Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.748
Filtrar
1.
PLoS One ; 19(5): e0303296, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38753743

RESUMEN

AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH. METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH. RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage. CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.


Asunto(s)
Hígado Graso , Células Estrelladas Hepáticas , Cirrosis Hepática , Lisofosfolípidos , Fosfotransferasas (Aceptor de Grupo Alcohol) , Receptores de Esfingosina-1-Fosfato , Esfingosina , Animales , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Lisofosfolípidos/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/genética , Cirrosis Hepática/etiología , Ratones , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Humanos , Receptores de Esfingosina-1-Fosfato/metabolismo , Hígado Graso/metabolismo , Hígado Graso/patología , Masculino , Ratones Noqueados , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/patología , Deficiencia de Colina/complicaciones , Deficiencia de Colina/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Lisoesfingolípidos/genética , Pirazoles , Piridinas
2.
Ned Tijdschr Tandheelkd ; 131(4): 163-166, 2024 04.
Artículo en Holandés | MEDLINE | ID: mdl-38591120

RESUMEN

Despite the availability of a wide range of (fluoridated) oral care products, there is a constant search under way for new substances that contribute to a healthy mouth. Laboratory research shows that the lipid phytosphingosine forms a molecular layer on hydroxyapatite and protects it against acid-induced demineralization and bacterial adhesion. In the future, phytosphingosine may be used in the future as a new ingredient in oral care products for the prevention of tooth erosion and biofilm-related disorders, such as caries, gingivitis and periodontitis.


Asunto(s)
Caries Dental , Gingivitis , Periodontitis , Esfingosina/análogos & derivados , Humanos , Caries Dental/prevención & control , Gingivitis/prevención & control , Periodontitis/prevención & control
3.
Science ; 384(6691): 66-73, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38574138

RESUMEN

Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.


Asunto(s)
Asma , Bronquios , Broncoconstricción , Animales , Humanos , Ratones , Asma/patología , Asma/fisiopatología , Broncoconstricción/efectos de los fármacos , Inflamación/patología , Transducción de Señal , Canales Iónicos/antagonistas & inhibidores , Lisofosfolípidos/antagonistas & inhibidores , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inhibidores , Bronquios/patología , Bronquios/fisiopatología
4.
Cell Physiol Biochem ; 58(2): 156-171, 2024 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-38639213

RESUMEN

BACKGROUND/AIMS: The physiological phenotype of individuals can influence and shape real-life phenomena in that it can contribute to the development of specific characteristics that can affect the immune response to specific stimuli. In this study we aimed to understand whether the sphingosine/sphingosine-1-phoshate (S1P) axis can modulate the immunotype of circulating cells. METHODS: To pursue this goal, we performed bioinformatic analyses of public datasets. RESULTS: The transcriptomic profile of healthy subjects of GSE192829 dataset identified two clusters with different transcriptional repertoire. Cluster 1 expressed higher levels of enzymes for S1P formation than cluster 0 which was characterized by enzymes that lead to ceramide formation, which represent the opposite metabolic direction. Inference analysis showed that cluster 1 was higher populated by monocytes, CD4+ T and B cells than cluster 0. Of particular interest was the phenotype of the monocytes in cluster 1 which showed an immunosuppressive nature compared to those in cluster 0. The role of S1P signature in healthy PBMCs was confirmed with other dataset analyses, supporting that circulating monocytes positive to the ceramidase, unlike the negative ones, had an immunosuppressive phenotype characterized by hub immunosuppressive markers (i.e. TYROBP, FCER1G, SYK, SIRPA, CSF1R, AIF1, FCGR2A, CLEC7A, LYN, PLCG2, LILRs, HCK, GAB2). This hub genes well discriminated the immunotype of healthy subjects. CONCLUSION: In conclusion this study highlights that S1P-associated hub markers can be useful to discriminate subjects with pronounced immunosuppression.


