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1.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500564

RESUMO

Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.


Assuntos
Cloridrato de Fingolimode/farmacologia , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/antagonistas & inibidores , Esfingosina/análogos & derivados , Animais , Células CHO , Cricetulus , Humanos , Contagem de Linfócitos/métodos , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingosina/agonistas , Esfingosina/antagonistas & inibidores , Esfingosina/metabolismo , Linfócitos T/metabolismo
2.
Sci Rep ; 11(1): 15308, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321503

RESUMO

Sphingosine 1-phosphate (S1P) is a bioactive signalling sphingolipid that is increased in diseases such as obesity and diabetes. S1P can modulate platelet function, however the direction of effect and S1P receptors (S1PRs) involved are controversial. Here we describe the role of S1P in regulating human platelet function and identify the receptor subtypes responsible for S1P priming. Human platelets were treated with protease-activated receptor 1 (PAR-1)-activating peptide in the presence or absence of S1P, S1PR agonists or antagonists, and sphingosine kinases inhibitors. S1P alone did not induce platelet aggregation but at low concentrations S1P enhanced PAR1-mediated platelet responses, whereas PAR1 responses were inhibited by high concentrations of S1P. This biphasic effect was mimicked by pan-S1PR agonists. Specific agonists revealed that S1PR1 receptor activation has a positive priming effect, S1PR2 and S1PR3 have no effect on platelet function, whereas S1PR4 and S1PR5 receptor activation have an inhibitory effect on PAR-1 mediated platelet function. Although platelets express both sphingosine kinase 1/2, enzymes which phosphorylate sphingosine to produce S1P, only dual and SphK2 inhibition reduced platelet function. These results support a role for SphK2-mediated S1P generation in concentration-dependent positive and negative priming of platelet function, through S1PR1 and S1PR4/5 receptors, respectively.


Assuntos
Lisofosfolipídeos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Receptores de Esfingosina-1-Fosfato/efeitos dos fármacos , Esfingosina/análogos & derivados , Plaquetas/efeitos dos fármacos , Plaquetas/ultraestrutura , Proteínas de Transporte/farmacologia , Forma Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Agregação Plaquetária/efeitos dos fármacos , Receptor PAR-1/agonistas , Esfingosina/agonistas , Esfingosina/antagonistas & inibidores , Esfingosina/farmacologia , Receptores de Esfingosina-1-Fosfato/fisiologia
3.
Front Immunol ; 11: 1102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670273

RESUMO

With the sudden outbreak of COVID-19 patient worldwide and associated mortality, it is critical to come up with an effective treatment against SARS-CoV-2. Studies suggest that mortality due to COVID 19 is mainly attributed to the hyper inflammatory response leading to cytokine storm and ARDS in infected patients. Sphingosine-1-phosphate receptor 1 (S1PR1) analogs, AAL-R and RP-002, have earlier provided in-vivo protection from the pathophysiological response during H1N1 influenza infection and improved mortality. Recently, it was shown that the treatment with sphingosine-1-phosphate receptor 1 analog, CYM5442, resulted in the significant dampening of the immune response upon H1N1 challenge in mice and improved survival of H1N1 infected mice in combination with an antiviral drug, oseltamivir. Hence, here we suggest to investigate the possible utility of using S1P analogs to treat COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Indanos/uso terapêutico , Lisofosfolipídeos/agonistas , Oxidiazóis/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Receptores de Esfingosina-1-Fosfato/metabolismo , Esfingosina/análogos & derivados , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , COVID-19 , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/prevenção & controle , Oseltamivir/uso terapêutico , Pandemias , SARS-CoV-2 , Esfingosina/agonistas
4.
Mol Cell Biochem ; 469(1-2): 89-95, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32301060

