1 (ZO‑1) and nuclear factor of activated T‑cell 1 (NFATc1) were identified using immunofluorescent microscopy and western blot analysis. The TEER value was decreased following hypoxia, but increased following treatment with FK506 (1 and 10 µM) for 24 and 48 h. The protein expression of ZO‑1 was also increased following FK506 treatment for 24 h at 1 and 10 µM. By contrast, following treatment with FK506 (1 and 10 µM) for 24 and 48 h, the elevated cell permeability in the hypoxia group was significantly downregulated. Similarly, the concentrations of inflammatory cytokines, including cyclooxygenase‑2, inducible nitric oxide synthase, monocyte chemoattractant protein‑1, interleukin‑6, intercellular adhesion molecule‑1 and vascular cell adhesion molecule‑1, were downregulated following treatment with FK506 for 24 h at 1 and 10 µM. Following treatment with FK506, the level of total NFATc1 was downregulated and the level of phosphorylated NFATc1 was upregulated. Taken together, FK506 suppressed injury to the tight junctions and downregulated the expression of inflammatory cytokines in hypoxia‑induced mRMECs via the CaN‑NFATc1 signaling pathway. This suggests a potentially effective therapy for hypoxia‑induced retinal microangiopathy.
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Affiliation(s)
- Yaguang Hu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China
| | - Boyu Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China
| | - Yue Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China
| | - Li Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China
| | - Ching-Kit Tsui
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China
| | - Xiaoling Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China
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Cyclosporine-immunosuppression does not affect survival of transplanted skin-derived precursor Schwann cells in the injured rat spinal cord. Neurosci Lett 2017; 658:67-72. [PMID: 28843345 DOI: 10.1016/j.neulet.2017.08.045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/01/2017] [Accepted: 08/17/2017] [Indexed: 12/16/2022]
Abstract
A major goal of Schwann cell (SC) transplantation for spinal cord injury (SCI) is to fill the injury site to create a bridge for regenerating axons. However, transplantation of peripheral nerve SCs requires an invasive biopsy, which may result in nerve damage and donor site morbidity. SCs derived from multipotent stem cells found in skin dermis (SKP-SCs) are a promising alternative. Regardless of source, loss of grafted SCs post-grafting is an issue in studies of regeneration, with survival rates ranging from ∼1 to 20% after ≥6 weeks in rodent models of SCI. Immune rejection has been implicated in these low survival rates. Therefore, our aim was to explore the role of the immune response on grafted SKP-SC survival in Fischer rats with a spinal hemisection injury. We compared SKP-SC survival 6 weeks post-transplantation in: (I) cyclosporine-immunosuppressed rats (n=8), (II) immunocompetent rats (n=9), and (III) rats of a different sub-strain than the SKP-SC donor rats (n=7). SKP-SC survival was similar in all groups, suggesting immune rejection was not a main factor in SKP-SC loss observed in this study. SKP-SCs were consistently found on laminin expressed at the injury site, indicating detachment-mediated apoptosis (i.e., anoikis) might play a major role in grafted cell loss.
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Tacrolimus downregulates inflammation by regulating pro‑/anti‑inflammatory responses in LPS‑induced keratitis. Mol Med Rep 2017; 16:5855-5862. [PMID: 28849181 PMCID: PMC5865761 DOI: 10.3892/mmr.2017.7353] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 07/12/2017] [Indexed: 01/28/2023] Open
Abstract
Lipopolysaccharide (LPS)-induced keratitis is a progressive infectious ocular disease in which innate inflammatory responses often cause clinical tissue damage and vision loss. The present study aimed to investigate the effects of tacrolimus, an effective immunomodulator, on LPS-induced innate immune responses. The effects of tacrolimus on the apoptotic rate and viability of human corneal epithelial cells (HCECs), polymorphonuclear neutrophils (PMNs) and monocytes (THP-1 cells) were examined using flow cytometry and MTT assays. Subsequently, the role of tacrolimus on LPS-induced inflammation in HCECs, PMNs and THP-1 cells was evaluated by detecting the expression levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6 and matrix metallopeptidase 9; anti-inflammatory cytokines, including IL-10 and transforming growth factor-β; and proangiogenic factors, including vascular endothelial growth factor and tumor necrosis factor-α using quantitative polymerase chain reaction. The results demonstrated that tacrolimus had good biocompatibility with HCECs, while promoting apoptosis and decreasing the viability of PMNs and THP-1 cells. Furthermore, tacrolimus effectively reduced the expression levels of pro-inflammatory cytokines and increased anti-inflammatory cytokines in LPS-induced keratitis in vitro. Notably, tacrolimus decreased the levels of proangiogenic factors, which are highly increased following LPS stimulation. Conclusively, tacrolimus appears to be a safe and effective treatment to suppress neutrophil and monocyte activity, modulate the balance of pro-/anti-inflammatory cytokines, and reduce the inflammatory response and angiogenic activity in LPS-induced bacterial keratitis.
