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1.
J Neuroimmunol ; 349: 577392, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33007647

RESUMO

Multiple sclerosis (MS) is an autoimmune disorder where auto-aggressive T cells target the central nervous system (CNS), causing demyelination. The trans-endothelial migration of leucocytes across the blood-brain barrier (BBB) is one of the earliest CNS events in MS pathogenesis. We examined the effect of the disease state and treatment with fingolimod on the transmigration of peripheral blood mononuclear cells (PBMCs) in an in vitro BBB model. Patients' leucocyte numbers, subsets and phenotypes were assessed by flow cytometry. As expected, fingolimod treatment induced a significant reduction in T cell and B cell numbers compared to untreated MS patients and healthy controls. Interestingly fingolimod led to a marked reduction of CD4+ and a significant increase in CD8+ cell numbers. In migrated cells, only CD3+ cell numbers were reduced in fingolimod-treated, compared to untreated patients; it had no effect on B cell or monocyte transmigration. T cells were then differentiated into naïve, effector and memory subsets based on their expression of CCR7. This showed that MS patients had increased numbers of effector memory CD4+ cells re-expressing CD45RA (TEMRA) and a decrease in central memory (CM) CD8+ cells. The former was corrected by fingolimod, while the latter was not. CM CD4+ and CD8+ cells migrated across BBB more efficiently in fingolimod-treated patients. We found that while fingolimod reduced the proportions of naïve CD19+ B cells, it significantly increased the proportions of these cells which migrated. When B cells were further stratified based on CD24, CD27 and CD38 expression, the only effect of fingolimod was an enhancement of CD24hiCD27+ B cell migration, compared to untreated MS patients. The migratory capacities of CD8hi Natural Killer (NK), CD8dim NK and NK-T cells were also reduced by fingolimod. While the disease-modifying effects of fingolimod are currently explained by its effect on reducing circulating auto-aggressive lymphocytes, our data suggests that fingolimod may also have a direct though differential effect on the trans-endothelial migration of circulating lymphocyte populations.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Subpopulações de Linfócitos/efeitos dos fármacos , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Feminino , Cloridrato de Fingolimode/farmacologia , Humanos , Imunossupressores/farmacologia , Subpopulações de Linfócitos/metabolismo , Masculino , Migração Transendotelial e Transepitelial/fisiologia , Resultado do Tratamento
2.
Life Sci ; 263: 118582, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058911

RESUMO

Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-κB/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also improved the depression-like behavior and cognitive function of the rats. It also inhibited NF-κB activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-α, IL-6 and IL-1ß, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Depressão/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Estresse Psicológico/fisiopatologia
3.
Life Sci ; 260: 118077, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810509

RESUMO

AIMS: Multiple myeloma (MM) is the second hematological plasma cell malignany and sensitive to fingolimod (FTY720), a novel immunosuppressant. Previous study shows FTY720-induced apoptosis and autophagy can cause cell death in MM cells, however, the high death rate cannot fully be explained. The study aims to investigate further mechanism of how FTY720 kills MM cells. MATERIALS AND METHODS: Experiments are performed on 25 human primary cell samples and two MM cell lines by flow cytometry, fluorescence microscopy, and transmission electron microscopy. Expressions of relative factors are tested by qRT-PCR or western blot. KEY FINDINGS: Ferroptosis-specific inhibitors, deferoxamine mesylate (DFOM) and ferropstatin-1 (Fer-1), reverse FTY720-induced cell death in MM cells. Glutathione peroxidase 4 (GPX4) and soluble carrier family 7 member 11 (SLC7A11), key regulators of ferroptosis, are highly expressed in primary MM cells and can be decreased by FTY720 at the mRNA and protein level in MM cells. In addition, FTY720 induces other characteristic changes of ferroptosis. Furthermore, FTY720 can dephosphorylate AMP-activated protein kinase subunit ɑ (AMPKɑ) at the Thr172 site by activating protein phosphatase 2A (PP2A) and reduce the expression of phosphorylated eukaryotic elongation factor 2 (eEF2), finally cause MM cell death. Using LB-100, a PP2A inhibitor, AICAR, an agonist of AMPK, and bafilomycin A1 (Baf-A1), an autophagy inhibitor, we discover that FTY720 induces ferroptosis and autophagy through the PP2A/AMPK pathway, and ferroptosis and autophagy can reinforce each other. SIGNIFICANCE: These results provide a new perspective on the treatment of MM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Cloridrato de Fingolimode/farmacologia , Mieloma Múltiplo/patologia , Proteína Fosfatase 2/metabolismo , Sistema y+ de Transporte de Aminoácidos/efeitos dos fármacos , Sistema y+ de Transporte de Aminoácidos/fisiologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cicloexilaminas/farmacologia , Desferroxamina/farmacologia , Humanos , Mieloma Múltiplo/tratamento farmacológico , Fenilenodiaminas/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/fisiologia , Transdução de Sinais/efeitos dos fármacos
4.
PLoS Pathog ; 16(8): e1008679, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790802

