Article
Cell & Tissue Engineering
Jaime M. Brozowski, Roman G. Timoshchenko, D. Stephen Serafin, Brittney Allyn, Jessica Koontz, Emily M. Rabjohns, Rishi R. Rampersad, Yinshi Ren, Amanda M. Eudy, Taylor F. Harris, David Abraham, Daniel Mattox, Clinton T. Rubin, Matthew J. Hilton, Janet Rubin, Nancy L. Allbritton, Matthew J. Billard, Teresa K. Tarrant
Summary: Our study reveals that G protein receptor kinase 3 (GRK3) regulates the function of bone marrow mesenchymal stem cells by modulating sphingosine-1-phosphate receptor signaling. Deficiency of GRK3 leads to hypercellular bone marrow and leukocytosis, as well as enhanced osteogenic differentiation of mesenchymal stem cells. These findings highlight the important role of GRK3 in the bone marrow niche.
STEM CELL RESEARCH & THERAPY
(2022)
Review
Pharmacology & Pharmacy
Shun Yaginuma, Jumpei Omi, Kuniyuki Kano, Junken Aoki
Summary: Accumulating evidence suggests that lysophospholipids (LPL) serve as lipid mediators that exert their diverse pathophysiological functions via G protein-coupled receptors. These LPLs can be detected and quantified in various biological fluids and are potential biomarkers for pathological conditions. This review discusses the potential of LPLs and their synthetic enzymes as pathological biomarkers, including methods and problems in their measurement.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Rachel S. Resop, Bradley Salvatore, Shawn J. Kim, Brent R. Gordon, Bianca Blom, Dimitrios N. Vatakis, Christel H. Uittenbogaart
Summary: HIV-1 infection leads to upregulation of S1P receptor 1 (S1PR1) in the human thymus, potentially increasing the number and speed of thymocyte egress. This may have implications for immune function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Shanthi Nagarajan, Zu Yuan Qian, Parthiban Marimuthu, Nabil J. Alkayed, Sanjiv Kaul, Anthony P. Barnes
Summary: Through a combined computational and experimental approach, critical residues and properties within the lipid-binding pocket responsible for detecting 14,15-EET and other eicosanoids were identified. The study suggests that hydrophobic and positively charged residues in the receptor-binding pocket are prerequisites for recognizing lipid ligands, aiding in understanding the binding mechanism of GPCRs to 14,15-EET.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Jt Toebbe, Mary Beth Genter
Summary: Olfactory neurons play a crucial role in the entry of the SARS-CoV-2 virus into the brain, and expressing ACE2 and S1P receptors. Recent studies have confirmed the expression of S1P and LPA receptors in rodent olfactory mucosa, suggesting that targeting these receptors may help prevent the transmission of the virus from the nasal cavity to the brain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Haonan Liu, Molly L. Jackson, Lucy J. Goudswaard, Samantha F. Moore, James L. Hutchinson, Ingeborg Hers
Summary: Sphingosine 1-phosphate (S1P) plays a crucial role in regulating human platelet function, with different receptor subtypes having either positive or negative effects on platelet function.
SCIENTIFIC REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Na Wang, Jing-Yi Li, Bo Zeng, Gui-Lan Chen
Summary: Sphingosine-1-phosphate (S1P) is a crucial sphingolipid molecule that regulates cardiovascular functions through binding and activating multiple G protein-coupled receptors in different cell types. It affects cell proliferation, migration, differentiation, and apoptosis through various downstream signaling pathways. Abnormal S1P levels are associated with cardiovascular disorders, and further research is needed to explore the potential therapeutic use of S1P in these diseases.
Review
Cell Biology
Kana Masuda-Kuroki, Shahrzad Alimohammadi, Anna Di Nardo
Summary: Psoriasis is a chronic skin condition that lacks a complete cure. Recent studies have identified sphingolipid metabolites as significant contributors to psoriasis, particularly ceramide and sphingosine-1-phosphate (S1P). The modulation of S1P and its receptor has shown potential in improving psoriasis inflammation.
