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1.
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 , 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 , Esfingosina/agonistas
2.
Life Sci ; 249: 117542, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32169519

RESUMO

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that regulates lymphocyte trafficking, glial cell activation, vasoconstriction, endothelial barrier function, and neuronal death pathways in the brain. Research has increasingly implicated S1P in the pathology of cerebral ischemia reperfusion (IR) injury. As a high-affinity agonist of S1P receptor, fingolimod exhibits excellent neuroprotective effects against ischemic challenge both in vivo and in vitro. By summarizing recent progress on how S1P participates in the development of brain IR injury, this review identifies potential therapeutic targets for the treatment of brain IR injury.


Assuntos
Encéfalo/irrigação sanguínea , Cloridrato de Fingolimode/uso terapêutico , Lisofosfolipídeos/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Receptores de Esfingosina-1-Fosfato/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Humanos , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo
3.
Ecotoxicol Environ Saf ; 194: 110407, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146198

RESUMO

Extremely low-frequency electromagnetic fields (ELF-EMFs) present a kind of common non-ionizing radiation in public and occupational environments. Previous studies have suggested that ELF-EMF exposure might have a potential impact on co-carcinogenesis and the progression of tumorigenesis by inducing cell proliferation. However, the underlying mechanisms remain largely unknown. In this study, we investigated the possible role of the sphingosine-1-phosphate (S1P)-related pathway in regulating cell proliferation induced by 50-Hz, 0.4-mT magnetic-field (MF) exposure. The results showed that MF exposure significantly promoted sphingosine kinase 1 (SphK1) activity, and that inhibition of the SphK1-S1P-S1P receptor (S1PR) pathway could remarkably reverse MF-induced cell proliferation. Additionally, we could infer indirectly from an exogenous-S1P experiment that MF-induced S1P might act on S1PR1/3 in a paracrine and/or autocrine manner to mediate the proliferation effect. Notably, although the MF activated the extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) pathways, the SphK1-S1P-S1PR1/3 cascade regulated MF-induced proliferation by activating the ERK rather than the Akt pathway. Taken together, the findings of this study indicated that the SphK1-S1P-S1PR1/3 cascade played an important role in MF-induced proliferation by mediating the ERK signaling pathway, which could bring new insights into understanding and preventing the adverse effects of MFs.


Assuntos
Âmnio , Células Epiteliais/metabolismo , Lisofosfolipídeos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Campos Magnéticos/efeitos adversos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Esfingosina/análogos & derivados , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo
4.
Plant Mol Biol ; 103(1-2): 173-184, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32100164

RESUMO

KEY MESSAGE: Arabidopsis LONG-CHAIN BASE KINASE 1 (LCBK1) interacts with MEDEA, a component of PCR2 complex that negatively regulates immunity. LCBK1 phosphorylates phytosphingosine and thereby promotes stomatal immunity against bacterial pathogens. Arabidopsis polycomb-group repressor complex2 (PRC2) protein MEDEA (MEA) suppresses both pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). MEA represses the expression of RPS2 and thereby attenuates AvrRpt2 effector-mediated ETI. However, the mechanism of MEA-mediated PTI diminution was not known. By screening the Arabidopsis cDNA library using yeast-2-hybrid interaction, we identified LONG-CHAIN BASE KINASE1 (LCBK1) as an MEA-interacting protein. We found that lcbk1 mutants are susceptible to virulent bacterial pathogens, such as Pseudomonas syringae pv maculicola (Psm) and P. syringae pv tomato (Pst) but not the avirulent strain of Pst that carries AvrRpt2 effector. Pathogen inoculation induces LCBK1 expression, especially in guard cells. We found that LCBK1 has a positive regulatory role in stomatal closure after pathogen inoculation. WT plants close stomata within an hour of Pst inoculation or flg22 (a 22 amino acid peptide from bacterial flagellin protein that activates PTI) treatment, but not lcbk1 mutants. LCBK1 phosphorylates phytosphingosine (PHS). Exogenous application of phosphorylated PHS (PHS-P) induces stomatal closure and rescues loss-of-PTI phenotype of lcbk1 mutant plants. MEA overexpressing (MEA-Oex) plants are defective, whereas loss-of-function mea-6 mutants are hyperactive in PTI-induced stomatal closure. Exogenous application of PHS-P rescues loss-of-PTI in MEA-Oex plants. Results altogether demonstrate that LCBK1 is an interactor of MEA that positively regulates PTI-induced stomatal closure in Arabidopsis.


