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1.
Neurochem Res ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482256

RESUMO

Neuroinflammation and brain edema are major complications in the pathophysiology of surgical brain injury (SBI). Programmed death-ligand 1 (PD-L1), an immune inhibitory receptor ligand, has been increasingly investigated for inhibition of T cell-mediated immunity and braking inflammatory response. However, the negative immunomodulatory capacity of PD-L1 and their possible mechanism in SBI is not yet clear. This study aimed to evaluate the expression and the role of PD-L1 in a mouse model of SBI induced inflammation and to further study the potential therapeutic effects of PD-L1 on SBI. Here we showed that PD-L1 expression was markedly elevated in the surrounding peri-resection brain tissue post-SBI in vivo. PD-L1 was up-regulated through ERK signal pathway in LPS-treated BV-2 cells in vitro. Furthermore, blockade of the PD-L1 checkpoint using PD-L1 antibody significantly enhanced brain edema, exacerbated apoptosis and increased neurodeficits post-SBI. Moreover, activated PD-1/PD-L1 with PD-L1 protein significantly attenuated the inflammation responses and brain edema post-SBI. These results suggest that enhanced expression of PD-L1 post-SBI exerts self-protection from inflammation and promotes neurological repair. PD-L1 signal may have therapeutic potential for neurodegenerative disorders.

2.
Emerg Microbes Infect ; 8(1): 1122-1125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31347462

RESUMO

The Xinjiang Uygur Autonomous Region locating in Northwest of China was not considered the epidemic area of severe fever with thrombocytopenia syndrome (SFTS). Here we report the first laboratory-confirmed SFTS case that a female patient had tick bite in Xinjiang and illness onset after returning to Hainan Province. Laboratory tests identified SFTS virus (SFTSV) infection, and the virus was isolated from the patient's serum sample. Furthermore, SFTSV prevalence among tick groups was identified, and IgM response to SFTSV from febrile patients was identified. The findings suggested that there have been risks of SFTSV infection due to exposure to ticks in Xinjiang.

3.
Curr Drug Deliv ; 16(6): 538-547, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30674259

RESUMO

BACKGROUND: Fenofibrate (FNB) is an effective drug for the treatment of hypertriglyceridemia, hypercholesterolemia as well as mixed hyperlipidemia. However, due to its poor aqueous solubility, FNB has the problem of poor oral absorption followed by low bioavailability. OBJECTIVE: The aim of this research was to construct FNB amorphous solid dispersion employing PVP VA64 as the carrier by hot-melt extrusion method, in order to improve the oral bioavailability. Additionally, the cell transport experiment was conducted to further investigate the mechanism of promoted osmotic absorption. METHODS: The physical state of the obtained solid dispersion was characterized using SEM, DSC and XRD. Besides, in vitro Caco-2 cells were used to evaluate the cytotoxicity of the carrier and mimic gastrointestinal drug permeation. At last, in vitro dissolution test and in vivo bioavailability study were also carried out. RESULTS: The prepared FNB solid dispersion was found to be an amorphous state after hot-melt extrusion process. In vitro cytotoxicity test on Caco-2 cells confirmed the excellent biocompatibility of the carrier PVP VA64. Besides, transwell cell transport assay and in vitro dissolution test revealed that FNB released from amorphous solid dispersion was equipped with an improved transmembrane transport and dissolution rate. Moreover, pharmacokinetic study in beagle dogs showed that comparing with commercial micronized product Lipanthyl®, the oral bioavailability of FNB solid dispersion was significantly enhanced (2.45 fold). CONCLUSION: In conclusion, PVP VA64 can be regarded as a promising polymer to enhance the bioavailability of poorly water-soluble drugs such as FNB processed by hot-melt extrusion. Besides, investigations on the mechanism of the enhanced penetration are expected to lay a foundation on the subsequent development of effective and practical solid dispersion.

4.
AAPS PharmSciTech ; 20(2): 85, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30673901

RESUMO

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03 µm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.