Asunto(s)
Monocitos , Esfingosina , Esfingosina/análogos & derivados , Humanos , Esfingosina/metabolismo , Monocitos/metabolismo , Lisofosfolípidos/metabolismo , Inmunosupresores , Fenotipo
5.
Int Immunopharmacol ; 133: 112113, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38657498

RESUMEN

BACKGROUND: Phytosphingosine and its derivative are known for their skin-protective properties. While mYG-II-6, a phytosphingosine derivative, has shown anti-inflammatory and antipsoriatic effects, its potential antipruritic qualities have yet to be explored. This study aimed to investigate mYG-II-6's antipruritic properties. METHODS: The calcium imaging technique was employed to investigate the activity of ion channels and receptors. Mast cell degranulation was confirmed through the ß-hexosaminidase assay. Additionally, in silico molecular docking and an in vivo mouse scratching behavior test were utilized. RESULTS: Using HEK293T cells transfected with H1R and TRPV1, we examined the impact of mYG-II-6 on histamine-induced intracellular calcium rise, a key signal in itch-mediating sensory neurons. Pretreatment with mYG-II-6 significantly reduced histamine-induced calcium levels and inhibited TRPV1 activity, suggesting its role in blocking the calcium influx channel. Additionally, mYG-II-6 suppressed histamine-induced calcium increase in primary cultures of mouse dorsal root ganglia, indicating its potential antipruritic effect mediated by histamine. Interestingly, mYG-II-6 exhibited inhibitory effects on human MRGPRX2, a G protein-coupled receptor involved in IgE-independent mast cell degranulation. However, it did not inhibit mouse MrgprB2, the ortholog of human MRGPRX2. Molecular docking analysis revealed that mYG-II-6 selectively interacts with the binding pocket of MRGPRX2. Importantly, mYG-II-6 suppressed histamine-induced scratching behaviors in mice. CONCLUSIONS: Our findings show that mYG-II-6 can alleviate histamine-induced itch sensation through dual mechanisms. This underscores its potential as a versatile treatment for various pruritic conditions.


Asunto(s)
Degranulación de la Célula , Histamina , Mastocitos , Simulación del Acoplamiento Molecular , Receptores Acoplados a Proteínas G , Canales Catiónicos TRPV , Animales , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Humanos , Canales Catiónicos TRPV/metabolismo , Degranulación de la Célula/efectos de los fármacos , Células HEK293 , Histamina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Ratones , Masculino , Prurito/tratamiento farmacológico , Calcio/metabolismo , Antipruriginosos/farmacología , Antipruriginosos/uso terapéutico , Esfingosina/análogos & derivados , Esfingosina/farmacología , Esfingosina/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de Neuropéptido/metabolismo , Ratones Endogámicos C57BL
6.
Int J Biol Macromol ; 267(Pt 1): 131323, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38574912

RESUMEN

Sphingolipids serve as essential components of biomembrane and possess significant bioactive properties. Sphingosine-1-phophate (S1P) plays a key role in plant resistance to stress, but its specific impact on plant growth and development remains to be fully elucidated. Cotton fiber cells are an ideal material for investigating the growth and maturation of plant cells. In this study, we examined the content and composition of sphingosine (Sph) and S1P throughout the progression of fiber cell development. The content of S1P elevated gradually during fiber elongation but declined during the transition stage. Exogenous application of S1P promoted fiber elongation while using of FTY720 (an antagonist of S1P), and DMS (an inhibitor of LCBK) hindered fiber elongation. Cotton Long Chain Base Kinase 1 (GhLCBK1) was notably expressed during the fiber elongation stage, containing all conserved domains of LCBK protein and localized in the endoplasmic reticulum. Overexpression GhLCBK1 increased the S1P content and promoted fiber elongation while retarded secondary cell wall (SCW) deposition. Conversely, downregulation of GhLCBK1 reduced the S1P levels, and suppressed fiber elongation, and accelerated SCW deposition. Transcriptome analysis revealed that upregulating GhLCBK1 or applying S1P induced the expression of GhEXPANSIN and auxin related genes. Furthermore, the levels of IAA were elevated and reduced in the fibers when up-regulating or down-regulating GhLCBK1, respectively. Our investigation demonstrated that GhLCBK1 and its product S1P facilitated the elongation of fiber cells by affecting auxin biosynthesis. This study contributes novel insights into the intricate regulatory pathways involved in fiber cell elongation, identifying GhLCBK1 as a potential target gene and laying the groundwork for enhancing fiber quality via genetic manipulation.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , Gossypium , Ácidos Indolacéticos , Lisofosfolípidos , Fosfotransferasas (Aceptor de Grupo Alcohol) , Esfingosina , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Gossypium/genética , Gossypium/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacología , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Lisofosfolípidos/metabolismo , Fibra de Algodón , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Pared Celular/metabolismo , Pared Celular/efectos de los fármacos
8.
Sci Immunol ; 9(94): eadg8817, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38640251