RESUMO

Lysophosphatidic acid (LPA) signaling through LPA receptors (LPA1 to LPA6) regulates a variety of malignant properties in cancer cells. Recently, we show that LPA2 expression is elevated by long-term cisplatin (CDDP) treatment in melanoma A375 cells. In the present study, we investigated whether LPA2-mediated signaling is involved in the modulation of chemoresistance in A375 cells. In cell survival assay, cells were treated with CDDP and dacarbazine (DTIC) every 24 h for 2 days. The cell survival rates to CDDP and DTIC were markedly increased by an LPA2 agonist, GRI-977143. To validate the effects of LPA2 on cell survival, LPA2 knockdown cells were generated from A375 cells. The cell survival rates elevated by GRI-977143 were suppressed by LPA2 knockdown. To evaluate the roles of LPA2-mediated signaling in cell survival, cells were pretreated with a Gi protein inhibitor, pertussis toxin (PTX). In the presence of GRI-977143, the cell survival rates to CDDP and DTIC were significantly lower in PTX-treated cells than in untreated cells. In addition, pretreatment of an adenylyl cyclase inhibitor, SQ22536, increased the cell survival of A375 cells treated with CDDP and DTIC. These results suggest that LPA2-mediated signaling plays an important role in the enhancement of chemoresistance of A375 cells treated with anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Lisofosfolipídeos/metabolismo , Melanoma/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/genética , Melanoma/genética , Toxina Pertussis/toxicidade , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
5.
Transplant Proc ; 51(6): 2081-2098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399186

RESUMO

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of 5 G protein-coupled receptors (S1P1 to S1P5). Among these, S1P1 is a major regulator of lymphocyte trafficking. Fingolimod, whose active metabolite, fingolimod phosphate, acts as a nonselective S1P-receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating lymphocyte trafficking via downregulation of S1P1 expression on lymphocytes. Here, we describe the pharmacologic profile of a novel S1P1 agonist, ASP1126. ASP1126 preferentially activated S1P1 compared to S1P3 in rat and human guanosine-5'-(γ-thio)-triphosphate (GTPγS) assays. Oral single administration of ASP1126 decreased the number of peripheral lymphocytes and repeated dosing showed a cumulative effect on lymphopenia in both rats and monkeys. ASP1126 prolonged allograft survival in a rat heterotopic heart transplantation model in combination with a subtherapeutic dose of tacrolimus that was independent of drug-drug interactions. In addition, in nonhuman primate (NHP) renal transplantation, pretreatment with ASP1126 reduced not only the number of naive T cells and central memory T cells but also effector memory T cells in the peripheral blood, all of which could contribute to acute graft rejection and prolonged allograft survival in combination with tacrolimus. Further, we confirmed that ASP1126 has a broad ranging safety margin with respect to its effect on lung weight in rats and bradycardia in NHPs, which were the adverse events found in clinical studies of fingolimod. ASP1126 with improved safety profile has the potential to be an adjunct therapy in combination with tacrolimus in clinical transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Aloenxertos/efeitos dos fármacos , Aloenxertos/metabolismo , Animais , Bradicardia/induzido quimicamente , Sinergismo Farmacológico , Humanos , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Ratos , Esfingosina/agonistas , Tacrolimo/farmacologia , Transplante Homólogo/métodos
6.
J Crohns Colitis ; 12(suppl_2): S633-S640, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30137311

RESUMO

Studies in the 1990s using animal models of intestinal inflammation delineated the crucial molecules involved in leukocyte attraction and retention to the inflamed gut and associated lymphoid tissues. The first drug targeting leukocyte trafficking tested in inflammatory bowel diseases was the anti-ICAM-1 antisense oligonucleotide alicaforsen, showing only modest efficacy. Subsequently, the anti-α4 monoclonal antibody natalizumab proved efficacious for induction and maintenance of remission in Crohn's disease, but was associated with progressive multifocal leukoencephalopathy due to its ability to interfere with both α4ß1 and α4ß7 function. Later developments in this area took advantage of the fairly selective expression of MAdCAM-1 in the digestive organs, showing that vedolizumab, a more specific monoclonal antibody selectively blocking MAdCAM-1 binding to integrin α4ß7, was efficacious for induction and maintenance of remission in ulcerative colitis and Crohn's disease, and it was not associated with neurological complications. Currently, other drugs targeting the ß7 subunit, immunoglobulin superfamily molecules expressed on the endothelium, as well as blockade of lymphocyte recirculation in lymph nodes through modulation of sphingosine 1-phosphate receptors are under development. The potential use and risks of combined anti-trafficking therapy will be examined in this review.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Integrinas/antagonistas & inibidores , Leucócitos/fisiologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Moléculas de Adesão Celular , Comunicação Celular/efeitos dos fármacos , Células Endoteliais/fisiologia , Cloridrato de Fingolimode/uso terapêutico , Fármacos Gastrointestinais/farmacologia , Trato Gastrointestinal/imunologia , Humanos , Imunoglobulinas , Imunossupressores/uso terapêutico , Indanos/uso terapêutico , Molécula 1 de Adesão Intercelular , Lisofosfolipídeos/agonistas , Mucoproteínas/antagonistas & inibidores , Natalizumab/uso terapêutico , Oxidiazóis/uso terapêutico , Oligonucleotídeos Fosforotioatos/uso terapêutico , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas , Esfingosina/análogos & derivados
7.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1863(9): 980-990, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29787912