RESUMO

Antiretroviral drugs that target various stages of the Human Immunodeficiency Virus (HIV) life cycle have been effective in curbing the AIDS epidemic. However, drug resistance, off-target effects of antiretroviral therapy (ART), and varying efficacy in prevention underscore the need to develop novel and alternative therapeutics. In this study, we investigated whether targeting the signaling molecule Sphingosine-1-phosphate (S1P) would inhibit HIV-1 infection and generation of the latent reservoir in primary CD4 T cells. We show that FTY720 (Fingolimod), an FDA-approved functional antagonist of S1P receptors, blocks cell-free and cell-to-cell transmission of HIV and consequently reduces detectable latent virus. Mechanistically, FTY720 impacts the HIV-1 life cycle at two levels. Firstly, FTY720 reduces the surface density of CD4, thereby inhibiting viral binding and fusion. Secondly, FTY720 decreases the phosphorylation of the innate HIV restriction factor SAMHD1 which is associated with reduced levels of total and integrated HIV, while reducing the expression of Cyclin D3. In conclusion, targeting the S1P pathway with FTY720 could be a novel strategy to inhibit HIV replication and reduce the seeding of the latent reservoir.


Assuntos
Cloridrato de Fingolimode/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/crescimento & desenvolvimento , Proteína 1 com Domínio SAM e Domínio HD/antagonistas & inibidores , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Linfócitos T/imunologia , Replicação Viral , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Lisofosfolipídeos/metabolismo , Fosforilação , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Linfócitos T/efeitos dos fármacos , Latência Viral
5.
J Neuroimmunol ; 347: 577353, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745802

RESUMO

This study aims to compare NK cells obtained from multiple sclerosis (MS) patients receiving interferon-ß1 and fingolimod therapies. Fingolimod reduced the CD56bright NK cell subset. The remaining CD56dim NK cells displayed NKG2D, NKp46, CD107a, and IFN-γ levels similar to those from the patients under interferon-ß1 therapy. Alternatively, comparative transcriptomics and pathway analyses revealed significant distinctions between two therapy modalities. Molecular signature of the CD56dim NK cells from fingolimod-treated MS patients was closely associated to those from healthy subjects. The basic assets of NK cells were modestly influenced by interferon-ß1 and fingolimod, however transcriptomics showed profound alterations in NK responses.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Interferon beta/uso terapêutico , Células Matadoras Naturais/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Transcriptoma/fisiologia , Adulto , Feminino , Cloridrato de Fingolimode/farmacologia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Interferon beta/farmacologia , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/genética , Transcriptoma/efeitos dos fármacos , Adulto Jovem
6.
Clin Sci (Lond) ; 134(12): 1475-1489, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32538435

RESUMO

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1ß in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Cloridrato de Fingolimode/uso terapêutico , Peroxidase/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Anticorpos/imunologia , Apoptose , Feminino , Cloridrato de Fingolimode/farmacologia , Hematúria/complicações , Humanos , Células Jurkat , Rim/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proteinúria/complicações , Ratos Endogâmicos WKY , Transdução de Sinais
7.
Neurology ; 94(22): e2373-e2383, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430312