Assuntos
Arabidopsis/imunologia , Estômatos de Plantas/imunologia , Arabidopsis/enzimologia , Arabidopsis/microbiologia , Proteínas de Arabidopsis/metabolismo , Doenças das Plantas/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo
5.
Adv Exp Med Biol ; 1223: 129-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030688

RESUMO

Sphingosine-1-phosphate (S1P), together with other phosphosphingolipids, has been found to regulate complex cellular function in the tumor microenvironment (TME) where it acts as a signaling molecule that participates in cell-cell communication. S1P, through intracellular and extracellular signaling, was found to promote tumor growth, angiogenesis, chemoresistance, and metastasis; it also regulates anticancer immune response, modulates inflammation, and promotes angiogenesis. Interestingly, cancer cells are capable of releasing S1P and thus modifying the behavior of the TME components in a way that contributes to tumor growth and progression. Therefore, S1P is considered an important therapeutic target, and several anticancer therapies targeting S1P signaling are being developed and tested in clinics.


Assuntos
Lisofosfolipídeos/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Esfingosina/análogos & derivados , Microambiente Tumoral , Humanos , Neoplasias/patologia , Esfingosina/metabolismo
6.
Int J Mol Sci ; 21(1)2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31906427

RESUMO

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.


Assuntos
Doença da Altitude/metabolismo , Fibrose Cística/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/fisiopatologia , Ferro/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Esfingolipídeos/metabolismo , Adaptação Fisiológica , Ceramidas/metabolismo , Hepcidinas/metabolismo , Humanos , Hipóxia/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
7.
Nat Commun ; 11(1): 507, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980612

RESUMO

The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aß) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aß burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Animais , Núcleo Celular/metabolismo , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/patologia , Simulação por Computador , Modelos Animais de Doenças , Retículo Endoplasmático/patologia , Retículo Endoplasmático/ultraestrutura , Feminino , Proteína HMGB1/líquido cefalorraquidiano , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Camundongos Transgênicos , Necrose , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Imagem com Lapso de Tempo
8.
Biochem J ; 477(2): 359-380, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31899485

RESUMO

The lysosomal storage disorder Fabry disease is characterized by a deficiency of the lysosomal enzyme α-Galactosidase A. The observation that missense variants in the encoding GLA gene often lead to structural destabilization, endoplasmic reticulum retention and proteasomal degradation of the misfolded, but otherwise catalytically functional enzyme has resulted in the exploration of alternative therapeutic approaches. In this context, we have investigated proteostasis regulators (PRs) for their potential to increase cellular enzyme activity, and to reduce the disease-specific accumulation of the biomarker globotriaosylsphingosine in patient-derived cell culture. The PRs also acted synergistically with the clinically approved 1-deoxygalactonojirimycine, demonstrating the potential of combination treatment in a therapeutic application. Extensive characterization of the effective PRs revealed inhibition of the proteasome and elevation of GLA gene expression as paramount effects. Further analysis of transcriptional patterns of the PRs exposed a variety of genes involved in proteostasis as potential modulators. We propose that addressing proteostasis is an effective approach to discover new therapeutic targets for diseases involving folding and trafficking-deficient protein mutants.


Assuntos
Doença de Fabry/genética , Doenças por Armazenamento dos Lisossomos/genética , Proteostase/genética , alfa-Galactosidase/genética , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Biomarcadores/metabolismo , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Doença de Fabry/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/enzimologia , Lisossomos/genética , Lisossomos/metabolismo , Mutação de Sentido Incorreto/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Transporte Proteico/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-31954174