RESUMO

Given their important role in neuronal function, there has been an increasing focus on altered lipid levels in brain disorders. The effect of a high-fat (HF) diet on the lipid profiles of the cortex, hippocampus, hypothalamus, and olfactory bulb of the mouse brain was investigated using nanoflow ultrahigh pressure liquid chromatography-electrospray ionization-tandem mass spectrometry in the current study. For 8 weeks, two groups of 5-week-old mice were fed either an HF or normal diet (6 mice from each group analyzed as the F and N groups, respectively). The remaining mice in both groups then received a 4-week normal diet. Each group was then subdivided into two groups for another 4-week HF or normal diet. Quantitative analysis of 270 of the 359 lipids identified from brain tissue revealed that an HF diet significantly affected the brain lipidome in all brain regions that were analyzed. The HF diet significantly increased diacylglycerols, which play a role in insulin resistance in all regions that were analyzed. Although the HF diet increased most lipid species, the majority of phosphatidylserine species were decreased, while lysophosphatidylserine species, with the same acyl chain, were substantially increased. This result can be attributed to increased oxidative stress due to the HF diet. Further, weight-cycling (yo-yo effect) was found more critical for the perturbation of brain lipid profiles than weight gain without a preliminary experience of an HF diet. The present study reveals systematic alterations in brain lipid levels upon HF diet analyzed either by lipid class and molecular levels.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Metaboloma , Bulbo Olfatório/efeitos dos fármacos , Animais , Química Encefálica , Córtex Cerebral/metabolismo , Cromatografia Líquida de Alta Pressão , Diglicerídeos/agonistas , Diglicerídeos/metabolismo , Hipocampo/metabolismo , Hipotálamo/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bulbo Olfatório/metabolismo , Estresse Oxidativo , Fosfatidilserinas/antagonistas & inibidores , Fosfatidilserinas/metabolismo , Espectrometria de Massas por Ionização por Electrospray
8.
Theriogenology ; 95: 8-17, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28460684

