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Sridhar A, Bakke I, Gopalakrishnan S, Osoble NMM, Hammarqvist EP, Pettersen HPS, Sandvik AK, Østvik AE, Hansen MD, Bruland T. Tofacitinib and budesonide treatment affect stemness and chemokine release in IBD patient-derived colonoids. Sci Rep 2025; 15:3753. [PMID: 39885201 PMCID: PMC11782514 DOI: 10.1038/s41598-025-86314-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/09/2025] [Indexed: 02/01/2025] Open
Abstract
Restoration of the intestinal epithelial barrier is crucial for achieving mucosal healing, the therapeutic goal for inflammatory bowel disease (IBD). During homeostasis, epithelial renewal is maintained by crypt stem cells and progenitors that cease to divide as they differentiate into mature colonocytes. Inflammation is a major effector of mucosal damage in IBD and has been found to affect epithelial stemness, regeneration and cellular functions. However, the impact of immune cell-modulating IBD drugs on epithelial homeostasis and repair is poorly understood. It is likely that these drugs will have distinct mechanisms of action (MOA) in intestinal epithelium relevant for homeostasis that will vary among patients. We investigated cellular effects of pan-Janus Kinase (JAK) inhibitor tofacitinib and the corticosteroid budesonide on uninflamed and TNF + Poly(I:C) stimulated human colon organoids (colonoids) from healthy donors and IBD-patients. Our findings reveal that although both tofacitinib and budesonide exhibit anti-inflammatory effects, tofacitinib increased colonoid size and proliferation during differentiation, and promoted epithelial stemness. In contrast, budesonide decreased colonoid size and showed no consistent effect on proliferation or stemness. Our study demonstrates the value of employing human colonoids to investigate how IBD drugs affect intestinal epithelial cells and inter-individual variations relevant to mucosal healing and personalized IBD treatment.
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Affiliation(s)
- Arun Sridhar
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Ingunn Bakke
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway.
- Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway.
| | - Shreya Gopalakrishnan
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
| | - Nimo Mukhtar Mohamud Osoble
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
| | - Emilie Prytz Hammarqvist
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
| | - Henrik P Sahlin Pettersen
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
- Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway
- Department of Pathology, St. Olav's University Hospital, Trondheim, Norway
| | - Arne Kristian Sandvik
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Ann Elisabet Østvik
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Marianne Doré Hansen
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
- Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Torunn Bruland
- Department of Clinical and Molecular Medicine (IKOM), Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Prinsesse Kristinas gt. 1, Trondheim, 7030, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
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Andriolo IRL, Venzon L, da Silva LM. Perspectives About Ascorbic Acid to Treat Inflammatory Bowel Diseases. Drug Res (Stuttg) 2024; 74:149-155. [PMID: 38467159 DOI: 10.1055/a-2263-1388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
It is known that reactive oxygen species cause abnormal immune responses in the gut during inflammatory bowel diseases (IBD). Therefore, oxidative stress has been theorized as an agent of IBD development and antioxidant compounds such as vitamin C (L-ascorbic acid) have been studied as a new tool to treat IBD. Therefore, the potential of vitamin C to treat IBD was reviewed here as a critical discussion about this field and guide future research. Indeed, some preclinical studies have shown the beneficial effects of vitamin C in models of ulcerative colitis in mice and clinical and experimental findings have shown that deficiency in this vitamin is associated with the development of IBD and its worsening. The main mechanisms that may be involved in the activity of ascorbic acid in IBD include its well-established role as an antioxidant, but also others diversified actions. However, some experimental studies employed high doses of vitamin C and most of them did not perform dose-response curves and neither determined the minimum effective dose nor the ED50. Allometric extrapolations were also not made. Also, clinical studies on the subject are still in their infancy. Therefore, it is suggested that the research agenda in this matter covers experimental studies that assess the effective, safe, and translational doses, as well as the appropriate administration route and its action mechanism. After that, robust clinical trials to increase knowledge about the role of ascorbic acid deficiency in IBD patients and the effects of their supplementation in these patients can be encouraged.
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Affiliation(s)
| | - Larissa Venzon
- Pharmaceutical Sciences Graduate Program - University of Itajai Valley, Itajai, SC, Brazil
| | - Luisa Mota da Silva
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
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Paparo L, Coppola S, Nocerino R, Pisapia L, Picariello G, Cortese M, Voto L, Maglio M, Miele E, Carucci L, Oglio F, Trinchese G, Mollica MP, Bruno C, De Vita S, Tarallo A, Damiano C, Cerulo M, Esposito C, Fogliano V, Parenti G, Troncone R, Berni Canani R. How dietary advanced glycation end products could facilitate the occurrence of food allergy. J Allergy Clin Immunol 2024; 153:742-758. [PMID: 38042501 DOI: 10.1016/j.jaci.2023.11.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/04/2023] [Accepted: 11/02/2023] [Indexed: 12/04/2023]
Abstract
BACKGROUND Food allergy (FA) is one of the most common chronic conditions in children with an increasing prevalence facilitated by the exposure to environmental factors in predisposed individuals. It has been hypothesized that the increased consumption of ultra-processed foods, containing high levels of dietary advanced glycation end products (AGEs), could facilitate the occurrence of FA. OBJECTIVE We sought to provide preclinical and clinical evidence on the potential role of AGEs in facilitating the occurrence of FA. METHODS Human enterocytes, human small intestine organ culture, and PBMCs from children at risk for allergy were used to investigate the direct effect of AGEs on gut barrier, inflammation, TH2 cytokine response, and mitochondrial function. Intake of the 3 most common glycation products in Western diet foods, Nε-(carboxymethyl) lysine, Nε-(1-carboxyethyl) lysin, and Nδ-(5-hydro-5- methyl-4-imidazolone-2-yl)-ornithine (MG-H1), and the accumulation of AGEs in the skin were comparatively investigated in children with FA and in age-matched healthy controls. RESULTS Human enterocytes exposed to AGEs showed alteration in gut barrier, AGE receptor expression, reactive oxygen species production, and autophagy, with increased transepithelial passage of food antigens. Small intestine organ cultures exposed to AGEs showed an increase of CD25+ cells and proliferating crypt enterocytes. PBMCs exposed to AGEs showed alteration in proliferation rate, AGE receptor activation, release of inflammatory and TH2 cytokines, and mitochondrial metabolism. Significant higher dietary AGE intake and skin accumulation were observed children with FA (n = 42) compared with age-matched healthy controls (n = 66). CONCLUSIONS These data, supporting a potential role for dietary AGEs in facilitating the occurrence of FA, suggest the importance of limiting exposure to AGEs children as a potential preventive strategy against this common condition.
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Affiliation(s)
- Lorella Paparo
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Serena Coppola
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Rita Nocerino
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Laura Pisapia
- Institute of Genetics and Biophysics, National Research Council, Naples, Italy
| | | | - Maddalena Cortese
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Luana Voto
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Mariantonia Maglio
- Department of Translational Medical Science, University Federico II, Naples, Italy; European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
| | - Erasmo Miele
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | - Laura Carucci
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Franca Oglio
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | | | | | - Cristina Bruno
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Simone De Vita
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy
| | - Antonietta Tarallo
- Department of Translational Medical Science, University Federico II, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Carla Damiano
- Department of Translational Medical Science, University Federico II, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Mariapina Cerulo
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | - Ciro Esposito
- Department of Translational Medical Science, University Federico II, Naples, Italy
| | - Vincenzo Fogliano
- Food Quality and Design Group, Wageningen University and Research, Wageningen, The Netherlands
| | - Giancarlo Parenti
- Department of Translational Medical Science, University Federico II, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Riccardo Troncone
- Department of Translational Medical Science, University Federico II, Naples, Italy; European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy
| | - Roberto Berni Canani
- Department of Translational Medical Science, University Federico II, Naples, Italy; ImmunoNutritionLab at CEINGE Advanced Biotechnologies, University Federico II, Naples, Italy; European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy; Task Force for Microbiome Studies, University Federico II, Naples, Italy; Task Force for Nutraceuticals and Functional Foods, University Federico II, Naples, Italy.
