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[PMID]:28460443
[Au] Autor:Fan Q; Cheng Y; Chang HM; Deguchi M; Hsueh AJ; Leung PCK
[Ad] Endereço:Department of Obstetrics and Gynaecology, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
[Ti] Título:Sphingosine-1-phosphate promotes ovarian cancer cell proliferation by disrupting Hippo signaling.
[So] Source:Oncotarget;8(16):27166-27176, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epithelial ovarian carcinomas account for more than 90% of human ovarian cancers and have become the primary cause of death for gynecological malignancies. Unlimited cell proliferation and resistance to cell apoptosis contribute to the development of ovarian cancers. However, the underlying mechanisms involved in these processes in epithelial ovarian carcinomas are yet poorly understood. In the present study, we examined the Hippo signaling gene expression and investigated the effects of Sphingosine 1-phosphate (S1P) on cell proliferation and the underlying mechanisms in human ovarian cancer cell lines, OVCAR3 and SKOV3. Our results demonstrate that S1P disrupts Hippo signaling by reducing YAP phosphorylation and increasing the expression of CCN1 and CCN2 in both ovarian cancer cells. Furthermore, the increase in CCN1/CCN2 expression contributes to the S1P-induced increase in cancer cell proliferation.
[Mh] Termos MeSH primário: Lisofosfolipídeos/farmacologia
Neoplasias Ovarianas/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esfingosina/análogos & derivados
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Fator de Crescimento do Tecido Conjuntivo/genética
Fator de Crescimento do Tecido Conjuntivo/metabolismo
Proteína Rica em Cisteína 61/genética
Proteína Rica em Cisteína 61/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteínas Nucleares/metabolismo
Neoplasias Ovarianas/genética
Neoplasias Ovarianas/mortalidade
Neoplasias Ovarianas/patologia
Fosforilação
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Prognóstico
Esfingosina/farmacologia
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cysteine-Rich Protein 61); 0 (Lysophospholipids); 0 (Nuclear Proteins); 0 (Transcription Factors); 0 (YY1AP1 protein, human); 139568-91-5 (Connective Tissue Growth Factor); 26993-30-6 (sphingosine 1-phosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.- (sphingosine kinase); EC 2.7.1.91 (sphingosine kinase 2, human); EC 2.7.11.1 (Hippo protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15677


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[PMID]:29373815
[Au] Autor:Deshpande GP; Imamdin A; Lecour S; Opie LH
[Ad] Endereço:Hatter Institute for cardiovascular Research in Africa, Department of Medicine, University of Cape Town, South Africa. Electronic address: gdeshpande@sun.ac.za.
[Ti] Título:Sphingosine-1-phosphate (S1P) activates STAT3 to protect against de novo acute heart failure (AHF).
[So] Source:Life Sci;196:127-132, 2018 Mar 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Acute heart failure (AHF) is a burden disease, with high mortality and re-hospitalisations. Using an ex-vivo model of AHF, we have previously reported that sphingosine-1-phosphate (S1P) confers cardioprotection. However, the mechanisms remain to be elucidated. In the present study, we aimed to examine the role of the cardioprotective signal transducer and activator of transcription 3 (STAT3) in S1P mediated improved functional recovery in AHF. MATERIAL AND METHODS: Isolated hearts from male Long-Evans rats were subjected to hypotensive AHF for 35 min followed by a recovery phase of 30 min (n ≥ 4/group). S1P (10 nM) was given during either the hypotensive or the recovery phase with/without an inhibitor of STAT3, AG490. Functional parameters were recorded throughout the experiment. KEY FINDINGS: Following an AHF insult, S1P, given during the recovery phase, improved the heart rate (HR) compared to the control (175.2 ±â€¯30.7 vs. 71.6 ±â€¯27.4 beats per minute (BPM); p < 0.05), with no changes in the left ventricular developed pressure. This effect was associated with an increase in phosphorylated STAT3 levels in the nucleus. Addition of AG490 with S1P abolished the cardioprotective effect of S1P (42.3 ±â€¯17.1 vs. 148.8 ±â€¯26.4 BPM for S1P; p < 0.05). SIGNIFICANCE: Our data suggest that S1P protects in an ex-vivo rat heart model of AHF by activation of STAT3 and provide further evidence for the usage of S1P as a potential therapy in patients suffering from AHF.
