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1.
J Neurochem ; 151(5): 595-607, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520526

RESUMO

High-mobility group box-1 (HMGB-1) acts as a pro-inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro-inflammatory effects of HMGB-1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB-1 and explored whether this process is involved in the pro-inflammatory effects of HMGB-1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB-1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague-Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB-1. Increased levels of tumor necrosis factor and IL-1ß were observed in the P815 cells, as well as in the rats' brains, after HMGB-1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)-siRNA inhibited the HMGB-1-induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor-κB (NF-κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB-1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood-brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB-1-induced pro-inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro-inflammatory effect of HMGB-1 on the CNS, probably via activating the RAGE/NF-κB pathway.

2.
J Surg Oncol ; 120(3): 508-517, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31140623

RESUMO

BACKGROUND AND OBJECTIVES: To build nomogram incorporating potential prognostic factors for predicting survival outcomes of testicular germ cell tumors (TGCT) patients after resection of the primary tumor. METHODS: Data of TGCT patients from the Surveillance, Epidemiology, and End Results database (2010-2016) who underwent resection of the primary tumor were collected. Overall survival (OS) and cancer-specific survival (CSS) were analyzed by using Cox regression models, nomogram, Kaplan-Meier method, and log-rank test. RESULTS: We identified 7272 TGCT patients. Age at diagnosis, histology, tumor size, American Joint Committee on Cancer (AJCC) staging system, and number of metastases sites were independent prognostic factors and were integrated into nomograms. The nomograms had higher C-indexes for both OS and CSS compared with the AJCC 7th staging system (0.881 vs 0.831 and 0.895 vs 0.856, respectively). Moreover, the new stratification of risk groups based on the nomograms showed a more significant distinction between Kaplan-Meier curves for survival outcomes than the AJCC staging system. Retroperitoneal lymph node dissection was associated with statistically improved survival probability in the nomogram middle-risk group in resected TGCT patients. CONCLUSION: The novel nomogram-based staging system could provide satisfactory risk stratification and survival prediction ability beyond traditional AJCC staging systems.


Assuntos
Linfonodos/cirurgia , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/cirurgia , Nomogramas , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/cirurgia , Adulto , Humanos , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/patologia , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Espaço Retroperitoneal , Estudos Retrospectivos , Programa de SEER , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto Jovem
3.
Andrologia ; 51(2): e13198, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30443968

RESUMO

Recent studies have examined the impact of phosphodiesterase type 5 inhibitors (PDE5-Is) use on the risk of prostate cancer, and biochemical recurrence (BCR) in prostate cancer patients, but the results were inconsistent. A meta-analysis was conducted to assess the associations with all published studies. Databases (PubMed, Web of Science and MEDLINE) were retrieved to identify relevant studies which explored the impact of PDE5-Is use on the risk of prostate cancer, and BCR in prostate cancer patients. The summary results along with 95% confidence intervals (CIs) were calculated. Nine articles were eligible for the inclusion criteria. The pooled analysis showed that PDE5-Is use was not related to the increased risk of prostate cancer (odds ratio (OR), 0.71; 95% CI, 0.40-1.29). Moreover, PDE5-Is use was not linked to BCR risk in prostate cancer patients with erectile dysfunction (ED) following radical prostatectomy or radiation therapy (relative risk (RR), 1.09; 95% CI, 0.89-1.34). The heterogeneity test suggested moderate heterogeneity across studies. PDE5-Is use does not influence the risk of prostate cancer, and BCR in prostate cancer patients. More well-designed studies are warranted to confirm the findings of our analyses.


Assuntos
Recidiva Local de Neoplasia/etiologia , Inibidores da Fosfodiesterase 5/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/etiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Fatores de Risco
4.
Front Cell Neurosci ; 12: 222, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30104960