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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5
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Gastrointestinal consequences of lipopolysaccharide-induced lung inflammation. Inflamm Res 2023; 72:57-74. [PMID: 36322182 PMCID: PMC9628607 DOI: 10.1007/s00011-022-01657-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 09/15/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI) symptoms. Why respiratory inflammation is accompanied by GI dysfunction remains unclear. Here, we investigate the effect of lipopolysaccharide (LPS)-induced lung inflammation on intestinal barrier integrity, tight-junctions, enteric neurons and inflammatory marker expression. METHODS Female C57bl/6 mice (6-8 weeks) were intratracheally administered LPS (5 µg) or sterile saline, and assessed after either 24 or 72 h. Total and differential cell counts in bronchoalveolar lavage fluid (BALF) were used to evaluate lung inflammation. Intestinal barrier integrity was assessed via cross sectional immunohistochemistry of tight junction markers claudin-1, claudin-4 and EpCAM. Changes in the enteric nervous system (ENS) and inflammation in the intestine were quantified immunohistochemically using neuronal markers Hu + and nNOS, glial markers GFAP and S100β and pan leukocyte marker CD45. RESULTS Intratracheal LPS significantly increased the number of neutrophils in BALF at 24 and 72 h. These changes were associated with an increase in CD45 + cells in the ileal mucosa at 24 and 72 h, increased goblet cell expression at 24 h, and increased expression of EpCAM at 72 h. LPS had no effect on the expression of GFAP, S100β, nor the number of Hu + neurons or proportion of nNOS neurons in the myenteric plexus. CONCLUSIONS Intratracheal LPS administration induces inflammation in the ileum that is associated with enhanced expression of EpCAM, decreased claudin-4 expression and increased goblet cell density, these changes may contribute to systemic inflammation that is known to accompany many inflammatory diseases of the lung.
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Mortier E, Maillasson M, Quéméner A. Counteracting Interleukin-15 to Elucidate Its Modes of Action in Physiology and Pathology. J Interferon Cytokine Res 2023; 43:2-22. [PMID: 36651845 DOI: 10.1089/jir.2022.0198] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Interleukin (IL)-15 belongs to the common gamma-dependent cytokine family, along with IL-2, IL-4, IL-7, IL-9, and IL-21. IL-15 is crucial for the homeostasis of Natural Killer (NK) and memory CD8 T cells, and to fight against cancer progression. However, dysregulations of IL-15 expression could occur and participate in the emergence of autoimmune inflammatory diseases as well as hematological malignancies. It is therefore important to understand the different modes of action of IL-15 to decrease its harmful action in pathology without affecting its beneficial effects in the immune system. In this review, we present the different approaches used by researchers to inhibit the action of IL-15, from most broad to the most selective. Indeed, it appears that it is important to selectively target the mode of action of the cytokine rather than the cytokine itself as they are involved in numerous biological processes.
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Affiliation(s)
- Erwan Mortier
- Nantes Université, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Mike Maillasson
- Nantes Université, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
| | - Agnès Quéméner
- Nantes Université, CNRS, Inserm, CRCI2NA, Nantes, France.,LabEX IGO, Immuno-Onco-Greffe, Nantes, France
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Natural Sympathomimetic Drugs: From Pharmacology to Toxicology. Biomolecules 2022; 12:biom12121793. [PMID: 36551221 PMCID: PMC9775352 DOI: 10.3390/biom12121793] [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: 11/08/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022] Open
Abstract
Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. Compounds from this group, both used therapeutically or abused, comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. Although synthetic sympathomimetic agents are mostly seen as toxic, natural sympathomimetic agents are considered more complacently in the terms of safety in the vision of the lay public. Here, we aim to discuss the pharmacological and mainly toxicological aspects related to sympathomimetic natural agents, in particular of trace amines, compounds derived from plants like ephedra and khat, and finally cocaine. The main purpose of this review is to give a scientific and updated view of those agents and serve as a reminder on the safety issues of natural sympathomimetic agents most used in the community.
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Furukawa R, Hara Y, Furuya K, Takahashi K, Nishimura R, Shingaki T, Osada H, Kondo H, Ohmori K. Expression of genes encoding interleukin 15 and its receptor subunits in the duodenal and colonic mucosae of dogs with chronic enteropathy. Vet Anim Sci 2022; 17:100256. [PMID: 35784585 PMCID: PMC9240857 DOI: 10.1016/j.vas.2022.100256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Rintaro Furukawa
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
- Advanced Animal Medical Center, 1075 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-0934, Japan
| | - Yuna Hara
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Keiko Furuya
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Kaho Takahashi
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Rinka Nishimura
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Tomoaki Shingaki
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Hironari Osada
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
| | - Hirotaka Kondo
- Laboratory of Veterinary Pathology, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan
| | - Keitaro Ohmori
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan
- Corresponding author.
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Kinoshita N, Kakimoto K, Shimizu H, Nishida K, Numa K, Kawasaki Y, Tawa H, Nakazawa K, Koshiba R, Hirata Y, Sakiyama N, Koubayashi E, Takeuchi T, Miyazaki T, Higuchi K, Nakamura S, Nishikawa H. Serum IL-13 Predicts Response to Golimumab in Bio-Naïve Ulcerative Colitis. J Clin Med 2022; 11:jcm11174952. [PMID: 36078882 PMCID: PMC9456517 DOI: 10.3390/jcm11174952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/17/2022] [Accepted: 08/20/2022] [Indexed: 11/28/2022] Open
Abstract
A certain number of patients with ulcerative colitis (UC) are refractory to anti-TNF-α antibodies; biomarkers are thus needed to predict treatment efficacy. This study aimed to evaluate whether serum biomarkers that were reported to be associated with UC or anti-TNF-α antibody could predict the response to golimumab, a human anti-TNF-α monoclonal antibody, in bio-naïve patients with UC. We prospectively enrolled 23 consecutive patients with UC who were treated with golimumab. Serum samples were collected before the first golimumab dose. Eleven molecules were measured by electrochemiluminescence (ECL) or enzyme-linked immunosorbent assay (ELISA) and their association with efficacy after 10 weeks of golimumab treatment. Among the serum biomarkers, IL-13 levels were significantly higher in the non-remission group than in the remission group (p = 0.014). IL-15 levels were significantly lower in the non-response group than in the response group (p = 0.04). For clinical remission at week 10, the IL-13 0.20 concentration of pg/mL was associated with a sensitivity and specificity of 82.4% and 83.3%, respectively. Serum IL-13 may be a biomarker to predict golimumab efficacy in biologic-naïve patients with UC, and thus may help to tailor personalized treatment strategies.