Article
Multidisciplinary Sciences
Elizaveta Lyapina, Egor Marin, Anastasiia Gusach, Philipp Orekhov, Andrey Gerasimov, Aleksandra Luginina, Daniil Vakhrameev, Margarita Ergasheva, Margarita Kovaleva, Georgii Khusainov, Polina Khorn, Mikhail Shevtsov, Kirill Kovalev, Sergey Bukhdruker, Ivan Okhrimenko, Petr Popov, Hao Hu, Uwe Weierstall, Wei Liu, Yunje Cho, Ivan Gushchin, Andrey Rogachev, Gleb Bourenkov, Sehan Park, Gisu Park, Hyo Jung Hyun, Jaehyun Park, Valentin Gordeliy, Valentin Borshchevskiy, Alexey Mishin, Vadim Cherezov
Summary: This study reports the crystal structure of the S1P(5) receptor in complex with a selective inverse agonist, revealing an allosteric subpocket and shedding light on inverse agonism in S1P receptors.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Oscar Mammoliti, Adeline Palisse, Caroline Joannesse, Sandy El Bkassiny, Brigitte Allart, Alex Jaunet, Christel Menet, Beatrice Coornaert, Kathleen Sonck, Inge Duys, Philippe Clement-Lacroix, Line Oste, Monica Borgonovi, Emanuelle Wakselman, Thierry Christophe, Nicolas Houvenaghel, Mia Jans, Bertrand Heckmann, Laurent Saniere, Reginald Brys
Summary: Studies suggest that blocking S1P2 receptor signaling could be effective for treating idiopathic pulmonary fibrosis, with only a few antagonists disclosed so far. A chemical enablement strategy led to the discovery of a pyridine series with good antagonist activity, and further optimization identified a compound with potent activity in a phenotypic IL8 release assay and bleomycin-induced model of pulmonary fibrosis.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
D. Roselyn Cerutis, Michael D. Weston, Takanari Miyamoto
Summary: Oral health is important for overall health, and periodontal disease (PDD) is a chronic inflammatory disease. Our research on lysophosphatidic acid (LPA) and its receptors (LPARs) in the oral system has implications for understanding cancer and immune responses. Further exploration of LPA's potential for controlling complex immune responses and signaling in the cellular microenvironment is needed to improve treatment for diseases like PDD, cancer, and emerging diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Rachel S. Knipe, Jillian J. Spinney, Elizabeth A. Abe, Clemens K. Probst, Alicia Franklin, Amanda Logue, Francesca Giacona, Matt Drummond, Jason Griffith, Patricia L. Brazee, Lida P. Hariri, Sydney B. Montesi, Katherine E. Black, Timothy Hla, Andrew Kuo, Andreane Cartier, Eric Engelbrecht, Christina Christoffersen, Barry S. Shea, Andrew M. Tager, Benjamin D. Medoff
Summary: Idiopathic pulmonary fibrosis is a chronic disease that causes respiratory failure. This study reveals the importance of vascular permeability in lung repair and fibrosis following injury, and the potential role of lipid mediator S1P in regulating this process.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Leiye Yu, Licong He, Bing Gan, Rujuan Ti, Qingjie Xiao, Hongli Hu, Lizhe Zhu, Sheng Wang, Ruobing Ren
Summary: This study reveals the activation and regulation mechanism of human S1PR1 receptor through cryo-electron microscopy analysis. The S1PR1 receptor plays an essential role in the immune and vascular systems, and understanding its function in depth contributes to the development of related therapeutic approaches.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Clinical Neurology
Ben Gaastra, John Zhang, Will Tapper, Diederik Bulters, Ian Galea
Summary: Sphingosine-1-phosphate (S1P) plays a role in the pathophysiology of neurological injury after aneurysmal subarachnoid haemorrhage (aSAH). The literature agrees that S1P increases in cerebrospinal fluid following aSAH and contributes to cerebral artery vasospasm. However, the role of S1P in the parenchyma is less clear, with conflicting studies suggesting both beneficial and harmful effects. This review provides a concise interpretation of the conflicting data and discusses the potential repurposing of S1P receptor modulators for aSAH.
TRANSLATIONAL STROKE RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Mingyu Lee, Suh Yeon Lee, Yoe-Sik Bae
Summary: Immunology: Membrane lipids play important roles in immunity and disease. Advances in laboratory techniques and genetic databases have allowed the detection of sphingolipids, a complex family of lipids found in cell membranes, revealing their involvement in cell signaling, metabolism, and disease. Changes in sphingolipid levels can be influenced by gut bacteria and are associated with various diseases. Analyzing sphingolipid content in blood could assist in diagnosis, as damaged organs express unique patterns of sphingolipid products. The balance of different sphingolipids is crucial for directing immune responses and maintaining overall health.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2023)
Review
Hematology
Eric Engelbrecht, Calum A. MacRae, Timothy Hla
Summary: Membrane phospholipid metabolism produces lysophospholipids, which act as ligands for G-protein-coupled receptors influencing various biological processes. Lysophosphatidic acid and S1P are particularly significant in vascular development and cardiovascular diseases, with potential connections to the Wnt pathway. These findings highlight the importance of lysophospholipid signaling in cardiovascular disease and the potential for novel therapeutic strategies.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
Anja Nitzsche, Marine Poittevin, Ammar Benarab, Philippe Bonnin, Giuseppe Faraco, Hiroki Uchida, Julie Favre, Lidia Garcia-Bonilla, Manuela C. L. Garcia, Pierre-Louis Leger, Patrice Therond, Thomas Mathivet, Gwennhael Autret, Veronique Baudrie, Ludovic Couty, Mari Kono, Aline Chevallier, Hira Niazi, Pierre-Louis Tharaux, Jerold Chun, Susan R. Schwab, Anne Eichmann, Bertrand Tavitian, Richard L. Proia, Christiane Charriaut-Marlangue, Teresa Sanchez, Nathalie Kubis, Daniel Henrion, Costantino Iadecola, Timothy Hla, Eric Camerer
Summary: This study explores the role of endothelial cell S1P(1) in the naive and ischemic brain as a potential target for cerebrovascular therapy. Endothelial S1P(1) plays a critical vascular protective role in the mouse brain, sustaining endothelial functions and expanding during ischemia. Disruption of this pathway exacerbates brain injury in ischemic stroke models, highlighting the importance of S1P signaling in maintaining perfusion and microvascular patency in the ischemic penumbra.
CIRCULATION RESEARCH
(2021)
Letter
Multidisciplinary Sciences
Timothy Hla
Letter
Multidisciplinary Sciences
Jianping Li, Xiaoqian Zhu, Dengsheng Wu
Article
Biochemistry & Molecular Biology
De Yu Mao, Matthew L. Kleinjan, Irina Jilishitz, Bhairavi Swaminathan, Hideru Obinata, Yulia A. Komarova, Kayla J. Bayless, Timothy Hla, Jan K. Kitajewski
Summary: CLIC1 and CLIC4 play crucial roles in regulating GPCR pathways associated with vascular development and disease in endothelial cells. They translocate to the plasma membrane in response to S1P and mediate the activation of small GTPases downstream of S1PR1 and S1PR2/3, respectively. These CLIC-mediated mechanisms are essential for S1P-induced stimulation of barrier function in endothelial cell monolayers.
Article
Biochemistry & Molecular Biology
Rachel S. Knipe, Jillian J. Spinney, Elizabeth A. Abe, Clemens K. Probst, Alicia Franklin, Amanda Logue, Francesca Giacona, Matt Drummond, Jason Griffith, Patricia L. Brazee, Lida P. Hariri, Sydney B. Montesi, Katherine E. Black, Timothy Hla, Andrew Kuo, Andreane Cartier, Eric Engelbrecht, Christina Christoffersen, Barry S. Shea, Andrew M. Tager, Benjamin D. Medoff
Summary: Idiopathic pulmonary fibrosis is a chronic disease that causes respiratory failure. This study reveals the importance of vascular permeability in lung repair and fibrosis following injury, and the potential role of lipid mediator S1P in regulating this process.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Review
Pathology
Kuniyuki Kano, Junken Aoki, Timothy Hla
Summary: Lysophospholipids, such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are important extracellular lipid mediators that signal through specific G protein-coupled receptors. They play crucial roles in various biological processes and diseases, including cellular stress signaling, inflammation, and host defense responses. LPA is involved in regulating fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and neuroectodermal developmental disorders, while S1P controls collective behavior, apoptotic cell clearance, and immunesurveillance of cancers. The study of lysophospholipids has led to the development of new therapeutics for autoimmune diseases and holds promise for future treatments of fibrotic disorders, vascular diseases, and cancer.
ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE
(2022)
Article
Surgery
Lawrence N. Diebel, David M. Liberati, Timothy Hla, Steven Swendeman
Summary: The study found that carrier-based sphingosine 1-phosphate may have a protective effect in early hemorrhagic shock resuscitation, with apolipoprotein M+ sphingosine 1-phosphate showing the most significant effect.
Article
Hematology
Pascal Yazbeck, Xavier Cullere, Paul Bennett, Vijay Yajnik, Huan Wang, Kenji Kawada, Vanessa M. Davis, Asit Parikh, Andrew Kuo, Vijayashree Mysore, Timothy Hla, David S. Milstone, Tanya N. Mayadas
Summary: The study reveals that DOCK4, an atypical Rho family GTPase GEF, plays a critical role in lung vascular barrier function by regulating AJs. DOCK4 deficiency leads to lung hemorrhage, increased microvascular permeability, and impaired response to S1P-induced permeability changes. Additionally, S1P may act as a potential upstream regulator of DOCK4 activity.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2022)
Retraction
Oncology
Kotha Subbaramaiah, Louise R. Howe, Priya Bhardwaj, Baoheng Du, Claudia Gravaghi, Rhonda K. Yantiss, Xi Kathy Zhou, Victoria A. Blaho, Timothy Hla, Peiying Yang, Levy Kopelovich, Clifford A. Hudis, Andrew J. Dannenberg
CANCER PREVENTION RESEARCH
(2022)
Review
Rheumatology
Nathalie Burg, Jane E. Salmon, Timothy Hla
Summary: Sphingosine 1-phosphate plays essential roles in autoimmune rheumatic diseases, and modulating its signaling may offer potential therapeutic approaches. Understanding the S1P-S1PR signaling axis could provide novel insights into the treatment of systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.
NATURE REVIEWS RHEUMATOLOGY
(2022)
Correction
Biochemistry & Molecular Biology
Xulai Shia, Wanshan Wang, Jia Li, Ting Wang, Yan Lin, Siqi Huang, Aarti Kuver, Chengshui Chen, Timothy Hla, Xi Li, Kezhi Dai
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
(2022)
Article
Medicine, Research & Experimental
Michel Levesque, Timothy Hla
Summary: S1P and its receptors (S1PRs) play important roles in vascular development, homeostasis, and diseases as well-studied examples of GPCR signaling axis. The rapid biochemical cascades involved in S1P signaling are well understood, but the gene-expression regulation by S1PRs is less clear. This review focuses on how S1PRs regulate nuclear chromatin changes and gene transcription to modulate vascular and lymphatic endothelial phenotypic changes during embryonic development and adult homeostasis. These findings are crucial for understanding stimulus-evoked gene regulation in the vascular endothelium and developing therapeutic drugs for autoimmune and vascular diseases, considering the adverse events caused by S1PR-targeted drugs.
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE
(2023)
Article
Biology
Andrew Kuo, Antonio Checa, Colin Niaudet, Bongnam Jung, Zhongjie Fu, Craig E. Wheelock, Sasha A. Singh, Masanori Aikawa, Lois E. Smith, Richard L. Proia, Timothy Hla
Summary: This study reveals the crucial role of endothelial sphingolipid biosynthesis in regulating vascular development, maintaining circulatory and peripheral organ sphingolipid levels, and contributing to lipid raft formation and efficient signaling. The deletion of SPTLC1 in endothelial cells leads to impaired proliferation, differentiation, and delayed retinal vascular development. Furthermore, EC-derived sphingolipid metabolites are in constant flux between the vasculature, circulation, and non-CNS organs, and play a role in hepatocyte response to stress.
Article
Medicine, Research & Experimental
Colin Niaudet, Bongnam Jung, Andrew Kuo, Steven Swendeman, Edward Bull, Takahiro Seno, Reed Crocker, Zhongjie Fu, Lois E. H. Smith, Timothy Hla
Summary: This study reveals the significance of S1P in vascular development. Activation of endothelial S1PR1 by circulating HDL-S1P can suppress neovascularization in retinopathy. These findings suggest that circulating HDL-S1P activation of endothelial S1PR1 serves as a protective mechanism against neovascular retinopathy.
EMBO MOLECULAR MEDICINE
(2023)