RESUMO

Recent research has revealed that uncontrolled chronic neuroinflammation is closely associated with diverse neurodegenerative diseases, by impairing blood-brain barrier (BBB) function and astrocytic reaction. Endoplasmic reticulum (ER) stress is conventionally linked to the loss of neuronal structure and function and should be widely attenuated. This notion has been questioned by recent experimental studies, which have shown that non-harmful levels of ER stress had numerous beneficial roles against neurodegeneration, including neuroprotection and inhibition of cytokine production. Here, we investigated the mild ER stress-based regulation of LPS-induced inflammatory responses in astrocytes. Primary astrocytes were exposed to tunicamycin (TM), a compound that activates ER stress, with or without the ER-stress inhibitor sodium 4-phenylbutyrate (4-PBA) before LPS treatment. Astrocytic activation, proinflammatory factor production, and the extent of ER stress were assessed. In addition, the effect of mild ER stress on astrocytes and BBB function was determined in vivo. Male Sprague-Dawley rats received intracerebroventricular injections of TM with or without intraperitoneal 4-PBA before LPS administration. The levels of astrocytic activation and BBB permeability were measured after treatment. Our results showed that lower doses of TM resulted in a mild ER-stress response without inducing cytotoxicity and tissue toxicity. Non-toxic ER-stress preconditioning ameliorated LPS-induced overactivation and inflammatory responses in astrocytes. Moreover, pre-exposure to non-lethal doses of TM improved LPS-induced BBB impairment and cognitive ability dysfunction in rats. However, 4-PBA, reversed the protective effect of TM preconditioning in vitro and in vivo. We conclude that mild ER stress ("preconditioning") can alleviate LPS-induced astrocytic activation and BBB disruption. Our findings provide a better understanding for the regulatory role of ER stress in neuroinflammation and indicate that mild ER stress might have therapeutic value for the treatment of neurodegenerative diseases.

5.
J Neuroinflammation ; 15(1): 41, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29433511

RESUMO

BACKGROUND: Astrocytes have attracted increasing attention over recent decades for their role in neuroinflammation. Histamine, a major aminergic brain neurotransmitter, has an important influence on the main activities of astrocytes, such as ion homeostasis, energy metabolism, and neurotransmitter clearance. However, little is known about the impact of histamine on astrocyte immunomodulatory function. METHODS: The expression of all known histamine receptor subtypes was examined in primary astrocytes. Then, primary astrocytes were pretreated with selective histamine receptor antagonists and stimulated with histamine. Cellular activation, proinflammatory cytokine production, and expression of neurotrophic factors were assessed. RESULTS: Astrocytes could constitutively express three histamine receptors (H1R, H2R, and H3R), and these three histamine receptors could be selectively upregulated to varying degrees upon histamine treatment. Histamine also dose-dependently stimulated astrocyte activation and subsequent production of glial cell-derived neurotrophic factor (GDNF), whereas it suppressed the secretion of the proinflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß). The effects of histamine were completely abolished by either an H1R or H3R antagonist, while an H2R antagonist attenuated the effects partly. CONCLUSIONS: The present study identified the expression of H1R, H2R, and H3R on astrocytes. We also demonstrated that negative regulation of astrocytic TNF-α and IL-1ß production and the enhancement of astrocytic GDNF stimulated by histamine were receptor-mediated processes in which all three of the expressed histamine receptors (H1R, H2R, and H3R) were involved. These findings may further clarify the involvement and mechanism of astrocyte activation in neuroinflammation.


Assuntos
Astrócitos/metabolismo , Histamina/farmacologia , Fármacos Neuroprotetores/metabolismo , Receptores Histamínicos/biossíntese , Regulação para Cima/fisiologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos/farmacologia , Mediadores da Inflamação/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos/genética , Regulação para Cima/efeitos dos fármacos
6.
J Neuroinflammation ; 14(1): 233, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29179727

RESUMO

BACKGROUND: Neuroinflammation, which ultimately leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. The neuroinflammatory process is characterized by the activation of glial cells such as microglia. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. Recently, it was confirmed that nonharmful levels of ER stress protected against experimental Parkinson's disease. Here, we investigated mild ER stress-based regulation of lipopolysaccharide (LPS)-driven neuroinflammation in rats and in primary microglia. METHODS: Male Sprague-Dawley (SD) rats received the intracerebroventricular injection of the ER stress activator tunicamycin (TM) with or without intraperitoneal injection of the ER stress stabilizer sodium 4-phenylbutyrate (4-PBA) 1 h before LPS administration. The levels of neuroinflammation and memory dysfunction were assessed 24 h after treatment. In addition, the effect of mild ER stress on microglia was determined in vitro. RESULTS: Here, we found that low doses of TM led to mild ER stress without cell or organism lethality. We showed that mild ER stress preconditioning reduced microglia activation and neuronal death as well as improved LPS-induced memory impairment in rats. In addition, pre-exposure to nonlethal doses of TM in microglia showed significant protection against LPS-induced proinflammatory cytokine production and M1/2b polarization. However, sodium 4-PBA, a compound that ameliorates ER stress, ablated this protective effect in vivo and in vitro. CONCLUSIONS: Based on our findings, we conclude that the mild ER stress not only limits the accumulation of misfolded proteins but also protects tissues from harmful endotoxemia insults. Therefore, ER stress preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Inflamação/fisiopatologia , Microglia/metabolismo , Animais , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Degeneração Neural/fisiopatologia , Ratos , Ratos Sprague-Dawley
7.
Toxicol Mech Methods ; 27(9): 687-696, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28701067

