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1.
Acta Biochim Biophys Sin (Shanghai) ; 51(4): 402-410, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877755

RESUMO

Epicardial progenitor cells (EpiCs) which are derived from the proepicardium have the potential to differentiate into coronary vascular smooth muscle cells during development. Whether sphingosine 1-phosphate (S1P), a highly hydrophobic zwitterionic lysophospholipid in signal transduction, induces the differentiation of EpiCs is unknown. In the present study, we demonstrated that S1P significantly induced the expression of smooth muscle cell specific markers α-smooth muscle actin and myosin heavy chain 11 in the EpiCs. And the smooth muscle cells differentiated from the EpiCs stimulated by S1P were further evaluated by gel contraction assay. To further confirm the major subtype of sphingosine 1-phosphate receptors (S1PRs) involved in the differentiation of EpiCs, we used the agonists and antagonists of different S1PRs. The results showed that the S1P1/S1P3 antagonist VPC23019 and the S1P2 antagonist JTE013 significantly attenuated EpiCs differentiation, while the S1P1 agonist SEW2871 and antagonist W146 did not affect EpiCs differentiation. These results collectively suggested that S1P, principally through its receptor S1P3, increases EpiCs differentiation into VSMCs and thus indicated the importance of S1P signaling in the embryonic coronary vasculature, while S1P2 plays a secondary role.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Células-Tronco Embrionárias Murinas/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Pericárdio/citologia , Esfingosina/análogos & derivados , Actinas/genética , Actinas/metabolismo , Animais , Diferenciação Celular/genética , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Embrionárias Murinas/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Pericárdio/embriologia , Fosfosserina/análogos & derivados , Fosfosserina/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/genética , Esfingosina/farmacologia
2.
J Neuroinflammation ; 16(1): 54, 2019 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-30825874

RESUMO

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune-mediated inflammatory disease of the peripheral nervous system characterized by a response directed against certain myelin proteins and for which therapies are limited. Previous studies have suggested a beneficial role of FTY720, a sphingosine 1-phosphate (S1P) receptor agonist, known to deplete lymphocytes from the peripheral blood by sequestering them into lymph nodes, in the treatment of experimental autoimmune neuritis (EAN). Therefore, we investigated whether FTY720 is also beneficial in chronic experimental autoimmune neuritis (c-EAN), a recently developed rat model mimicking human CIDP. METHODS: c-EAN was induced in Lewis rats by immunization with S-palm P0(180-199) peptide. Rats were treated with FTY720 (1 mg/kg) or vehicle intraperitoneally once daily from the onset of clinical signs for 18 days; clinical signs were assessed daily until 60 days post-immunization (dpi). Electrophysiological and histological features were examined at different time points. We also evaluated the serum levels of different pro- and anti-inflammatory cytokines by ELISA or flow cytometry at 18, 40, and 60 dpi. RESULTS: Our data demonstrate that FTY720 decreased the severity and abolished the chronicity of the disease in c-EAN rats. Therapeutic FTY720 treatment reversed electrophysiological and histological anomalies, suggesting that myelinated fibers were subsequently preserved, it inhibited macrophage and IL-17+ cell infiltration in PNS, and it significantly reduced circulating pro-inflammatory cytokines. CONCLUSIONS: FTY720 treatment has beneficial effects on c-EAN, a new animal model mimicking human CIDP. We have shown that FTY720 is an effective immunomodulatory agent, improving the disease course of c-EAN, preserving the myelinated fibers, attenuating the axonal degeneration, and decreasing the number of infiltrated inflammatory cells in peripheral nerves. These data confirm the interest of testing FTY720 or molecules targeting S1P in human peripheral neuropathies.


Assuntos
Cloridrato de Fingolimode/farmacologia , Imunossupressores/farmacologia , Neurite Autoimune Experimental/patologia , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Animais , Masculino , Neuritos/efeitos dos fármacos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Ratos , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Índice de Gravidade de Doença
3.
Pharmazie ; 74(2): 107-110, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782260