[Mh] Termos MeSH primário: Cardiotônicos/farmacologia
Insuficiência Cardíaca/prevenção & controle
Lisofosfolipídeos/farmacologia
Fator de Transcrição STAT3/metabolismo
Esfingosina/análogos & derivados
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Pressão Sanguínea/efeitos dos fármacos
Frequência Cardíaca/efeitos dos fármacos
Técnicas In Vitro
Masculino
Fosforilação/efeitos dos fármacos
Ratos
Ratos Long-Evans
Fator de Transcrição STAT3/antagonistas & inibidores
Fator de Transcrição STAT3/efeitos dos fármacos
Esfingosina/farmacologia
Tirfostinas/farmacologia
Disfunção Ventricular Esquerda/induzido quimicamente
Disfunção Ventricular Esquerda/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiotonic Agents); 0 (Lysophospholipids); 0 (STAT3 Transcription Factor); 0 (Stat3 protein, rat); 0 (Tyrphostins); 0 (alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide); 26993-30-6 (sphingosine 1-phosphate); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE


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[PMID]:28463779
[Au] Autor:Tessema EN; Gebre-Mariam T; Schmelzer CEH; Neubert RHH
[Ad] Endereço:Department of Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle Saale, Germany.
[Ti] Título:Isolation and structural characterization of glucosylceramides from Ethiopian plants by LC/APCI-MS/MS.
[So] Source:J Pharm Biomed Anal;141:241-249, 2017 Jul 15.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chronic skin conditions such as atopic dermatitis, psoriasis and aged skin are characterized by defective skin barrier and dryness which are associated with reduced levels of skin ceramides (CERs). The beneficial effects of plant-derived CERs for skin hydration and skin barrier recovery have been shown in several studies. Although plenty of glucosylceramide (GlcCER)-based dietary supplements meant for skin barrier improvement have been marketed, there are limited commercial sources of plant GlcCERs. In an attempt to explore alternative GlcCER sources, a reversed phase LC-MS/MS method with atmospheric pressure chemical ionization (APCI) interface was developed for separation and structural identification of GlcCERs isolated from three plants. The GlcCERs were extracted from the seeds of grass pea (Lathyrus sativus L.), Ethiopian mustard (Brassica carinata) and haricot bean (Phaseolus vulgaris) and purified by column chromatography and preparative LC-MS. The individual GlcCER species were further separated and qualitatively analyzed by LC/APCI-MS/MS. The amount of GlcCERs in each plant was quantified by HPTLC. All GlcCER species detected in the three plants consisted of C18 di/trihydroxy sphingoid bases amide linked with hydroxy fatty acids (C14-C24). The trihydroxy SBs were acylated with very long chain FAs (C22-C24). The major GlcCERs derived from grass pea, Ethiopian mustard and haricot bean are composed of sphingenine (d18:1) linked to hydroxypalmitic acid (h16:0), 4-hydroxy-8-sphingenine (t18:1) coupled with hydroxynervonic acid (h24:1) and sphingadienine (d18:2) joined with h16:0, respectively. The GlcCERs contents in haricot bean (161.2mg/kg) and grass pea (130.0mg/kg) were found to be higher compared to Ethiopian mustard (71.8mg/kg). This qualitative and quantitative information suggests that the two plants of the Fabaceae family (haricot bean and grass pea) are potential alternative sources of GlcCERs for their use in products meant for the recovery of skin barrier function. The LC/APCI-MS/MS method described here has proven to be reliable for the screening of other potential plants containing GlcCERs.