RESUMO

Veratrum nigrum L. (VN) is a poisonous traditional Chinese medicine herb present since thousands of years in China. Clinical studies have shown that VN has the ability to cause hepatotoxicity, which severely limits its clinical use. The mechanism of its hepatotoxicity has not been fully elucidated. The purpose of this study was to develop and characterize a model of acute and chronic hepatotoxicity induced by Veratrum nigrum L. extract (VNE) to understand the mechanism of liver tissue metabolomics approach using on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS). Mice were administered with VNE in the acute and chronic phases. Histopathologic inspections and biochemistry analysis disclosed severe liver damage after exposure to VNE. A partial least-squares discriminant analysis (PLS-DA) of the metabolomic profiles of rat liver tissues highlighted a number of metabolic disturbances induced by VNE, focusing on purine and pyrimidine metabolism, tryptophan metabolism, phospholipid metabolism, sphingolipid metabolism and fatty acid metabolism. These findings could well explain VNE-induced acute and chronic hepatotoxicity and reveal several potential biomarkers associated with this toxicity. This indicates that UHPLC-Q-TOFMS-based metabolomics approach demonstrated its feasibility and allowed a better understanding of VNE-induced liver toxicity dynamically.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fígado/efeitos dos fármacos , Espectrometria de Massas/métodos , Metabolômica , Extratos Vegetais/toxicidade , Veratrum/química , Animais , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Behav Brain Res ; 332: 145-153, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28587818

RESUMO

Neuroinflammation induced by peripheral trauma plays a key role in the development of postoperative cognitive dysfunction (POCD). Substantial evidence points to reactive glia as a pivotal factor during the inflammation process. However, little is known about the functional interactions between astrocytes and microglia. Recent evidence suggests the involvement of the CCL2-CCR2 pathway in CNS inflammation-related diseases. Our previous studies have suggested that astrocyte-derived CCL2 can induce microglial activation in vitro. Within this context, we sought to determine if the CCL2/CCR2 axis is involved in the crosstalk between astrocytes and microglia, contributing to increased neuroinflammation. Here, we show that tibial fracture surgery promoted CCL2 upregulation in activated astrocytes, increased CCR2 expression in activated microglia, and induced deficits in learning and memory. Site-directed pre-injection of RS504393, a CCR2 antagonist, inhibited this effect by reducing microglial activation, M1 polarization, inflammatory cytokines, and neuronal injury and death and improving cognitive function. Taken together, these data implicate CCL2-CCR2 signaling in astrocyte-mediated microglial activation in central nervous system (CNS) inflammation and suggest that interference with CCL2 signaling could constitute another potential therapeutic target for POCD.


Assuntos
Astrócitos/metabolismo , Quimiocina CCL2/metabolismo , Disfunção Cognitiva/metabolismo , Inflamação/metabolismo , Microglia/metabolismo , Complicações Pós-Operatórias/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Benzoxazinas/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Masculino , Microglia/efeitos dos fármacos , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Nootrópicos/farmacologia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/psicologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Fraturas da Tíbia/complicações , Fraturas da Tíbia/metabolismo , Fraturas da Tíbia/patologia , Fraturas da Tíbia/cirurgia
9.
Hematology ; 22(10): 578-584, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28580841