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Murata K, Motomura Y, Tanaka T, Kanno S, Yano T, Onimaru M, Shimoyama A, Nishio H, Sakai Y, Oh-Hora M, Hara H, Fukase K, Takada H, Masuda S, Ohga S, Yamasaki S, Hara T. Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signalling pathway in a murine model of Kawasaki disease. Clin Exp Immunol 2017. [PMID: 28640392 DOI: 10.1111/cei.13002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.
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Affiliation(s)
- K Murata
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Y Motomura
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - T Tanaka
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - S Kanno
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - T Yano
- Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
| | - M Onimaru
- Division of Pathophysiological and Experimental Pathology, Department of Pathology, Kyushu University, Fukuoka, Japan
| | - A Shimoyama
- Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan
| | - H Nishio
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Y Sakai
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - M Oh-Hora
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - H Hara
- Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - K Fukase
- Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan
| | - H Takada
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - S Masuda
- Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
| | - S Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - S Yamasaki
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - T Hara
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.,Fukuoka Children's Hospital, Fukuoka, Japan
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Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models. Sci Rep 2016; 6:32087. [PMID: 27580845 PMCID: PMC5007516 DOI: 10.1038/srep32087] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 08/02/2016] [Indexed: 12/12/2022] Open
Abstract
Podocyte injury and the appearance of proteinuria are features of minimal-change disease (MCD). Cyclosporin A (CsA) and tacrolimus (FK506) has been reported to reduce proteinuria in patients with nephrotic syndrome, but mechanisms remain unknown. We, therefore, investigated the protective mechanisms of CsA and FK506 on proteinuria in a rat model of MCD induced by puromycin aminonucleoside (PAN) and in vitro cultured mouse podocytes. Our results showed that CsA and FK506 treatment decreased proteinuria via a mechanism associated to a reduction in the foot-process fusion and desmin, and a recovery of synaptopodin and podocin. In PAN-treated mouse podocytes, pre-incubation with CsA and FK506 restored the distribution of the actin cytoskeleton, increased the expression of synaptopodin and podocin, improved podocyte viability, and reduced the migrating activities of podocytes. Treatment with CsA and FK506 also inhibited PAN-induced podocytes apoptosis, which was associated with the induction of Bcl-xL and inhibition of Bax, cleaved caspase 3, and cleaved PARP expression. Further studies revealed that CsA and FK506 inhibited PAN-induced p38 and JNK signaling, thereby protecting podocytes from PAN-induced injury. In conclusion, CsA and FK506 inhibit proteinuria by protecting against PAN-induced podocyte injury, which may be associated with inhibition of the MAPK signaling pathway.