RESUMO

In previous work, an EP2 prostanoid receptor (EP2R) agonist in vivo increased mRNA expression of luteal LH receptors (LHR), unoccupied and occupied luteal; LHR, and circulating progesterone, while an EP3R or FPR agonist decreased; mRNA expression of luteal LHR, unoccupied and occupied luteal LHR, and; circulating progesterone. An EP4R and lysophosphatidic acid (LPA) LPA2R and LPA3R agonists were reported to inhibit luteal function and sirtuins have been proposed to increase prostaglandin synthesis. The objectives were to determine; whether an EP4R, LPA2R, or LPA3R agonist affect ovine luteal function in vivo or; in vitro. In addition, whether sirtuin (SIRT)-1, 2, or 3; LPA2R or LPA3R; or EP1R, EP2R, EP3R, or EP4R agonists affect caruncular endometrial PGF2α or PGE (PGE1+PGE2) secretion in vitro. Day-10 nonpregnant ewes received a single injection of Vehicle (N = 5); an LPA2R (N = 5); LPA3R (N = 6); or EP4R (N = 5) agonist given into the interstitial tissue of the ovarian vascular pedicle adjacent to the luteal-containing ovary to determine effects on circulating progesterone, mRNA expression of luteal LHR, and luteal unoccupied and occupied LHR. In addition, agonists for LPA2R, LPA3R, EP1R, EP2R, EP3R, or EP4R or SIRT-1, SIRT-2, or SIRT-3 activators were incubated with caruncular endometrial slices in vitro to determine their effect on caruncular endometrial PGF2α, or PGE secretion. LPA2R, LPA3R, or an EP4R agonist in vivo did not affect (P ≥ 0.05) luteal weight, circulating progesterone, or occupied luteal LHR. However, an LPA2R or EP4R agonist, but; not LPA3R agonist, in vivo increased (P ≤ 0.05) mRNA expression of luteal LHR. An; LPA2R, LPA3R, or EP4R agonist increased (P ≤ 0.05) luteal unoccupied LHR, but; not occupied LHR. An LPA2R, LPA3R, or an EP4R agonist did not affect (P ≥ 0.05); luteal progesterone secretion in vitro. An LPA2R or LPA3R agonist did not affect (P ≥ 0.05) luteal PGF2α, or PGE secretion in vitro. However, an EP4R agonist tended to decrease (P < 0.066) luteal PGF2α secretion and increased (P ≤ 0.05) luteal PGE; secretion in vitro. EP1R, EP2R, EP3R, or an EP4R agonist did not affect (P ≥ 0.05); caruncular endometrial PGF2α secretion in vitro. However, EP1R, EP3R, or an EP4R agonist increased caruncular endometrial PGE secretion in vitro, while two different EP2R agonists did not affect (P ≥ 0.05) caruncular endometrial PGE; secretion. A SIRT-1 activator, but not SIRT-2 or SIRT-3 activators, increased (P ≤ 0.05) caruncular endometrial PGE secretion, while sirtuin 1, 2, or 3 activators did not affect (P ≥ 0.05) caruncular endometrial PGF2α secretion. In conclusion, receptors for EP4, LPA2, and LPA3 do not appear to be involved; in luteolysis, but EP4R and LPA2R might participate in preventing luteolysis by maintaining luteal mRNA expression for LHR and preventing loss of unoccupied luteal LHR. In addition, SIRT-1, EP1R, EP3R, and EP4R might be involved in; regulating caruncular endometrial PGE secretion, but not PGF2α secretion.


Assuntos
Corpo Lúteo/efeitos dos fármacos , Endométrio/efeitos dos fármacos , Prostaglandinas E/metabolismo , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E/agonistas , Sirtuínas/farmacologia , Alprostadil/metabolismo , Animais , Corpo Lúteo/fisiologia , Dinoprosta/metabolismo , Endométrio/fisiologia , Feminino , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/antagonistas & inibidores , Progesterona/sangue , Progesterona/metabolismo , RNA Mensageiro/metabolismo , Ovinos
9.
Stroke ; 47(12): 3053-3056, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27827329

RESUMO

BACKGROUND AND PURPOSE: Growing evidence supports that the immunomodulatory drug fingolimod is protective in stroke. Fingolimod binds to 4 of 5 sphingosine-1-phosphate (S1P) receptors and, among other actions, it induces lymphopenia. In this study, we investigated whether a selective S1P1 agonist is protective in experimental stroke. METHODS: Drug selectivity was studied in vitro in cells overexpressing the human S1P receptors. Mice (n=54) received different doses of LASW1238 (3 or 10 mg/kg), fingolimod (1 mg/kg), or the vehicle intraperitoneal, and lymphopenia was studied at different time points. After intraluminal middle cerebral artery occlusion for 45 minutes and immediately after reperfusion, mice (n=56) received the drug treatment. At 24 hours, a neurological test was performed and infarct volume was measured. Treatment and all the analyses were performed in a blind fashion. RESULTS: In vitro functional assays showed that LASW1238 is a selective agonist of the S1P1 receptor. At 10 mg/kg, this compound induced sustained lymphopenia in mice comparable with fingolimod, whereas at 3 mg/kg it induced short-lasting lymphopenia. After ischemia, both LASW1238 (10 mg/kg) and fingolimod reduced infarct volume, but only LASW1238 (10 mg/kg) showed statistically significant differences versus the vehicle. The neurological function and plasma cytokine levels were not different between groups. CONCLUSIONS: The selective S1P1 agonist LASW1238 reduces infarct volume after ischemia/reperfusion in mice, but only when lymphopenia is sustained for at least 24 hours. S1P1 and lymphocytes are potential targets for drug treatment in stroke. Defining the best drug dosing regimens to control the extent and duration of lymphopenia is critical to achieve the desired effects.