[Mh] Termos MeSH primário: Glucosilceramidas/análise
[Mh] Termos MeSH secundário: Pressão Atmosférica
Cromatografia Líquida
Plantas
Esfingosina/análogos & derivados
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-hydroxy-8-sphingenine); 0 (Glucosylceramides); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180125
[Lr] Data última revisão:
180125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:29277758
[Au] Autor:Ahn EH; Lee MB; Seo DJ; Lee J; Kim Y; Gupta K
[Ad] Endereço:Department of Pathology, School of Medicine, University of Washington, Seattle, WA, U.S.A. ahneun@uw.edu.
[Ti] Título:Sphingosine Induces Apoptosis and Down-regulation of in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of Mutation.
[So] Source:Anticancer Res;38(1):71-76, 2018 01.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Rhabdomyosarcoma is the most common type of pediatric soft-tissue sarcoma. Among the subsets of this disease, alveolar rhabdomyosarcoma (ARMS) expressing paired box 3 (PAX3) and forkhead box O1 (PAX3-FOXO1) fusion oncoprotein has the worst prognosis. The goal of this study was to investigate the chemotherapeutic effects of sphingosine on PAX3-FOXO1-positive ARMS cells [tumor protein p53 (TP53)-mutated RH30 and TP53 wild-type RH18 cells]. MATERIALS AND METHODS: The proliferation, cell death, apoptosis, cell cycle, and MYCN proto-oncogene (MYCN) expression of RH30 and RH18 cells were determined. RESULTS: Sphingosine inhibited the growth and caused cell death in a dose-dependent manner in both cell lines. Sphingosine triggered cell death by inducing apoptosis without affecting the cell cycle. MYCN expression was down-regulated within 2 and 4 h of sphingosine treatment in both RH30 and RH18 cells. CONCLUSION: Sphingosine exerts antiproliferative and pro-apoptotic effects via MYCN down-regulation independently of TP53 mutation status in PAX3-FOXO1-positive ARMS cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Proteína Proto-Oncogênica N-Myc/genética
Rabdomiossarcoma Alveolar/genética
Esfingosina/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Regulação para Baixo/efeitos dos fármacos
Proteína Forkhead Box O1/metabolismo
Seres Humanos
Mutação
Fator de Transcrição PAX3/metabolismo
Rabdomiossarcoma Alveolar/metabolismo
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (FOXO1 protein, human); 0 (Forkhead Box Protein O1); 0 (MYCN protein, human); 0 (N-Myc Proto-Oncogene Protein); 0 (PAX3 Transcription Factor); 0 (PAX3 protein, human); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


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[PMID]:29214311
[Au] Autor:Xiao W; Fu S; Xu K; Feng R; Sun F; Ye W
[Ad] Endereço:Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China.
[Ti] Título:Fingolimod Suppresses a Cascade of Core Vicious Cycle in Dry Eye NOD Mouse Model: Involvement of Sphingosine-1-Phosphate Receptors in Infiltrating Leukocytes.