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40
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The Ineffectiveness of Tacrolimus in an Infant With a Mutation in the IL-10 Receptor. J Clin Gastroenterol 2016; 50:352-3. [PMID: 26828243 DOI: 10.1097/mcg.0000000000000480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Qing-dai powder promotes recovery of colitis by inhibiting inflammatory responses of colonic macrophages in dextran sulfate sodium-treated mice. Chin Med 2015; 10:29. [PMID: 26464580 PMCID: PMC4604072 DOI: 10.1186/s13020-015-0061-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 09/29/2015] [Indexed: 02/06/2023] Open
Abstract
Background Qing-dai powder (QDP), comprising Indigo naturalis (Qing-dai) and dried alum (Ku-fan), was used in Chinese medicine to treat the conditions associated with mucosal hemorrhage, such as ulcerative colitis (UC). This study aims to investigate the effects and potential mechanism of QDP on dextran sulfate sodium (DSS)-induced acute colitis in mice and to examine the regulatory effects of QDP on macrophages. Methods Seven- to eight-week-old male C57BL/6 mice were challenged with 2.0 % DSS in drinking water for 5 days and then the colitic mice were arbitrarily allocated into five groups (n = 10 for each group). QDP (0.77, 1.54 and 3.08 g/kg) and sulfasalazine (SASP) (0.20 g/kg) were orally administered for 7 days. The disease activity index was determined by scores of body weight loss, diarrhea and rectal bleeding; histological signs of damage was analyzed by H&E staining; myeloperoxidase activity was measured by colorimetric method, levels of proinflammatory cytokines were determined by ELISA; changes in macrophages in the colon were analyzed by immunohistochemistry (IHC) and flow cytometry. Lipopolysaccharide (LPS)-induced RAW264.7 cells were treated with or without QDP, then the production of TNF-α and IL-6 were measured by ELISA; and protein molecules such as COX-2, iNOS, IкB-α were determined by Western blot. Results Oral administration of QDP at dosages of 1.54 and 3.08 g/kg significantly reduced disease activity index on day 12 (P < 0.001 for 1.54 g/kg and P < 0.0008 for 3.08 g/kg), colon shortening (P = 0.012 for 1.54 g/kg, P = 0.001 for 3.08 g/kg), histological damage (P < 0.001 for 1.54 g/kg, P < 0.001 for 3.08 g/kg) and colonic myeloperoxidase activity (P = 0.002 for 1.54 g/kg, P < 0.001 for 3.08 g/kg) of DSS-treated mice. Moreover, QDP treatment (1.54 and 3.08 g/kg) significantly decreased DSS-induced infiltration of macrophages, and production of TNF-α (P = 0.005 for 1.54 g/kg, P = 0.002 for 3.08 g/kg), IL-1β (P = 0.008 for 1.54 g/kg, P = 0.002 for 3.08 g/kg) and IL-6 (P = 0.011 for 1.54 g/kg, P = 0.004 for 3.08 g/kg) in colonic tissues, and also reduced serum MCP-1 levels (P = 0.001 for 1.54 g/kg, P < 0.001 for 3.08 g/kg). In RAW264.7 cells, QDP significantly suppressed LPS-induced production of TNF-α and IL-6 (Both P < 0.001 for 1.0 μg/mL QDP treatment) and expression levels of COX-2 (P = 0.002 and P = 0.001 for 1 and 3 μg/mL QDP treatment, respectively) and iNOS (P < 0.001 for 3 μg/mL QDP treatment) by inhibiting IкB-α degradation (P = 0.007 and P = 0.004 for 1 and 3 μg/mL QDP treatment, respectively) and NF-кB p65 nuclear translocation. Conclusion QDP suppressed the inflammatory responses of colonic macrophages in DSS-induced UC in mice and LPS-induced RAW264.7 cells.
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Van der Perren A, Macchi F, Toelen J, Carlon MS, Maris M, de Loor H, Kuypers DRJ, Gijsbers R, Van den Haute C, Debyser Z, Baekelandt V. FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson's disease. Neurobiol Aging 2015; 36:1559-68. [PMID: 25660193 DOI: 10.1016/j.neurobiolaging.2015.01.014] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2014] [Indexed: 10/24/2022]
Abstract
Alpha-synuclein (α-synuclein) is considered a key player in Parkinson's disease (PD), but the exact relationship between α-synuclein aggregation and dopaminergic neurodegeneration remains unresolved. There is increasing evidence that neuroinflammatory processes are closely linked to dopaminergic cell death, but whether the inflammatory process is causally involved in PD or rather reflects secondary consequences of nigrostriatal pathway injury is still under debate. We evaluated the therapeutic effect of the immunophilin ligand FK506 in a rAAV2/7 α-synuclein overexpression rat model. Treatment with FK506 significantly increased the survival of dopaminergic neurons in a dose-dependent manner. No reduction in α-synuclein aggregation was apparent in this time window, but FK506 significantly lowered the infiltration of both T helper and cytotoxic T cells and the number and subtype of microglia and macrophages. These data suggest that the anti-inflammatory properties of FK506 decrease neurodegeneration in this α-synuclein-based PD model, pointing to a causal role of neuroinflammation in the pathogenesis of PD.