Assuntos
Infarto Cerebral/tratamento farmacológico , Linfopenia/induzido quimicamente , Lisofosfolipídeos/agonistas , Fármacos Neuroprotetores/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Traumatismo por Reperfusão/tratamento farmacológico , Esfingosina/análogos & derivados , Animais , Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esfingosina/agonistas
10.
Bioorg Med Chem Lett ; 26(10): 2470-2474, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27055941

RESUMO

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas
11.
J Med Chem ; 59(6): 2820-40, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26924461

RESUMO

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.


Assuntos
Isoxazóis/síntese química , Isoxazóis/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Animais , Artrite Experimental/tratamento farmacológico , Células CHO , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Sistema Linfático/citologia , Sistema Linfático/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Esfingosina/agonistas , Relação Estrutura-Atividade , Timo/citologia , Timo/efeitos dos fármacos
12.
Stem Cell Rev Rep ; 12(1): 121-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26400757

RESUMO

Successful clinical outcomes from transplantation of hematopoietic stem cells (HSCs) depend upon efficient HSC homing to bone marrow (BM), subsequent engraftment, and, finally, BM repopulation. Homing of intravenously administered HSCs from peripheral blood (PB) through the circulation to the BM stem cell niches, which is the first critical step that precedes their engraftment, is enforced by chemotactic factors released in the BM microenvironment that chemoattract HSCs. These chemotactic factors include α-chemokine stromal-derived factor 1 (SDF-1), the bioactive phosphosphingolipids sphingosine-1-phosphate (S1P) and ceramid-1-phosphate (C1P), and the extracellular nucleotides ATP and UTP. Stem cells may also respond to a Ca(2+) or H(+) gradient by employing calcium- or proton-sensing receptors, respectively. In this review, we will present emerging strategies based on ex vivo manipulation of graft HSCs that are aimed at enhancing the responsiveness of HSCs to BM-secreted chemoattractants and/or promoting HSC adhesion and seeding efficiency in the BM microenvironment.


Assuntos
Fatores Quimiotáticos/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Trifosfato de Adenosina/agonistas , Trifosfato de Adenosina/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Ceramidas/agonistas , Ceramidas/imunologia , Ceramidas/farmacologia , Quimiocina CXCL12/agonistas , Quimiocina CXCL12/imunologia , Quimiocina CXCL12/farmacologia , Fatores Quimiotáticos/agonistas , Fatores Quimiotáticos/imunologia , Quimiotaxia/efeitos dos fármacos , Dinoprostona/uso terapêutico , Células-Tronco Hematopoéticas/química , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/imunologia , Lisofosfolipídeos/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Receptores CXCR4/agonistas , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Esfingosina/agonistas , Esfingosina/análogos & derivados , Esfingosina/imunologia , Esfingosina/farmacologia , Nicho de Células-Tronco/imunologia , Uridina Trifosfato/agonistas , Uridina Trifosfato/imunologia , Ácido Valproico/uso terapêutico
13.
Clin Exp Pharmacol Physiol ; 43(2): 166-73, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26582369

RESUMO

There is growing evidence that diabetes mellitus causes attenuation of the bioactive metabolite of membrane sphingolipids, sphingosine-1-phosphate, and this may be a key mechanism in the decreased cardioprotective effect of ischaemic preconditioning (IPC) in the diabetic heart. Thus, this study has been designed to investigate the role and pharmacological potential of sphingosine-1-phosphate in diabetic rat heart. Diabetes was produced in Wistar rats by administration of a low dose of streptozotocin (STZ) (35 mg/kg, i.p., once) and feeding a high fat diet (HFD) for 6 weeks. Isolated rat heart was subjected to 30 min ischaemia followed by 120 min of reperfusion (I/R). The heart was subjected to pre-ischaemic treatment (before ischaemia for 20 min) and pharmacological preconditioning with the S1P agonist FTY720 (0.6 µmol/L) with and without atractyloside (an mPTP opener; in the last episode of reperfusion before I/R). Myocardial infarction was assessed in terms of increase in lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), myeloperoxidase (MPO) level and infarct size (triphenyltetrazolium chloride staining). Immunohistochemistry analysis was done for assessment of tumour necrosis factor (TNF)-α and glycogen synthase kinase (GSK)-3ß level in cardiac tissue. Pre-ischaemic treatment and pharmacological preconditioning with FTY720 significantly decreased I/R-induced myocardial infarction, TNF-alpha, GSK-3ß level and release of LDH and CK-MB as compared to control group. The cardioprotective effect of S1P agonist was significantly attenuated by atractyloside. It may be concluded that S1P agonist FTY720 prevents the diabetic heart from ischaemic reperfusion injury, possibly through inhibition of GSK-3ß and regulation of opening of mitochondrial permeability transition pore.