[So] Source:Invest Ophthalmol Vis Sci;58(14):6123-6132, 2017 Dec 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The purpose of this study was to evaluate the inhibitory mechanism of fingolimod and the involvement of sphingosine-1-phosphate receptors (S1PRs) and cytokines-matrix metalloproteinases (MMPs)/MAP kinases (MAPKs) signaling in a dry eye disease (DED) mouse model. Methods: Sixty-four male NOD mice (DED model) and 16 age-matched BALB/c mice were used. In a preliminary experiment, 16 NOD mice were randomly divided into a positive control group and fingolimod-treated groups, with 8 BALB/c mice serving as wild-type control. In a subsequent, separate study, 48 NOD mice were randomly divided into 6 groups: fingolimod-treated groups at three different concentrations (0.05%, 0.005%, and 0.001%), normal saline group, untreated group, and fingolimod+W146 group. Animals received normal saline or fingolimod eyedrops three times daily until euthanasia 2 months later. Mice in the fingolimod+W146 group received daily intraperitoneal injections of W146 (0.1 mg/kg/day). Proinflammatory mediators were assessed by a protein array. Activities of MMP-2 and MMP-9 were evaluated by zymography. MAPKs and S1PRs were examined by Western blots and immunohistochemistry. Infiltrating cells and inhibitory mechanisms were assessed. Results: In the positive control group, levels of inflammatory mediators and S1PRs were upregulated. By comparison, fingolimod treatment significantly suppressed such markers which were significantly reversed by W146 (P < 0.01). Importantly, by double immunofluorescence staining, leukocytes were confirmed involved in DED in the NOD mouse model. Conclusions: Leukocytes are involved in DED in the NOD mouse model. The therapeutic mechanisms of fingolimod may be associated with inhibitory roles of "cytokines-MMPs/MAPKs" cycle in NOD mouse ocular surface tissues by mediating S1PRs in infiltrating leukocytes.
[Mh] Termos MeSH primário: Síndromes do Olho Seco/tratamento farmacológico
Cloridrato de Fingolimode/farmacologia
Leucócitos/metabolismo
Receptores de Lisoesfingolipídeo/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Modelos Animais de Doenças
Síndromes do Olho Seco/metabolismo
Síndromes do Olho Seco/patologia
Imuno-Histoquímica
Imunossupressores/farmacologia
Leucócitos/patologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos NOD
Esfingosina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunosuppressive Agents); 0 (Receptors, Lysosphingolipid); G926EC510T (Fingolimod Hydrochloride); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171215
[Lr] Data última revisão:
171215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-21445


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[PMID]:29023478
[Au] Autor:Mensah SA; Cheng MJ; Homayoni H; Plouffe BD; Coury AJ; Ebong EE
[Ad] Endereço:Department of Bioengineering, Northeastern University, Boston, Massachusetts, United States of America.
[Ti] Título:Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication.
[So] Source:PLoS One;12(10):e0186116, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vasculoprotective endothelium glycocalyx (GCX) shedding plays a critical role in vascular disease. Previous work demonstrated that GCX degradation disrupts endothelial cell (EC) gap junction connexin (Cx) proteins, likely blocking interendothelial molecular transport that maintains EC and vascular tissue homeostasis to resist disease. Here, we focused on GCX regeneration and tested the hypothesis that vasculoprotective EC function can be stimulated via replacement of GCX when it is shed. We used EC with [i] intact heparan sulfate (HS), the most abundant GCX component; [ii] degraded HS; or [iii] HS that was restored after enzyme degradation, by cellular self-recovery or artificially. Artificial HS restoration was achieved via treatment with exogenous HS, with or without the GCX regenerator and protector sphingosine 1- phosphate (S1P). In these cells we immunocytochemically examined expression of Cx isotype 43 (Cx43) at EC borders and characterized Cx-containing gap junction activity by measuring interendothelial spread of gap junction permeable Lucifer Yellow dye. With intact HS, 60% of EC borders expressed Cx43 and dye spread to 2.88 ± 0.09 neighboring cells. HS degradation decreased Cx43 expression to 30% and reduced dye spread to 1.87± 0.06 cells. Cellular self-recovery of HS restored baseline levels of Cx43 and dye transfer. Artificial HS recovery with exogenous HS partially restored Cx43 expression to 46% and yielded dye spread to only 1.03 ± 0.07 cells. Treatment with both HS and S1P, recovered HS and restored Cx43 to 56% with significant dye transfer to 3.96 ± 0.23 cells. This is the first evidence of GCX regeneration in a manner that effectively restores vasculoprotective EC communication.