RESUMO

SYL-927 is a selective sphingosine-1-phosphate receptor 1 (S1P1) agonist for autoimmune diseases. It undergoes phosphorylation to the active SYL-927-P in vivo, which activates S1P1 on lymphocytes, causing lymphopenia by retention of lymphocytes in the lymph nodes. The aim of this study was to identify the involvement of blood cells in the phosphorylation of SYL-927. In addition, pharmacokinetics of SYL-927 and SYL-927-P in blood and plasma were compared in rats. The results demonstrated that SYL-927 can be converted to SYL-927-P in rat blood, but not in rat plasma. However, both rat blood and plasma are capable of dephosphorylating SYL-927-P to SYL-927. SYL-927-P generation and release were observed after incubating SYL-927 with rat and human erythrocytes and platelets. The addition of sphingosine kinases (SPHKs) inhibitors N,N-dimethylsphingosine (DMS) and FTY720 significantly inhibited SYL-927-P generation, indicating the involvement of SPHKs. In addition, SYL-927 and SYL-927-P levels in blood were significantly higher than those in plasma after oral administration of SYL-927 in rats, suggesting the blood cells for the production of SYL-927-P. In summary, the blood cells such as erythrocytes and platelets contribute to the generation and release of SYL-927-P, which is important for maintaining plasma active phosphate levels for prolonged effects.


Assuntos
Plaquetas/metabolismo , Eritrócitos/metabolismo , Cloridrato de Fingolimode/análogos & derivados , Imunossupressores/sangue , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/sangue , Humanos , Imunossupressores/administração & dosagem , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/sangue , Ratos , Esfingosina/administração & dosagem , Esfingosina/análogos & derivados , Esfingosina/sangue
4.
Heart Vessels ; 34(6): 1052-1063, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30604190

RESUMO

It has been demonstrated that S1P receptors affect heart ischaemia-reperfusion (IR) induced injury. However, whether S1P receptors affect IR-induced cardiac death has not been investigated. The aim of this paper is to demonstrate the role of S1P receptors in IR-induced cardiac death. Healthy adult male Sprague-Dawley rats were assigned to the following groups: non-operation control group, sham operation group, IR group, IR group pretreated with DMSO, IR group pretreated with S1P3 agonist, IR group pretreated with an antagonist of S1P3, IR group pretreated with S1P2 and S1P3 antagonists, IR group pretreated with heptanol and antagonists of S1P2/3, and IR group pretreated with Gap26 and antagonists of S1P2/3 (heptanol acts as a Cx43 uncoupler and the mimic peptide Gap26 as Cx43 blocker). The groups with S1P2 or S1P3 agonist application before reperfusion were used to assess whether these can be used for therapy of IR. The haemodynamics, electrocardiograms (ECG), infarction area, and mortality rates were recorded. Immunohistological connexin 43 (Cx43) expression in the heart was detected in each group. Blocking S1P2/3 receptors with specific antagonists resulted in an increment of IR-induced mortality, increased infarction size, redistribution of Cx43 expression, as well as affecting the heart function. The infarction size, heart function, and mortality were totally or partially restored in the S1P2, S1P3 agonist-pretreated IR group, and the heptanol/Gap26-treated S1P2/3-blocked IR group. The S1P receptor S1P2/3 and Cx43 are involved in the IR-induced cardiac death.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Peptídeos/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Animais , Conexina 43/antagonistas & inibidores , Conexina 43/metabolismo , Morte Súbita Cardíaca/etiologia , Heptanol/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
5.
Infect Immun ; 87(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30510103

RESUMO

Incidence of whooping cough (pertussis), a bacterial infection of the respiratory tract caused by the bacterium Bordetella pertussis, has reached levels not seen since the 1950s. Antibiotics fail to improve the course of disease unless administered early in infection. Therefore, there is an urgent need for the development of antipertussis therapeutics. Sphingosine-1-phosphate receptor (S1PR) agonists have been shown to reduce pulmonary inflammation during Bordetella pertussis infection in mouse models. However, the mechanisms by which S1PR agonists attenuate pertussis disease are unknown. We report the results of a transcriptome sequencing study examining pulmonary transcriptional responses in B. pertussis-infected mice treated with S1PR agonist AAL-R or vehicle control. This study identified peptidoglycan recognition protein 4 (PGLYRP4) as one of the most highly upregulated genes in the lungs of infected mice following S1PR agonism. PGLYRP4, a secreted, innate mediator of host defenses, was found to limit early inflammatory pathology in knockout mouse studies. Further, S1PR agonist AAL-R failed to attenuate pertussis disease in PGLYRP4 knockout (KO) mice. B. pertussis virulence factor tracheal cytotoxin (TCT), a secreted peptidoglycan breakdown product, induces host tissue damage. TCT-oversecreting strains were found to drive an early inflammatory response similar to that observed in PGLYRP4 KO mice. Further, TCT-oversecreting strains induced significantly greater pathology in PGLYRP4-deficient animals than their wild-type counterparts. Together, these data indicate that S1PR agonist-mediated protection against pertussis disease is PGLYRP4 dependent. Our data suggest PGLYRP4 functions, in part, by preventing TCT-induced airway damage.