RESUMO

OBJECTIVES: Increasing numbers of clinical studies have been carried out to investigate the therapeutic effect of Ofatumumab for patients with chronic lymphocytic leukemia (CLL) but no studies have yet reported a pooled estimate of the treatment effect. We performed a meta-analysis of evidence from 13 clinical trials to assess effectiveness and safety of Ofatumumab-based therapy in patients with CLL. METHODS: Relevant publications from PubMed, Web of Science, Embase, and ClinicalTrials.gov were searched. The primary efficacy outcomes were progression-free survival (PFS) and overall survival (OS). The second endpoint was the adverse events. RESULTS: The pooled efficacy analysis showed that there were no significant difference in PFS [hazard ratios (HR) = 0.88, 95% confidence interval (CI) = 0.47-1.63, p = 0.677, I2 = 94.9%] and OS (HR = 0.97, 95% CI = 0.70-1.36, p = 0.878, I2 = 58.7%) between Ofatumumab-based therapy and non-Ofatumumab therapy. The pooled toxicity analysis showed that Ofatumumab-based therapy was associated with an increased risk of infusion-related reaction but decreased risk of thrombocytopenia and anemia compared with non-Ofatumumab-based therapy. Moreover, infections, and infusion-related reaction occurred more frequently in participants with single Ofatumumab studies. DISCUSSION: Our analysis showed PFS was statistically significantly improved with Ofatumumab-based treatments (including Ofatumumab alone, Ofatumumab plus chemotherapy) for CLL compared with observation or chemotherapy-based regimen groups. Ofatumumab had no statistically significant improvement on the OS of patients with CLL. The Ofatumumab-based therapy could generally decrease the risk of adverse effects except infusion-related reaction and infections.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Intervalo Livre de Doença , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Análise de Sobrevida
10.
Neurosci Lett ; 647: 85-90, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28302538

RESUMO

Neuroinflammatory processes have a vital role in the pathogenesis of neuropathic pain. Garcinol, harvested from Garcinia indica, is known to exert potent anti-inflammatory properties. Recent studies have indicated that Garcinol may inhibit activation of nuclear factor-κB (NF-κB) by inhibiting NF-κB/p65 acetylation. These findings prompted us to evaluate the protective effects of Garcinol in the lumbar fifth spinal nerve ligation (SNL)-induced rat model of neuropathic pain and Lipopolysaccharide(LPS)-stimulated primary cultured microglia. In the present study, we found that intrathecal administration of Garcinol significantly attenuated SNL-induced nociceptive behaviors. Garcinol suppressed microglial activation as well as the expression of interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase (iNOS)/nitric oxide (NO), and cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) in the spinal cord of SNL rats. It also reduced the nuclear translocation of NF-κB by decreasing acetyl-p65 protein expression. Similarly, in the in vitro study, Garcinol decreased the production of NO/iNOS, PGE2/COX-2, and proinflammatory cytokines in LPS-exposed microglia. Likewise, Garcinol inhibited the NF-κB signaling pathway by downregulating acetyl-p65 levels in LPS-challenged microglia. Our findings suggest that Garcinol may have protective effects against neuropathic pain that are associated with the inhibition of neuroinflammation in microglia. Therefore, Garcinol could be a promising agent in the treatment of neuropathic pain.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Microglia/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Terpenos/uso terapêutico , Transporte Ativo do Núcleo Celular , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Núcleo Celular/metabolismo , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Dinoprostona/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Microglia/metabolismo , NF-kappa B/metabolismo , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Cultura Primária de Células , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Nervos Espinhais/lesões , Terpenos/farmacologia
11.
J Genet ; 96(6): 993-1003, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29321359

RESUMO

A number of studies have investigated the association of lactase (LCT,C/T-13910) gene polymorphismwith bonemineral density (BMD) and fracture risk, but previous results were inconclusive. In this study, a meta-analysis was performed to quantify the association of LCT (C/T-13910) polymorphism with BMD and fracture risk. Eligible publications were searched in the PubMed, Web of Science, Embase databases, Google Scholar, Yahoo and Baidu. Pooled weighed mean difference (WMD) or odds ratio (OR) with their 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. A total of nine articles with 8871 subjects were investigated in the presentmeta-analysis. Overall, the TT/TC genotypes of LCT 13910 C/T polymorphism showed significantly higher BMD than those with the CC genotype at femur neck (FN) (WMD = 0.011 g/cm2, 95% CI = 0.004-0.018, P = 0.003). Besides, LCT 13910 C/T polymorphism may decrease the risk of any site fractures (for TT versus TC+CC, OR = 0.813, 95% CI = 0.704-0.938, P = 0.005; for T allele versus C allele, OR = 0.885, 95% CI = 0.792-0.989, P = 0.032). However, there was no significant association of LCT 13910 C/T polymorphism with BMD at lumbar spine and risk of vertebral fractures under all genetic contrast models (all P values were >0.05). The meta-analysis suggests that there are significant effects of LCT 13910 C/T polymorphism on BMD and fracture risk. Large-scale studies with different ethnic populations will be needed to further investigate the possible race-specific effect of LCT 13910 C/T polymorphism on BMD and fracture risk.