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Affiliation(s)
| | - Kazuki Kakimoto
- Correspondence: ; Tel.: +81-726-83-1221; Fax: +81-726-84-6532
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Kautzman AM, Mobulakani JMF, Marrero Cofino G, Quenum AJI, Cayarga AA, Asselin C, Fortier LC, Ilangumaran S, Menendez A, Ramanathan S. Interleukin 15 in murine models of colitis. Anat Rec (Hoboken) 2022; 306:1111-1130. [PMID: 35899872 DOI: 10.1002/ar.25044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/28/2022] [Accepted: 07/05/2022] [Indexed: 11/09/2022]
Abstract
Inflammatory bowel diseases (IBDs) are characterized by abnormal, non-antigen specific chronic inflammation of unknown etiology. Genome-wide association studies show that many IBD genetic susceptibility loci map to immune function genes and compelling evidence indicate that environmental factors play a critical role in IBD pathogenesis. Clinical and experimental evidence implicate the pro-inflammatory cytokine IL-15 in the pathogenesis of IBD. IL-15 and IL-15α expression is increased in the inflamed mucosa of IBD patients. IL-15 contributes to the maintenance of different cell subsets in the intestinal mucosa. However, very few studies have addressed the role of IL-15 in pre-clinical models of colitis. In this study, we use three well-characterized models of experimental colitis to determine the contribution of IL-15 to pathological intestinal inflammation.
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Affiliation(s)
- Alicia Molina Kautzman
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | | | - Gisela Marrero Cofino
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | | | - Anny Armas Cayarga
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Claude Asselin
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.,CRCHUS, Sherbrooke, Quebec, Canada
| | - Louis-Charles Fortier
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.,CRCHUS, Sherbrooke, Quebec, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.,CRCHUS, Sherbrooke, Quebec, Canada
| | - Alfredo Menendez
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada.,CRCHUS, Sherbrooke, Quebec, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.,CRCHUS, Sherbrooke, Quebec, Canada
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Paparo L, Maglio MA, Cortese M, Bruno C, Capasso M, Punzo E, Ferrucci V, Lasorsa VA, Viscardi M, Fusco G, Cerino P, Romano A, Troncone R, Zollo M. A New Butyrate Releaser Exerts a Protective Action against SARS-CoV-2 Infection in Human Intestine. Molecules 2022; 27:862. [PMID: 35164139 PMCID: PMC8838168 DOI: 10.3390/molecules27030862] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/12/2022] [Accepted: 01/25/2022] [Indexed: 12/12/2022] Open
Abstract
Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.
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Affiliation(s)
- Lorella Paparo
- Dipartimento di Scienze Mediche Translazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.A.M.); (M.C.); (C.B.); (E.P.); (R.T.)
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
| | - Maria Antonia Maglio
- Dipartimento di Scienze Mediche Translazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.A.M.); (M.C.); (C.B.); (E.P.); (R.T.)
| | - Maddalena Cortese
- Dipartimento di Scienze Mediche Translazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.A.M.); (M.C.); (C.B.); (E.P.); (R.T.)
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
| | - Cristina Bruno
- Dipartimento di Scienze Mediche Translazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.A.M.); (M.C.); (C.B.); (E.P.); (R.T.)
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
| | - Mario Capasso
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy
| | - Erika Punzo
- Dipartimento di Scienze Mediche Translazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.A.M.); (M.C.); (C.B.); (E.P.); (R.T.)
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
| | - Veronica Ferrucci
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy
| | - Vito Alessandro Lasorsa
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
| | - Maurizio Viscardi
- DAI Medicina di Laboratorio e Trasfusionale, AOU Azienda Ospedaliera, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.V.); (G.F.); (P.C.)
| | - Giovanna Fusco
- DAI Medicina di Laboratorio e Trasfusionale, AOU Azienda Ospedaliera, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.V.); (G.F.); (P.C.)
| | - Pellegrino Cerino
- DAI Medicina di Laboratorio e Trasfusionale, AOU Azienda Ospedaliera, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.V.); (G.F.); (P.C.)
| | - Alessia Romano
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
| | - Riccardo Troncone
- Dipartimento di Scienze Mediche Translazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.A.M.); (M.C.); (C.B.); (E.P.); (R.T.)
| | - Massimo Zollo
- CEINGE—Advanced Biotechnologies s.c.ar.l., Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.C.); (V.F.); (V.A.L.); (A.R.); (M.Z.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy
- DAI Medicina di Laboratorio e Trasfusionale, AOU Azienda Ospedaliera, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy; (M.V.); (G.F.); (P.C.)
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12
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Pan HX, Zhang CS, Lin CH, Chen MM, Zhang XZ, Yu N. Mucin 1 and interleukin-11 protein expression and inflammatory reactions in the intestinal mucosa of necrotizing enterocolitis children after surgery. World J Clin Cases 2021; 9:7372-7380. [PMID: 34616804 PMCID: PMC8464442 DOI: 10.12998/wjcc.v9.i25.7372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/30/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) of the newborn is a frequently occurring clinical disease in infants. The mortality rate of NEC in premature infants is as high as 50%, and the morbidity rate is on the rise. NEC has already caused serious impacts on newborn survival and poses serious threats to both children and families.
AIM To investigate the expression and significance of mucin 1 (MUC1) and interleukin-11 (IL-11) in the intestinal mucosa of infants with neonatal NEC after surgery.
METHODS Forty-eight postoperative intestinal mucosal specimens from children with NEC (NEC group) and twenty-two intestinal mucosal specimens from children with congenital intestinal atresia (control group) were collected in our hospital. Immunohistochemical staining and Western blot analysis were used to examine the protein expression of MUC-1 and IL-11 in the two groups. The serum levels of tumor necrosis factor-α (TNF-α) and IL-1β in the two groups were measured by enzyme-linked immunosorbent assay, and the relationship between MUC-1 and IL-11 protein expression and serum TNF-α and IL-1β levels was analyzed by the linear correlation method.
RESULTS The protein expression of MUC-1 and IL-11 in the NEC group was significantly lower than that in the control group, and the difference was statistically significant (P < 0.05). The levels of serum TNF-α and IL-1β in the NEC group were significantly higher than those in the control group (P < 0.05). The protein expression of MUC-1 and IL-11 in the NEC group negatively correlated with serum TNF-α and IL-1β levels (P < 0.05). There was a significant negative correlation between the protein expression of MUC-1 and IL-11 and the levels of serum TNF-α and IL-1β in the NEC group.
CONCLUSION The protein expression of MUC1 and IL-11 in the intestinal mucosa of children with NEC is significantly downregulated after surgery. This downregulation may be involved in the pathogenesis of this disease and has a certain correlation with inflammatory response factors in children with NEC.
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Affiliation(s)
- Hong-Xia Pan
- Department of Clinical Laboratory Medicine, Suzhou BenQ Medical Center, Affiliated BenQ Hospital of Nanjing Medical University, Suzhou 215011, Jiangsu Province, China
| | - Chang-Song Zhang
- Department of Clinical Laboratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital, Nanjing Medical University, Suzhou 215153, Jiangsu Province, China
| | - Chia-Hui Lin
- General Manager's Office, Suzhou Gallant Biotech Biotechnology Co. Ltd, Suzhou 215163, Jiangsu Province, China
| | - Min-Min Chen
- Department of Clinical Laboratory Medicine, Suzhou BenQ Medical Center, Affiliated BenQ Hospital of Nanjing Medical University, Suzhou 215011, Jiangsu Province, China
| | - Xiao-Zhong Zhang
- Department of Cardiology, National High Tech Development Zone Hospital, Suzhou 215129, Jiangsu Province, China
| | - Nong Yu
- Department of Laboratory Medicine, National High Tech Development Zone Hospital, Suzhou 215129, Jiangsu Province, China
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Wan Y, Zhang D, Xing T, Liu Q, Chi Y, Zhang H, Qian H. The impact of visceral obesity on chronic constipation, inflammation, immune function and cognitive function in patients with inflammatory bowel disease. Aging (Albany NY) 2021; 13:6702-6711. [PMID: 33675295 PMCID: PMC7993735 DOI: 10.18632/aging.202526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022]
Abstract
Objective: Obesity has gained attention among patients with inflammatory bowel disease (IBD). The impact of visceral obesity on chronic constipation, inflammation, immune function and cognition after diagnosis of IBD is still unknown. Methods: This is a cross-sectional study of 150 IBD patients. Patients’ visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured and were grouped according to visceral obesity. The potential impact of visceral obesity on cognitive function were evaluated using Mini-Mental State Examination. We evaluated patients’ incidence of chronic constipation, levels of interleukin-6 (IL-6), T cells and body mass index in two groups. Results: The prevalence of visceral obesity was 51% (37 out of 72) for Crohn’s disease (CD) patients and 26% for UC patients (20 out of 78 patients). CD patients with visceral obesity has higher incidence of chronic constipation (81% vs. 57%, P = 0.028), higher IL-6 levels (15.28 pg/ml vs. 9.429 pg/ml, P = 0.007) and lower CD4+ T cells (32.7% vs. 44.0%, P < 0.001). VAT/SAT ratio is associated with BMI (P < 0.001). Conclusions: IBD patients had high risks of visceral obesity. CD Patients with visceral obesity had higher prevalence of chronic constipation, higher inflammation levels, decreased immune function.