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Affiliation(s)
- Anke Van der Perren
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium
| | - Francesca Macchi
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium
| | - Jaan Toelen
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium
| | - Marianne S Carlon
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium
| | - Michael Maris
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium
| | - Henriette de Loor
- Division of Nephrology and Renal Transplantation, Department of Microbiology and Immunology, Leuven University Hospital and KU Leuven, Leuven, Belgium
| | - Dirk R J Kuypers
- Division of Nephrology and Renal Transplantation, Department of Microbiology and Immunology, Leuven University Hospital and KU Leuven, Leuven, Belgium
| | - Rik Gijsbers
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium
| | - Chris Van den Haute
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium
| | - Zeger Debyser
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium
| | - Veerle Baekelandt
- Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
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Autocrine pathways involving S100A8 and/or S100A9 that are postulated to regulate the immunological functions of macrophages in rats. Biochem Biophys Res Commun 2014; 456:415-20. [PMID: 25485702 DOI: 10.1016/j.bbrc.2014.11.099] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2014] [Accepted: 11/25/2014] [Indexed: 01/25/2023]
Abstract
The development of ulcerative colitis (UC) is closely associated with abnormally functioning macrophages. Rat S100A8 (r-S100A8) and r-S100A9 (S100 proteins) is abundantly expressed in immune cells of myeloid origin, macrophages; however, it remains unclear why r-S100A9 is dominantly expressed in the macrophages of UC rats (UCR). The purpose of this study was to verify the immunological roles of S100 proteins in UCR. We observed the distribution of S100 protein-positive macrophages in the large colons of UCR using a fluorescent immunological staining method, so that S100 protein-positive macrophages were restricted to the rectal tissues of the UCR, and that the mRNA levels of r-S100A8 and r-S100A9 were up-regulated by stimulation with recombinant rat S100A8 (rr-S100A8) alone and rr-S100A9 alone, respectively. When the changes in the mRNA levels of r-S100A8 and r-S100A9 in macrophages were examined in in vitro study by PCR and real-time PCR, the mRNA levels of anti-inflammatory and inflammatory cytokines increased selectively after stimulation with rr-S100A8 alone and rr-S100A9 alone, respectively. These results suggest that autocrine signal transduction pathways involving S100 proteins regulate the immunological functions of macrophages to maintain homeostasis in the gastrointestinal tract. This may be depended on expression balance of S100 proteins in macrophages. It is strongly suggested that in UCR the immune functions of macrophages are regulated in a complex manner by r-S100A8 and/or r-S100A9 through undefined autocrine pathways on the cells.
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Role in calcineurin inhibitors for inflammatory bowel disease in the biologics era: when and how to use. Inflamm Bowel Dis 2014; 20:2151-6. [PMID: 25029618 DOI: 10.1097/mib.0000000000000130] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ulcerative colitis and Crohn's disease, which is the 2 major forms of inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. During the last 30 years, the therapy for patients with refractory inflammatory bowel diseases is still challenging despite the fact that morbidity and mortality rates have been obviously reduced. The conventional management with corticosteroids has been modified by the introduction of calcineurin inhibitors and biologics. In this review, we focus on role in calcineurin inhibitors for patients with inflammatory bowel disease in the currently clinical practice.