Assuntos
Bordetella pertussis/imunologia , Proteínas de Transporte/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Coqueluche/imunologia , Animais , Modelos Animais de Doenças , Regulação Bacteriana da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
Mult Scler Relat Disord ; 27: 276-280, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30447536

RESUMO

BACKGROUND: Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for treatment of relapsing-remitting multiple sclerosis (RRMS). S1P receptors that fingolimod acts upon have also been shown to be expressed on atrial myocytes. This expression pattern has been linked with the drug's cardiovascular effects, such as bradycardia. We aimed to evaluate the clinical and electrocardiographic predictors of heart rate (HR) reduction in patients receiving first-dose fingolimod. METHODS: We retrospectively analyzed subjects diagnosed with RRMS who were allocated to fingolimod treatment. HR, systolic and diastolic blood pressure values and electrocardiography during the first dose of fingolimod were accessed. RESULTS: A total of 114 RRMS patients (65.8% female, 33.58 ±â€¯8.63 years) were included. After the initial dose of fingolimod, the heart rate decreased significantly at each hour (each p < 0.001). Nadir heart rate was reached at 4 h. The multivariate binary logistic regression analysis revealed that BMI (OR: 0.878, p = 0.045), optic nerve involvement (OR: 3.205, p = 0.018), baseline HR (OR: 1.079, p = 0.002) and T-peak-T-end interval (OR: 1.046, p = 0.030) were independent predictors of greater HR reduction. During 6-h monitorization, none of the patients had relevant adverse reactions. CONCLUSION: Our findings provide an insight on clinical and electrocardiographic predictors of HR reduction that occurs in RRMS patients receiving first dose of fingolimod.


Assuntos
Bradicardia/induzido quimicamente , Bradicardia/diagnóstico , Cloridrato de Fingolimode/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Eletrocardiografia , Feminino , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Receptores de Lisoesfingolipídeo/agonistas , Estudos Retrospectivos
7.
Bioorg Chem ; 82: 41-57, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30268973

RESUMO

Agonism of S1P1 receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P1 modulators. In this paper we described a series of oxadiazole-based S1P1 direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P1 receptor and favorable selectivity against S1P3 receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16-3b and the activated S1P1 model was also studied.


Assuntos
Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetulus , Desenho de Drogas , Humanos , Linfócitos/efeitos dos fármacos , Linfopenia/induzido quimicamente , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
Folia Neuropathol ; 56(3): 196-205, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30509041

RESUMO

Alzheimer's disease (AD) is characterized by alterations of amyloid precursor protein (APP) metabolism, accumulation of amyloid  peptides (A), hyperphosphorylation of Tau proteins and also by sphingolipids disturbances. These changes lead to oxidative stress, mitochondria dysfunction, synaptic loss and neuro-inflammation. It is known that A may promote ceramides formation and reversely, ceramides could stimulate A peptides release. However, the effect of ceramide and sphingosine-1-phosphate (S1P) on APP metabolism has not been fully elucidated. In this study we investigated the role of ceramide and S1P on APP metabolism. Moreover, the effect of ceramide and SEW 2871 (agonist for S1P receptor-1) on Sirt1 (NAD+-dependent nuclear enzyme responsible for stress response) gene expression under A toxicity was analyzed. Experiments were carried out using pheochromocytoma cells (PC-12) transfected with: an empty vector (used as a control), human wild-type APP gene (APPwt) and Swedish mutated (K670M/N671L) APP gene (APPsw). Our results indicated that C2-ceramide significantly decreased the viability of the APPwt, APPsw as well as empty vector-transfected PC12 cells. It was observed that C2-ceramide had no significant effect on the mRNA level of - and -secretase in APPwt and APPsw cells. However, it significantly decreased transcription of -secretase in control cells. Results also showed a significant increase in Psen1 (crucial subunit of -secretase) gene expression in APPsw cells after incubation with C2-ceramide. We observed that SEW 2871 significantly upregulated the mRNA level of -secretase in control-empty vector-transfected cells subjected to C2-ceramide toxicity. The same tendency, though insignificant, was observed in APPwt and APPsw cells. Moreover, SEW 2871 enhanced the mRNA level of -secretase and Psen1 in APPsw cells after C2-ceramide treatment. Additionally, SEW 2871 significantly upregulated a gene expression of Sirt1 in APPwt and also APPsw cells subjected to C2-ceramide toxicity. Furthermore, it was observed that SEW 2871 significantly enhanced the viability of all investigated cells' lines probably through its positive influence on Sirt1.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ceramidas/farmacologia , Lisofosfolipídeos/metabolismo , Oxidiazóis/farmacologia , Esfingosina/análogos & derivados , Tiofenos/farmacologia , Animais , Ceramidas/metabolismo , Humanos , Modelos Teóricos , Neurônios/metabolismo , Oxidiazóis/metabolismo , Células PC12 , Ratos , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/metabolismo , Tiofenos/metabolismo , Transcrição Genética/efeitos dos fármacos
9.
Bioorg Med Chem Lett ; 28(23-24): 3585-3591, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30409535