RESUMO

Perinatal and long-term offspring morbidities are strongly dependent on the preservation of placental vascular homeostasis during pregnancy. In adults, the HDL-apoM-S1P complex protects the endothelium and maintains vascular integrity. However, the metabolism and biology of cord blood-derived HDLs (referred to as neonatal HDL, nHDL) strikingly differ from those in adults. Here, we investigate the role of neonatal HDLs in the regulation of placental vascular function. We show that nHDL is a major carrier of sphingosine-1-phosphate (S1P), which is anchored to the particle through apoM (rs = 0.90, p < 0.0001) in the fetal circulation. Furthermore, this complex interacts with S1P receptors on the feto-placental endothelium and activates specifically extracellular signal-regulated protein kinases 1 and 2 (ERK) and phospholipase C (PLC) downstream signaling, promotes endothelial cell proliferation and calcium flux. Notably, the nHDL-S1P complex triggers actin filaments reorganization, leading to an enhancement of placental endothelial barrier function. Additionally, nHDL induces vasorelaxation of isolated placental chorionic arteries. Taken together, these results suggest that circulating nHDL exerts vasoprotective effects on the feto-placental endothelial barrier mainly via S1P signaling.


Assuntos
Sangue Fetal/metabolismo , Lipoproteínas HDL/metabolismo , Lisofosfolipídeos/metabolismo , Placenta/irrigação sanguínea , Esfingosina/análogos & derivados , Apolipoproteínas M/sangue , Apolipoproteínas M/metabolismo , Células Cultivadas , Endotélio Vascular/metabolismo , Feminino , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/sangue , Sistema de Sinalização das MAP Quinases , Gravidez , Esfingosina/sangue , Esfingosina/metabolismo , Fosfolipases Tipo C/metabolismo
10.
BMB Rep ; 53(1): 28-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31818364

RESUMO

Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes that function as signaling molecules for regulating a diverse range of cellular processes, including cell proliferation, growth, survival, immune-cell trafficking, vascular and epithelial integrity, and inflammation. Recently, several studies have highlighted the pivotal role of sphingolipids in neuroinflammatory regulation. Sphingolipids have multiple functions, including induction of the expression of various inflammatory mediators and regulation of neuroinflammation by directly effecting the cells of the central nervous system. Accumulating evidence points to sphingolipid engagement in neuroinflammatory disorders, including Alzheimer's and Parkinson's diseases. Abnormal sphingolipid alterations, which involves an increase in ceramide and a decrease in sphingosine kinase, are observed during neuroinflammatory disease. These trends are observed early during disease development, and thus highlight the potential of sphingolipids as a new therapeutic and diagnostic target for neuroinflammatory diseases. [BMB Reports 2020; 53(1): 28-34].


Assuntos
Doença de Alzheimer/metabolismo , Sistema Nervoso Central/metabolismo , Inflamação/metabolismo , Doença de Parkinson/metabolismo , Esfingolipídeos/metabolismo , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Ceramidas/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Microglia/citologia , Microglia/metabolismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de Sinais/genética , Esfingolipídeos/farmacologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo
11.
Oncogene ; 39(2): 368-384, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31477835

RESUMO

Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. ß3-adrenoreceptor (ß3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that ß3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P2) axis. The specific antagonism of ß3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P2 signaling.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Neuroblastoma/tratamento farmacológico , Receptores Adrenérgicos beta 3/genética , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Receptores de Esfingosina-1-Fosfato/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Lisofosfolipídeos/metabolismo , Camundongos , Neuroblastoma/genética , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Propanolaminas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Hipóxia Tumoral/efeitos dos fármacos
12.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801289

RESUMO

The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.


Assuntos
Neoplasias do Colo/enzimologia , Regulação Neoplásica da Expressão Gênica , Lactosilceramidas/metabolismo , Metabolismo dos Lipídeos/genética , Esfingolipídeos/metabolismo , Ceramidase Ácida/genética , Ceramidase Ácida/metabolismo , Ceramidase Alcalina/genética , Ceramidase Alcalina/metabolismo , Animais , Ceramidas/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Humanos , Lisofosfolipídeos/metabolismo , Ceramidase Neutra/genética , Ceramidase Neutra/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Esfingosina N-Aciltransferase/genética , Esfingosina N-Aciltransferase/metabolismo , Células Tumorais Cultivadas
13.
Neurol Neurochir Pol ; 53(6): 484-491, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31804702

