scholarly journals Activation of Purinergic Signaling Pathways during the Development of Inflammatory Bowel Disease

2020 ◽  
Vol 5 (6) ◽  
pp. 17-26
Author(s):  
O. S. Zherebyatiev ◽  
◽  
O. V. Voitovich ◽  
T. Yu. Motilonok ◽  
A. A. Egorov ◽  
...  

Inflammatory bowel disease is an important illness of unclear pathogenesis associated with major defects in mucosal immunoregulation and develops in genetically susceptible individuals. These abnormalities often occur in association with microbial dysbiosis and result in unfettered inflammation of the intestine and extraintestinal tissues. Such events result in long-term morbidity and possibly even death, in otherwise healthy adults and children. Dampening inflammation and re-establishing immune tolerance in inflammatory bowel disease remain the major therapeutic goal. However, existing inflammatory bowel disease therapies albeit providing recent advances, still largely rely on broad-based immunosuppression. For example, only around half of the patients treated with anti-TNF agents show substantive clinical responses. These improvements are often self-limited, while unfortunately increasing the risk of opportunistic infections. The purpose of the study was to investigate the control of mucosal immune responses, which are based on fundamental signaling pathways. Long-term interests in the regulation of purinergic signaling are now being leveraged to develop innovative and hopefully non-toxic therapies for inflammatory bowel disease. This review and the accompanying articles in this special issue address new therapeutic concepts in inflammatory bowel disease, as based on recent, linked work in hypoxia and purinergic signaling, mucosal barrier functions and microRNA biology. In several recent, comprehensive reviews, have already addressed the biological functions of ectoenzymes, such as CD39, CD73, and CD38, in the regulation of purinergic signaling and control of extracellular adenosine levels. Others, have noted the importance of these mechanisms in immunomodulation, as in cancer and inflammation. The ectonucleotidases of the CD39 family, in particular, have major impacts on the dynamic equilibrium of proinflammatory extracellular ATP, ADP nucleotides vs. the immunosuppressive potential of adenosine nucleosides. CD39 plays a dominant role in purinergic regulation of vascular inflammation, thrombosis, and the immune response in such settings. The relevance and importance of these purinergic signaling pathways in selected neoplastic states (lymphoma and chronic leukemia) and inflammatory diseases (sepsis and autoimmunity) have been already alluded to in recent work. A brief synopsis of the major components of purinergic signaling; chiefly for those not familiar to this field, will focus on very recent work detailing the immunomodulation of CD39 on T cells and other immune cells by both genetic and environmental factors in the setting of inflammatory bowel disease and experimental colitis, inclusive of the new roles for natural metabolites such as bilirubin, and will also briefly cover the role of CD39 expression on exosomes and microparticles, in control of inflammation in the gut and touch on the relevance of the microbiome. Lastly, it will cover the emerging importance of other NTPDases of the CD39 family and speculate on their role in controlling gut inflammation. Conclusion. Review of the literature with own data is devoted to description of the recent advances in the study purinergic signaling pathways implicated in immune dysregulation, in the pathogenesis of inflammatory bowel disease. Our focus in this review is on novel aspects of the functions of CD39 and related nucleoside triphosphate diphosphohydrolases in inflammatory bowel disease

2019 ◽  
Vol 25 (1) ◽  
pp. 57-63 ◽  
Author(s):  
Clara Yzet ◽  
Stacy S. Tse ◽  
Maia Kayal ◽  
Robert Hirten ◽  
Jean-Frédéric Colombel

The emergence of biologic therapies has revolutionized the management of inflammatory bowel disease (IBD) by halting disease progression, increasing remission rates and improving long-term clinical outcomes. Despite these well-described benefits, many patients are reluctant to commence therapy due to drug safety concerns. Adverse events can be detected at each stage of drug development and during the post-marketing period. In this article, we review how to best assess the safety parameters of new IBD medications, from the earliest stage of development to population-based registries, with a focus on the special populations often excluded from the evaluation process.


Author(s):  
Stefanie Howaldt ◽  
Eugeni Domènech ◽  
Nicholas Martinez ◽  
Carsten Schmidt ◽  
Bernd Bokemeyer

Abstract Background Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. Methods In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center’s standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. Results For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. Conclusions Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated.


2015 ◽  
Vol 148 (4) ◽  
pp. S-463
Author(s):  
Ioannis E. Koutroubakis ◽  
Claudia Ramos Rivers ◽  
Miguel Regueiro ◽  
Efstratios Koutroumpakis ◽  
Benjamin H. Click ◽  
...  

2009 ◽  
Vol 136 (5) ◽  
pp. A-663 ◽  
Author(s):  
Alessandro Armuzzi ◽  
Fabio De Vincentis ◽  
Manuela Marzo ◽  
Giammarco Mocci ◽  
Carla Felice ◽  
...  

2017 ◽  
Vol 152 (5) ◽  
pp. S391 ◽  
Author(s):  
Eve Sedillot-Daniel ◽  
Audrey Désilets ◽  
Alexandra Verreault ◽  
France Gervais ◽  
Colette Deslandres ◽  
...  

2014 ◽  
Vol 20 (3) ◽  
pp. 502-507 ◽  
Author(s):  
Ming-Shian Tsai ◽  
Cheng-Li Lin ◽  
Hsin-Pao Chen ◽  
Po-Huang Lee ◽  
Fung-Chang Sung ◽  
...  

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