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Affiliation(s)
- Yemin Wan
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Dan Zhang
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Ting Xing
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Qiaoling Liu
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yumeng Chi
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Huixiang Zhang
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Haihua Qian
- Department of Anorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
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Nature-Identical Compounds and Organic Acids Ameliorate and Prevent the Damages Induced by an Inflammatory Challenge in Caco-2 Cell Culture. Molecules 2020; 25:molecules25184296. [PMID: 32961674 PMCID: PMC7570934 DOI: 10.3390/molecules25184296] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/11/2020] [Accepted: 09/17/2020] [Indexed: 01/24/2023] Open
Abstract
Bioactive compounds, such as organic acids (OA) and nature-identical compounds (NIC), can exert a role in the protection of intestinal mucosa functionality due to their biological properties. The aim of this study was to understand the role of 2 OA (citric and sorbic acid) and 2 NIC (thymol and vanillin), alone or combined in a blend (OA + NIC), on intestinal barrier functionality, either during homeostatic condition or during an inflammatory challenge performed with pro-inflammatory cytokines and lipopolysaccharides (LPS). The study was performed on the human epithelial cell line Caco-2, a well-known model of the intestinal epithelial barrier. The results showed how OA and NIC alone can improve transepithelial electrical resistance (TEER) and mRNA levels of tight junction (TJ) components, but OA + NIC showed stronger efficacy compared to the single molecules. When an inflammatory challenge occurred, OA + NIC blend was able both to ameliorate, and prevent, damage caused by the pro-inflammatory stimulus, reducing or preventing the drop in TEER and improving the TJ mRNA expression. The data support the role of OA + NIC in modulating gut barrier functionality and reducing the negative effects of inflammation in intestinal epithelial cells, thereby supporting the gut barrier functionality.
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15
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Allard-Chamard H, Mishra HK, Nandi M, Mayhue M, Menendez A, Ilangumaran S, Ramanathan S. Interleukin-15 in autoimmunity. Cytokine 2020; 136:155258. [PMID: 32919253 DOI: 10.1016/j.cyto.2020.155258] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 08/13/2020] [Indexed: 12/15/2022]
Abstract
Interleukin-15 (IL-15) is a member of the IL-2 family of cytokines, which use receptor complexes containing the common gamma (γc) chain for signaling. IL-15 plays important roles in innate and adaptative immune responses and is implicated in the pathogenesis of several immune diseases. The IL-15 receptor consists of 3 subunits namely, the ligand-binding IL-15Rα chain, the β chain (also used by IL-2) and the γc chain. IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is 'trans-presented' to responder cells that expresses the IL-2/15Rβγc receptor complex. IL-15 is subject to post-transcriptional and post-translational regulation, and evidence also suggests that IL-15 cis-signaling can occur under certain conditions. IL-15 has been implicated in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, coeliac disease and psoriasis. Studies with pre-clinical models have shown the beneficial effects of targeting IL-15 signaling in autoimmunity. Unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in humans. We discuss the complexities of IL-15 signaling in autoimmunity and explore potential immunotherapeutic approaches to target the IL-15 signaling pathway.
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Affiliation(s)
- Hugues Allard-Chamard
- Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada; Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada.
| | - Hemant K Mishra
- Vet & Biomedical Sciences, University of Minnesota, Minneapolis, MN, USA
| | - Madhuparna Nandi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Marian Mayhue
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Alfredo Menendez
- Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Subburaj Ilangumaran
- Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Sheela Ramanathan
- Centre de Recherche Clinique, Centre Hospitalier d'Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
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16
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Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line. Int J Mol Sci 2020; 21:ijms21082726. [PMID: 32326391 PMCID: PMC7215722 DOI: 10.3390/ijms21082726] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/09/2020] [Accepted: 04/13/2020] [Indexed: 12/13/2022] Open
Abstract
A key morphological feature of inflammatory bowel disease (IBD) is the loss of the barrier function of intestinal epithelial cells. The present study investigates endoplasmic reticulum (ER) stress in addition to alterations in protein and membrane trafficking in a dextran sulfate sodium (DSS)-induced IBD-like phenotype of intestinal Caco-2 cells in culture. DSS treatment significantly reduced the transepithelial electric resistance (TEER) and increased the epithelial permeability of Caco-2 cells, without affecting their viability. This was associated with an alteration in the expression levels of inflammatory factors in addition to an increase in the expression of the ER stress protein markers, namely immunoglobulin-binding protein (BiP), C/EBP homologous protein (CHOP), activation transcription factor 4 (ATF4), and X-box binding protein (XBP1). The DSS-induced ER-stress resulted in impaired intracellular trafficking and polarized sorting of sucrase-isomaltase (SI) and dipeptidyl peptidase-4 (DPPIV), which are normally sorted to the apical membrane via association with lipid rafts. The observed impaired sorting was caused by reduced cholesterol levels and subsequent distortion of the lipid rafts. The data presented confirm perturbation of ER homeostasis in DSS-treated Caco-2 cells, accompanied by impairment of membrane and protein trafficking resulting in altered membrane integrity, cellular polarity, and hence disrupted barrier function.
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17
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Vitale S, Strisciuglio C. The potential use of gene expression profile to identify useful biomarkers for the diagnosis and the treatment of pediatric inflammatory bowel diseases. Pediatr Res 2020; 87:805-806. [PMID: 31896123 DOI: 10.1038/s41390-019-0732-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/07/2019] [Accepted: 11/06/2019] [Indexed: 11/09/2022]
Affiliation(s)
- Serena Vitale
- Institute of Biochemistry and Cell Biology-National Research Council (IBBC-CNR), Naples, Italy.,Collaboration with Italian Foundation for the Celiac Disease-FC and Italian Society for the Celiac Disease-AIC, Naples, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.