[Mh] Termos MeSH primário: Comunicação Celular
Células Endoteliais/citologia
Glicocálix/metabolismo
Heparitina Sulfato/metabolismo
Lisofosfolipídeos/metabolismo
Esfingosina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Conexina 43/metabolismo
Células Endoteliais/metabolismo
Junções Comunicantes/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Ratos
Esfingosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Connexin 43); 0 (GJA1 protein, mouse); 0 (Lysophospholipids); 26993-30-6 (sphingosine 1-phosphate); 9050-30-0 (Heparitin Sulfate); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186116


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[PMID]:28970286
[Au] Autor:Werth S; Müller-Fielitz H; Raasch W
[Ad] Endereço:Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity of Lübeck, Lübeck, Germany.
[Ti] Título:Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism.
[So] Source:J Endocrinol;235(3):251-265, 2017 Dec.
[Is] ISSN:1479-6805
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. release of S1P (100-300 µg/kg ) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely.
[Mh] Termos MeSH primário: Aldosterona/metabolismo
Lisofosfolipídeos/fisiologia
Obesidade/metabolismo
Receptores de Lisoesfingolipídeo/fisiologia
Esfingosina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Dieta Hiperlipídica
Seres Humanos
Lisofosfolipídeos/metabolismo
Masculino
Obesidade/sangue
Obesidade/etiologia
Ratos
Ratos Endogâmicos SHR
Ratos Sprague-Dawley
Ratos Zucker
Receptores de Lisoesfingolipídeo/metabolismo
Transdução de Sinais/fisiologia
Esfingosina/metabolismo
Esfingosina/fisiologia
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lysophospholipids); 0 (Receptors, Lysosphingolipid); 26993-30-6 (sphingosine 1-phosphate); 4964P6T9RB (Aldosterone); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1530/JOE-16-0550


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[PMID]:28934733
[Au] Autor:Du Y; Li D; Han C; Wu H; Xu L; Zhang M; Zhang J; Chen X
[Ad] Endereço:Department of Transplantation and Hepatic Surgery, PLA No. 107 Hospital, Yantaii, China.
[Ti] Título:Exosomes from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway.
[So] Source:Cell Physiol Biochem;43(2):611-625, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: This study aimed to evaluate the effects of exosomes produced by human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic ischemia-reperfusion (I/R) injury, as well as the underlying mechanisms. METHODS: Exosomes derived from hiPSC-MSCs were isolated and characterized both biochemically and biophysically. hiPSC-MSCs-Exo were injected systemically into a murine ischemia/reperfusion injury model via the inferior vena cava, and then the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as histological changes were examined. Primary hepatocytes and human hepatocyte cell line HL7702 were used to test whether exosomes could induce hepatocytes proliferation in vitro. In addition, the expression levels of proliferation markers (proliferation cell nuclear antigen, PCNA; Phosphohistone-H3, PHH3) were measured by immunohistochemistry and Western blot. Moreover, SK inhibitor (SKI-II) and S1P1 receptor antagonist (VPC23019) were used to investigate the role of sphingosine kinase and sphingosine-1-phosphate-dependent pathway in the effects of hiPSC-MSCs-Exo on hepatocytes. RESULTS: hiPSCs were efficiently induced into hiPSC-MSCs that had typical MSC characteristics. hiPSC-MSCs-Exo had diameters ranging from 100 to 200 nm and expressed exosome markers (Alix, CD63 and CD81). After hiPSC-MSCs-Exo administration, hepatocyte necrosis and sinusoidal congestion were markedly suppressed in the ischemia/reperfusion injury model, with lower histopathological scores. The levels of hepatocyte injury markers AST and ALT were significantly lower in the treatment group compared to control, and the expression levels of proliferation markers (PCNA and PHH3) were greatly induced after hiPSC-MSCs-Exo administration. Moreover, hiPSC-MSCs-Exo also induced primary hepatocytes and HL7702 cells proliferation in vitro in a dose-dependent manner. We found that hiPSC-MSCs-Exo could directly fuse with target hepatocytes or HL7702 cells and increase the activity of sphingosine kinase and synthesis of sphingosine-1-phosphate (S1P). Furthermore, the inhibition of SK1 or S1P1 receptor completely abolished the protective and proliferative effects of hiPSC-MSCs-Exo on hepatocytes, both in vitro and in vivo. CONCLUSIONS: Our results demonstrated that hiPSC-MSCs-Exo could alleviate hepatic I/R injury via activating sphingosine kinase and sphingosine-1-phosphate pathway in hepatocytes and promote cell proliferation. These findings represent a novel mechanism that potentially contributes to liver regeneration and have important implications for new therapeutic approaches to acute liver disease.
