scholarly journals S1P and the birth of platelets

2012 ◽  
Vol 209 (12) ◽  
pp. 2137-2140 ◽  
Author(s):  
Timothy Hla ◽  
Sylvain Galvani ◽  
Shahin Rafii ◽  
Ralph Nachman
Keyword(s):  
Therapeutic Strategy ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Biological Functions ◽  
Platelet Production ◽  
S1p1 Receptor ◽  
Sphingosine 1 Phosphate ◽  
Trafficking Organization ◽  
Cxcr4 Axis ◽  
Novel Therapeutic

Recent work has highlighted the multitude of biological functions of sphingosine 1-phosphate (S1P), which include roles in hematopoietic cell trafficking, organization of immune organs, vascular development, and neuroinflammation. Indeed, a functional antagonist of S1P1 receptor, FTY720/Gilenya, has entered the clinic as a novel therapeutic for multiple sclerosis. In this issue of the JEM, Zhang et al. highlight yet another function of this lipid mediator: thrombopoiesis. The S1P1 receptor is required for the growth of proplatelet strings in the bloodstream and the shedding of platelets into the circulation. Notably, the sharp gradient of S1P between blood and the interstitial fluids seems to be essential to ensure the production of platelets, and S1P appears to cooperate with the CXCL12–CXCR4 axis. Pharmacologic modulation of the S1P1 receptor altered circulating platelet numbers acutely, suggesting a potential therapeutic strategy for controlling thrombocytopenic states. However, the S1P4 receptor may also regulate thrombopoiesis during stress-induced accelerated platelet production. This work reveals a novel physiological action of the S1P/S1P1 duet that could potentially be harnessed for clinical translation.

scholarly journals Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing

2019 ◽  
Vol 3 (11) ◽  
pp. 1702-1713 ◽  
Author(s):  
Hira Niazi ◽  
Nesrine Zoghdani ◽  
Ludovic Couty ◽  
Alexandre Leuci ◽  
Anja Nitzsche ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Lipid Mediator ◽  
Gradient Sensing ◽  
Platelet Production ◽  
Platelet Counts ◽  
Sphingosine Kinase 2 ◽  
Clinical Observations ◽  
Sphingosine 1 Phosphate ◽  
Hematopoietic Niche

Abstract The bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P1 receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)–derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P1. Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by S1pr1 deletion selectively in MKs. Moreover, S1P1 expression and signaling were both undetectable in mature MKs in situ, and MK S1pr1 deletion did not affect platelet aggregation or spreading. When S1pr1 deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted Sphk2 deletion and was reversed by compound deletion of either Sphk1 or S1pr2, suggesting that this phenotype arises from increased S1P export and S1P2 activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P1 in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P1, and can further suppress thrombopoiesis through S1P2 when aberrantly secreted in the hematopoietic niche.

Design of Sphingosine Kinases Inhibitors: Challenges and Recent Developments

2019 ◽  
Vol 25 (9) ◽  
pp. 956-968 ◽  
Author(s):  
Elisa Magli ◽  
Angela Corvino ◽  
Ferdinando Fiorino ◽  
Francesco Frecentese ◽  
Elisa Perissutti ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Biochemical Properties ◽  
Lipid Mediator ◽  
Compensatory Mechanism ◽  
Biological Functions ◽  
Wide Range ◽  
Sphingosine 1 Phosphate ◽  
Recent Developments ◽  
Sphingosine Kinases ◽  
Review Reports

Background:Sphingosine kinases (SphKs) catalyze the phosphorylation of sphingosine to form the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P is an important lipid mediator with a wide range of biological functions; it is also involved in a variety of diseases such as inflammatory diseases, Alzheimer’s disease and cancer.Methods:This review reports the recent advancement in the research of SphKs inhibitors. Our purpose is also to provide a complete overview useful for underlining the features needed to select a specific pharmacological profile.Discussion:Two distinct mammalian SphK isoforms have been identified, SphK1 and SphK2. These isoforms are encoded by different genes and exhibit distinct subcellular localizations, biochemical properties and functions. SphK1 and SphK2 inhibition can be useful in different pathological conditions.Conclusion:SphK1 and SphK2 have many common features but different and even opposite biological functions. For this reason, several research groups are interested in understanding the therapeutic usefulness of a selective or non-selective inhibitor of SphKs. Moreover, a compensatory mechanism for the two isoforms has been demonstrated, thus leading to the development of dual inhibitors.

