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Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases

World Journal of Gastroenterology 2023年第1期29卷 110-125页

作者： evanthia tourkochristou Athanasia Mouzaki Christos Triantos Division of Gastroenterology Department of Internal MedicineMedical SchoolUniversity of PatrasPatras 26504Greece Division of Hematology Department of Internal MedicineMedical SchoolUniversity of PatrasPatras 26504Greece

Inflammatory bowel disease(IBD)is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide.The increasing disease burden worldwide,lack of response to current biologic therapeutics,and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy.Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics.Sphingosine-1-phosphate(S1P)receptor(S1PR)modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement.S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival,differentiation,migration,proliferation,immune response,and lymphocyte trafficking.T lymphocytes play an important role in regulating inflammatory responses.In inflamed IBD tissue,an imbalance between T helper(Th)and regulatory T lymphocytes and Th cytokine levels was found.The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD.S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking,lymphocyte number,lymphocyte activity,cytokine production,and contributing to gut barrier function.

关键词： Inflammatory bowel disease Sphingosine-1-phosphate Intestinal inflammation T helper 1/T helper 17 Sphingosine 1 phosphate Modulators Immune responses

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Role of NLRP3 inflammasome in inflammatory bowel diseases

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World Journal of Gastroenterology 2019年第33期25卷 4796-4804页

作者： evanthia tourkochristou Ioanna Aggeletopoulou Christos Konstantakis Christos Triantos Division of Gastroenterology Department of Internal Medicine Medical School University of Patras

Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β(IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases(IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.

关键词： NLRP3 inflammasome Inflammatory bowel diseases Mucosal immune system Interleukin 1β Interleukin 18 NLRP3 gene polymorphisms

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Toward a new era of hepatitis B virus therapeutics:The pursuit of a functional cure

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World Journal of Gastroenterology 2021年第21期27卷 2727-2757页

作者： Efthymios P Tsounis evanthia tourkochristou Athanasia Mouzaki Christos Triantos Division of Gastroenterology Department of Internal MedicineMedical SchoolUniversity of PatrasPatras 26504Greece Division of Hematology Department of Internal MedicineMedical SchoolUniversity of PatrasPatras 26504Greece

Hepatitis B virus(HBV)infection,although preventable by vaccination,remains a global health problem and a major cause of chronic liver disease.Although current treatment strategies suppress viral replication very efficiently,the optimal endpoint of hepatitis B surface antigen(HBsAg)clearance is rarely achieved.Moreover,the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored.Therefore,the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV,defined as undetectable HBV DNA and HBsAg loss over a limited treatment period.A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms,including inhibition of viral entry,transcriptional silencing,epigenetic manipulation,interference with capsid assembly,and disruption of HBsAg release.In parallel,another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses.Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment.Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses.In addition,several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting.Ultimately,it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs.This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.

关键词： Chronic hepatitis B Functional cure Direct-acting antivirals Gene silencing Immunotherapy Therapeutic vaccination

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