Assuntos
Diabetes Mellitus Experimental/complicações , Cloridrato de Fingolimode/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Lisofosfolipídeos/agonistas , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Esfingosina/análogos & derivados , Animais , Glicemia/metabolismo , Cardiotônicos/farmacologia , Creatina Quinase Forma MB/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glicogênio Sintase Quinase 3 beta , Precondicionamento Isquêmico , Lipídeos/sangue , Masculino , Poro de Transição de Permeabilidade Mitocondrial , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Wistar , Esfingosina/agonistas
14.
J Biomed Mater Res A ; 104(4): 942-56, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26704185

RESUMO

In this study, the wound closure of mouse skin defects was examined in terms of recruitment of mesenchymal stem cells (MSC) and macrophages. For the cells recruitment, stromal derived factor-1 (SDF-1) of a MSC recruitment agent and sphingosine-1 phosphate agonist (SEW2871) of a macrophages recruitment agent were incorporated into gelatin hydrogels, and then released in a controlled fashion. When applied to a skin wound defect of mice, gelatin hydrogels incorporating mixed 500 ng SDF-1 and 0.4, 0.8, or 1.6 mg SEW2871-micelles recruited a higher number of both MSC and macrophages than those incorporating SDF-1 or phosphate buffered saline. However, the number of M1 phenotype macrophages for the hydrogel incorporating mixed SDF-1 and SEW2871-micelles recruited was remarkably low to a significant extent compared with that for those hydrogel incorporating 0.4, 0.8, or 1.6 mg SEW2871-micelles. On the other hand, the number of M2 macrophages 3 days after the implantation of the hydrogels incorporating SDF-1 and 0.4 mg SEW2871-micelles significantly increased compared with that for other hydrogels. In vivo experiments revealed the hydrogels incorporating SDF-1 and 0.4 mg SEW2871-micelles promoted the wound closure of skin defect to a significant stronger extent than those incorporating SEW2871-micelles, SDF-1, and a mixture of SDF-1 and higher doses of SEW2871-micelles. It is concluded that the in vivo recruitment of MSC and macrophages to the defects may contribute to the tissue regeneration of skin wound.


Assuntos
Quimiocina CXCL12/administração & dosagem , Preparações de Ação Retardada/química , Gelatina/química , Macrófagos/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Oxidiazóis/administração & dosagem , Tiofenos/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Bovinos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/farmacologia , Hidrogéis/química , Lisofosfolipídeos/agonistas , Macrófagos/citologia , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos Endogâmicos C57BL , Oxidiazóis/farmacologia , Pele/efeitos dos fármacos , Pele/lesões , Esfingosina/agonistas , Esfingosina/análogos & derivados , Suínos , Tiofenos/farmacologia
15.
Nature ; 523(7560): 342-6, 2015 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-26053123

RESUMO

Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P1 signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.


Assuntos
Apolipoproteínas/metabolismo , Sistema Nervoso Central/patologia , Lipoproteínas HDL/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Linfopoese , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Apolipoproteínas/deficiência , Apolipoproteínas/genética , Apolipoproteínas M , Barreira Hematoencefálica/patologia , Movimento Celular , Proliferação de Células/genética , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Cloridrato de Fingolimode/farmacologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Linfócitos/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/sangue , Lisofosfolipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Esfingosina/agonistas , Esfingosina/sangue , Esfingosina/genética , Esfingosina/metabolismo
16.
J Clin Invest ; 125(4): 1379-87, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25831442

RESUMO

Membrane sphingolipids are metabolized to sphingosine-1-phosphate (S1P), a bioactive lipid mediator that regulates many processes in vertebrate development, physiology, and pathology. Once exported out of cells by cell-specific transporters, chaperone-bound S1P is spatially compartmentalized in the circulatory system. Extracellular S1P interacts with five GPCRs that are widely expressed and transduce intracellular signals to regulate cellular behavior, such as migration, adhesion, survival, and proliferation. While many organ systems are affected, S1P signaling is essential for vascular development, neurogenesis, and lymphocyte trafficking. Recently, a pharmacological S1P receptor antagonist has won approval to control autoimmune neuroinflammation in multiple sclerosis. The availability of pharmacological tools as well as mouse genetic models has revealed several physiological actions of S1P and begun to shed light on its pathological roles. The unique mode of signaling of this lysophospholipid mediator is providing novel opportunities for therapeutic intervention, with possibilities to target not only GPCRs but also transporters, metabolic enzymes, and chaperones.


