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1.
Front Immunol ; 12: 764825, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733292

RESUMO

Eosinophils are a minor component of circulating granulocytes, which are classically viewed as end-stage effector cells in host defense against helminth infection and promoting allergic responses. However, a growing body of evidence has emerged showing that eosinophils are versatile leukocytes acting as an orchestrator in the resolution of inflammation. Rheumatoid arthritis (RA) is the most common chronic inflammatory disease characterized by persistent synovitis that hardly resolves spontaneously. Noteworthy, a specific population of eosinophils, that is, regulatory eosinophils (rEos), was identified in the synovium of RA patients, especially in disease remission. Mechanistically, the rEos in the synovium display a unique pro-resolving signature that is distinct from their counterpart in the lung. Herein, we summarize the latest understanding of eosinophils and their emerging role in promoting the resolution of arthritis. This knowledge is crucial to the design of new approaches to rebalancing immune homeostasis in RA, considering that current therapies are centered on inhibiting pro-inflammatory cytokines and mediators rather than fostering the resolution of inflammation.

2.
Front Physiol ; 12: 724470, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34483973

RESUMO

Cardiac fibrosis is evident even in the situation without a significant cardiomyocyte loss in diabetic cardiomyopathy and a high glucose (HG) level independently activates the cardiac fibroblasts (CFs) and promotes cell proliferation. Mitochondrial respiration and glycolysis, which are key for cell proliferation and the mitochondria-associated membranes (MAMs), are critically involved in this process. However, the roles and the underlying mechanism of MAMs in the proliferation of HG-induced CFs are largely unknown. The proliferation and apoptosis of CFs responding to HG treatment were evaluated. The MAMs were quantified, and the mitochondrial respiration and cellular glycolytic levels were determined using the Seahorse XF analyzer. The changes of signal transducer and activator of transcription 3 (STAT3) and mitofusin-2 (MFN2) in responding to HG were also determined, the effects of which on cell proliferation, MAMs, and mitochondrial respiration were assessed. The effects of STAT3 on MFN2 transcription was determined by the dual-luciferase reporter assay (DLRA) and chromatin immunoprecipitation (CHIP). HG-induced CFs proliferation increased the glycolytic levels and adenosine triphosphate (ATP) production, while mitochondrial respiration was inhibited. The MAMs and MFN2 expressions were significantly reduced on the HG treatment, and the restoration of MFN2 expression counteracted the effects of HG on cell proliferation, mitochondrial respiration of the MAMs, glycolytic levels, and ATP production. The mitochondrial STAT3 contents were not changed by HG, but the levels of phosphorylated STAT3 and nuclear STAT3 were increased. The inhibition of STAT3 reversed the reduction of MFN2 levels induced by HG. The DLRA and CHIP directly demonstrated the negative regulation of MFN2 by STAT3 at the transcription levels via interacting with the sequences in the MFN2 promoter region locating at about -400 bp counting from the start site of transcription. The present study demonstrated that the HG independently induced CFs proliferation via promoting STAT3 translocation to the nucleus, which switched the mitochondrial respiration to glycolysis to produce ATP by inhibiting MAMs in an MFN2-depression manner.

3.
Am J Physiol Cell Physiol ; 320(6): C1055-C1073, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33788630

RESUMO

Vascular smooth muscle (VSM) cell phenotypic expression and autophagic state are dynamic responses to stress. Vascular pathologies, such as hypoxemia and ischemic injury, induce a synthetic VSM phenotype and autophagic flux resulting in a loss of vascular integrity and VSM cell death respectfully. Both clinical pilot and experimental stroke studies demonstrate that sphingosine-1-phosphate receptor (S1PR) modulation improves stroke outcome; however, specific mechanisms associated with a beneficial outcome at the level of the cerebrovasculature have not been clearly elucidated. We hypothesized that ozanimod, a selective S1PR type 1 ligand, will attenuate VSM synthetic phenotypic expression and autophagic flux in primary human brain VSM cells following acute hypoxia plus glucose deprivation (HGD; in vitro ischemic-like injury) exposure. Cells were treated with ozanimod and exposed to normoxia or HGD. Crystal violet staining, standard immunoblotting, and immunocytochemical labeling techniques assessed cellular morphology, vacuolization, phenotype, and autophagic state. We observed that HGD temporally decreased VSM cell viability and concomitantly increased vacuolization, both of which ozanimod reversed. HGD induced a simultaneous elevation and reduction in levels of pro- and antiautophagic proteins respectfully, and ozanimod attenuated this response. Protein levels of VSM phenotypic biomarkers, smoothelin and SM22, were decreased following HGD. Furthermore, we observed an HGD-induced epithelioid and synthetic morphological appearance accompanied by disorganized cytoskeletal filaments, which was rescued by ozanimod. Thus, we conclude that ozanimod, a selective S1PR1 ligand, protects against acute HGD-induced phenotypic switching and promotes cell survival, in part, by attenuating HGD-induced autophagic flux thus improving vascular patency in response to acute ischemia-like injury.


Assuntos
Autofagia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Glucose/metabolismo , Hipóxia/tratamento farmacológico , Indanos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Oxidiazóis/farmacologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Hipóxia/metabolismo , Ligantes , Masculino , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fenótipo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo
4.
Neurosci Lett ; 735: 135160, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32561451

RESUMO

Endothelial sphingosine-1-phosphate receptors are emerging as relevant therapeutic targets during acute ischemic stroke (AIS). Physiologically, the cerebrovascular endothelium plays a vital role in maintaining barrier integrity and cerebrovascular homeostasis. During a cerebral ischemic event, products from parenchymal cell death are released and trigger vascular endothelial dysfunction and vascular inflammation leading to barrier integrity disruption. Endothelial dysfunction, inflammation, and a breach in barrier property play a significant role in contributing to a vicious cycle which promotes brain edema formation and exacerbates neuronal injury post stroke. Data from experimental stroke models and clinical trials suggest that selective sphingosine-1-phosphate receptor type 1 (S1PR1) modulation improves endothelial health and function and, as a result, contributes to improved neurological outcome post ischemic injury. This review highlights the impact of sphingosine-1-phosphate (S1P)/S1PR1 signaling involved in blood brain barrier (BBB) integrity and cerebrovascular inflammation following AIS. We focus on the beneficial actions of S1PR1 signaling during ischemic injury including barrier protection to lessen brain edema formation and reduction in the development and progression of vascular inflammation by attenuating endothelial cell activation resulting in reduced neurovascular inflammation. Potential gaps and future directions related to the role of S1PR during AIS are also discussed.


Assuntos
Barreira Hematoencefálica/metabolismo , Inflamação/metabolismo , AVC Isquêmico/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Barreira Hematoencefálica/patologia , Humanos , Inflamação/patologia , AVC Isquêmico/patologia
5.
BMC Ophthalmol ; 20(1): 227, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532239

RESUMO

BACKGROUND: Tuberculosis (TB) remains a severe health burden worldwide. The manifestation of concurrent tuberculous cerebral and ocular involvements associated with TB is uncommon. CASE PRESENTATION: We report a 17-year-old girl with concurrent tuberculous cerebral and ocular involvements and visual impairment due to choroidal neovascularization. This study emphasizes the definite diagnosis with the combination of ophthalmological examination, multimodal imaging and routine tuberculosis testing, and the proper management with intravitreal anti-VEGF injection accompanied by systemic anti-tuberculosis therapy. CONCLUSION: Combined applications of routine TB tests, fundus multimodal imaging and diagnostic therapy greatly help the clinician to establish a precise diagnosis and in monitoring the therapeutic response.


Assuntos
Coriorretinite/complicações , Neovascularização de Coroide/complicações , Angiofluoresceinografia/métodos , Tomografia de Coerência Óptica/métodos , Tuberculose Meníngea/complicações , Tuberculose Ocular/complicações , Adolescente , Coriorretinite/diagnóstico , Neovascularização de Coroide/diagnóstico , Feminino , Fundo de Olho , Humanos , Tomografia Computadorizada por Raios X , Tuberculose Meníngea/diagnóstico , Tuberculose Ocular/diagnóstico
6.
Stroke ; 51(3): 967-974, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32019481

RESUMO

Background and Purpose- Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods- Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15tg). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results- In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1ß, and TNF-α is markedly increased in GFAP-IL-15tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15tg mice. Conclusions- Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.


Assuntos
Astrócitos/imunologia , Lesões Encefálicas/imunologia , Hemorragia Cerebral/imunologia , Interleucina-15/imunologia , Microglia/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/patologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Feminino , Humanos , Interleucina-15/genética , Masculino , Camundongos , Camundongos Transgênicos , Microglia/patologia
7.
World J Gastroenterol ; 24(34): 3834-3848, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30228778

RESUMO

Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Imunoconjugados/farmacologia , Evasão Tumoral/efeitos dos fármacos , Alfa-Amanitina/farmacologia , Alfa-Amanitina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia/métodos , Instabilidade de Microssatélites/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , RNA Polimerase II/antagonistas & inibidores , Resultado do Tratamento , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética
8.
Proc Biol Sci ; 285(1881)2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29925613

RESUMO

Chancelloriids are an extinct group of spiny Cambrian animals of uncertain phylogenetic position. Despite their sponge-like body plan, their spines are unlike modern sponge spicules, but share several features with the sclerites of certain Cambrian bilaterians, notably halkieriids. However, a proposed homology of these 'coelosclerites' implies complex transitions in body plan evolution. A new species of chancelloriid, Allonnia nuda, from the lower Cambrian (Stage 3) Chengjiang Lagerstätte is distinguished by its large size and sparse spination, with modified apical sclerites surrounding an opening into the body cavity. The sclerite arrangement in A. nuda and certain other chancelloriids indicates that growth involved sclerite addition in a subapical region, thus maintaining distinct zones of body sclerites and apical sclerites. This pattern is not seen in halkieriids, but occurs in some modern calcarean sponges. With scleritome assembly consistent with a sponge affinity, and in the absence of cnidarian- or bilaterian-grade features, it is possible to interpret chancelloriids as sponges with an unusually robust outer epithelium, strict developmental control of body axis formation, distinctive spicule-like structures and, by implication, minute ostia too small to be resolved in fossils. In this light, chancelloriids may contribute to the emerging picture of high disparity among early sponges.


Assuntos
Evolução Biológica , Fósseis , Poríferos/crescimento & desenvolvimento , Animais , China , Fósseis/anatomia & histologia , Poríferos/anatomia & histologia
9.
J Neuroimmunol ; 316: 107-111, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29310942

RESUMO

BACKGROUND: Rituximab is a mouse-human chimeric anti-CD20 monoclonal antibody and has been increasingly used for preventing relapses in NMOSDs. The clinical relevance of Anti-Rituximab antibodies (ARA) against Rituximab in NMOSDs is unknown. METHODS: Nineteen NMOSDs patients receiving repeated 100mg Rituximab treatment were recruited. The ARA was quantitatively analyzed by enzyme linked immunoassay. Annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) were analyzed concurrently. RESULTS: ARR was reduced markedly since starting Rituximab therapy in the majority (78.9%) of NMOSDs patients. 36.9% (7/19) patients were ARA positive. There was no significant difference in the improvement of ARR and EDSS after treatment with Rituximab in either ARA positive or negative groups. The frequency of Rituximab reinfusion was higher in patients with ARA, suggesting that the presence of ARA led to an increased frequency of Rituximab reinfusion to maintain B cell depletion. CONCLUSION: The majority of (78.9%) patients with NMOSDs were responsive to low dose Rituximab. The presence of ARA is associated with the requirement for increased frequency of Rituximab reinfusion to maintain treatment response in NMOSDs. In patients with ARA it might be necessary to detect ARA levels and monitor B cell depletion closely, or even attempt other treatments.


Assuntos
Anticorpos/sangue , Fatores Imunológicos/imunologia , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Rituximab/imunologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Recidiva , Rituximab/uso terapêutico , Adulto Jovem
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 37(1): 24-29, 2017 01 20.
Artigo em Chinês | MEDLINE | ID: mdl-28109094

RESUMO

OBJECTIVE: To investigate whether Lactobacillus rhamnosus GG conditioned medium(LGG-CM)has preventive effect against E. coli K1-induced neuropathogenicity in vitro by inhibiting nuclear factor-κB (NF-κB) signaling pathway. METHODS: An in vitro blood-brain barrier (BBB) model was constructed using human brain microvascular endothelial cells (HBMECs). The effect of LGG-CM on E. coli-actived NF-κB signaling pathway was assayed using Western blotting. Invasion assay and polymorphonuclear leukocyte (PMN) transmigration assay were performed to explore whether LGG-CM could inhibit E. coli invasion and PMN transmigration across the BBB in vitro. The expressions of ZO-1 and CD44 were detected using Western blotting and immunofluorescence. The changes of trans-epithelial electric resistance (TEER) and bacterial translocation were determined to evaluate the BBB permeability. RESULTS: Pre-treament with LGG-CM inhibited E. coli-activated NF-κB signaling pathway in HBMECs and decreased the invasion of E. coli K1 and transmigration of PMN. Western blotting showed that LGG-CM could alleviate E. coli-induced up-regulation of CD44 and down-regulation of ZO-1 expressions in HBMECs. In addition, pre-treatment with LGG-CM alleviated E. coli K1-induced reduction of TEER and suppressed bacterial translocation across the BBB in vitro. CONCLUSION: LGG-CM can block E. coli-induced activation of NF-κB signaling pathway and thereby prevents E. coli K1-induced neuropathogenicity by decreasing E. coli K1 invasion rates and PMN transmigration.


Assuntos
Meios de Cultivo Condicionados/farmacologia , Escherichia coli/efeitos dos fármacos , Lactobacillus rhamnosus , Meningite devida a Escherichia coli/prevenção & controle , NF-kappa B/antagonistas & inibidores , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Barreira Hematoencefálica , Escherichia coli/fisiologia , Humanos , NF-kappa B/metabolismo , Neutrófilos/fisiologia , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Migração Transendotelial e Transepitelial/fisiologia
12.
Neurosci Bull ; 31(6): 755-62, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25958190

RESUMO

Intracerebral hemorrhage (ICH) leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage (ICH). The results showed that fingolimod decreased the numbers of circulating CD4(+) T, CD8(+) T, CD19(+) B, NK, and NKT cells and they recovered quickly after the drug was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.


Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Mediadores da Inflamação/sangue , Separação Celular , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Humanos , Linfócitos/efeitos dos fármacos , Método Simples-Cego
13.
Neurol Neuroimmunol Neuroinflamm ; 2(3): e94, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25918736

RESUMO

OBJECTIVES: We investigated the sleep structure of patients with neuromyelitis optica spectrum disorder (NMOSD) and the association of abnormalities with brain lesions. METHODS: This was a prospective cross-sectional study. Thirty-three patients with NMOSD and 20 matched healthy individuals were enrolled. Demographic and clinical characteristics of patients were collected. Questionnaires were used to assess quality of sleep, daytime sleepiness, fatigue, and depression. Nocturnal polysomnography was performed. RESULTS: Compared with healthy controls, patients with NMOSD had decreases in sleep efficiency (7%; p = 0.0341), non-REM sleep N3 (12%; p < 0.0001), and arousal index (6; p = 0.0138). REM sleep increased by 4% (p = 0.0423). There were correlations between arousal index and REM% or Epworth Sleepiness Scale (r = -0.0145; p = 0.0386, respectively). Six patients with NMOSD (18%, 5 without infratentorial lesions and 1 with infratentorial lesions) had a hypopnea index >5, and all of those with sleep apnea had predominantly the peripheral type. The periodic leg movement (PLM) index was higher in patients with NMOSD than in healthy controls (20 vs 2, p = 0.0457). Surprisingly, 77% of the patients with PLM manifested infratentorial lesions. CONCLUSIONS: Sleep architecture was markedly disrupted in patients with NMOSD. Surveillance of nocturnal symptoms and adequate symptomatic control are expected to improve the quality of life of patients with NMOSD.

14.
Eur J Med Chem ; 94: 447-57, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25828827

RESUMO

A series of novel pyrazoline-containing derivatives (15-47) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC50 = 0.07 µM, 0.05 µM, 0.03 µM, respectively) and the tubulin polymerization inhibitory activity (IC50 = 1.88 µM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Pirazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
15.
J Neuroimmunol ; 278: 239-46, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25468778

RESUMO

While follicular helper T (Tfh) cells have been shown to be involved in many autoimmune diseases, the association of Tfh cells with the disease activity of neuromyelitis optica spectrum disorders (NMOSDs) remains unclear. In this study, the CD4(+)CXCR5(+)PD-1(+) Tfh cell population in peripheral blood mononuclear cells (PBMCs) obtained from NMOSD patients, age- and gender-matched healthy controls, and multiple sclerosis patients was compared by flow cytometry. The serum levels of IL-21, IL-6, IL-17, TNF-α and IL-10 were analyzed by ELISA assays. We found that in NMOSD, the Tfh cell frequency is higher than that of healthy subjects and multiple sclerosis (MS) patients. There are more Tfh cells in the relapsing stage than the remitting stage of NMOSD, thus demonstrating the close association of the Tfh cell population with disease activity. Methylprednisolone, which is used to control disease relapses, significantly decreased the proportion of Tfh cells in NMOSD patients.


Assuntos
Citocinas/metabolismo , Esclerose Múltipla/patologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Leucócitos Mononucleares , Masculino , Metilprednisolona/farmacologia , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Neuromielite Óptica/tratamento farmacológico , Índice de Gravidade de Doença , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/patologia , Adulto Jovem
16.
Proc Natl Acad Sci U S A ; 111(51): 18315-20, 2014 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-25489101

RESUMO

Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. -1, respectively (P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Imunossupressores/uso terapêutico , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Cloridrato de Fingolimode , Humanos , Imunossupressores/efeitos adversos , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Propilenoglicóis/efeitos adversos , Método Simples-Cego , Esfingosina/efeitos adversos , Esfingosina/uso terapêutico
17.
JAMA Neurol ; 71(9): 1092-101, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25003359

RESUMO

IMPORTANCE: Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH. OBJECTIVE: To investigate whether oral administration of fingolimod, a Food and Drug Administration-approved sphingosine 1-phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH. DESIGN, SETTING, AND PARTICIPANTS: In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 mL. Clinical and neuroimaging feature-matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital, Tianjin, China. INTERVENTIONS: All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5 mg, orally for 3 consecutive days. Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms. MAIN OUTCOMES AND MEASURES: Neurologic status and hematomal and PHE volumes (Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months. RESULTS: Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (100% vs 50%, P = .01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5 (P < .001). Neurologic functions improved in these patients in the first week coincident with a reduction of circulating lymphocyte counts. At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions (modified Barthel Index score range, 95-100; 63% vs 0%; P = .001; modified Rankin Scale score range, 0-1; 63% vs 0%; P = .001), and fewer reported ICH-related lung infections. Perihematomal edema volume and rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P < .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events. CONCLUSIONS AND RELEVANCE: In patients with small- to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT02002390.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Imunossupressores/farmacologia , Propilenoglicóis/farmacologia , Esfingosina/análogos & derivados , Idoso , Hemorragia Cerebral/sangue , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Feminino , Cloridrato de Fingolimode , Escala de Coma de Glasgow , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Propilenoglicóis/administração & dosagem , Propilenoglicóis/efeitos adversos , Recuperação de Função Fisiológica/efeitos dos fármacos , Índice de Gravidade de Doença , Método Simples-Cego , Esfingosina/administração & dosagem , Esfingosina/efeitos adversos , Esfingosina/farmacologia , Resultado do Tratamento
18.
Bioorg Med Chem ; 22(15): 4312-22, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24909678

RESUMO

A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 µM, 0.06 µM and 0.05 µM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC50=1.73 µM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.


Assuntos
Amidas/química , Amidas/farmacologia , Antineoplásicos/síntese química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Amidas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Células MCF-7 , Conformação Molecular , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Moduladores de Tubulina/química
19.
Carbohydr Res ; 344(15): 2056-9, 2009 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-19616773

RESUMO

Peracetylated 2-deoxy-d-erythro-pentose (2-deoxy-d-ribose) was synthesized through the acetylation of 2-deoxy-d-ribose with acetic anhydride in pyridine, and the products (including all four ring forms) exist in form of either a white solid or a syrup. A single crystal of 1,3,4-tri-O-acetyl-2-deoxy-beta-d-erythro-pentopyranose was obtained from the syrup and its structure was determined by X-ray diffraction. The crystal adopts the (1)C(4) conformation, presenting an orthorhombic system, space group P2(1)2(1)2(1) with Z=4, unit cell dimensions a=7.2274 (3)A, b=8.0938 (5)A, and c=22.0517 (11)A.


Assuntos
Cristalografia por Raios X/métodos , Monossacarídeos/química , Configuração de Carboidratos , Estrutura Molecular , Ribose/análogos & derivados , Ribose/química
20.
Zhong Yao Cai ; 31(10): 1526-8, 2008 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-19230407

RESUMO

OBJECTIVE: To observe the influence of Qingxiang San (QS) on substance P (SP), somatostatin (SS) in rats model of spleen and stomach wet heat syndrome. METHODS: 24 rats were divided into 3 groups (each group 8 rats) randomly: the normal control group (NCG), wet heat group (WHG), QS group (QSG). We set up the spleen and stomach wet heat syndrome of rats model by the composite factors such as greasy and sweet food, wet and hot environment, pathogen and so on. Then the contents of SP, SS were detected by radioimmuno assay. RESULTS: The content of SP, SS in WHG were obviously lower than NCG (P<0.01); QSG compared with WHG, the content of SP, SS increased (P<0.01); The content of SP obviously increased when QSG compared with NCG (P<0.01); About the content of SS, there was no significant difference between QSG and NCG (P>0.05), illustrating that QS can increase the content of SP, SS which had decreased. CONCLUSION: QS can regulate the content of SP and SS and increase them which had decreased.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Somatostatina/metabolismo , Esplenopatias/metabolismo , Gastropatias/metabolismo , Substância P/metabolismo , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Hormônios Gastrointestinais/metabolismo , Masculino , Plantas Medicinais/química , Antro Pilórico/efeitos dos fármacos , Antro Pilórico/metabolismo , Radioimunoensaio , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Esplenopatias/tratamento farmacológico , Gastropatias/tratamento farmacológico , Deficiência da Energia Yin/tratamento farmacológico , Deficiência da Energia Yin/metabolismo
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