RESUMO

OBJECTIVE: Disease-modifying treatments (DMTs) are the gold standard for slowing disability progression in multiple sclerosis (MS), but their effects on cognitive impairment, a key symptom of the disease, are mostly unknown. We conducted a systematic review and meta-analysis to evaluate the differential effects of DMTs on cognitive test performance in relapsing-remitting MS (RRMS). METHODS: PubMed, Scopus, and Cochrane Library were searched for studies reporting longitudinal cognitive performance data related to all major DMTs. The standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used as the main effect size measure. RESULTS: Forty-four studies, including 55 distinct MS patient samples, were found eligible for the systematic review. Twenty-five studies were related to platform therapies (mainly ß-interferon [n = 17] and glatiramer acetate [n = 4]), whereas 22 studies were related to escalation therapies (mainly natalizumab [n = 14] and fingolimod [n = 6]). Reported data were mostly confined to the cognitive domain processing speed. A meta-analysis including 41 studies and 7,131 patients revealed a small to moderate positive effect on cognitive test performance of DMTs in general (g = 0.27, 95% confidence interval [CI] = [0.21-0.33]), but no statistically significant differences between platform (g = 0.27, 95% CI = [0.18-0.35]) and escalation therapies (g = 0.28, 95% CI = [0.19-0.37]) or between any single DMT and ß-interferon. CONCLUSIONS: DMTs are effective in improving cognitive test performance in RRMS, but a treatment escalation mainly to amend cognition is not supported by the current evidence. Given the multitude of DMTs and their widespread use, the available data regarding differential treatment effects on cognitive impairment are remarkably scant. Clinical drug trials that use more extensive cognitive outcome measures are urgently needed.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Cognição/fisiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/farmacologia , Acetato de Glatiramer/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
8.
Eur J Pharm Biopharm ; 148: 1-9, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917332

RESUMO

Metastatic tumors are the main cause of cancer-related death, as the invading cancer cells disrupt normal functions of distant organs and are nearly impossible to eradicate by traditional cancer therapeutics. This is of special concern when the cancer has created multiple metastases and extensive surgery would be too dangerous to execute. Therefore, combination chemotherapy is often the selected treatment form. However, drug cocktails often have severe adverse effects on healthy cells, whereby the development of targeted drug delivery could minimize side-effects of drugs and increase the efficacy of the combination therapy. In this study, we utilized the folate antagonist methotrexate (MTX) as targeting ligand conjugated onto mesoporous silica nanoparticles (MSNs) for selective eradication of folate receptor-expressing invasive thyroid cancer cells. The MSNs was subsequently loaded with the drug fingolimod (FTY720), which has previously been shown to efficiently inhibit proliferation and invasion of aggressive thyroid cancer cells. To assess the efficiency of our carrier system, comprehensive in vitro methods were employed; including flow cytometry, confocal microscopy, viability assays, invasion assay, and label-free imaging techniques. The in vitro results show that MTX-conjugated and FTY720-loaded MSNs potently attenuated both the proliferation and invasion of the cancerous thyroid cells while keeping the off-target effects in normal thyroid cells reasonably low. For a more physiologically relevant in vivo approach we utilized the chick chorioallantoic membrane (CAM) assay, showing decreased invasive behavior of the thyroid derived xenografts and an increased necrotic phenotype compared to tumors that received the free drug cocktail. Thus, the developed multidrug-loaded MSNs effectively induced apoptosis and immobilization of invasive thyroid cancer cells, and could potentially be used as a carrier system for targeted drug delivery for the treatment of diverse forms of aggressive cancers that expresses folate receptors.