Assuntos
Fraturas Ósseas/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Lactase/genética , Adulto , Idoso , Densidade Óssea/genética , Feminino , Colo do Fêmur/patologia , Fraturas Ósseas/patologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
12.
Cell Physiol Biochem ; 40(1-2): 104-116, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27855371

RESUMO

BACKGROUND: Astrocytes, the major glial cell type that has been increasingly recognized as contributing to neuroinflammation, are critical in the occurrence and development of postoperative cognitive dysfunction (POCD). Although emerging evidence showed that brain mast cells (MCs) are the "first responders" in neuroinflammation, little is known about the functional communication between MCs and astrocytes. METHODS: In this study, we investigated the potential regulation of astrocyte activation by MCs. Rats received an intracerebroventricular injection of Cromolyn (an MC stabilizer) or sterile saline 30 min before undergoing open tibial fracture surgery, and the levels of neuroinflammation and the degree of memory dysfunction were evaluated at 1 day and 3 days after surgery. In the in vitro study, the effect of activated MCs on astrocytes were further clarified. RESULTS: Surgery increased the number of MCs, the astrocyte activation and the production of inflammatory factors, and resulted in cognitive deficits. Site-directed pre-injection of Cromolyn can inhibit this effect. In the vitro study, the conditioned medium from C48/80-stimulated mast cells (P815) could induce primary astrocyte activation and subsequent production of inflammatory cytokines, which could be inhibited by Cromolyn. CONCLUSION: These findings indicate that activated MCs could trigger astrocyte activation, be involved in neuroinflammation and possibly contribute to POCD. Interactions between MCs and astrocytes could provide potential therapeutic targets for POCD.


Assuntos
Astrócitos/patologia , Cérebro/patologia , Disfunção Cognitiva/patologia , Mastócitos/patologia , Complicações Pós-Operatórias/patologia , Animais , Astrócitos/efeitos dos fármacos , Contagem de Células , Degranulação Celular/efeitos dos fármacos , Cromolina Sódica/farmacologia , Citocinas/biossíntese , Ativação Enzimática/efeitos dos fármacos , Hipocampo/patologia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Ratos Sprague-Dawley , Tíbia/cirurgia
13.
J Cancer ; 7(11): 1388-95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27471554

RESUMO

Cervical cancer is a second leading cancer death in women world-wide, with most cases in less developed countries. Notch signaling is highly conserved with its involvement in many cancers. In the present study, we established stable cervical cell lines with Notch activation and inactivation and found that Notch activation played a suppressive role in cervical cancer cells. Meanwhile, the transient overexpression of the active intracellular domain of all four Notch receptors (ICN1, 2, 3, and 4) also induced the suppression of cervical cancer Hela cell growth. ICN1 also induced cell cycle arrest at phase G1. Notch1 signaling activation affected the expression of serial genes, especially the genes associated with cAMP signaling, with an increase of genes like THBS1, VCL, p63, c-Myc and SCG2, a decrease of genes like NR4A2, PCK2 and BCL-2. Particularly, The nuclear receptor NR4A2 was observed to induce cell proliferation via MTT assay and reduce cell apoptosis via FACS assay. Furthermore, NR4A2's activation could reverse ICN1-induced suppression of cell growth while erasing ICN1-induced increase of tumor suppressor p63. These findings support that Notch signaling mediates cervical cancer cell growth suppression with the involvement of nuclear receptor NR4A2. Notably, Notch/NR4A2/p63 signaling cascade possibly is a new signling pathway undisclosed.