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Romano B, Borrelli F, Fasolino I, Capasso R, Piscitelli F, Cascio M, Pertwee R, Coppola D, Vassallo L, Orlando P, Di Marzo V, Izzo A. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis. Br J Pharmacol 2014; 169:213-29. [PMID: 23373571 DOI: 10.1111/bph.12120] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 12/13/2012] [Accepted: 01/09/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. EXPERIMENTAL APPROACH Murine peritoneal macrophages were activated in vitro by LPS. Nitrite levels were measured using a fluorescent assay; inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2) and cannabinoid (CB1 and CB2 ) receptors were analysed by RT-PCR (and/or Western blot analysis); colitis was induced by dinitrobenzene sulphonic acid (DNBS). Endocannabinoid (anandamide and 2-arachidonoylglycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry. Colonic inflammation was assessed by evaluating the myeloperoxidase activity as well as by histology and immunohistochemistry. KEY RESULTS LPS caused a significant production of nitrites, associated to up-regulation of anandamide, iNOS, COX-2, CB1 receptors and down-regulation of CB2 receptors mRNA expression. Cannabichromene significantly reduced LPS-stimulated nitrite levels, and its effect was mimicked by cannabinoid receptor and TRPA1 agonists (carvacrol and cinnamaldehyde) and enhanced by CB1 receptor antagonists. LPS-induced anandamide, iNOS, COX-2 and cannabinoid receptor changes were not significantly modified by cannabichromene, which, however, increased oleoylethanolamide levels. In vivo, cannabichromene ameliorated DNBS-induced colonic inflammation, as revealed by histology, immunohistochemistry and myeloperoxidase activity. CONCLUSION AND IMPLICATIONS Cannabichromene exerts anti-inflammatory actions in activated macrophages - with tonic CB1 cannabinoid signalling being negatively coupled to this effect - and ameliorates experimental murine colitis.
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Affiliation(s)
- B Romano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy; Endocannabinoid Research Group
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Chun J, Lee C, Hwang SW, Im JP, Kim JS. Ursolic acid inhibits nuclear factor-κB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice. Life Sci 2014; 110:23-34. [PMID: 24992474 DOI: 10.1016/j.lfs.2014.06.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 06/16/2014] [Accepted: 06/18/2014] [Indexed: 01/04/2023]
Abstract
AIMS Ursolic acid (UA), a natural pentacyclic triterpenoid acid, has been reported to show immunomodulatory activity. This study investigated the effects of UA on nuclear factor-kappa B (NF-κB) signaling in cells and experimental murine colitis. MAIN METHODS Human intestinal epithelial cells (IECs) COLO 205 and peritoneal macrophages from IL-10-deficient (IL-10(-/-)) mice were pretreated with UA and then stimulated with tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS), respectively. The expression of pro-inflammatory cytokines was determined by real-time RT-PCR and ELISA. The effect of UA on NF-κB signaling was examined by immunoblot analysis to detect IκBα phosphorylation/degradation and electrophoretic mobility shift assay to assess the DNA binding activity of NF-κB. For in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in C57BL/6 wild-type mice and chronic colitis in IL-10(-/-) mice were treated with or without UA. Colitis was quantified by histopathologic evaluation. Immunohistochemical staining for phosphorylated IκBα was performed in the colonic tissue. KEY FINDINGS UA significantly inhibited the production of pro-inflammatory cytokines, IκBα phosphorylation/degradation and NF-κB DNA binding activity in both IEC and IL-10(-/-) peritoneal macrophages stimulated with TNF-α and LPS, respectively. UA significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histopathology. UA also significantly ameliorated the severity of colitis in IL-10(-/-) mice. Furthermore, UA suppressed IκBα phosphorylation in the colonic tissue. SIGNIFICANCE UA inhibits NF-κB activation in both IECs and macrophages, and attenuates experimental murine colitis. These results suggest that UA is a potential therapeutic agent for inflammatory bowel disease.