RESUMEN

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.


Asunto(s)
Neoplasias , Esfingosina , Linfocitos T Reguladores , Receptor de Muerte Celular Programada 1/metabolismo , Serina/metabolismo , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Microambiente Tumoral
9.
J Immunol ; 212(11): 1843-1854, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38568091

RESUMEN

Intraepithelial lymphocytes (IELs) are T cells important for the maintenance of barrier integrity in the intestine. Colon IELs are significantly reduced in both MyD88-deficient mice and those lacking an intact microbiota, suggesting that MyD88-mediated detection of bacterial products is important for the recruitment and/or retention of these cells. Here, using conditionally deficient MyD88 mice, we show that myeloid cells are the key mediators of TCRαß+ IEL recruitment to the colon. Upon exposure to luminal bacteria, myeloid cells produce sphingosine-1-phosphate (S1P) in a MyD88-dependent fashion. TCRαß+ IEL recruitment may be blocked using the S1P receptor antagonist FTY720, confirming the importance of S1P in the recruitment of TCRαß+ IELs to the colon epithelium. Finally, using the TNFΔARE/+ model of Crohn's-like bowel inflammation, we show that disruption of colon IEL recruitment through myeloid-specific MyD88 deficiency results in reduced pathology. Our results illustrate one mechanism for recruitment of a subset of IELs to the colon.


Asunto(s)
Colon , Mucosa Intestinal , Linfocitos Intraepiteliales , Lisofosfolípidos , Ratones Noqueados , Células Mieloides , Factor 88 de Diferenciación Mieloide , Receptores de Antígenos de Linfocitos T alfa-beta , Esfingosina , Animales , Lisofosfolípidos/metabolismo , Ratones , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Colon/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Ratones Endogámicos C57BL , Clorhidrato de Fingolimod/farmacología , Enfermedad de Crohn/inmunología
10.
Asian Pac J Cancer Prev ; 25(3): 725-733, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38546054

RESUMEN

OBJECTIVE: Availability of multimodal treatment strategies, including targeted therapies and immunotherapies, have improved the survival of non-small cell lung carcinoma (NSCLC). However, some patients still progress or respond poorly due to inherent resistance, acquired resistance, or lack of druggable driver mutations. Sphingosine-1-phosphate (S1P) and receptor tyrosine kinase-like orphan receptor (ROR1/2) signaling pathways are activated during lung carcinogenesis. METHODS: In this study, we have evaluated the crosstalk of S1P and ROR1/2 signaling pathways in lung cancer cells. RESULTS: S1P treatment of lung cancer cells decreases ROR1 and ROR2 transcript levels. While treatment with PF-543, a pharmacological SphK1 inhibitor or genetic knockdown of SPHK1 by shRNA, raises ROR1 and ROR2. Furthermore, simultaneous inhibition of SphK1 along with ROR1 reduced the migration of lung cancer cells. CONCLUSION: These findings demonstrate the reciprocal regulation of both pathways, suggesting that both pathways have an inverse relation i.e, in the absence of one pathway, another pathway may take charge of the other pathway. Therefore, simultaneously targeting both pathways could serve as a potential therapeutic target for lung cancer treatment.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Lisofosfolípidos , Esfingosina/análogos & derivados , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Transducción de Señal , Pulmón/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo
11.
Biomolecules ; 14(3)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38540716