Assuntos
Lisofosfolipídeos/fisiologia , Esfingosina/análogos & derivados , Lesão Pulmonar Aguda/tratamento farmacológico , Anemia Falciforme/sangue , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Cardiovasculares/metabolismo , Fenômenos Fisiológicos Celulares/fisiologia , Modelos Animais de Doenças , Cloridrato de Fingolimode , Mobilização de Células-Tronco Hematopoéticas , Humanos , Influenza Humana/metabolismo , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/antagonistas & inibidores , Lipídeos de Membrana/metabolismo , Camundongos , Esclerose Múltipla/tratamento farmacológico , Neoplasias/sangue , Neovascularização Fisiológica/fisiologia , Neurogênese/fisiologia , Propilenoglicóis/uso terapêutico , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/fisiologia , Esfingolipídeos/metabolismo , Esfingosina/agonistas , Esfingosina/antagonistas & inibidores , Esfingosina/fisiologia , Esfingosina/uso terapêutico
17.
Immunity ; 41(3): 440-450, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25238098

RESUMO

Pathologically swollen lymph nodes (LNs), or buboes, characterize Yersinia pestis infection, yet how they form and function is unknown. We report that colonization of the draining LN (dLN) occurred due to trafficking of infected dendritic cells and monocytes in temporally distinct waves in response to redundant chemotactic signals, including through CCR7, CCR2, and sphingosine-1-phospate (S1P) receptors. Retention of multiple subsets of phagocytes within peripheral LNs using the S1P receptor agonist FTY720 or S1P1-specific agonist SEW2871 increased survival, reduced colonization of downstream LNs, and limited progression to transmission-associated septicemic or pneumonic disease states. Conditional deletion of S1P1 in mononuclear phagocytes abolished node-to-node trafficking of infected cells. Thus, Y. pestis-orchestrated LN remodeling promoted its dissemination via host cells through the lymphatic system but can be blocked by prevention of leukocyte egress from DLNs. These findings define a novel trafficking route of mononuclear phagocytes and identify S1P as a therapeutic target during infection.


Assuntos
Linfonodos/patologia , Lisofosfolipídeos/genética , Peste/patologia , Receptores de Lisoesfingolipídeo/imunologia , Esfingosina/análogos & derivados , Yersinia pestis/patogenicidade , Animais , Antígenos CD11/metabolismo , Antígeno CD11b/metabolismo , Movimento Celular , Quimiocina CCL21/genética , Células Dendríticas/microbiologia , Feminino , Cloridrato de Fingolimode , Cadeias alfa de Integrinas/metabolismo , Linfonodos/citologia , Linfonodos/microbiologia , Lisofosfolipídeos/agonistas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/microbiologia , Oxidiazóis/farmacologia , Fagócitos/imunologia , Peste/imunologia , Propilenoglicóis/farmacologia , Receptores CCR2/imunologia , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistas , Esfingosina/genética , Esfingosina/farmacologia , Tiofenos/farmacologia , Yersinia pestis/imunologia
18.
J Immunol ; 193(4): 1966-74, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25015824