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Affiliation(s)
- Jaeyoung Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Changhyun Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sung Wook Hwang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Oxymatrine prevents NF-κB nuclear translocation and ameliorates acute intestinal inflammation. Sci Rep 2014; 3:1629. [PMID: 23568217 PMCID: PMC3620667 DOI: 10.1038/srep01629] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 03/25/2013] [Indexed: 12/11/2022] Open
Abstract
Oxymatrine is a traditional Chinese herbal product that exhibits anti-inflammatory effects in models of heart, brain and liver injury. We investigated the impact of oxymatrine in an acute model of intestinal injury and inflammation. Oxymatrine significantly decreased LPS-induced NF-κB-driven luciferase activity, correlating with diminished induction of Cxcl2, Tnfα and Il6 mRNA expression in rat IEC-6 and murine BMDC. Although oxymatrine decreased LPS-induced p65 nuclear translocation and binding to the Cxcl2 gene promoter, this effect was independent of IκBα degradation/phosphorylation. DSS-induced weight loss and histological damage were ameliorated in oxymatrine-treated C57BL/6-WT-mice. While this effect correlated with reduced colonic Il6 and Il1β mRNA accumulation, global NF-κB activity as measured in NF-κBEGFP mice was unaffected. Our data demonstrate that oxymatrine reduces LPS-induced NF-κB nuclear translocation and activity independently of IκBα status, prevents intestinal inflammation through blockade of inflammatory signaling and ameliorates overall intestinal inflammation in vivo.
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Siebelt M, van der Windt AE, Groen HC, Sandker M, Waarsing JH, Müller C, de Jong M, Jahr H, Weinans H. FK506 protects against articular cartilage collagenous extra-cellular matrix degradation. Osteoarthritis Cartilage 2014; 22:591-600. [PMID: 24561282 DOI: 10.1016/j.joca.2014.02.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 01/22/2014] [Accepted: 02/06/2014] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Osteoarthritis (OA) is a non-rheumatologic joint disease characterized by progressive degeneration of the cartilage extra-cellular matrix (ECM), enhanced subchondral bone remodeling, activation of synovial macrophages and osteophyte growth. Inhibition of calcineurin (Cn) activity through tacrolimus (FK506) in in vitro monolayer chondrocytes exerts positive effects on ECM marker expression. This study therefore investigated the effects of FK506 on anabolic and catabolic markers of osteoarthritic chondrocytes in 2D and 3D in vitro cultures, and its therapeutic effects in an in vivo rat model of OA. METHODS Effects of high and low doses of FK506 on anabolic (QPCR/histochemistry) and catabolic (QPCR) markers were evaluated in vitro on isolated (2D) and ECM-embedded chondrocytes (explants, 3D pellets). Severe cartilage damage was induced unilaterally in rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with FK506 orally and compared to twenty untreated controls. Subchondral cortical and trabecular bone changes (longitudinal microCT) and macrophage activation (SPECT/CT) were measured. Articular cartilage was analyzed ex vivo using contrast enhanced microCT and histology. RESULTS FK506 treatment of osteoarthritic chondrocytes in vitro induced anabolic (mainly collagens) and reduced catabolic ECM marker expression. In line with this, FK506 treatment clearly protected ECM integrity in vivo by markedly decreasing subchondral sclerosis, less development of subchondral pores, depletion of synovial macrophage activation and lower osteophyte growth. CONCLUSION FK506 protected cartilage matrix integrity in vitro and in vivo. Additionally, FK506 treatment in vivo reduced OA-like responses in different articular joint tissues and thereby makes Cn an interesting target for therapeutic intervention of OA.