RESUMEN

The severity of COVID-19 is linked to an imbalanced immune response. The dysregulated metabolism of small molecules and bioactive lipids has also been associated with disease severity. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyze over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). This is the third publication in a series, and it reports the results of comprehensive lipidome profiling using targeted LC-MS/MS. We identified 1076 lipid features across 25 subclasses, including glycerophospholipids, sterols, glycerolipids, and sphingolipids, among which 531 lipid features were dramatically changed in the plasma of intensive care unit (ICU) patients compared to patients in the ward. Patients in the ICU showed 1.3-57-fold increases in ceramides, (lyso-)glycerophospholipids, diglycerides, triglycerides, and plasmagen phosphoethanolamines, and 1.3-2-fold lower levels of a cyclic lysophosphatidic acid, sphingosine-1-phosphates, sphingomyelins, arachidonic acid-containing phospholipids, lactosylceramide, and cholesterol esters compared to patients in the ward. Specifically, phosphatidylinositols (PIs) showed strong fatty acid saturation-dependent behavior, with saturated fatty acid (SFA)- and monosaturated fatty acid (MUFA)-derived PI decreasing and polystaturated (PUFA)-derived PI increasing. We also found ~4000 significant Spearman correlations between lipids and multiple clinical markers of immune response with |R| ≥ 0.35 and FDR corrected Q < 0.05. Except for lysophosphatidic acid, lysophospholipids were positively associated with the CD4 fraction of T cells, and the cytokines IL-8 and IL-18. In contrast, sphingosine-1-phosphates were negatively correlated with innate immune markers such as CRP and IL-6. Further indications of metabolic changes in moderate COVID-19 disease were demonstrated in recovering ward patients compared to those at the start of hospitalization, where 99 lipid species were altered (6 increased by 30-62%; 93 decreased by 1.3-2.8-fold). Overall, these findings support and expand on early reports that dysregulated lipid metabolism is involved in COVID-19.


Asunto(s)
COVID-19 , Esfingosina/análogos & derivados , Humanos , Lipidómica , Cromatografía Liquida , Espectrometría de Masas en Tándem , Ácidos Grasos/metabolismo , Glicerofosfolípidos , Lisofosfolípidos , Biomarcadores , Gravedad del Paciente , Fosfatos
12.
Int J Mol Sci ; 25(6)2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38542280

RESUMEN

Cardiomyocyte survival is a critical contributing process of host adaptive responses to cardiovascular diseases (CVD). Cells of the cardiovascular endothelium have recently been reported to promote cardiomyocyte survival through exosome-loading cargos. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, mediates protection against myocardial infarction (MI). Nevertheless, the mechanism of SPC delivery by vascular endothelial cell (VEC)-derived exosomes (VEC-Exos) remains uncharacterized at the time of this writing. The present study utilized a mice model of ischemia/reperfusion (I/R) to demonstrate that the administration of exosomes via tail vein injection significantly diminished the severity of I/R-induced cardiac damage and prevented apoptosis of cardiomyocytes. Moreover, SPC was here identified as the primary mediator of the observed protective effects of VEC-Exos. In addition, within this investigation, in vitro experiments using cardiomyocytes showed that SPC counteracted myocardial I/R injury by activating the Parkin and nuclear receptor subfamily group A member 2/optineurin (NR4A2/OPTN) pathways, in turn resulting in increased levels of mitophagy within I/R-affected myocardium. The present study highlights the potential therapeutic effects of SPC-rich exosomes secreted by VECs on alleviating I/R-induced apoptosis in cardiomyocytes, thereby providing strong experimental evidence to support the application of SPC as a potential therapeutic target in the prevention and treatment of myocardial infarction.


