Abstract
Multiple lines of evidence suggest that macrophages have a critical role in the disease pathology of inflammatory bowel disease (IBD) by secreting inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)- 1β, IL-6 and IL-8. Therapies for IBD target one or more of these inflammatory mediators. Recent advances in drug development for IBD have involved the use of monoclonal antibodies to inhibit specific inflammatory cytokines. In particular, the anti-TNF-α antibodies, CDP571 and Infliximab have been used clinically to treat Crohns disease with some success. The inflammatory cytokines and lipopolysaccharide (LPS) cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM), to generate a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related IBD. We synthesized a series of difluoromethylene analogues of SM (SMAs). This review discusses recent data from our laboratories on the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated releases of the cytokines from macrophages and intestinal epithelial cells and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. Our findings suggest a central role of SMase/ceramide signaling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in IBD.
Keywords: Sphingomyelinase inhibitor, ceramide, nuclear factor-κB, inflammatory cytokines, macrophages, inflammatory bowel disease
Current Drug Therapy
Title: Sphingomyelinase Inhibition Suggests a Possible New Strategy for the Treatment of Inflammatory Bowel Disease
Volume: 3 Issue: 3
Author(s): Shinji Soeda, Akira Sakata, Takashi Ochiai, Kazuya Yasuda, Yukako Kuramoto, Hiroshi Shimeno, Akihisa Toda, Reiko Eyanagi, Sadao Hikishima, Tsutomu Yokomastu and Shirashi Shibuya
Affiliation:
Keywords: Sphingomyelinase inhibitor, ceramide, nuclear factor-κB, inflammatory cytokines, macrophages, inflammatory bowel disease
Abstract: Multiple lines of evidence suggest that macrophages have a critical role in the disease pathology of inflammatory bowel disease (IBD) by secreting inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)- 1β, IL-6 and IL-8. Therapies for IBD target one or more of these inflammatory mediators. Recent advances in drug development for IBD have involved the use of monoclonal antibodies to inhibit specific inflammatory cytokines. In particular, the anti-TNF-α antibodies, CDP571 and Infliximab have been used clinically to treat Crohns disease with some success. The inflammatory cytokines and lipopolysaccharide (LPS) cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM), to generate a lipid messenger ceramide. The design of SMase inhibitors may offer new therapies for the treatment of LPS- and cytokine-related IBD. We synthesized a series of difluoromethylene analogues of SM (SMAs). This review discusses recent data from our laboratories on the effects of the most potent SMase inhibitor, SMA-7, on the LPS-mediated releases of the cytokines from macrophages and intestinal epithelial cells and the pathology of dextran sulphate sodium (DSS)-induced colitis in mice. Our findings suggest a central role of SMase/ceramide signaling in the pathology of DSS-induced colitis in mice, indicating a possible preventive or therapeutic role for SMase inhibitor in IBD.
Export Options
About this article
Cite this article as:
Soeda Shinji, Sakata Akira, Ochiai Takashi, Yasuda Kazuya, Kuramoto Yukako, Shimeno Hiroshi, Toda Akihisa, Eyanagi Reiko, Hikishima Sadao, Yokomastu Tsutomu and Shibuya Shirashi, Sphingomyelinase Inhibition Suggests a Possible New Strategy for the Treatment of Inflammatory Bowel Disease, Current Drug Therapy 2008; 3 (3) . https://dx.doi.org/10.2174/157488508785747853
DOI https://dx.doi.org/10.2174/157488508785747853 |
Print ISSN 1574-8855 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3903 |
Call for Papers in Thematic Issues
Novel Therapeutic Approaches and Biomarkers for Chronic Kidney Disease (CKD)
The thematic issue on "Novel Therapeutic Approaches and Biomarkers for CKD" aims to provide a comprehensive exploration of cutting-edge strategies for the management of chronic kidney disease (CKD). This issue will delve into emerging therapeutic targets, focusing on critical aspects such as podocyte injury, endothelial dysfunction, and tubulointerstitial fibrosis, which ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Modulation of Transient Receptor Potential Vanilloid Subtype 1 (TRPV<sub>1</sub>) and Norepinephrine Transporters (NET) Protect Against Oxidative Stress, Cellular Injury, and Vascular Dementia
Current Neurovascular Research Oral and Topical Administration of ROQUETTE Schizochytrium sp. Alleviate Skin Inflammation and Improve Wound Healing in Mice
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Pharmacology of Nitric Oxide: Molecular Mechanisms and Therapeutic Strategies
Current Pharmaceutical Design Determinants of Paraoxonase 1 Status: Genes, Drugs and Nutrition
Current Medicinal Chemistry The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia
Current Pharmaceutical Design Inhibitors of Nitric Oxide Synthase: What's up and What's Next?
Current Enzyme Inhibition Antibiotics and Non-Steroidal Anti-Inflammatory Drugs in Outpatient Practice: Indications and Unwanted Effects in a Gastroenterological Setting
Current Drug Safety Ventilator-Associated Tracheobronchitis: Pathophysiology, Prevention and Treatment
Current Respiratory Medicine Reviews The Molecular Basis of Class Side Effects Due to Treatment with Inhibitors of the VEGF/VEGFR Pathway
Current Clinical Pharmacology Recent Advances in Synthesis of PAR Ligands as Therapeutic Strategy for Inflammatory Diseases
Mini-Reviews in Medicinal Chemistry Inhibitors of the 5-Lipoxygenase Pathway in Atherosclerosis
Current Pharmaceutical Design Biological Roles of the Eclectic Chromogranin-A-derived Peptide Catestatin
Current Medicinal Chemistry Modulation of Cardiovascular Function by Adipokines
Cardiovascular & Hematological Disorders-Drug Targets Bioactivities of Iridoids
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Phenolic Compounds: the Role of Redox Regulation in Neurodegenerative Disease and Cancer
Mini-Reviews in Medicinal Chemistry Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation
Current Drug Targets PDE5 Inhibitor Treatment Options for Urologic and Non-Urologic Indications: 2012 Update
Current Pharmaceutical Design Low Molecular Weight Compounds with Transition Metals as Free Radical Scavengers and Novel Therapeutic Agents
Cardiovascular & Hematological Agents in Medicinal Chemistry Churg-Strauss Syndrome Presenting as Acute Necrotizing Eosinophilic Myocarditis: Concise Review of the Literature
Current Hypertension Reviews Extracellular Vesicles Isolated from Mesenchymal Stromal Cells Primed with Hypoxia: Novel Strategy in Regenerative Medicine
Current Stem Cell Research & Therapy