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De Felice B, Damiano S, Montanino C, Del Buono A, La Rosa G, Guida B, Santillo M. Effect of beta- and alpha-glucans on immune modulating factors expression in enterocyte-like Caco-2 and goblet-like LS 174T cells. Int J Biol Macromol 2020; 153:600-607. [PMID: 32165203 DOI: 10.1016/j.ijbiomac.2020.03.046] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 03/06/2020] [Accepted: 03/07/2020] [Indexed: 12/11/2022]
Abstract
Glucans are complex polysaccharides consisting of repeated units of d-glucose linked by glycosidic bonds. The nutritional contribution in α-glucans is mainly given by starch and glycogen while in β-glucans by mushrooms, yeasts and whole grains, such as barley and spelt well represented in the Mediterranean Diet. Numerous and extensive studies performed on glucans highlighted their marked anti-tumor, antioxidant and immunomodulatory activity. It has recently been shown that rather than merely being a passive barrier, the intestinal epithelium is an essential modulator of immunity. Indeed, epithelial absorptive enterocytes and mucin secreting goblet cells can produce specific immune modulating factors, driving innate immunity to pathogens as well as preventing autoimmunity. Despite the clear evidence of the effects of glucans on immune system cells, there are only limited data about their effects on immune activity of mucosal intestinal cells strictly related to intestinal barrier integrity. The aim of the study was to evaluate the effects of α and β glucans, alone or in combination with other substances with antioxidant properties, on reactive oxygen species (ROS) levels, on the expression of ROS-generating enzyme DUOX-2 and of the immune modulating factors Tumor Necrosis Factor (TNF-α), Interleukin 1 β (IL-1β) and cyclooxygenase-2 (COX-2) in two intestinal epithelial cells, the enterocyte-like Caco-2 cells and goblet cell-like LS174T. In our research, the experiments were carried out incubating the cells with glucans for 18 h in culture medium containing 0.2% FBS and measuring ROS levels fluorimetrically as dihydrodichlorofluoresce diacetate (DCF-DA) fluorescence, protein levels of DUOX-2 by Western blotting and mRNA levels of, TNF-α, IL-1β and COX-2 by qRT-PCR. α and β glucans decreased ROS levels in Caco-2 and LS 174T cells. The expression levels of COX-2, TNF-α, and IL-1β were also reduced by α- and β-glucans. Additive effects on the expression of these immune modulating factors were exerted by vitamin C. In Caco-2 cells, the dual oxidase DUOX-2 expression is positively modulated by ROS. Accordingly, in Caco-2 or LS174T cells treated with α and β-glucans alone or in combination with Vitamin C, the decrease of ROS levels was associated with a reduced expression of DUOX-2. The treatment of cells with the NADPH oxidase (NOX) inhibitor apocynin decrease ROS, DUOX-2, COX-2, TNF-α and IL-1β levels indicating that NOX dependent ROS regulate the expression of immune modulating factors of intestinal cells. However, the combination of vitamin C, α and β-glucans with apocynin did not exert an additive effect on COX-2, TNF-α and IL-1β levels when compared with α-, β-glucans and Vitamin C alone. The present study showing a modulatory effect of α and β-glucans on ROS and on the expression of immune modulating factors in intestinal epithelial cells suggests that the assumption of food containing high levels of these substances or dietary supplementation can contribute to normal immunomodulatory function of intestinal barrier.
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Affiliation(s)
- Bruna De Felice
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DISTABIF), University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100 Caserta, Italy.
| | - Simona Damiano
- Department of Clinical Medicine and Surgery, University of Naples "Federico II, Italy
| | - Concetta Montanino
- Department of Clinical Medicine and Surgery, University of Naples "Federico II, Italy
| | | | - Giuliana La Rosa
- Department of Clinical Medicine and Surgery, University of Naples "Federico II, Italy
| | - Bruna Guida
- Department of Clinical Medicine and Surgery, University of Naples "Federico II, Italy
| | - Mariarosaria Santillo
- Department of Clinical Medicine and Surgery, University of Naples "Federico II, Italy
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Abstract
Abstract
Peripheral blood lymphocytes (PBL) are able to synthesize various cytokines that play key roles in the immune response and intercellular signaling. Since alterations in cytokine production and/or activity occur in many pathological processes, the study of cytokine synthetic capacity of PBL is a valuable tool for assessing the immune profile. In this paper, we aimed to investigate the variability of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-γ) synthetic capacity of CD4+/CD8+ T-cells stimulated ex-vivo in healthy subjects, by means of a commercial intracellular cytokine staining (ICS) protocol. Peripheral blood mononuclear cells were isolated from 16 healthy subjects by Ficoll gradient centrifugation and activated ex-vivo with PMA/Ionomycin/Brefeldin-A for 4 hours. Activated PBL were surface-stained for CD3/CD4/CD8, fixed and permeabilized. ICS was performed using anti-human IL-2/TNF-α/IFN-γ and samples were analyzed on a BD-FACSAria-III flow cytometer. We recorded high post-isolation and post-activation mean viabilities: 82.1% and 82.4% respectively, p=0.84. Both CD4+/CD8+ subpopulations were found to partially produce each of the three cytokines, but in different proportions. On average, a significantly greater percentage of CD4+ cells was shown to produce IL-2 and TNF-α, compared with CD8+ cells (61.5%+/-5.8 vs. 25%+/-5.6 and 26.9%+/-11 vs. 7.5%+/-3.3 respectively, p---lt---0.0001 for both). Contrarily, IFN-γ was produced by a higher proportion of CD8+ cells (8.4%+/-3.9 vs. 6.8%+/-3.2, p=0.01). These results show that the employed ICS protocol elicits a satisfactory and consistent cytokine response from PBL of healthy subjects. The collected data may be used to outline a preliminary reference range for future studies on both healthy/pathological subjects.
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20
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Castilla-Madrigal R, Gil-Iturbe E, López de Calle M, Moreno-Aliaga MJ, Lostao MP. DHA and its derived lipid mediators MaR1, RvD1 and RvD2 block TNF-α inhibition of intestinal sugar and glutamine uptake in Caco-2 cells. J Nutr Biochem 2020; 76:108264. [DOI: 10.1016/j.jnutbio.2019.108264] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 09/06/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022]
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Hnatyszyn A, Hryhorowicz S, Kaczmarek-Ryś M, Lis E, Słomski R, Scott RJ, Pławski A. Colorectal carcinoma in the course of inflammatory bowel diseases. Hered Cancer Clin Pract 2019; 17:18. [PMID: 31338130 PMCID: PMC6626407 DOI: 10.1186/s13053-019-0118-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 07/01/2019] [Indexed: 02/08/2023] Open
Abstract
Background Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are the most prevalent diseases of the digestive system, and their association is unequivocal. A long-standing inflammatory process is one of the causes of sporadic as well as inherited cancers as it impacts on malignant transformation in a wide variety of neoplastic diseases, including colorectal cancer. Methods An extensive publication search was performed in Medline and PubMed database. The keywords: colorectal carcinoma, inflammation, Crohn disease, ulcerative colitis and inflammatory bowel disease were used. Results The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll like receptor (TLR) signaling pathways are clearly involved in the inflammatory process and are therefore implicated in the transformation of normal colonic mucosa to premalignant and malignant disease. Focal sites of inflammation could significantly increase the risk of initiation and development of cancer. Altered inflammatory activity is likely to be a result of either a disturbance of intestinal bacterial flora or an inadequate cellular response to it. Additionally, increasing the level of inflammation-related factors may also interfere with the control of cellular proliferation. Conclusions This review shows an overview of the genetic and environmental factors that appear to influence both the occurrence of IBD and CRC with particular reference to NOD2 and TLRs as well as pro- and anti-inflammatory cytokines associated with tumor initiation and progression (encompassing both tumor invasion and metastases), as they constitute potential targets for therapeutic intervention.