Assuntos
Cloridrato de Fingolimode/administração & dosagem , Metotrexato/administração & dosagem , Nanopartículas , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/patologia , Sistemas de Liberação de Medicamentos , Cloridrato de Fingolimode/farmacologia , Receptores de Folato com Âncoras de GPI/metabolismo , Humanos , Metotrexato/farmacologia , Invasividade Neoplásica/prevenção & controle , Dióxido de Silício/química , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Drug Dev Ind Pharm ; 46(2): 318-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31976771

RESUMO

Uncontrolled distribution of nanoparticles (NPs) within the body can significantly decrease the efficiency of drug therapy and is considered among the main restrictions of NPs application. The aim of this study was to develop a depot combination delivery system (CDS) containing fingolimod loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) NPs dispersed into a matrix of oleic acid-grafted-aminated alginate (OA-g-AAlg) to minimize the nonspecific biodistribution (BD) of PHBV NPs. OA-g-AAlg was synthesized in two step; First, Alg was aminated by using adipic dihydrazide (ADH). The degree of hyrazide group substitution of Alg was determined by trinitro-benzene-sulfonic acid (TNBS) assay. Second, OA was attached to AAlg through formation of an amide bond. Chemical structure of OA-g-AAlg was confirmed with FTIR and HNMR spectroscopy. Furthermore, rheological properties of OA-g-AAlg with different grafting ratios were evaluated. In-vitro release studies indicated that 47% of fingolimod was released from the CDS within 28 days. Blood and tissue samples were analyzed using liquid chromatography/tandem mass spectrometry following subcutaneous (SC) injection of fingolimod-CDS into Wistar rats. The elimination phase half-life of CDS-fingolimod was significantly higher than that of fingolimod (∼32 d vs. ∼20 h). To investigate the therapeutic efficacy, lymphocyte count was assessed over a 40 day period in Wistar rats. Peripheral blood lymphocyte count decreased from baseline by 27 ± 8% in 2 days after injection. Overall, the designed CDS represented promising results in improving the pharmacokinetic properties of fingolimod. Therefore, we believe that this sustained release formulation has a great potential to be applied to delivery of various therapeutics.


Assuntos
Alginatos/química , Cloridrato de Fingolimode/química , Nanopartículas/química , Poliésteres/química , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Cloridrato de Fingolimode/farmacocinética , Cloridrato de Fingolimode/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
10.
Reg Anesth Pain Med ; 45(3): 230-238, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31969447

RESUMO

BACKGROUND AND OBJECTIVES: FTY720 ((2-amino-2-)2-[4-octylphenyl]ethyl)-1,3-propanediol) is an Food and Drug Administration (FDA)-approved immunomodulatory drug for treating multiple sclerosis. It inhibits lymphocyte egression from lymphoid tissues by downregulating sphingosine-1 phosphate receptor (S1PR). To date, there has been no study on the effects of FTY720 on the chronic stage of the complex regional pain syndrome (CRPS) rodent model, despite its antiallodynic effect in previous studies. Thus, the aim of this study is to investigate the effect of FTY720 in a chronic stage of the CRPS mouse model. METHOD: The authors used a mouse model of CRPS, involving tibia fracture/cast immobilization, to test the efficacy of intrathecal FTY720 (2.5 or 25 ng daily; 6 days) or vehicle during the chronic (7 weeks after fracture) stage of CRPS. RESULTS: Intrathecal recombinant FTY720 administration was antiallodynic in the chronic stage of the CRPS mouse model, and such an effect of FTY720 developed by modulating astrocyte activation in the spinal cord. Additionally, according to the in vitro data, the FTY720 treatment inhibited S1P-induced increase in the nitric oxide production and suppression of the NF-κB pathway, by inhibiting the phosphorylation of NF-κB/p65 in astrocytes without toxic effect on astrocytes. CONCLUSION: Collectively, these results demonstrate that intrathecally administered FTY720 attenuates mechanical allodynia in the chronic stage of the CRPS mouse model.


Assuntos
Astrócitos/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Citocinas/metabolismo , Cloridrato de Fingolimode/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medula Espinal/metabolismo
11.
Phytother Res ; 34(2): 295-305, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31667949

RESUMO

Changes in the global economy resulted in sedentary lifestyle and excessive calorie intake, increasing the incidence of metabolic diseases, which subsequently became a universal public concern. The difficulties of managing chronic diseases did not dampen researchers' enthusiasm for studying new therapeutics or adjuvant treatments. Cordyceps spp. is a kind of traditional Chinese herbal medicine; however, our understanding of this medicine remains at an initial stage. Recently, an increasing number of studies have demonstrated the potential of Cordyceps as a therapeutic agent for the effective treatment of metabolic-related disorders by exerting a variety of activities, including but not limited to anti-inflammatory, immunoregulatory, hypoglycemic, renoprotective and cardiovascular-protective effects. This article reviews the potential efficacy and underlying mechanisms of Cordyceps and its major bioactive ingredients in metabolic syndrome and its associated comorbidities.