RESUMO

BACKGROUND: Brain imaging in stroke diagnostics is a powerful tool, but one that can fail in more challenging cases, and one that is not particularly useful in identifying transient ischaemic attacks (TIAs). Thus, new reliable blood biomarkers of cerebral ischaemia are constantly sought. OBJECTIVE: We studied the potential usefulness of sphingolipids (SFs) as biomarkers of acute ischaemic stroke and TIA. MATERIAL AND METHODS: Levels of individual ceramide species and sphingosine-1-phosphate (Sph-1-P) in blood serum of patients with acute ischaemic stroke, TIA, and age-matched neurological patients without cerebral ischaemia, were assessed by tandem mass spectrometry liquid chromatography (LC- MS / MS). RESULTS: We found significant increases of several sphingolipid levels, with particularly strong elevations of Cer-C20:0 in patients with acute stroke. Cer-C24:1 was the only ceramide species to decrease as a result of acute stroke. Moreover, its levels inversely correlated with the number of days after stroke onset, suggesting that Cer-C24:1 is an independent parameter related to the course of stroke. To increase the sensitivity of sphingolipid-based tests in stroke diagnostics, we calculated the values of ratios of Sph-1-P / individual ceramide species and Cer-C24:1 individual ceramide species. We found several ratios significantly changed in stroke patients. Two ratios, Sph-1-P / Cer-C24:1 and Cer-C24:0 / Cer-C24:1, presented especially strong increments in patients with acute stroke. Moreover, Sph-1-P / Cer-C24:1 values were augmented in TIA patients. CONCLUSION: Serum SFs could be good candidates to be ischaemic stroke biomarkers. We have identified two SF ratios, Sph-1-P / Cer-C24:1 and Cer-C24:0 / Cer-C24:1, with strong diagnostic potential in ischaemic stroke. We found Sph-1-P / Cer-C24:1 ratio to be possibly useful in TIA diagnostics, also in the long term after ischaemic incidence.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Biomarcadores , Ceramidas , Humanos , Lisofosfolipídeos , Esfingosina/análogos & derivados
14.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842389

RESUMO

Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease.


Assuntos
Suscetibilidade a Doenças , Cardiopatias/etiologia , Cardiopatias/metabolismo , Lipoproteínas HDL/metabolismo , Lisofosfolipídeos/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Esfingosina/análogos & derivados , Animais , Transporte Biológico , Biomarcadores/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/sangue , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Transdução de Sinais , Esfingosina/sangue , Esfingosina/metabolismo , Disfunção Ventricular , Remodelação Ventricular
15.
Int J Mol Sci ; 20(24)2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861195

RESUMO

Sphingosine-1-phosphate (S1P) has been implicated recently in the physiology and pathology of the cardiovascular system including regulation of vascular tone. Pilot experiments showed that the vasoconstrictor effect of S1P was enhanced markedly in the presence of phenylephrine (PE). Based on this observation, we hypothesized that S1P might modulate α1-adrenergic vasoactivity. In murine aortas, a 20-minute exposure to S1P but not to its vehicle increased the Emax and decreased the EC50 of PE-induced contractions indicating a hyperreactivity to α1-adrenergic stimulation. The potentiating effect of S1P disappeared in S1P2 but not in S1P3 receptor-deficient vessels. In addition, smooth muscle specific conditional deletion of G12/13 proteins or pharmacological inhibition of the Rho-associated protein kinase (ROCK) by Y-27632 or fasudil abolished the effect of S1P on α1-adrenergic vasoconstriction. Unexpectedly, PE-induced contractions remained enhanced markedly as late as three hours after S1P-exposure in wild-type (WT) and S1P3 KO but not in S1P2 KO vessels. In conclusion, the S1P-S1P2-G12/13-ROCK signaling pathway appears to have a major influence on α1-adrenergic vasoactivity. This cooperativity might lead to sustained vasoconstriction when increased sympathetic tone is accompanied by increased S1P production as it occurs during acute coronary syndrome and stroke.