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Affiliation(s)
- Andrzej Hnatyszyn
- Health Care Center, Independent Public Hospital, Chałubińskiego 7, 67-100 Nowa Sól, Poland
| | - Szymon Hryhorowicz
- 2Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland
| | - Marta Kaczmarek-Ryś
- 2Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland
| | - Emilia Lis
- 2Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland
| | - Ryszard Słomski
- 2Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland.,3Department of Biochemistry and Biotechnology, University of Life Sciences, Dojazd 11, 60-632 Poznań, Poland
| | - Rodney J Scott
- Division of Molecular Medicine, NSW Health Pathology (Newcastle) New South Wales, Newcastle, NSW 2308 Australia.,5School of Biomedical Sciences, University of Newcastle, Newcastle, NSW 2308 Australia
| | - Andrzej Pławski
- 2Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479 Poznań, Poland.,6Department of General and Endocrine Surgery and Gastroenterological Oncology, Poznań University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznań, Poland
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22
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Cao L, Xu H, Wang G, Liu M, Tian D, Yuan Z. Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization. Int Immunopharmacol 2019; 72:264-274. [PMID: 31005036 DOI: 10.1016/j.intimp.2019.04.020] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) have shown repairing effects in tissue damage. However, their efficacy and mechanism in the treatment of ulcerative colitis (UC), a type of chronic inflammatory bowel disease, are unclear. To investigate the effects and possible mechanism of EVs in UC treatment, we established an in vitro model using lipopolysaccharide (LPS)-treated macrophages and an in vivo dextran sulfate sodium (DSS)-induced mouse model to mimic UC. In vitro, EVs promoted the proliferation and suppressed inflammatory response in LPS-induced macrophages, as demonstrated by the up-regulation of pro-inflammatory factors (TNF-α, IL-6, and IL-12) and down-regulation of the anti-inflammatory factor IL-10. In the in vivo model, EV administration ameliorated the symptoms of UC by reducing weight loss, disease activity index, and colon mucosa damage and severity while increasing colon length. This was additionally accompanied by the increase in IL-10 and TGF-β levels and the decline in VEGF-A, IFN-γ, IL-12, TNF-α, CCL-24, and CCL-17 levels. In terms of the mechanism, EVs promoted M2-like macrophage polarization, characterized by the increase in the M2 marker CD163. Furthermore, the positive effect of EVs on UC repair seemed to be related to the JAK1/STAT1/STAT6 signaling pathway. Collectively, BMSC-derived EVs exerted positive therapeutic effects against DSS-induced UC, which could be due to a negative inflammatory response.
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Affiliation(s)
- Li Cao
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Hanxin Xu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, Hubei, China
| | - Ge Wang
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Mei Liu
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Dean Tian
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei, China
| | - Zhenglin Yuan
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, Hubei, China.
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23
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Simčič S, Berlec A, Stopinšek S, Štrukelj B, Orel R. Engineered and wild-type L. lactis promote anti-inflammatory cytokine signalling in inflammatory bowel disease patient's mucosa. World J Microbiol Biotechnol 2019; 35:45. [PMID: 30810891 DOI: 10.1007/s11274-019-2615-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 02/06/2019] [Indexed: 12/19/2022]
Abstract
Dysbiosis of intestinal microbiota and aberrant inflammatory responses in gastrointestinal mucosa plays important roles in the development of inflammatory bowel disease (IBD). The purpose of this study was to demonstrate the probiotic activity of Lactococcus lactis and the ability of TNF-α-binding by recombinant L. lactis bearing TNF-α-binding affibodies. Various concentrations of recombinant L. lactis were exposed to TNF-α and its binding measured by ELISA. Mucosal biopsies of patients with active IBD were incubated with various L. lactis strains or E. coli DH5α strain and concentrations of TNF-α, IL-23, and IL-10 in the supernatants determined by ELISA. Recombinant L. lactis, at 1 × 109 and 1 × 108 CFU/mL, bound 22.6% and 18.4%, respectively of TNF-α (p < 0.05). When IBD-mucosa was incubated with any L. lactis strain at 1 × 109 CFU/mL, levels of TNF-α and IL-23 were significantly decreased and that of IL-10 increased relative to that for the sterile culture. Opposite trends were observed with E. coli cultures. Recombinant L. lactis at 1 × 108 CFU/mL bound as much as 62.8% (p = 0.026) of TNF-α in IBD-mucosa supernatants compared with the control strain. L. lactis strains are reported, for the first time, to induce an ex vivo anti-inflammatory cytokine profile in IBD inflamed mucosa. L. lactis could therefore constitute a promising alternative approach for treating IBD.
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Affiliation(s)
- Saša Simčič
- Institute of Microbiology and Immunology, University of Ljubljana, Faculty of Medicine, 1000, Ljubljana, Slovenia
| | - Aleš Berlec
- Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia
| | - Sanja Stopinšek
- Institute of Microbiology and Immunology, University of Ljubljana, Faculty of Medicine, 1000, Ljubljana, Slovenia.
| | - Borut Štrukelj
- Department of Biotechnology, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia.,Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
| | - Rok Orel
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital, Bohoričeva 20, 1000, Ljubljana, Slovenia
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24
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Figliuolo da Paz V, Jamwal DR, Gurney M, Midura-Kiela M, Harrison CA, Cox C, Wilson JM, Ghishan FK, Kiela PR. Rapid Downregulation of DAB2 by Toll-Like Receptor Activation Contributes to a Pro-Inflammatory Switch in Activated Dendritic Cells. Front Immunol 2019; 10:304. [PMID: 30873168 PMCID: PMC6400992 DOI: 10.3389/fimmu.2019.00304] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/06/2019] [Indexed: 12/12/2022] Open
Abstract
Dendritic cells (DCs) are pivotal in regulating tolerogenic as well as immunogenic responses against microorganisms by directing both the innate and adaptive immune response. In health, phenotypically different DC subsets found in the gut mucosa are maintained in their tolerogenic state but switch to a pro-inflammatory phenotype during infection or chronic autoinflammatory conditions such as inflammatory bowel disease (IBD). The mechanisms that promote the switch among the mucosal DCs from a tolerogenic to an immunogenic, pro-inflammatory phenotype are incompletely understood. We hypothesized that disabled homolog 2 (DAB2), recently described as a negative regulator of DC immunogenicity during their development, is regulated during intestinal inflammation and modulates mucosal DC function. We show that DAB2 is highly expressed in colonic CD11b+CD103− DCs, a subset known for its capacity to induce inflammatory Th1/Th17 responses in the colon, and is downregulated predominantly in this DC subset during adoptive T cell transfer colitis. Administration of Dab2-deficient DCs (DC2.4Dab2−/− cells) modulated the course of DSS colitis in wild-type mice, enhanced mucosal expression of Tnfa, Il6, and Il17a, and promoted neutrophil recruitment. In bone-marrow derived dendritic cells (BMDC), DAB2 expression correlated with CD11b levels and DAB2 was rapidly and profoundly inhibited by TLR ligands in a TRIF- and MyD88-dependent manner. The negative modulation of DAB2 was biphasic, initiated with a quick drop in DAB2 protein, followed by a sustained reduction in Dab2 mRNA. DAB2 downregulation promoted a more functional and activated DC phenotype, reduced phagocytosis, and increased CD40 expression after TLR activation. Furthermore, Dab2 knockout in DCs inhibited autophagy and promoted apoptotic cell death. Collectively, our results highlight the immunoregulatory role for DAB2 in the intestinal dendritic cells and suggest that DAB2 downregulation after microbial exposure promotes their switch to an inflammatory phenotype.
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Affiliation(s)
| | - Deepa R Jamwal
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Michael Gurney
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | | | - Christy A Harrison
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Christopher Cox
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States
| | - Jean M Wilson
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States
| | - Fayez K Ghishan
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Pawel R Kiela
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States.,Department of Immunobiology, University of Arizona, Tucson, AZ, United States
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25
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Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:177-201. [PMID: 30612460 DOI: 10.1142/s0192415x19500095] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn’s disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4[Formula: see text]) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.