RESUMO

Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists.


Assuntos
Doenças Autoimunes/patologia , Receptores de Lisoesfingolipídeo/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Disponibilidade Biológica , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/farmacocinética , Cloridrato de Fingolimode/uso terapêutico , Humanos , Imunossupressores/química , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Oxidiazóis/química , Oxidiazóis/farmacocinética , Oxidiazóis/uso terapêutico , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingolipídeos/metabolismo
10.
Biopharm Drug Dispos ; 39(9): 431-436, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30362120

RESUMO

SYL-927, a novel and selective S1P1 agonist, is transferred to its active phosphate for the regulation of lymphocyte recirculation. This in vitro metabolism study is to elucidate the P450-mediated oxidation pathway of SYL-927 in human liver microsomes (HLMs). The results demonstrated that the ω-1 hydroxylated metabolite SYL-927-M was formed after incubation of SYL-927 with HLMs. Recombinant human CYP1A1 and CYP2J2 can efficiently catalyse SYL-927-M formation, followed by markedly less substrate conversion with CYP1A2, CYP2C19 and CYP2D6. Inhibition studies with chemical inhibitors and antibodies suggested that arachidonic acid, the substrate of CYP2J2, and CYP2J2-specific antibody effectively inhibited the formation of SYL-927-M in HLMs whereas no significant inhibition was observed with the inhibitors for CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, demonstrating that CYP2J2 was primarily responsible for the formation of SYL-927-M.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Cloridrato de Fingolimode/análogos & derivados , Microssomos Hepáticos/enzimologia , Receptores de Lisoesfingolipídeo/agonistas , Inibidores das Enzimas do Citocromo P-450/farmacologia , Humanos , Hidroxilação
11.
Chem Commun (Camb) ; 54(90): 12758-12761, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30362470

RESUMO

Ginkgolic acid obtained as a sphingomyelin synthase inhibitor from a plant extract library inspired the concept of sphingolipid mimics. Ginkgolic acid-derived N-acyl anilines and ginkgolic acid 2-phosphate (GA2P) respectively mimic ceramide and sphingosine 1-phosphate (S1P) in structure and function. The GA2P-induced phosphorylation of ERK and internalization of S1P receptor 1 (S1P1) indicated potent agonist activity. Docking studies revealed that GA2P adopts a similar binding conformation to the bound ligand ML5, which is a strong antagonist of S1P1.


Assuntos
Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Salicilatos/farmacologia , Esfingolipídeos/agonistas , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de Lisoesfingolipídeo/metabolismo , Salicilatos/síntese química , Salicilatos/química , Esfingolipídeos/metabolismo , Relação Estrutura-Atividade , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
12.
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 , 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
13.
Front Immunol ; 9: 1696, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30127782