[Mh] Termos MeSH primário: Exossomos/metabolismo
Células-Tronco Pluripotentes Induzidas/citologia
Fígado/metabolismo
Lisofosfolipídeos/metabolismo
Células Mesenquimais Estromais/citologia
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Traumatismo por Reperfusão/terapia
Esfingosina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Proliferação Celular
Células Cultivadas
Hepatócitos/citologia
Hepatócitos/metabolismo
Hepatócitos/patologia
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Fígado/patologia
Masculino
Células Mesenquimais Estromais/metabolismo
Camundongos Endogâmicos C57BL
Traumatismo por Reperfusão/metabolismo
Traumatismo por Reperfusão/patologia
Transdução de Sinais
Esfingosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lysophospholipids); 26993-30-6 (sphingosine 1-phosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.- (sphingosine kinase); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1159/000480533


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[PMID]:28846923
[Au] Autor:Kuchler L; Sha LK; Giegerich AK; Knape T; Angioni C; Ferreirós N; Schmidt MV; Weigert A; Brüne B; von Knethen A
[Ad] Endereço:Institute of Biochemistry I - Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
[Ti] Título:Elevated intrathymic sphingosine-1-phosphate promotes thymus involution during sepsis.
[So] Source:Mol Immunol;90:255-263, 2017 Oct.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sepsis mouse models revealed thymus atrophy, characterised by decreased thymus weight and loss of thymocytes due to apoptosis. Mice suffered from lymphopenia, a lack of T cells in the periphery, which attenuates their ability to fight against recurring and secondary infections during sepsis progression. Key players in thymus atrophy are IL-6, which is directly involved in thymus involution, and the sphingosine-1-phosphate - sphingosine-1-phosphate receptor 1 signaling, influencing thymocytes emigration. In healthy individuals a sphingosine-1-phosphate (S1P) gradient from lymphoid organs to the circulatory system serves as signal for mature T cell egress. In the present study we investigated, whether inhibition of S1P generation improves thymus involution. In sepsis, induced by cecal ligation and puncture (CLP), S1P in the thymus increased, while it decreased in serum, thus disrupting the naturally occurring S1P gradient. As a potential source of S1P we identified increased numbers of apoptotic cells in the thymic cortex of septic mice. Pharmacological inhibition of the S1P generating sphingosine kinases, by 4- [[4-(4-Chlorophenyl)-2-thiazolyl]amino]phenol (SK I-II), administered directly following CLP, prevented thymus atrophy. This was reflected by lymphocytosis, diminished apoptosis, decreased IL-6 expression, and an unaltered thymus weight. In addition SK I-II-treatment preserved the S1P balance and prevented S1P-dependent internalization of the sphingosine-1-phosphate receptor 1. Our data suggest that inhibition of sphingosine kinase and thus, S1P generation during sepsis restores thymic T cell egress, which might improve septic outcome.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Apoptose/fisiologia
Lisofosfolipídeos/sangue
Lisofosfolipídeos/metabolismo
Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores
Sepse/patologia
Esfingosina/análogos & derivados
Timócitos/metabolismo
Timo/patologia
[Mh] Termos MeSH secundário: Aminofenóis/farmacologia
Animais
Atrofia/patologia
Atrofia/prevenção & controle
Ceco/cirurgia
Modelos Animais de Doenças
Interleucina-6/biossíntese
Interleucina-6/imunologia
Linfocitose
Linfopenia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Receptores de Lisoesfingolipídeo/metabolismo
Esfingosina/sangue
Esfingosina/metabolismo
Tiazóis/farmacologia
Timócitos/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-((4-(4-chlorophenyl)-2-thiazolyl)amino)phenol); 0 (Aminophenols); 0 (Interleukin-6); 0 (Lysophospholipids); 0 (Receptors, Lysosphingolipid); 0 (Thiazoles); 0 (interleukin-6, mouse); 26993-30-6 (sphingosine 1-phosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.- (sphingosine kinase); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


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[PMID]:28806736
[Au] Autor:Nicholas SE; Rowsey TG; Priyadarsini S; Mandal NA; Karamichos D
[Ad] Endereço:Department of Ophthalmology/ Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
[Ti] Título:Unravelling the interplay of sphingolipids and TGF-ß signaling in the human corneal stroma.
[So] Source:PLoS One;12(8):e0182390, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To delineate the role of Sphingolipids (SPLs) in the human cornea and their cross-talks with transforming growth factor beta (TGF-ß) in order to develop novel, non-invasive therapies. METHODS: Human corneal fibroblasts (HCFs) were harvested from healthy donors, stimulated with Vitamin C to promote extracellular matrix assembly, treated with exogenous sphingosine-1-phosphate (S1P) or sphingosine kinase inhibitor 2 (SPHK I2) and isolated after 4 weeks for further analysis. RESULTS: Data showed that S1P led to a significant decrease in cellular migration where SPHK I2 just delayed it for 24h. Significant modulation of the sphingolipid pathway was also noted. Sphingosine kinase-1 (SphK1) was significantly downregulated upon exogenous stimulation with S1P at a concentration of 5µM and Sphingosine kinase-2 (SphK2) was also significantly downregulated at concentrations of 0.01µM, 0.1µM, and 5µM; whereas no effects were observed upon stimulation with SPHK I2. S1PR3 was significantly downregulated by 0.1µM and 5µM S1P and upregulated by 5µM and 10µM SPHK I2. Furthermore, both S1P and SPHK I2 regulated corneal fibrosis markers such as alpha-smooth muscle actin, collagen I, III, and V. We also investigated the interplay between two TGF-ß isoforms and S1P/SPHK I2 treatments and found that TGF-ß1 and TGF-ß3 were both significantly upregulated with the 0.1µM S1P but were significantly downregulated with the 5µM S1P concentration. When TGF-ß1 was compared directly to TGF-ß3 expression, we observed that TGF-ß3 was significantly downregulated compared to TGF-ß1 in the 5µM concentration of S1P. No changes were observed upon SPHK I2 treatment. CONCLUSION: Our study delineates the role of sphingolipids in the human cornea and highlights their different activities based on the cell/tissue type.
[Mh] Termos MeSH primário: Substância Própria/metabolismo
Transdução de Sinais
Esfingolipídeos/metabolismo
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Western Blotting
Extratos Celulares
Movimento Celular/efeitos dos fármacos
Substância Própria/efeitos dos fármacos
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Fibrose
Seres Humanos
Lisofosfolipídeos/farmacologia
Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Isoformas de Proteínas/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Transdução de Sinais/efeitos dos fármacos
Esfingosina/análogos & derivados
Esfingosina/farmacologia
Cicatrização/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Extracts); 0 (Lysophospholipids); 0 (Protein Isoforms); 0 (Protein Kinase Inhibitors); 0 (Sphingolipids); 0 (Transforming Growth Factor beta); 26993-30-6 (sphingosine 1-phosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.- (sphingosine kinase); NGZ37HRE42 (Sphingosine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182390



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