Asunto(s)
Exosomas , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Fosforilcolina/análogos & derivados , Esfingosina/análogos & derivados , Ratones , Animales , Daño por Reperfusión Miocárdica/metabolismo , Mitofagia , Miocitos Cardíacos/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Células Endoteliales/metabolismo , Exosomas/metabolismo , Apoptosis
13.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38542328

RESUMEN

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.


Asunto(s)
Neoplasias de la Mama , Esfingosina/análogos & derivados , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Lisofosfolípidos , Transducción de Señal , Microambiente Tumoral
14.
Sci Adv ; 10(11): eadg9278, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38478616

RESUMEN

Canonical Wnt and sphingosine-1-phosphate (S1P) signaling pathways are highly conserved systems that contribute to normal vertebrate development, with key consequences for immune, nervous, and cardiovascular system function; despite these functional overlaps, little is known about Wnt/ß-catenin-S1P cross-talk. In the vascular system, both Wnt/ß-catenin and S1P signals affect vessel maturation, stability, and barrier function, but information regarding their potential coordination is scant. We report an instance of functional interaction between the two pathways, including evidence that S1P receptor 1 (S1PR1) is a transcriptional target of ß-catenin. By studying vascular smooth muscle cells and arterial injury response, we find a specific requirement for the ß-catenin carboxyl terminus, which acts to induce S1PR1, and show that this interaction is essential for vascular remodeling. We also report that pharmacological inhibition of the ß-catenin carboxyl terminus reduces S1PR1 expression, neointima formation, and atherosclerosis. These findings provide mechanistic understanding of how Wnt/ß-catenin and S1P systems collaborate during vascular remodeling and inform strategies for therapeutic manipulation.


Asunto(s)
Aterosclerosis , Cateninas , Lisofosfolípidos , Esfingosina/análogos & derivados , Humanos , Cateninas/metabolismo , beta Catenina/metabolismo , Remodelación Vascular , Transducción de Señal
15.
Front Immunol ; 15: 1362459, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38482014

RESUMEN

Inflammation is an important immune response of the body. It is a physiological process of self-repair and defense against pathogens taken up by biological tissues when stimulated by damage factors such as trauma and infection. Inflammation is the main cause of high morbidity and mortality in most diseases and is the physiological basis of the disease. Targeted therapeutic strategies can achieve efficient toxicity clearance at the inflammatory site, reduce complications, and reduce mortality. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, is involved in immune cell transport by binding to S1P receptors (S1PRs). It plays a key role in innate and adaptive immune responses and is closely related to inflammation. In homeostasis, lymphocytes follow an S1P concentration gradient from the tissues into circulation. One widely accepted mechanism is that during the inflammatory immune response, the S1P gradient is altered, and lymphocytes are blocked from entering the circulation and are, therefore, unable to reach the inflammatory site. However, the full mechanism of its involvement in inflammation is not fully understood. This review focuses on bacterial and viral infections, autoimmune diseases, and immunological aspects of the Sphks/S1P/S1PRs signaling pathway, highlighting their role in promoting intradial-adaptive immune interactions. How S1P signaling is regulated in inflammation and how S1P shapes immune responses through immune cells are explained in detail. We teased apart the immune cell composition of S1P signaling and the critical role of S1P pathway modulators in the host inflammatory immune system. By understanding the role of S1P in the pathogenesis of inflammatory diseases, we linked the genomic studies of S1P-targeted drugs in inflammatory diseases to provide a basis for targeted drug development.