Assuntos
Cordyceps/química , Medicina Tradicional Chinesa , Doenças Metabólicas/terapia , Animais , Desoxiadenosinas/farmacologia , Cloridrato de Fingolimode/farmacologia , Polissacarídeos Fúngicos/farmacologia , Humanos , Síndrome Metabólica/terapia , Peptídeos/farmacologia
12.
Int J Mol Sci ; 20(24)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31835656

RESUMO

BACKGROUND: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation. METHODS: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways. RESULTS: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index. CONCLUSIONS: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest.


Assuntos
Reanimação Cardiopulmonar , Cloridrato de Fingolimode/uso terapêutico , Parada Cardíaca/tratamento farmacológico , Miocárdio/patologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Cloridrato de Fingolimode/farmacologia , Parada Cardíaca/sangue , Parada Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Mediadores da Inflamação/sangue , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Nucleotídeos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
13.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861585

RESUMO

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that "higher" levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Interleucina-1/sangue , Interleucina-1/genética , Esclerose Múltipla/tratamento farmacológico , Adulto , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Simulação por Computador , Progressão da Doença , Doenças em Gêmeos/tratamento farmacológico , Doenças em Gêmeos/genética , Doenças em Gêmeos/imunologia , Feminino , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Recidiva , Gêmeos Monozigóticos/genética , Regulação para Cima
14.
J Neuroinflammation ; 16(1): 228, 2019 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31733652

RESUMO

BACKGROUND: In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. METHODS: Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. RESULTS: While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. CONCLUSION: Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. TRIAL REGISTRATION: Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).


Assuntos
Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Esclerose Múltipla Recidivante-Remitente/imunologia , Natalizumab/farmacologia , Adulto , Linfócitos B/imunologia , Células Cultivadas , Fumarato de Dimetilo/farmacologia , Feminino , Cloridrato de Fingolimode/farmacologia , Acetato de Glatiramer/farmacologia , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
15.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614447

RESUMO

Ceramide and sphingosine display a unique profile during brain development, indicating their critical role in myelinogenesis. Employing advanced technology such as gas chromatography-mass spectrometry, high performance liquid chromatography, and immunocytochemistry, along with cell culture and molecular biology, we have found an accumulation of sphingosine in brain tissues of patients with multiple sclerosis (MS) and in the spinal cord of rats induced with experimental autoimmune encephalomyelitis. The elevated sphingosine leads to oligodendrocyte death and fosters demyelination. Ceramide elevation by serine palmitoyltransferse (SPT) activation was the primary source of the sphingosine elevation as myriocin, an inhibitor of SPT, prevented sphingosine elevation and protected oligodendrocytes. Supporting this view, fingolimod, a drug used for MS therapy, reduced ceramide generation, thus offering partial protection to oligodendrocytes. Sphingolipid synthesis and degradation in normal development is regulated by a series of microRNAs (miRNAs), and hence, accumulation of sphingosine in MS may be prevented by employing miRNA technology. This review will discuss the current knowledge of ceramide and sphingosine metabolism (synthesis and breakdown), and how their biosynthesis can be regulated by miRNA, which can be used as a therapeutic approach for MS.


Assuntos
Ceramidas/biossíntese , MicroRNAs/genética , Esclerose Múltipla/genética , Serina C-Palmitoiltransferase/metabolismo , Esfingosina/biossíntese , Animais , Encéfalo/metabolismo , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Humanos , MicroRNAs/antagonistas & inibidores , Terapia de Alvo Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Ratos , Serina C-Palmitoiltransferase/antagonistas & inibidores
16.
J Neurol ; 266(12): 3098-3107, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31535270

RESUMO

BACKGROUND: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. OBJECTIVE: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. METHODS: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. RESULTS: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-ß1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-ß1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]. CONCLUSION: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-ß1a to FTY.