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Affiliation(s)
- M Siebelt
- Department of Orthopedics, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - A E van der Windt
- Department of Orthopedics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - H C Groen
- Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M Sandker
- Department of Orthopedics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - J H Waarsing
- Department of Orthopedics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - C Müller
- Center for Radiopharmaceutical Sciences PSI-ETH-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland
| | - M de Jong
- Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - H Jahr
- Department of Orthopedics, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Orthopedic Surgery, University Hospital RWTH, Aachen, Germany
| | - H Weinans
- Department of Biomechanical Engineering, TU Delft, The Netherlands; Department of Orthopaedics, UMC Utrecht, The Netherlands; Department of Rheumatology, UMC Utrecht, The Netherlands
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Lee C, Chun J, Hwang SW, Kang SJ, Im JP, Kim JS. The effect of intestinal alkaline phosphatase on intestinal epithelial cells, macrophages and chronic colitis in mice. Life Sci 2014; 100:118-124. [PMID: 24548630 DOI: 10.1016/j.lfs.2014.02.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/25/2014] [Accepted: 02/03/2014] [Indexed: 01/01/2023]
Abstract
AIMS Intestinal alkaline phosphatase (IAP) is an intestinal brush border enzyme that is shown to function as a gut mucosal defense factor, but its defensive mechanism remains unclear. The aims of this study were to evaluate the effect of IAP on intestinal epithelial cells and macrophages, and on chronic colitis in interleukin-10-deficient (IL-10(-/-)) mice. MAIN METHODS Human intestinal epithelial cells COLO 205 and peritoneal macrophages from IL-10(-/-) mice were pretreated with IAP and then stimulated with lipopolysaccharide (LPS). IL-8 secretion from COLO205 cells and TNF-α, IL-6, IL-12 from peritoneal macrophages were measured by ELISA. Electrophoretic mobility shift assay was used to assess the DNA binding activity of NF-κB and IκBα phosphorylation/degradation was evaluated by immunoblot assay in COLO 205. For the in vivo study, colitis was induced in IL-10(-/-) mice with piroxicam, the mice were then treated with 100 or 300 units of IAP by oral gavage for 2 weeks. Colitis was quantified by histopathologic scoring, and the phosphorylation of IκBα in the colonic mucosa was assessed using immunohistochemistry. KEY FINDINGS IAP significantly inhibited LPS-induced inflammatory cytokine production in both IECs and peritoneal macrophages. IAP also attenuated LPS-induced NF-κB binding activity and IκBα phosphorylation/degradation in IECs. Oral administration of IAP significantly reduced the severity of colitis and down-regulated colitis-induced IκBα phosphorylation in IL-10(-/-) mice. SIGNIFICANCE IAP may inhibit the activation of intestinal epithelial cells and peritoneal macrophages, and may attenuate chronic murine colitis. This finding suggests that IAP supplementation is a potential therapeutic option for inflammatory bowel disease.
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Affiliation(s)
- Changhyun Lee
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jaeyoung Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung Wook Hwang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Joo Kang
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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Lee C, Chun J, Hwang SW, Kang SJ, Im JP, Kim JS. Enalapril inhibits nuclear factor-κB signaling in intestinal epithelial cells and peritoneal macrophages and attenuates experimental colitis in mice. Life Sci 2013; 95:29-39. [PMID: 24239644 DOI: 10.1016/j.lfs.2013.11.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 10/28/2013] [Accepted: 11/02/2013] [Indexed: 02/06/2023]
Abstract
AIMS Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, has pleiotropic effects such as anti-inflammatory effects. This study investigated the effect of enalapril on the nuclear factor-kappa B (NF-κB) pathway and on experimental colitis. MAIN METHODS The human intestinal epithelial cell (IEC) line COLO 205 and peritoneal macrophages from C57BL/6 wild-type mice and IL-10-deficient (IL-10(-/-)) mice were prepared and subsequently stimulated with lipopolysaccharide (LPS) alone or LPS plus enalapril. The effect of enalapril on NF-κB signaling was examined by western blotting to detect IκBα phosphorylation/degradation; an electrophoretic mobility shift assay (EMSA) to assess the DNA binding activity of NF-κB; and ELISAs to qualify IL-8, TNF-α, IL-6, and IL-12 production. In in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in wild-type mice and chronic colitis in IL-10(-/-) mice were treated with or without enalapril. Colitis was quantified by histologic scoring, and the phosphorylation of IκBα in the colonic mucosa was assessed using immunohistochemistry. KEY FINDINGS Enalapril significantly inhibited LPS-induced IκBα phosphorylation/degradation, NF-κB binding activity, and pro-inflammatory cytokine production in both IEC and peritoneal macrophages. The administration of enalapril significantly reduced the severity of colitis, as assessed based on histology in both murine colitis models. Furthermore, in colon tissue, the up-regulation of IκBα phosphorylation with colitis induction was attenuated in enalapril-treated mice. SIGNIFICANCE Enalapril may block the NF-κB signaling pathway, inhibit the activation of IECs and macrophages, and attenuate experimental murine colitis by down-regulating IκBα phosphorylation. These findings suggest that enalapril is a potential therapeutic agent for inflammatory bowel disease.
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Affiliation(s)
- Changhyun Lee
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jaeyoung Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung Wook Hwang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Joo Kang
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
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