scholarly journals Sphingosine 1-phosphate: Lipid signaling in pathology and therapy

Science ◽  
2019 ◽  
Vol 366 (6463) ◽  
pp. eaar5551 ◽  
Author(s):  
Andreane Cartier ◽  
Timothy Hla
Keyword(s):  
Immune Cell ◽  
Clinical Medicine ◽  
Lipid Mediator ◽  
Cell Trafficking ◽  
Multidisciplinary Research ◽  
Adaptive Immune ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Fibrotic Diseases ◽  
G Protein Coupled

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein–coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Anti-OX40ligand treatment as a novel therapeutic strategy in a murine model of colitis

2001 ◽  
Vol 120 (5) ◽  
pp. A685-A685
Author(s):  
B SINGH ◽  
V MALMSTROM ◽  
F POWRIE
Keyword(s):  
Murine Model ◽  
Therapeutic Strategy ◽  
Novel Therapeutic

Anticancer Immunotoxins, Challenges, and Approaches

2020 ◽  
Vol 26 ◽  
Author(s):  
Maryam Dashtiahangar ◽  
Leila Rahbarnia ◽  
Safar Farajnia ◽  
Arash Salmaninejad ◽  
Arezoo Gowhari Shabgah ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Antibody Fragment ◽  
Clinical Use ◽  
Multiple Cancer ◽  
Main Obstacle ◽  
Cancer Types ◽  
Recombinant Immunotoxins ◽  
Cancerous Cells ◽  
High Immunogenicity ◽  
Novel Therapeutic

: The development of recombinant immunotoxins (RITs) as a novel therapeutic strategy has made a revolution in the treatment of cancer. RITs are resulting from the fusion of antibodies to toxin proteins for targeting and eliminating cancerous cells by inhibiting protein synthesis. Despite indisputable outcomes of RITs regarding inhibiting multiple cancer types, high immunogenicity has been known as the main obstacle in the clinical use of RITs. Various strategies have been proposed to overcome these limitations, including immunosuppressive therapy, humanization of the antibody fragment moiety, generation of immunotoxins originated from endogenous human cytotoxic enzymes, and modification of the toxin moiety to escape the immune system. This paper devoted to reviewing recent advances in the design of immunotoxins with lower immunogenicity.

scholarly journals Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0214250 ◽  
Author(s):  
Amanda H. Kahn-Kirby ◽  
Akiko Amagata ◽  
Celine I. Maeder ◽  
Janet J. Mei ◽  
Steve Sideris ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Therapeutic Strategy ◽  
Novel Therapeutic

scholarly journals Apohemoglobin-haptoglobin complex attenuates the pathobiology of circulating acellular hemoglobin and heme

2020 ◽  
Vol 318 (5) ◽  
pp. H1296-H1307 ◽  
Author(s):  
Carlos J. Munoz ◽  
Ivan S. Pires ◽  
Jin Hyen Baek ◽  
Paul W. Buehler ◽  
Andre F. Palmer ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Capillary Density ◽  
Microvascular Blood Flow ◽  
Systemic Hypertension ◽  
Proof Of Concept ◽  
Heme Transfer ◽  
Ligand Transfer ◽  
Novel Therapeutic

This study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. The apoHb-Hp complex reverses Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, preserves microvascular blood flow, and functional capillary density. In summary, the unique properties of the apoHb-Hp complex prevent adverse systemic and microvascular responses to Hb and heme-albumin exposure and introduce a novel therapeutic approach to facilitate simultaneous removal of extracellular Hb and heme.

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