Assuntos
Progressão da Doença , Cloridrato de Fingolimode/farmacologia , Fatores Imunológicos/farmacologia , Interferon beta-1a/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros , Índice de Gravidade de Doença , Adulto , Esquema de Medicação , Feminino , Cloridrato de Fingolimode/administração & dosagem , Humanos , Fatores Imunológicos/administração & dosagem , Interferon beta-1a/administração & dosagem , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
J Vet Med Sci ; 81(10): 1424-1430, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31527340

RESUMO

Osteosarcoma (OSA) is the most common bone tumor in dogs. Protein phosphatase 2A (PP2A), an evolutionary conserved serine/threonine protein phosphatase, is a crucial tumor suppressor. SET is a PP2A inhibitory protein that directly interacts with PP2A and suppresses its phosphatase activity. SET has been reported as a contributor of wide range of human and dog tumor malignancies. However, the role of SET in canine OSA (cOSA) remains unknown. In this study, we investigated the role of SET in cOSA by using 2 cOSA cell lines: POS (primary origin) and HM-POS (metastatic origin). Knockdown (KD) of SET expression was noted to slightly suppress POS cell proliferation only. Furthermore, SET KD effectively suppressed colony formation ability of both POS and HM-POS cells. SET KD was observed to repress ERK1/2, mTOR, E2F1, and NF-κB signaling in HM-POS cells, whereas it inhibited only ERK1/2 signaling in POS. Further, it was observed that SET-targeting drug, FTY720, exerted anti-cancer effects in both POS and HM-POS cells. Moreover, the drug also enhanced the anti-cancer effect of cisplatin. The data suggested that a combination therapy, based on SET targeting drugs and cisplatin, could be a potent strategy for cOSA.


Assuntos
Neoplasias Ósseas/veterinária , Inibidores de Calcineurina/farmacologia , Osteossarcoma/veterinária , Proteína Fosfatase 2/metabolismo , Animais , Anticarcinógenos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Inibidores de Calcineurina/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cães , Sinergismo Farmacológico , Cloridrato de Fingolimode/farmacologia , Osteossarcoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
18.
Expert Opin Drug Discov ; 14(11): 1199-1212, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31389262

RESUMO

Introduction: Fingolimod, the first oral disease-modifying treatment (DMT) in multiple sclerosis (MS), is a sphingosine 1-phosphate receptor (S1PR) ligand. Approved in 2010, fingolimod has been extensively studied and has been credited with several mechanisms of actions that contribute to its efficacy in MS, among which is the regulation of lymphocyte circulation between the central nervous system and the periphery. Concerns about toxicity, off-target effects, and real-life performance have been raised over time in post-marketing studies of such that next-generation sphingosine-1 phosphate receptor ligands are now being developed. Areas covered: Herein, the authors expand upon previous systematic reviews obtained via PubMed and through their expert opinion on fingolimod use in clinical practice. Long-term data including long-term efficacy, safety, tolerability, and management especially within growing DMT options and pre-treatment constellation in MS patients are discussed, together with the results of an increased understanding of the chemistry underlying the structure-activity relationship. Expert opinion: Despite the limitations illustrated in this article, fingolimod still constitutes a paradigm shift in MS treatment. However, although immunomodulation via S1PRs on lymphocytes has represented a major breakthrough in the clinical management of MS, modifying the evolution of progressive MS will likely require the development of approaches other than merely targeting S1PRs.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Administração Oral , Animais , Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Fingolimode/farmacologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Esclerose Múltipla/fisiopatologia , Moduladores do Receptor de Esfingosina 1 Fosfato/efeitos adversos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Relação Estrutura-Atividade
19.
J Immunol ; 203(7): 1808-1819, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462506