Assuntos
Lisofosfolipídeos/farmacologia , Receptores Adrenérgicos alfa 1/fisiologia , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Vasoconstrição/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Amidas/farmacologia , Animais , Sinergismo Farmacológico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilefrina/farmacologia , Piridinas/farmacologia , Esfingosina/farmacologia , Receptores de Esfingosina-1-Fosfato/genética , Receptores de Esfingosina-1-Fosfato/metabolismo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia , Quinases Associadas a rho/antagonistas & inibidores
16.
Int J Mol Sci ; 20(24)2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861214

RESUMO

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot-Marie-Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.


Assuntos
Lisofosfolipídeos/metabolismo , Doenças Neuromusculares/metabolismo , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/metabolismo , Esfingosina/análogos & derivados , Animais , Doença de Charcot-Marie-Tooth/metabolismo , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/metabolismo , Miastenia Gravis/metabolismo , Esfingosina/metabolismo
17.
Cell Physiol Biochem ; 53(6): 1015-1028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31854953

RESUMO

BACKGROUND/AIMS: Pulmonary infections with Pseudomonas aeruginosa (P. aeruginosa) or Staphylococcus aureus (S. aureus) are of utmost clinical relevance in patients with cystic fibrosis, chronic obstructive pulmonary disease, after trauma and burn, upon ventilation or in immuno-compromised patients. Many P. aeruginosa and S. aureus strains are resistant to many known antibiotics and it is very difficult or often impossible to eradicate the pathogens in patient´s lungs. We have recently shown that the sphingoid base sphingosine very efficiently kills many pathogens, including for instance P. aeruginosa, S. aureus or Acinetobacter baumannii, in vitro. In vivo experiments of our group on cystic fibrosis mice indicated that inhalation of sphingosine prevents or eliminates existing acute or chronic pneumonia with P. aeruginosa or S. aureus in these mice. We also demonstrated that sphingosine is safe to use for inhalation up to high doses, at least in mice. To facilitate development of sphingosine to an anti-bactericidal drug that can be used in humans for inhalation, safety data on non-rodents, larger animals are absolutely required. METHODS: Here, we inhaled mini pigs with increasing doses of sphingosine for 10 days and analyzed the uptake of sphingosine into epithelial cells of bronchi as well as into the trachea and lung and the systemic circulation. Moreover, we measured the generation of ceramide and sphingosine 1-phosphate that potentially mediate inflammation, the influx of leukocytes, epithelial cell death and disruption of the epithelial cell barrier. RESULTS: We demonstrate that inhalation of sphingosine results in increased levels of sphingosine in the luminal membrane of bronchi and the trachea, but not in systemic accumulation. Inhaled sphingosine had no side effects up to very high doses. CONCLUSION: In summary, we demonstrate that inhalation of sphingosine results in an increase of sphingosine concentrations in the luminal plasma membrane of tracheal and bronchial epithelial cells. The inhalation has no systemic or local side effects.


Assuntos
Antibacterianos/metabolismo , Esfingosina/metabolismo , Administração por Inalação , Animais , Antibacterianos/farmacologia , Brônquios/metabolismo , Brônquios/patologia , Ceramidas/análise , Humanos , Pulmão/patologia , Lisofosfolipídeos/análise , Espectrometria de Massas , Pseudomonas aeruginosa/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/análise , Esfingosina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Suínos , Porco Miniatura , Traqueia/metabolismo , Traqueia/patologia
18.
Acta Vet Hung ; 67(4): 578-587, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842605

RESUMO

Sphingosine-1-phosphate (S1P) has been reported as a matriptase activator. The aim of this study was to reveal if S1P can influence hepcidin production. Furthermore, we investigated how S1P can affect the viability and the redox status of primary hepatocytes. Rat primary hepatocytes were cultivated for 72 h and were treated with 50, 200, 1000 ng/ml S1P. Cell-free supernatants were collected every 24 h. Cell viability was tested by a colorimetric method using tetrazolium compound (MTS). The hepcidin levels in the cell-free supernatants were examined with hepcidin sandwich ELISA to determine the effect of S1P on the hepcidin-modulating ability of matriptase. In order to estimate the extent of S1P-generated oxidative stress, extracellular H2O2 measurements were performed by the use of fluorescent dye. Based on the findings, S1P treatment did not cause cell death for 72 h at concentrations up to 1000 ng/ml. S1P did not influence the extracellular H2O2 production for 72 h. The hepcidin levels were significantly suppressed in hepatocytes exposed to S1P treatment. Further studies would be needed to explore the exact mechanism of action of S1P.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepcidinas/biossíntese , Lisofosfolipídeos/administração & dosagem , Serina Endopeptidases/metabolismo , Esfingosina/análogos & derivados , Animais , Peróxido de Hidrogênio/metabolismo , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley , Esfingosina/administração & dosagem
19.
J Exp Clin Cancer Res ; 38(1): 448, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685029