RESUMO

Although much is described about the molecules involved in neutrophil migration from circulation into tissues, less is known about the molecular mechanisms that regulate neutrophil entry into lymph nodes (LNs) draining a local inflammatory site. In this study, we investigated neutrophil migration toward LNs in a context of inflammation induced by immunization of BALB/c mice with OVA emulsified in CFA. We demonstrated that neutrophils can enter LNs of OVA/CFA-immunized mice not only via lymphatic vessels but also from blood, across high endothelial venules. By adoptive transfer experiments, we showed that this influx was dependent on an inflammatory-state condition and previous neutrophil stimulation with OVA/anti-OVA immune complexes. Importantly, we have demonstrated that, in the migratory pattern to LNs, neutrophils used L-selectin and P-selectin glycoprotein ligand-1, macrophage-1 Ag and LFA-1 integrins, and CXCR4 to get access across high endothelial venules, whereas macrophage-1 Ag, LFA-1, and CXCR4 were involved in their trafficking through afferent lymphatics. Strikingly, we found that stimulation with immune complexes significantly upregulated the expression of sphingosine-1-phosphate receptor 4 on neutrophils, and that treatment with the sphingosine-1-phosphate agonist FTY720 altered neutrophil LN-homing ability. These findings summarized in this article disclose the molecular pattern that controls neutrophil recruitment to LNs.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Doenças do Sistema Imunitário/imunologia , Transtornos Leucocíticos/imunologia , Linfonodos/imunologia , Neutrófilos/imunologia , Transferência Adotiva , Animais , Movimento Celular/imunologia , Feminino , Cloridrato de Fingolimode , Imunossupressores/farmacologia , Inflamação/imunologia , Selectina L/imunologia , Linfonodos/citologia , Vasos Linfáticos/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Lisofosfolipídeos/agonistas , Antígeno de Macrófago 1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/transplante , Selectina-P/imunologia , Propilenoglicóis/farmacologia , Receptores CXCR4/imunologia , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/agonistas , Esfingosina/análogos & derivados , Esfingosina/farmacologia
19.
Acta Biomater ; 10(11): 4723-4729, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25038462

RESUMO

The objective of this study is to design a drug delivery system (DDS) for the in vivo promotion of macrophage recruitment. As the drug, a water-insoluble agonist of sphingosine-1-phosphate type 1 receptor (SEW2871) was selected. SEW2871 (SEW) was water-solubilized by micelle formation with gelatin grafted by L-lactic acid oligomer. SEW micelles were mixed with gelatin, followed by dehydrothermal crosslinking of gelatin to obtain gelatin hydrogels incorporating SEW micelles. SEW was released from the hydrogels incorporating SEW micelles in vitro and in vivo. The water-solubilized SEW showed in vitro macrophage migration activity. When implanted into the back subcutis or the skin wound defect of mice, the hydrogel incorporating SEW micelles promoted macrophage migration toward the tissue around the implanted site to a significantly great extent compared with SEW-free hydrogel and that mixed with SEW micelles. The hydrogel is a promising DDS to enhance macrophage recruitment in vivo.


Assuntos
Gelatina/química , Hidrogéis/química , Lisofosfolipídeos/agonistas , Macrófagos/citologia , Oxidiazóis/farmacologia , Esfingosina/análogos & derivados , Tiofenos/farmacologia , Animais , Bovinos , Contagem de Células , Movimento Celular/efeitos dos fármacos , Preparações de Ação Retardada , Humanos , Ácido Láctico/química , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Micelas , Solubilidade , Esfingosina/agonistas , Sus scrofa , Fatores de Tempo , Água/química
20.
Curr Top Microbiol Immunol ; 378: 149-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24728597

RESUMO

The development of fingolimod, an unselective functional antagonist of the interactions between sphingosine 1 phosphate (S1P) and sphingosine 1 phosphate receptors (S1PRs), as the first oral therapy for multiple sclerosis (MS) has been a milestone. The parallel intensive research on the role of S1P, sphingosine kinases, and the five known S1PRs, their tissue distribution and expression in physiological and pathological conditions have led to a wide range of interesting findings. The initial focus of this research in the context of developing fingolimod as a treatment of MS has been on its immunological effects. The wide distribution and important roles of sphingosine, its metabolites, and their receptors in the central nervous system (CNS) in general, in myelin, and in all cell types of this organ have spurred interest to examine S1P and its five receptors in the brain as well. The present review will concentrate on the latter area and give a brief overview of what is known about S1P/S1PR interactions in the CNS in physiological and pathological conditions.


Assuntos
Doenças do Sistema Nervoso Central/metabolismo , Lisofosfolipídeos/uso terapêutico , Esfingosina/análogos & derivados , Animais , Doenças do Sistema Nervoso Central/tratamento farmacológico , Humanos , Lisofosfolipídeos/agonistas , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/agonistas , Esfingosina/metabolismo , Esfingosina/uso terapêutico
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