RESUMO

Invariant NKT (iNKT) cells are innate-like T lymphocytes that recognize and respond to glycolipid Ags such as α-galactosylceramide (α-GalCer). This unique property has been exploited in clinical trials for multiple malignancies. While investigating mouse iNKT cell responses to α-GalCer in vivo, we found a dramatically enlarged tissue-resident population surprisingly coexpressing select dendritic cell, NK cell, and B cell markers. Further phenotypic and functional analyses revealed the identity of this B220+CD11c+MHC class II+NK1.1+ population as precursors to mature NK (pre-mNK) cells, which also expressed high levels of proliferation and tissue retention markers but diminished sphingosine-1-phosphate receptor 1, a receptor that facilitates tissue trafficking. Accordingly, FTY720, a sphingosine-1-phosphate receptor 1 antagonist, failed to prevent pre-mNK cells' intrahepatic accumulation. We found iNKT cell-driven expansion of pre-mNK cells to be dependent on IL-12 and IL-18. Although α-GalCer-transactivated pre-mNK cells lost their capacity to process a model tumor Ag, they selectively expressed granzyme A and directly lysed YAC-1 thymoma cells through granule exocytosis. They also contributed to ß2 microglobulin-deficient target cell destruction in vivo. Therefore, α-GalCer treatment skewed pre-mNK cell responses away from an APC-like phenotype and toward killer cell-like functions. Finally, the ability of α-GalCer to reduce the pulmonary metastatic burden of B16-F10 mouse melanoma was partially reversed by in vivo depletion of pre-mNK cells. To our knowledge, our findings shed new light on iNKT cells' mechanism of action and glycolipid-based immunotherapies. Therefore, we introduce pre-mNK cells as a novel downstream effector cell type whose anticancer properties may have been overlooked in previous investigations.


Assuntos
Antígenos de Neoplasias/imunologia , Galactosilceramidas/imunologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/imunologia , Células T Matadoras Naturais/imunologia , Timoma/imunologia , Animais , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Cloridrato de Fingolimode/farmacologia , Galactosilceramidas/genética , Imunoterapia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Células Matadoras Naturais/patologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Metástase Neoplásica , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/genética , Receptores de Esfingosina-1-Fosfato/imunologia , Timoma/genética , Timoma/patologia , Timoma/terapia
20.
Am J Physiol Cell Physiol ; 317(3): C502-C512, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241988

RESUMO

Sarcopenia, the age-associated loss of skeletal muscle mass and function, is coupled with declines in physical functioning leading to subsequent higher rates of disability, frailty, morbidity, and mortality. Aging and obesity independently contribute to muscle atrophy that is assumed to be a result of the activation of mutual physiological pathways. Understanding mechanisms contributing to the induction of skeletal muscle atrophy with aging and obesity is important for determining targets that may have pivotal roles in muscle loss in these conditions. We find that aging and obesity equally induce an anabolic resistance to acute skeletal muscle contraction as observed with decreases in anabolic signaling activation after contraction. Furthermore, treatment with the sphingosine-1-phosphate analog FTY720 for 4 wk increased lean mass and strength, and the anabolic signaling response to contraction was improved in obese but not older animals. To determine the role of chronic inflammation and different fatty acids on anabolic resistance in skeletal muscle cells, we overexpressed IKKß with and without exposure to saturated fatty acid (SFA; palmitic acid), polyunsaturated fatty acid (eicosapentaenoic acid), and monounsaturated fatty acid (oleic acid). We found that IKKß overexpression increased inflammation markers in muscle cells, and this chronic inflammation exacerbated anabolic resistance in response to SFA. Pretreatment with FTY720 reversed the inflammatory effects of palmitic acid in the muscle cells. Taken together, these data demonstrate chronic inflammation can induce anabolic resistance, SFA aggravates these effects, and FTY720 can reverse this by decreasing ceramide accumulation in skeletal muscle.


Assuntos
Envelhecimento/efeitos dos fármacos , Cloridrato de Fingolimode/uso terapêutico , Contração Muscular/efeitos dos fármacos , Obesidade/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Envelhecimento/metabolismo , Animais , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Cloridrato de Fingolimode/farmacologia , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Distribuição Aleatória , Sarcopenia/tratamento farmacológico , Sarcopenia/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia
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