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Affiliation(s)
- Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China
| | - Qiyuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xiaocheng Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, P. R. China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
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26
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Dendritic cell profiles in the inflamed colonic mucosa predict the responses to tumor necrosis factor alpha inhibitors in inflammatory bowel disease. Radiol Oncol 2018; 52:443-452. [PMID: 30511938 PMCID: PMC6287181 DOI: 10.2478/raon-2018-0045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 10/25/2018] [Indexed: 12/18/2022] Open
Abstract
Background Dendritic cells play crucial roles in the control of inflammation and immune tolerance in the gut. We aimed to investigate the effects of tumor necrosis factor alpha (TNFa) inhibitors on intestinal dendritic cells in patients with inflammatory bowel disease and the potential role of intestinal dendritic cells in predicting the response to treatment. Patients and methods Intestinal biopsies were obtained from 30 patients with inflammatory bowel disease before and after treatment with TNFa inhibitors. The proportions of lamina propria dendritic cell phenotypes were analysed using flow cytometry. Disease activity was endoscopically assessed at baseline and after the induction treatment. Results At baseline, the proportion of conventional dendritic cells was higher in the inflamed mucosa (7.8%) compared to the uninflamed mucosa (4.5%) (p = 0.003), and the proportion of CD103+ dendritic cells was lower in the inflamed mucosa (47.1%) versus the uninflamed mucosa (57.3%) (p = 0.03). After 12 weeks of treatment, the proportion of conventional dendritic cells in the inflamed mucosa decreased from 7.8% to 4.5% (p = 0.014), whereas the proportion of CD103+ dendritic cells remained unchanged. Eighteen out of 30 (60%) patients responded to their treatment by week 12. Responders had a significantly higher proportion of conventional dendritic cells (9.16% vs 4.4%, p < 0.01) with higher expression of HLA-DR (median fluorescent intensity [MFI] 12152 vs 8837, p = 0.038) in the inflamed mucosa before treatment compared to nonresponders. Conclusions A proportion of conventional dendritic cells above 7% in the inflamed inflammatory bowel disease mucosa before treatment predicts an endoscopic response to TNFa inhibitors.
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27
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Anandam KY, Alwan OA, Subramanian VS, Srinivasan P, Kapadia R, Said HM. Effect of the proinflammatory cytokine TNF-α on intestinal riboflavin uptake: inhibition mediated via transcriptional mechanism(s). Am J Physiol Cell Physiol 2018; 315:C653-C663. [PMID: 30156861 DOI: 10.1152/ajpcell.00295.2018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Riboflavin (RF), is essential for normal cellular metabolism/function. Intestinal RF absorption occurs via a specific carrier-mediated process that involves the apical transporter RFVT-3 ( SLC52A3) and the basolateral RFVT-1 (SLC52A1). Previously, we characterized different cellular/molecular aspects of the intestinal RF uptake process, but nothing is known about the effect of proinflammatory cytokines on the uptake event. We addressed this issue using in vitro, ex vivo, and in vivo models. First, we determined the level of mRNA expression of the human (h)RFVT-3 and hRFVT-1 in intestinal tissue of patients with inflammatory bowel disease (IBD) and observed a markedly lower level compared with controls. In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-α (TNF-α) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters. The latter effects appear to involve Sp1 and NF-κB sites in these promoters. Similarly, exposure of mouse small intestinal enteroids and wild-type mice to TNF-α led to a significant inhibition in physiological and molecular parameters of intestinal RF uptake. Collectively, these findings demonstrate that exposure of intestinal epithelial cells to TNF-α leads to inhibition in RF uptake and that this effect is mediated, at least in part, via transcriptional mechanism(s). These findings may explain the significantly low RF levels observed in patients with IBD.
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Affiliation(s)
- Kasin Yadunandam Anandam
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Omar A Alwan
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Veedamali S Subramanian
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Padmanabhan Srinivasan
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Rubina Kapadia
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
| | - Hamid M Said
- Department of Medicine, University of California , Irvine, California.,Department of Physiology/Biophysics, University of California , Irvine, California.,Department of Medical Research, Veterans Affairs Medical Center , Long Beach, California
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28
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Subramanian VS, Sabui S, Subramenium GA, Marchant JS, Said HM. Tumor necrosis factor alpha reduces intestinal vitamin C uptake: a role for NF-κB-mediated signaling. Am J Physiol Gastrointest Liver Physiol 2018; 315:G241-G248. [PMID: 29631379 PMCID: PMC6139644 DOI: 10.1152/ajpgi.00071.2018] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with increased serum and intestinal mucosa levels of tumor necrosis factor-α (TNF-α), which also exerts profound effects on the intestinal absorption process. Elevated levels of TNF-α have been linked to the pathogenesis of inflammatory bowel disease (IBD) and malabsorption of nutrients, and patients with this condition have low levels of vitamin C. To date, little is known about the effect of TNF-α on intestinal absorption of vitamin C. We studied the impact of TNF-α on ascorbic acid (AA) transport using a variety of intestinal preparations. The expression level of human SVCT-1 mRNA is significantly lower in patients with IBD. TNF-α treated Caco-2 cells and mice showed a significant inhibition of intestinal 14C-AA uptake. This inhibition was associated with significant decreases in SVCT-1 protein, mRNA, and heterogeneous nuclear RNA levels in TNF-α treated Caco-2 cells, mouse jejunum, and enteroids. Also, TNF-α caused a significant inhibition in the SLC23A1 promoter activity. Furthermore, treatment of Caco-2 cells with celastrol (NF-κB inhibitor) blocked the inhibitory effect caused by TNF-α on AA uptake, SVCT-1 protein, and mRNA expression, as well as the activity of SLC23A1 promoter. Treatment of TNF-α also led to a significant decrease in the expression of hepatocyte nuclear factor-1-α, which drives the basal activity of SLC23A1 promoter, and this effect was reversed by celastrol. Together, these findings show that TNF-α inhibits intestinal AA uptake, and this effect is mediated, at least in part, at the level of transcription of the SLC23A1 gene via the NF-κB pathway. NEW & NOTEWORTHY Our findings show that tumor necrosis factor-α inhibits intestinal ascorbic acid uptake in both in vitro and in vivo systems, and this inhibitory effect is mediated, at least in part, at the level of transcription of the SLC23A1 (sodium-dependent vitamin C transporter-1) gene via the NF-κB pathway.
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Affiliation(s)
- Veedamali S. Subramanian
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
| | - Subrata Sabui
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
| | - Ganapathy A. Subramenium
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
| | - Jonathan S. Marchant
- 4Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Hamid M. Said
- 1Department of Medicine, University of California, Irvine, California,2Department of Physiology and Biophysics, University of California, Irvine, California,3Department of Veterans Affairs Medical Center, Long Beach, California
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29
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Christian SL, Berry MD. Trace Amine-Associated Receptors as Novel Therapeutic Targets for Immunomodulatory Disorders. Front Pharmacol 2018; 9:680. [PMID: 30013475 PMCID: PMC6036138 DOI: 10.3389/fphar.2018.00680] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 06/05/2018] [Indexed: 12/14/2022] Open
Abstract
Trace amines and their receptors (trace amine-associated receptors; TAARs) are an emerging pharmacological target for the treatment of human disorders. While most studies have focused on their therapeutic potential for neurologic and psychiatric disorders, TAARs are also expressed throughout the periphery, including prominent expression in human leukocytes. Furthermore, recent independent, unbiased metabolomic studies have consistently identified one or more TAAR ligands as potential etiologic factors in inflammatory bowel disease (IBD). The putative role of TAARs in diseases such as IBD that are associated with hyperactive immune responses has not, however, previously been systematically addressed. Here, we review the current state of the knowledge of the effects of TAARs on leukocyte function, in particular in the context of mucosal epithelial cells that interface with the environment; developing a model whereby TAARs may be considered as a novel therapeutic target for disorders associated with dysregulated immune responses to environmental factors. In this model, we hypothesize that altered trace amine homeostasis results in hyperactivity of the immune system. Such loss of homeostasis can occur through many different mechanisms including TAAR polymorphisms and altered trace amine load due to changes in host synthesis and/or degradative enzymes, diet, or microbial dysbiosis. The resulting alterations in TAAR functioning can then lead to a loss of homeostasis of leukocyte chemotaxis, differentiation, and activation, as well as an altered ability of members of the microbiota to adhere to and penetrate the epithelial cell layers. Such changes would generate a pro-inflammatory state at mucosal epithelial barrier layers that can manifest as clinical symptomatology such as that seen in IBD. These alterations may also have the potential to induce systemic effects, which could possibly contribute to immunomodulatory disorders in other systems, including neurological diseases.