RESUMO

Hypoxic-ischemic injury to the developing brain remains a major cause of significant long-term morbidity and mortality. Emerging evidence from neonatal brain injury models suggests a detrimental role for peripheral lymphocytes. The immunomodulatory substance FTY720, a sphingosine-1-phosphate receptor agonist, was shown to reduce adult ischemia-induced neurodegeneration through its lymphopenic mode of action. In the present study, we hypothesized that FTY720 promotes neuroprotection by reducing peripheral lymphocytes and their infiltration into the injured neonatal brain. Term-born equivalent postnatal day 9 C57BL/6 mice were exposed to hypoxia ischemia (HI) followed by a single injection of 1 mg/kg FTY720 or vehicle (0.9% sodium chloride). Brain injury, microglia, and endothelial activation were assessed 7 days post HI using histology and western blot. Peripheral and cerebral leukocyte subsets were analyzed by multichannel flow cytometry. Whether FTY720s' effects could be attributed to its lymphopenic mode of action was determined in T cell-depleted mice. In contrast to our hypothesis, FTY720 exacerbated HI-induced neuropathology including loss of gray and white matter structures. While microglia and endothelial activation remained unchanged, FTY720 induced a strong and sustained depletion of peripheral T cells resulting in significantly reduced cerebral infiltration of CD4 T cells. CD4 T cell subset analysis revealed that circulating regulatory and effector T cells counts were similarly decreased after FTY720 treatment. However, since neonatal HI per se induces a selective infiltration of Foxp3 positive regulatory T cells compared to Foxp3 negative effector T cells effects of FTY720 on cerebral regulatory T cell infiltration were more pronounced than on effector T cells. Reductions in T lymphocytes, and particularly regulatory T cells coincided with an increased infiltration of innate immune cells, mainly neutrophils and inflammatory macrophages. Importantly anti-CD3-mediated T cell depletion resulted in a similar exacerbation of brain injury, which was not further enhanced by an additional FTY720 treatment. In summary, peripheral T cell depletion by FTY720 resulted in increased infiltration of innate immune cells concomitant to reduced T cell infiltration and exacerbation HI-induced brain injury. This study indicates that neonatal T cells may promote endogenous neuroprotection in the term-born equivalent hypoxic-ischemic brain potentially providing new opportunities for therapeutic intervention.


Assuntos
Cloridrato de Fingolimode/farmacologia , Hipóxia-Isquemia Encefálica/imunologia , Imunossupressores/farmacologia , Depleção Linfocítica , Fármacos Neuroprotetores/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Feminino , Inflamação , Subpopulações de Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Lisoesfingolipídeo/agonistas , Linfócitos T Reguladores/efeitos dos fármacos
14.
J Pharmacol Exp Ther ; 366(3): 509-518, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29945931

RESUMO

The immunomodulatory prodrug 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), which acts as an agonist for sphingosine-1-phosphate (S1P) receptors (S1PR) when phosphorylated, is proposed as a novel pain therapeutic. In this study, we assessed FTY720-mediated antinociception in the radiant heat tail-flick test and in the chronic constriction injury (CCI) model of neuropathic pain in mice. FTY720 produced antinociception and antiallodynia, respectively, and these effects were dose-dependent and mimicked by the S1PR1-selective agonist CYM-5442. Repeated administration of FTY720 for 1 week produced tolerance to acute thermal antinociception, but not to antiallodynia in the CCI model. S1PR-stimulated [35S]GTPγS autoradiography revealed apparent desensitization of G protein activation by S1P or the S1PR1 agonist 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (SEW-2871) throughout the brain. Similar results were seen in spinal cord membranes, whereby the Emax value of S1PR-stimulated [35S]GTPγS binding was greatly reduced in repeated FTY720-treated mice. These results suggest that S1PR1 is a primary target of FTY720 in alleviating both acute thermal nociception and chronic neuropathic nociception. Furthermore, the finding that tolerance develops to antinociception in the tail-flick test but not in chronic neuropathic pain suggests a differential mechanism of FTY720 action between these models. The observation that repeated FTY720 administration led to desensitized S1PR1 signaling throughout the central nervous system suggests the possibility that S1PR1 activation drives the acute thermal antinociceptive effects, whereas S1PR1 desensitization mediates the following: 1) tolerance to thermal antinociceptive actions of FTY720 and 2) the persistent antiallodynic effects of FTY720 in neuropathic pain by producing functional antagonism of pronociceptive S1PR1 signaling.