Asunto(s)
Inflamación , Esfingosina , Esfingosina/análogos & derivados , Humanos , Esfingosina/metabolismo , Inflamación/metabolismo , Lisofosfolípidos/metabolismo , Transducción de Señal/fisiología
16.
J Bone Miner Res ; 39(3): 357-372, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38477738

RESUMEN

Sphingosine-1-phosphate (S1P) plays multiple roles in bone metabolism and regeneration. Here, we have identified a novel S1P-regulated osteoanabolic mechanism functionally connecting osteoblasts (OBs) to the highly specialized bone vasculature. We demonstrate that S1P/S1PR3 signaling in OBs stimulates vascular endothelial growth factor a (VEGFa) expression and secretion to promote bone growth in an autocrine and boost osteogenic H-type differentiation of bone marrow endothelial cells in a paracrine manner. VEGFa-neutralizing antibodies and VEGF receptor inhibition by axitinib abrogated OB growth in vitro and bone formation in male C57BL/6J in vivo following S1P stimulation and S1P lyase inhibition, respectively. Pharmacological S1PR3 inhibition and genetic S1PR3 deficiency suppressed VEGFa production, OB growth in vitro, and inhibited H-type angiogenesis and bone growth in male mice in vivo. Together with previous work on the osteoanabolic functions of S1PR2 and S1PR3, our data suggest that S1P-dependent bone regeneration employs several nonredundant positive feedback loops between OBs and the bone vasculature. The identification of this yet unappreciated aspect of osteoanabolic S1P signaling may have implications for regular bone homeostasis as well as diseases where the bone microvasculature is affected such as age-related osteopenia and posttraumatic bone regeneration.


Sphingosine-1-phosphate (S1P) is a signaling lipid that regulates bone growth and regeneration. In the present study, a novel regenerative mechanism was connected to S1P signaling within the bone. Activation of its receptor S1PR3 in bone-forming osteoblasts led to secretion of vascular endothelial growth factor a (VEGFa), the most potent vessel-stimulating factor. This stimulated the development of specialized vessels of the bone marrow, the H-type vessels, that supported overall bone regeneration. These findings foster our understanding of regular bone metabolism and suggest that S1P-based drugs may help treat diseases such as age-related osteopenia and posttraumatic bone regeneration, conditions crucially dependent on functional bone microvasculature.


Asunto(s)
Lisofosfolípidos , Receptores de Lisoesfingolípidos , Esfingosina/análogos & derivados , Factor A de Crecimiento Endotelial Vascular , Masculino , Ratones , Animales , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Esfingosina-1-Fosfato , Factor A de Crecimiento Endotelial Vascular/metabolismo , Osteogénesis , Células Endoteliales/metabolismo , Ratones Endogámicos C57BL , Osteoblastos/metabolismo
17.
Cell Rep ; 43(4): 114020, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38554280

RESUMEN

Lymphatic endothelial cells (LECs) of the lymph node (LN) parenchyma orchestrate leukocyte trafficking and peripheral T cell dynamics. T cell responses to immunotherapy largely rely on peripheral T cell recruitment in tumors. Yet, a systematic and molecular understanding of how LECs within the LNs control T cell dynamics under steady-state and tumor-bearing conditions is lacking. Intravital imaging combined with immune phenotyping shows that LEC-specific deletion of the essential autophagy gene Atg5 alters intranodal positioning of lymphocytes and accrues their persistence in the LNs by increasing the availability of the main egress signal sphingosine-1-phosphate. Single-cell RNA sequencing of tumor-draining LNs shows that loss of ATG5 remodels niche-specific LEC phenotypes involved in molecular pathways regulating lymphocyte trafficking and LEC-T cell interactions. Functionally, loss of LEC autophagy prevents recruitment of tumor-infiltrating T and natural killer cells and abrogates response to immunotherapy. Thus, an LEC-autophagy program boosts immune-checkpoint responses by guiding systemic T cell dynamics.