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30
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Fu S, Liu H, Chen X, Qiu Y, Ye C, Liu Y, Wu Z, Guo L, Hou Y, Hu CAA. Baicalin Inhibits Haemophilus Parasuis-Induced High-Mobility Group Box 1 Release during Inflammation. Int J Mol Sci 2018; 19:ijms19051307. [PMID: 29702580 PMCID: PMC5983759 DOI: 10.3390/ijms19051307] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/04/2018] [Accepted: 04/24/2018] [Indexed: 02/07/2023] Open
Abstract
Haemophilus parasuis (H. parasuis) can cause Glässer’s disease in pigs. However, the molecular mechanism of the inflammation response induced by H. parasuis remains unclear. The high-mobility group box 1 (HMGB1) protein is related to the pathogenesis of various infectious pathogens, but little is known about whether H. parasuis can induce the release of HMGB1 in piglet peripheral blood monocytes. Baicalin displays important anti-inflammatory and anti-microbial activities. In the present study, we investigated whether H. parasuis can trigger the secretion of HMGB1 in piglet peripheral blood monocytes and the anti-inflammatory effect of baicalin on the production of HMGB1 in peripheral blood monocytes induced by H. parasuis during the inflammation response. In addition, host cell responses stimulated by H. parasuis were determined with RNA-Seq. The RNA-Seq results showed that H. parasuis infection provokes the expression of cytokines and the activation of numerous pathways. In addition, baicalin significantly reduced the release of HMGB1 in peripheral blood monocytes induced by H. parasuis. Taken together, our study showed that H. parasuis can induce the release of HMGB1 and baicalin can inhibit HMGB1 secretion in an H. parasuis-induced peripheral blood monocytes model, which may provide a new strategy for preventing the inflammatory disorders induced by H. parasuis.
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Affiliation(s)
- Shulin Fu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Huashan Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Xiao Chen
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Yinsheng Qiu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Chun Ye
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Yu Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Zhongyuan Wu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Ling Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Yongqing Hou
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan 430023, China.
| | - Chien-An Andy Hu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
- Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
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31
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Sabui S, Kapadia R, Ghosal A, Schneider M, Lambrecht NWG, Said HM. Biotin and pantothenic acid oversupplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects. Am J Physiol Cell Physiol 2018; 315:C73-C79. [PMID: 29669219 DOI: 10.1152/ajpcell.00319.2017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Intestinal absorption of the water-soluble vitamins biotin and pantothenic acid is carrier mediated and involves the sodium-dependent multivitamin transporter (SMVT; product of the SLC5A6 gene). We recently observed that intestinal-specific (conditional) knockout of the mouse Slc5a6 gene (SMVT-cKO) is associated with growth retardation, the development of spontaneous and severe inflammation, abnormal histology in the large intestine, altered gut permeability, and early death. Our aim in this study was to examine the possibility that biotin and pantothenic acid oversupplementation (BPS) of the SMVT-cKO mice could reverse the above-described abnormalities. BPS was provided in the drinking water to mice before conception, to dams during pregnancy and lactation, and to the SMVT-cKO mice throughout their life. Our findings showed that such a regimen prevents early death, as well as normalizes the growth rate, intestinal integrity, pathology, and inflammation in SMVT-cKO mice. These findings provide clear evidence for a role for biotin and/or pantothenic acid in the maintenance of normal intestinal integrity and health.
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Affiliation(s)
- Subrata Sabui
- Department of Medical Research, VA Medical Center , Long Beach, California.,Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Rubina Kapadia
- Department of Medical Research, VA Medical Center , Long Beach, California.,Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Abhisek Ghosal
- Department of Medical Research, VA Medical Center , Long Beach, California.,Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Michael Schneider
- Department of Medical Research, VA Medical Center , Long Beach, California.,Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Nils W G Lambrecht
- Department of Medical Research, VA Medical Center , Long Beach, California.,Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
| | - Hamid M Said
- Department of Medical Research, VA Medical Center , Long Beach, California.,Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California
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32
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Górski A, Jończyk-Matysiak E, Łusiak-Szelachowska M, Międzybrodzki R, Weber-Dąbrowska B, Borysowski J. Bacteriophages targeting intestinal epithelial cells: a potential novel form of immunotherapy. Cell Mol Life Sci 2018; 75:589-595. [PMID: 29164271 PMCID: PMC5769817 DOI: 10.1007/s00018-017-2715-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/07/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023]
Abstract
In addition to their established role as a physical barrier to invading pathogens and other harmful agents, intestinal epithelial cells (IEC) are actively involved in local immune reactions. In the past years, evidence has accumulated suggesting the role of IEC in the immunopathology of intestinal inflammatory disorders (IBD). Recent advances in research on bacteriophages strongly suggest that-in addition to their established antibacterial activity-they have immunomodulating properties that are potentially useful in the clinic. We suggest that these immunomodulating phage activities targeting IEC may open novel treatment perspectives in disorders of the alimentary tract, particularly IBD.
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Affiliation(s)
- Andrzej Górski
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland.
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, 02-006, Warsaw, Poland.
| | - Ewa Jończyk-Matysiak
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
| | - Marzanna Łusiak-Szelachowska
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
| | - Ryszard Międzybrodzki
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, 02-006, Warsaw, Poland
| | - Beata Weber-Dąbrowska
- Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114, Wrocław, Poland
| | - Jan Borysowski
- Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, 02-006, Warsaw, Poland
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33
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McConachie SM, Wilhelm SM, Bhargava A, Kale-Pradhan PB. Biologic-Induced Infections in Inflammatory Bowel Disease: The TNF-α Antagonists. Ann Pharmacother 2018; 52:571-579. [DOI: 10.1177/1060028018754896] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Objective: To review the mechanism and association of infectious risk among the tumor-necrosis factor α (TNF-α) antagonists used in inflammatory bowel disease. Data Sources: A PubMed literature search was performed using the following search terms: infliximab, adalimumab, certolizumab, golimumab, inflammatory bowel disease, crohn’s, ulcerative colitis, adverse effects, adverse events, safety, and infection. Study Selection and Data Extraction: Meta-analyses and cohort studies with outcomes pertaining to quantitative infectious risk were reviewed. Case reports and case series describing association between TNF-α inhibitors and infection were also reviewed. Data Synthesis: A total of 7 recent meta-analyses of randomized trials demonstrate inconclusive association of infection with TNF-α antagonists. Registry data suggest that medications carry an independent risk of opportunistic infections. Risk factors for infection include older age, malnutrition, diabetes, and possibly combination therapy. Reported infections vary widely but include intracellular and granulomatous bacteria, viruses, and fungi. Conclusion: TNF-α antagonists are associated with an increased risk of opportunistic infection, although this risk has not been demonstrated conclusively in randomized controlled trials. Knowledge of concomitant risk factors, mechanism of infectious risk, and available treatment options can improve patient care in the clinical setting.
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Affiliation(s)
- Sean M. McConachie
- Wayne State University, Detroit, MI, USA
- Harper University Hospital, Detroit, MI, USA
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