14.
Br J Biomed Sci ; 73(3): 134-139, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27400196

RESUMO

BACKGROUND: The aims of this study were to investigate the effects of rivaroxaban on routine coagulation assays using our local, widely available, reagents and to study the relationship between sensitive coagulation assays and bleeding risk caused by rivaroxaban. METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT) and anti-factor Xa (FXa) chromogenic assays (Biophen DiXaI) and inhibition of FXa activity were performed in normal pooled plasma (NPP) spiked with rivaroxaban and plasma samples from patients treated with rivaroxaban. RESULTS: In vitro, the linear correlation coefficient of measured concentrations of rivaroxaban, by Biophen DiXaI, and spiked concentrations of rivaroxaban was 0.99. PT and APTT showed good linear correlation with rivaroxaban concentrations, while other assays showed poor correlation. In vivo, PT showed a moderate linear correlation with rivaroxaban concentrations while APTT had a weak correlation with rivaroxaban concentrations. In vitro and in vivo, the rivaroxaban concentrations, measured by Biophen DiXaI, always showed good correlation with the inhibition of FXa activity, and PT values showed moderate correlation with the inhibition of FXa activity. CONCLUSIONS: Biophen DiXaI can be considered as a quantitative method to monitor the anticoagulation activity of rivaroxaban, and could be used to evaluate bleeding risk caused by rivaroxaban. The PT reagent (Thrombosis S) could be considered as a rough method to monitor the anticoagulation activity of rivaroxaban and evaluate bleeding risk caused by rivaroxaban.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Rivaroxabana/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Trombose Venosa/prevenção & controle , Adulto Jovem
15.
J Drug Target ; 24(2): 169-77, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26211366

RESUMO

BACKGROUND: Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization. MATERIALS AND METHODS: The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST). RESULTS: VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells. CONCLUSION: The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.


Assuntos
Proliferação de Células/efeitos dos fármacos , Peptídeos/metabolismo , Receptores de Peptídeos/metabolismo , Receptores de Somatostatina/metabolismo , Ácido Valproico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Camundongos Nus , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores Notch/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Org Lett ; 17(21): 5296-9, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26468610

RESUMO

A highly enantioselective synthesis of spirocycles and bridged rings has been developed through a formal [4 + 2] cycloaddition reaction between enones and N-sulfonylimines. The unprecedented strategy has been realized utilizing N-sulfonylimine as a novel dienophile through enamine-iminium tautomerism of N-sulfonylimine. In addition, a γ,ε-regioselective cycloaddition reaction proceeded by employing methylene chromene species as dienophiles.

17.
Neuroreport ; 26(12): 723-7, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26164461

RESUMO

Lamotrigine (LTG) has shown benefits in animal models of cerebral ischemia, but the mechanism involved was not fully studied. This study was carried out to examine the effects of LTG on cognitive dysfunction, ß-amyloid1-42 accumulation, and tau protein hyperphosphorylation in the hippocampus of ischemic rats. Transient ischemic stroke was induced by middle cerebral artery occlusion. The Morris water maze test was used to evaluate the cognitive function of rats. We found that LTG significantly attenuated ischemia-induced cognitive deficits and decreased neuronal injury in the hippocampal CA1 zone. Moreover, LTG reduced ß-amyloid1-42 and phosphorylated tau (AT8) in the hippocampus after ischemia. These results suggested that the cognition-protective effects of LTG after cerebral ischemia might involve inhibition of toxic ß-amyloid accumulation and tau hyperphosphorylation in the hippocampus.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Isquemia Encefálica/metabolismo , Transtornos Cognitivos/metabolismo , Hipocampo/metabolismo , Triazinas/uso terapêutico , Proteínas tau/metabolismo , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Hipocampo/efeitos dos fármacos , Lamotrigina , Masculino , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ratos , Ratos Sprague-Dawley , Triazinas/farmacologia
18.
Nat Commun ; 5: 4479, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25057788

RESUMO

One of the major challenges of modern asymmetric catalysis is the ability to selectively control the formation of all diastereoisomers of reaction products possessing multiple stereocenters. Pioneers of such diastereodivergent catalytic asymmetric processes have focused on reactions where the newly formed stereogenic centres are proximal to the active carbonyl group. To date, however, diastereodivergent reactions at remote positions remain an unmet challenge. Herein, we describe a catalyst-controlled diastereodivergence in the formation of remote stereocenters in the direct vinylogous Michael reactions of ß, γ-unsaturated butenolides to α, ß-unsaturated ketones. The reactions are enabled by two complementary, non-enantiomeric multifunctional catalysts, which mutually activate and organise both reactants, affording either the syn- or anti-adduct with high diastereo- and enantioselectivity. These two catalytic systems are also applicable in the Mukaiyama-Michael reactions and tandem Michael-Michael reactions.

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