Asunto(s)
Autofagia , Inhibidores de Puntos de Control Inmunológico , Ganglios Linfáticos , Esfingosina/análogos & derivados , Linfocitos T , Autofagia/efectos de los fármacos , Animales , Ganglios Linfáticos/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Ratones Endogámicos C57BL , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Células Endoteliales/metabolismo , Esfingosina/farmacología , Esfingosina/metabolismo , Humanos , Lisofosfolípidos/metabolismo , Inmunoterapia/métodos , Movimiento Celular
18.
Urogynecology (Phila) ; 30(3): 374-380, 2024 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-38484256

RESUMEN

IMPORTANCE: Sphingosine-1-phosphate (S1P) is a signaling molecule involved in inflammation and bladder contraction. OBJECTIVES: The aims of this case-control pilot study were to compare urinary S1P concentrations in bladder pain syndrome (BPS) participants to controls and determine whether these concentrations correlate with disease severity and duration. STUDY DESIGN: Adult females with BPS and controls were enrolled. Bladder pain syndrome participants completed an O'Leary-Sant questionnaire. Information on duration of symptoms and treatment history was obtained. Urinary S1P and creatinine concentrations were determined. Mann-Whitney U tests were used to compare groups, and Spearman correlation was used to test for associations between concentrations and duration and severity of symptoms. RESULTS: Twenty-five participants were in each group. Median S1P concentration was 1,225 ng/dL in the BPS group and 2,183 ng/dL in the control group, which was significantly different (P < 0.0001). This difference did not persist when normalized to urinary creatinine (P = 0.58). No differences were noted in urinary S1P concentrations between treated and untreated participants (P = 0.53) or with symptom scores of 13 or greater and less than 13 (P = 0.69). Sphingosine-1-phosphate levels did not correlate with O'Leary-Sant scores (P = 0.08) or duration of symptoms (P = 0.67). Results did not change when using S1P concentrations normalized to creatinine. CONCLUSIONS: This study demonstrated successful quantification of human urinary S1P concentrations. A difference in urinary S1P was found between BPS participants and controls but not when normalized to creatinine. While this is the first study to investigate urinary S1P as a biomarker for BPS, results suggest that it may have a potential role as a biomarker requiring further research.


Asunto(s)
Cistitis Intersticial , Lisofosfolípidos , Esfingosina/análogos & derivados , Adulto , Femenino , Humanos , Cistitis Intersticial/diagnóstico , Proyectos Piloto , Creatinina , Biomarcadores/orina
19.
Anal Chem ; 96(14): 5719-5726, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38544485

RESUMEN

Neuropathic pain is a chronic and severe syndrome for which effective therapy is insufficient and the release of ATP from microglia induced by sphingosine-1-phosphate (S1P) plays a vital role in neuropathic pain. Therefore, there is an urgent demand to develop highly sensitive and selective ATP biosensors for quantitative monitoring of low-concentration ATP in the complex nervous system, which helps in understanding the mechanism involved in neuropathic pain. Herein, we developed an electrochemical microsensor based on an entropy-driven bipedal DNA walker. First, the microsensor specifically recognized ATP via ATP aptamers, initiating the entropy-driven bipedal DNA walker. Subsequently, the bipedal DNA walker autonomously traversed the microelectrode interface, introducing methylene blue to the electrode surface and achieving cascade signal amplification. This microsensor showed excellent selectivity, stability, and a low limit of detection at 1.13 nM. The S1P-induced ATP release from BV2 cells was successfully monitored, and it was observed that dicumarol could inhibit this release, suggesting dicumarol as a potential treatment for neuropathic pain. The microsensor's small size exhibited significant potential for monitoring ATP level changes in neuropathic pain in vivo, which provides a new strategy for in situ and quantitative monitoring of nonelectroactive biomolecules associated with neurological diseases.


Asunto(s)
Técnicas Biosensibles , Lisofosfolípidos , Neuralgia , Esfingosina/análogos & derivados , Humanos , Entropía , Dicumarol , ADN/química , Microelectrodos , Adenosina Trifosfato , Técnicas Electroquímicas , Límite de Detección
20.
JCI Insight ; 9(8)2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38451736

RESUMEN

Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1-KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1-KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.


Asunto(s)
Modelos Animales de Enfermedad , Enfermedades por Almacenamiento Lisosomal , Lisosomas , Ratones Noqueados , Animales , Femenino , Humanos , Masculino , Ratones , Hígado/metabolismo , Lisofosfolípidos/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/patología , Lisosomas/metabolismo , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA