Review
Oncology
Eileen M. McGowan, Yiguang Lin, Size Chen
Summary: Obesity is closely associated with inflammation and increased cancer risk in the digestive system. Saturated fat diets and being overweight can cause chronic inflammation. Bioactive sphingolipids, signaling molecules made from saturated fats, play essential roles in maintaining healthy gastrointestinal immunity. Excessive levels of these molecules can lead to chronic inflammation, but drugs that block their activity have the potential to reduce gastrointestinal cancer risk.
Article
Medicine, Research & Experimental
Xuefeng Xu, Yi Han, Tianxin Zhu, Faxin Fan, Xin Wang, Yuqing Liu, Duosheng Luo
Summary: Osteoporosis is a common disease worldwide with significant economic burden. Understanding the role of SphK/S1P/S1PR signaling in regulating osteoblasts and osteoclasts is crucial for the treatment of osteoporosis. This review summarizes the effects of S1P on proliferation, differentiation, apoptosis, and functions, and focuses on S1P-based therapeutic approaches in bone metabolism.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Review
Pharmacology & Pharmacy
Gerhild van Echten-Deckert
Summary: Lipids are essential components of the CNS, and sphingolipids, a type of lipid, are highly concentrated in the brain. Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, has complex effects on the brain, which can be both beneficial and detrimental. However, the role of S1P in brain development and various brain pathologies is still controversial.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Cell Biology
Chiara D'Aprile, Simona Prioni, Laura Mauri, Alessandro Prinetti, Sara Grassi
Summary: Lipid rafts are specialized membrane domains enriched in gangliosides, sphingomyelin, cholesterol, and proteins involved in signal transduction, modulating cell homeostasis. Sphingosine 1-phosphate participates in various signal transduction processes, with enzymes and receptors often localized in lipid rafts.
CELLULAR SIGNALLING
(2021)
Article
Oncology
Vikas Satyananda, Masanori Oshi, Yoshihisa Tokumaru, Aparna Maiti, Nitai Hait, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe
Summary: High S1P export, driven by the simultaneous high expression of SphK1 and ABCC1, is associated with enhanced HCC progression and immune response, leading to significantly worse disease-specific survival and overall survival outcomes.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Chemistry, Medicinal
Shurui Zhang, Xiaoxu Chen, Chenglin Wu, Hui Xu, Xiong Xie, Mingshun Feng, Shulei Hu, Hudagula Bai, Feng Gao, Linjiang Tong, Jian Ding, Hong Liu, Zuoquan Xie, Jiang Wang
Summary: This study reports the structural optimization and activity relationship of a series of novel SphK1 inhibitors. The novel compound 28 selectively inhibits SphK1 and exhibits higher anti-proliferative activity compared to PF-543 in various cancer cells. Additionally, compound 28 can inhibit cell migration and suppress the growth and metastasis of solid tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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)
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)
Article
Biochemistry & Molecular Biology
Michela Terlizzi, Chiara Colarusso, Giusy Ferraro, Anna Falanga, Maria Chiara Monti, Pasquale Somma, Ilaria De Rosa, Luigi Panico, Aldo Pinto, Rosalinda Sorrentino
Summary: Sex is a biological variable that can affect the activity of the lipid mediator S1P in lung conditions. This study found sex differences in circulating S1P levels among lung cancer patients, with ADK patients having lower levels compared to SCC patients. Additionally, the expression of S1P receptors and metabolic enzymes differed between male and female patients with different lung cancer types. These findings highlight the importance of considering sex differences when studying S1P as a prognostic mediator in lung cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Ling-Wei Hii, Felicia Fei-Lei Chung, Chun-Wai Mai, Pei Yuen Ng, Chee-Onn Leong
Summary: SPHK1 is a conserved lipid enzyme that catalyzes the formation of S1P, and has been implicated in oncogenic functions, particularly in breast cancer. Recent evidence suggests a role for SPHK1 in regulating CSCs, indicating the therapeutic potential of targeting SPHK1 in refractory cancers enriched with CSCs.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Article
Neurosciences
Huitong Song, Holly P. McEwen, Thomas Duncan, Jun Yup Lee, Jonathan D. Teo, Anthony S. Don
Summary: SphK2 deficiency leads to decreased remyelination and maintenance of myelin with aging, possibly due to elevated levels of cytotoxic sphingosine and ceramide.
Review
Immunology
Liu Liu, Jiao Wang, Hong-jin Li, Shuo Zhang, Meng-zhu Jin, Si-ting Chen, Xiao-ying Sun, Ya-qiong Zhou, Yi Lu, Dan Yang, Ying Luo, Yi Ru, Bin Li, Xin Li
Summary: S1P receptor agonists and sphingosine kinase 2 inhibitors are potential methods for treating psoriasis by decreasing immune responses and inflammatory factors, as shown by both clinical and preclinical studies.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Celine Tolksdorf, Eileen Moritz, Robert Wolf, Ulrike Meyer, Sascha Marx, Sandra Bien-Moeller, Ulrike Garscha, Gabriele Jedlitschky, Bernhard H. Rauch
Summary: Sphingosine-1-phosphate (S1P) is a versatile signaling lipid that regulates various cellular processes. Platelets are an important source of S1P and can rapidly generate and release it to regulate cellular responses. Furthermore, platelet-generated and released S1P may also impact disease processes such as inflammation-driven vascular diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Neurosciences
Elisabetta Coppi, Francesca Cencetti, Federica Cherchi, Martina Venturini, Chiara Donati, Paola Bruni, Felicita Pedata, Anna Maria Pugliese
Summary: The myelination process in the brain is crucial for fast synaptic transmission, with A(2)(B) adenosine receptors and SphK/S1P signaling pathways playing important roles in regulating oligodendrocyte differentiation. Understanding the interaction between A(2)(B)Rs and S1P signaling may offer innovative targets for the treatment of demyelinating disorders like multiple sclerosis.
FRONTIERS IN NEUROSCIENCE
(2021)
Article
Cell Biology
Elia Paradiso, Clara Lazzaretti, Samantha Sperduti, Francesco Antoniani, Giulia Fornari, Giulia Brigante, Giulia Di Rocco, Simonetta Tagliavini, Tommaso Trenti, Daria Morini, Angela Immacolata Falbo, Maria Teresa Villani, Jerzy-Roch Nofer, Manuela Simoni, Francesco Poti, Livio Casarini
Summary: This study demonstrates that SIP may induce cAMP-independent activation of pCREB in granulosa cells, although this is insufficient to induce intracellular steroidogenic signals and progesterone synthesis. The activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development.
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2021)
Article
Chemistry, Medicinal
Molly Congdon, Russell G. Fritzemeier, Yugesh Kharel, Anne M. Brown, Vlad Serbulea, David R. Bevan, Kevin R. Lynch, Webster L. Santos
Summary: Elevated levels of Sphingosine 1-phosphate (S1P) and increased expression of Sphingosine kinase iso-forms (SphK1 and SphK2) are associated with various disease states. The development of selective inhibitors for SphK1 and SphK2 has become a focus of drug discovery, with studies focusing on optimizing binding in the SphK2 substrate binding site. The identification of indole-based compounds with 1,5-disubstitution as potent inhibitors highlights the potential for targeting SphK2 with improved potency and selectivity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Applied
R. Justin Grams, Monsurat M. Lawal, Connor Szwetkowski, Daniel Foster, Carol Ann Rosenblum, Carla Slebodnick, Valerie Vaissier Welborn, Webster L. Santos
Summary: A chemoselective, phosphine-catalyzed semireduction of primary and secondary propiolamides was reported, leading to the synthesis of acrylamides with excellent yield and (E)-stereoselectivity. The reaction tolerates various functional groups and DFT calculations revealed a clear energetic driving force for the (E)- over the (Z)-isomer.
ADVANCED SYNTHESIS & CATALYSIS
(2022)
Review
Chemistry, Multidisciplinary
Shubhankar Kumar Bose, Lujia Mao, Laura Kuehn, Udo Radius, Jan Nekvinda, Webster L. Santos, Stephen A. Westcott, Patrick G. Steel, Todd B. Marder
Summary: Organoboron reagents play a unique role in modern synthetic organic chemistry, offering unprecedented reactivity and stereocontrol. The use of first-row d-block transition metals as catalysts for the formation of carbon-boron bonds has expanded in various fields such as medicinal chemistry, agrochemistry, and materials science.
Article
Chemistry, Organic
Ashley M. Gates, Swetha Jos, Webster L. Santos
Summary: A ligand-free copper-catalyzed beta-borylation and defluorination reaction was reported for alpha-trifluoromethyl-alpha,beta-unsaturated esters, producing geminal-difluoroallyl boronic acid derivatives in moderate to good yield. The reaction exhibited tolerance towards various substrates, and the utility of products was demonstrated in the defluorinative functionalization of the difluoroalkene to yield enol ethers.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Russell Fritzemeier, Daniel Foster, Ashley Peralta, Michael Payette, Yugesh Kharel, Tao Huang, Kevin R. Lynch, Webster L. Santos
Summary: In this study, the researchers identified a novel Spns2 inhibitor called 16d, which effectively inhibits the release of S1P. In addition, administration of 16d in mice and rats replicated the phenotype observed in Spns2-deficient mice. This study provides a new research tool for further understanding the biological function of Spns2 and evaluating its potential as a drug target.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Swetha Jos, Connor Szwetkowski, Carla Slebodnick, Robert Ricker, Ka Lok Chan, Wing Chun Chan, Udo Radius, Zhenyang Lin, Todd B. Marder, Webster L. Santos
Summary: A transition metal-free, regio- and stereo-selective, phosphine-catalyzed method for the synthesis of (E)-1-boryl-1,3-enynes has been reported in this paper. The reaction proceeds with high selectivity for boron addition to the external carbon of the 1,3-diyne framework.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Education & Educational Research
Alana Vasconcelos, Anne Alilma Silva Souza Ferrete, Willian Lima Santos
Summary: This article problematizes the construction of professional knowledge about Digital Information and Communication Technologies (DICT) in a Pedagogy course at Federal University of Sergipe. It emphasizes the significance of experiential knowledge and dialogue between University Knowledge, Professional Knowledge, and Teaching Knowledge in the training of educators. The article also highlights the emerging need for public policies to integrate DICT in training spaces.
REVISTA PRAXIS EDUCACIONAL
(2022)
Article
Chemistry, Medicinal
Yumin Dai, Jose A. Santiago-Rivera, Stefan Hargett, Joseph M. Salamoun, Kyle L. Hoehn, Webster L. Santos
Summary: We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. Functionalization on the 2-position of the imidazole ring through a selection of orthoesters allowed the synthesis of a variety of imidazopyrazine derivatives. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Ariel L. Burgio, Christopher W. Shrader, Yugesh Kharel, Tao Huang, Joseph M. Salamoun, Kevin R. Lynch, Webster L. Santos
Summary: The S1P1 receptor is targeted by four drugs in the treatment of multiple sclerosis and ulcerative colitis. Targeting Spns2, an S1P exporter, upstream of S1P receptor engagement may provide an alternative strategy to mimic the efficacy of S1P receptor modulators without cardiac toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Ariel L. Burgio, Nicklas W. Buchbinder, Webster L. Santos
Summary: A facile method for the synthesis of (Z)-1,3-enynes is achieved through sequential copper-catalyzed regio- and stereoselective borylation-protodeboronation of 1,3-diynes. Pinacolborane, copper(II) acetate, and Xantphos are utilized as the ligand to efficiently introduce hydrogen and Bpin in a cis fashion, followed by rapid hydrolysis with water. The reaction exhibits wide substrate scope and proceeds in a chemoselective manner.
Article
Chemistry, Medicinal
Christopher W. Shrader, Daniel Foster, Yugesh Kharel, Tao Huang, Kevin R. Lynch, Webster L. Santos
Summary: Sphingosine-1-phosphate (S1P) is a chemotactic lipid that affects immune cell positioning. Inhibition of S1P transport by Spns2 may be a potential target for the treatment of inflammation and autoimmune diseases.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemical Research Methods
Yugesh Kharel, Tao Huang, Webster L. Santos, Kevin R. Lynch
Summary: The sphingosine-1-phosphate (S1P) pathway is an active area of research for drug discovery, with potential therapeutic candidates for autoimmune diseases. This study focuses on the transporter Spns2 and its inhibition, which has been found to be inversely proportional to the amount of S1P in the media. The development of a mammalian cell-based assay supports the investigation of S1P transport inhibition.
Article
Chemistry, Multidisciplinary
Johnathan Bowen, Carla Slebodnick, Webster L. Santos
Summary: We report an organocatalytic trans hydroboration of 3-substituted-propiolonitriles. In the presence of catalytic amounts of tributylphosphine and pinacolborane, regioselective hydroboration of the internal triple bond proceeded in a stereoselective fashion under mild conditions to afford the corresponding (E)-1,2-vinylcyanoborane derivatives. The mechanism is proposed to occur through a 1,2-phosphine addition instead of a canonical 1,4-conjugate addition pathway.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Organic
Connor Szwetkowski, Carla Slebodnick, Webster L. Santos
Summary: A highly efficient and selective method has been developed for allenoate borylation, resulting in the synthesis of Z-beta,gamma-unsaturated beta-boryl esters. The method is performed under mild conditions and achieves high yields.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Russell F. Snead, Jan Nekvinda, Webster L. Santos
Summary: A method has been developed for the facile Cu(ii)-catalyzed protoboration of monosubstituted allenes in aqueous media under atmospheric conditions, with good yields and site selectivity.
NEW JOURNAL OF CHEMISTRY
(2021)