RESUMO

BACKGROUND: A natural compound Jaspine B and its derivative possess potential anti-cancer activities; However, little is known about the underlying mechanism. Here, the role of a new autophagy inducer Jaspine B derivative C-2 in suppressing bladder cancer cells was researched in vitro and in vivo. METHODS: The underlying mechanisms and anticancer effect of C-2 in bladder cancer cells were investigated by MTT, western blotting, immunoprecipitation and immunofluorescence assays. The key signaling components were investigated by using pharmacological inhibitors or specific siRNAs. In vivo, we designed a C-2 and SP600125 combination experiment to verify the effectiveness of compound. RESULTS: C-2 exhibits cytotoxic effect on bladder cancer cells, and JNK activated by C-2 triggers autophagy and up-regulates SQSTM1/p62 proteins, contributing to activation of Nrf2 pathway. Utilization of JNK inhibitor SP600125 or knockdown of JNK by siRNA potentiate the cytotoxicity of C-2 through down-regulation of p62 and LC3II proteins and up-regulation of active-Caspase3 proteins, enhance the cell death effect, facilitating the switch from autophagy to apoptosis. In vivo study, C-2 suppresses tumor growth in a xenograft mouse model of EJ cells without observed toxicity. Combined treatment with SP600125 further enhances tumor inhibition of C-2 associated with enhanced activation of caspase3 and reduction of autophagy. CONCLUSIONS: It reveals a series of molecular mechanisms about SP600125 potentiate the cytotoxicity and tumor inhibition of C-2 in bladder cancer cells through promoting C-2-induced apoptosis, expecting it provides research basis and theoretical support for new drugs development.


Assuntos
Antracenos/administração & dosagem , Autofagia/efeitos dos fármacos , Esfingosina/análogos & derivados , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antracenos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , MAP Quinase Quinase 4 , Camundongos , Proteína Sequestossoma-1/metabolismo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Proc Natl Acad Sci U S A ; 116(47): 23551-23561, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685607

RESUMO

Angiogenesis frequently occurs in the context of acute or persistent inflammation. The complex interplay of proinflammatory and proangiogenic cues is only partially understood. Using an experimental model, permitting exposure of developing blood vessel sprouts to multiple combinations of diverse biochemical stimuli and juxtacrine cell interactions, we present evidence that a proinflammatory cytokine, tumor necrosis factor (TNF), can have both proangiogenic and antiangiogenic effects, depending on the dose and the presence of pericytes. In particular, we find that pericytes can rescue and enhance angiogenesis in the presence of otherwise-inhibitory high TNF doses. This sharp switch from proangiogenic to antiangiogenic effect of TNF observed with an escalating dose of this cytokine, as well as the effect of pericytes, are explained by a mathematical model trained on the biochemical data. Furthermore, this model was predictive of the effects of diverse combinations of proinflammatory and antiinflammatory cues, and variable pericyte coverage. The mechanism supports the effect of TNF and pericytes as modulating signaling networks impinging on Notch signaling and specification of the Tip and Stalk phenotypes. This integrative analysis elucidates the plasticity of the angiogenic morphogenesis in the presence of diverse and potentially conflicting cues, with immediate implications for many physiological and pathological settings.


Assuntos
Células Endoteliais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Pericitos/fisiologia , Fator de Necrose Tumoral alfa/farmacologia , Comunicação Celular , Técnicas de Cultura de Células , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Lisofosfolipídeos/farmacologia , Modelos Biológicos , Neovascularização Patológica/patologia , Pericitos/efeitos dos fármacos , Receptores Notch/fisiologia , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Engenharia Tecidual , Fator de Necrose Tumoral alfa/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/farmacologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
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