Assuntos
Cloridrato de Fingolimode/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Peptídeos Opioides/efeitos dos fármacos , Receptores de Lisoesfingolipídeo/metabolismo , Temperatura Ambiente , Animais , Modelos Animais de Doenças , Cloridrato de Fingolimode/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neuralgia/fisiopatologia , Receptores de Lisoesfingolipídeo/agonistas
15.
Acta Biochim Biophys Sin (Shanghai) ; 50(7): 651-657, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29901713

RESUMO

Ischemia/reperfusion (I/R) is a major cause of acute kidney injury (AKI), along with delayed graft function, which can trigger chronic kidney injury by stimulating epithelial to mesenchymal transition (EMT) in the kidney canaliculus. Sphingosine 1-phosphate receptor 1 (S1P1) is a G protein-coupled receptor that is indispensable for vessel homeostasis. This study aimed to investigate the influence of S1P1 on the mechanisms underlying I/R-induced EMT in the kidney using in vivo and in vitro models. Wild-type (WT) and S1P1-overexpressing kidney canaliculus cells were subject to hypoxic conditions followed by reoxygenation in the presence or absence of FTY720-P, a potent S1P1 agonist. In vivo, bilateral arteria renalis in wild-type mice and mice with silenced S1P1 were clamped for 30 min to obtain I/R models. We found that hypoxia/reoxygenation (H/R) significantly enhanced the expressions of EMT biomarkers and down-regulated S1P1 expression in wild-type canaliculus cells. In contrast, FTY720-P treatment or overexpression of S1P1 significantly suppressed EMT in wild-type canaliculus cells. Furthermore, after 48-72 h, a significant upregulation of EMT biomarker expression was triggered by I/R in mice with silenced S1P1, while the expressions of these markers did not change in wild-type mice. A kt activity was increased with H/R-induced EMT, suggesting that the protective influence of FTY720-P was due to its inhibition of PI3K/Akt. Therefore, the results of this study provide evidence that down-regulation of S1P1 expression is essential for the generation and progression of EMT triggered by I/R. S1P1 exhibits a prominent inhibitory effect on kidney I/R-induced EMT in the kidney by affecting the PI3K/Akt pathway.


Assuntos
Transição Epitelial-Mesenquimal , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Rim/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Organofosfatos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/genética , Traumatismo por Reperfusão/genética , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/farmacologia
16.
Arthritis Rheumatol ; 70(11): 1879-1889, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29781582

RESUMO

OBJECTIVE: Immune complex (IC) deposition activates polymorphonuclear neutrophils (PMNs), increases vascular permeability, and leads to organ damage in systemic lupus erythematosus and rheumatoid arthritis. The bioactive lipid sphingosine 1-phosphate (S1P), acting via S1P receptor 1 (S1P1 ), is a key regulator of endothelial cell (EC) barrier function. This study was undertaken to investigate whether augmenting EC integrity via S1P1 signaling attenuates inflammatory injury mediated by ICs. METHODS: In vitro barrier function was assessed in human umbilical vein endothelial cells (HUVECs) by electrical cell-substrate impedance sensing. Phosphorylation of myosin light chain 2 (p-MLC-2) and VE-cadherin staining in HUVECs were assessed by immunofluorescence. A reverse Arthus reaction (RAR) was induced in the skin and lungs of mice with S1P1 deleted from ECs (S1P1 EC-knockout [ECKO] mice) and mice treated with S1P1 agonists and antagonists. RESULTS: S1P1 agonists prevented loss of barrier function in HUVECs treated with IC-activated PMNs. S1P1 ECKO and wild-type (WT) mice treated with S1P1 antagonists had amplified RAR, whereas specific S1P1 agonists attenuated skin and lung RAR in WT mice. ApoM-Fc, a novel S1P chaperone, mitigated EC cell barrier dysfunction induced by activated PMNs in vitro and attenuated lung RAR. Expression levels of p-MLC-2 and disruption of VE-cadherin, each representing manifestations of cell contraction and destabilization of adherens junctions, respectively, that were induced by activated PMNs, were markedly reduced by treatment with S1P1 agonists and ApoM-Fc. CONCLUSION: Our findings indicate that S1P1 signaling in ECs modulates vascular responses to IC deposition. S1P1 agonists and ApoM-Fc enhance the EC barrier, limit leukocyte escape from capillaries, and provide protection against inflammatory injury. The S1P/S1P1 axis is a newly identified target to attenuate tissue responses to IC deposition and mitigate end-organ damage.


Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Permeabilidade Capilar/genética , Células Endoteliais/metabolismo , Receptores de Lisoesfingolipídeo/genética , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismo , Anilidas/farmacologia , Animais , Antígenos CD/efeitos dos fármacos , Antígenos CD/metabolismo , Apolipoproteínas M/farmacologia , Reação de Arthus , Caderinas/efeitos dos fármacos , Caderinas/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Miosinas Cardíacas/efeitos dos fármacos , Miosinas Cardíacas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Indanos/farmacologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Lisofosfolipídeos/farmacologia , Camundongos , Camundongos Knockout , Cadeias Leves de Miosina/efeitos dos fármacos , Cadeias Leves de Miosina/metabolismo , Organofosfonatos/farmacologia , Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/metabolismo , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Tiofenos/farmacologia
17.
Drug Metab Dispos ; 46(7): 1001-1013, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735753

RESUMO

Siponimod, a next-generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism, and excretion (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine, and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) and moderate distribution (Vz/F: 291 l). Siponimod was mainly cleared through biotransformation, predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 hours. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other cytochrome P450 enzymes.


Assuntos
Azetidinas/metabolismo , Compostos de Benzil/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Adolescente , Adulto , Animais , Biotransformação/fisiologia , Fezes , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo/fisiologia , Adulto Jovem
18.
Hum Mol Genet ; 27(14): 2490-2501, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29688337

RESUMO

Huntington's disease (HD) is the most common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approaches may open the door to new and more targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2 mice, a widely used HD animal model. Chronic administration of low-dose (0.1 mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2 mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HD mice from the classic progressive motor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5 may be also seen as an effective approach to target brain vasculature defects in the disease.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Proteína Huntingtina/genética , Doença de Huntington/tratamento farmacológico , Agregação Patológica de Proteínas/tratamento farmacológico , Receptores de Lisoesfingolipídeo/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Agregação Patológica de Proteínas/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Lisoesfingolipídeo/agonistas
19.
Trends Pharmacol Sci ; 39(5): 468-480, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29559169

RESUMO

Huntington's disease (HD) is a single-gene inheritable neurodegenerative disorder with an associated complex molecular pathogenic profile that renders it the most 'curable incurable' brain disorder. Continuous effort in the field has contributed to the recent discovery of novel potential pathogenic mechanisms. Findings in preclinical models of the disease as well as in human post-mortem brains from affected patients demonstrate that alteration of the sphingosine-1-phosphate (S1P) axis may represent a possible key player in the pathogenesis of the disease and may act as a potential actionable drug target for the development of more targeted and effective therapeutic approaches. The relevance of the path of this new 'therapeutic route' is underscored by the fact that some drugs targeting the S1P axis are currently in clinical trials for the treatment of other brain disorders.


Assuntos
Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Humanos , Doença de Huntington/enzimologia , Terapia de Alvo Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Esfingosina/metabolismo
20.
Biol Pharm Bull ; 41(4): 592-596, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29415945

RESUMO

Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment. Here, we test a newly developed selective S1P1 modulator, Syl930, in four different psoriasis animal models. Our data reveals that oral administration of Syl930 can induce strong anti-proliferative and anti-inflammatory effects. Specifically, Syl930 decreases the pathological thickening of back skin induced by sodium lauryl sulfate (SLS), inhibits the proliferation of basal cells in a vaginal epithelium model and increases the granular layer scales in a mouse tail assay. Moreover, Syl930 can ameliorate the parakeratosis and acanthosis as well as improve granular layer composition and decrease the thickening of epidermis in a propranolol-induced guinea pig psoriasis model. Therefore, we demonstrate that Syl930 is a promising candidate for psoriasis therapy in clinical.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Modelos Animais de Doenças , Oxazóis/uso terapêutico , Propanolaminas/uso terapêutico , Psoríase/tratamento farmacológico , Receptores de Lisoesfingolipídeo/agonistas , Pele/efeitos dos fármacos , Administração Oral , Animais , Animais não Endogâmicos , Anti-Inflamatórios não Esteroides/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Cloridrato de Fingolimode/administração & dosagem , Cloridrato de Fingolimode/uso terapêutico , Cobaias , Camundongos , Índice Mitótico , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Oxazóis/administração & dosagem , Propanolaminas/administração & dosagem , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Distribuição Aleatória , Receptores de Lisoesfingolipídeo/metabolismo , Reprodutibilidade dos Testes , Pele/imunologia , Pele/metabolismo , Pele/patologia , Organismos Livres de Patógenos Específicos , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/metabolismo , Vagina/patologia
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