Assuntos
Antibacterianos/administração & dosagem , Bronquiectasia/tratamento farmacológico , Ciprofloxacino/administração & dosagem , Administração por Inalação , Aerossóis , Inaladores de Pó Seco , Fibroínas , Humanos , Manitol/química , Tamanho da Partícula
5.
Biomed Res Int ; 2018: 6953506, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30420967

RESUMO

Background: BCL6 was a critical prooncogene of human B-cell lymphomas which promoted tumor progress and contributed to malignant behavior in several kinds of cancers. This study was to detect the expression of BCL6 and its biological effect on glioma. Methods: RT-PCR and Western blot were used to detect the expression of BCL6 mRNA and protein in tissues and glioblastoma cell lines. The expression of BCL6 was knockdown in two glioblastoma cell lines (U87 and U251) using BCL6 shRNA. The CCK8, colony-formation, flow cytometry, Transwell, and wound-healing assays were used to evaluate the malignant phenotypic change of glioblastoma cells. Results: The expression of BCL6 was higher in glioma tissues and glioblastoma cell lines than normal tissues. Knockdown of BCL6 expression reduced the proliferation, migration, and invasion of glioblastoma cells. Moreover, knockdown of BCL6 changed expression of proteins related to malignant behaviors of glioblastoma cells. The suppression of BCL6 could increase chemosensitivity of U87 and U251 to temozolomide. Downregulation of BCL6 levels suppressed the expression of BCL2, cyclin D1, MMP2, and MMP9 proteins as well as two classic signaling pathway proteins p-AKT and p-ERK. Simultaneously, BAX and p21 protein levels were upregulated along with knockdown of BCL6. Conclusions: Our results indicated that BCL6 may be a tumor oncogene involved in the progression of glioma via affecting AKT and MAPK signaling pathways.

6.
Oncol Rep ; 40(5): 3049-3059, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226603

RESUMO

Epsin 3 (EPN3) expression is limited to gastric parietal cells and wounded or pathological tissue rather than normal brain tissue, and although it has been identified as an oncogene in estrogen receptor­positive breast cancer and non­small cell lung cancer, its function in cancer is poorly understood. The present study aimed to investigate the association of EPN3 expression with the clinicopathological features of patients with glioma, as well as the effects of EPN3 on glioblastoma cells and the potential molecular mechanisms for its effects on glioblastoma cell behavior. EPN3 expression was assessed by immunohistochemistry in tissue samples from 167 patients with glioma, as well as by western blotting in 5 glioblastoma cell lines. The U87 and U251 glioblastoma cell lines were used to investigate the effects of EPN3 on glioblastoma cell invasion and migration through gain and loss of EPN3 expression experiments; expression levels were further investigated by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blot analyses. The results demonstrated that EPN3 expression levels were upregulated in high­grade glioma tissues compared with low­grade tissues, and there were varying expression levels of EPN3 in the five glioblastoma cell lines. No significant differences were observed in EPN3 expression in relation to patient age, sex or tumor size. Overexpression of EPN3 promoted glioblastoma cell migration and invasion, which we hypothesized was through affecting epithelial­mesenchymal transition (EMT). RT­qPCR and western blotting revealed that EPN3 upregulation increased the expression of Notch1 intracellular domain, ß­catenin, Slug, Twist and zinc­finger E­box­binding homeobox (ZEB)­1. These results suggested that EPN3 enhances the migration and invasion of glioblastoma cells by activating the transcription factors Slug, Twist and ZEB1, but not Snail 1 or ZEB2, to induce EMT in glioma cells; EPN3 involvement in the Notch and WNT/ß­catenin signaling pathways may contribute to this process.

7.
Biochem Biophys Res Commun ; 503(4): 2436-2442, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-29969628

RESUMO

MiR-124-3p and EphA2 are aberrantly expressed in glioma tissue specimens. In the present study, we firstly investigated that miR-124-3p inhibits EphA2 expression mediated by binding its 3'-UTR to regulate the progression of human glioma. The U87MG and LN229 cells were transfected with miR-124-3p mimics and/or siRNA-EphA2, and then the role of miR-124-3p and EphA2 in the colony-formation, cell-cycle, migration and invasion of glioma cells in vitro were examined. Proteins involved in the epithelial-mesenchymal transition were examined using western blot. The results showed that miR-124-3p was significantly downregulated in glioma tissues, whereas a marked upregulation of EphA2 expression was found. Colony-formation and flow cytometry assays demonstrated that EphA2 downregulation or miR-124-3p mimics caused growth and cell-cycle inhibition in glioma. Transwell migration and invasion assays demonstrated that EphA2 downregulation or miR-124-3p mimics suppressed the migration and invasion of glioma cells. EphA2 downregulation or miR-124-3p mimics reduced the level of vimentin in U87MG and LN229 cells. In conclusion, miR-124-3p was found to suppress the growth, migration and invasion of glioma cells in vitro via EphA2. Furthermore, we validated miR-124-3p enforced its biological modulation via targeting EphA2 through the rescue experiment. Conclusively, our study proclaimed that miR-124-3p can counteract the malignant phenotypes of glioma cells by the inhibitory effect of the EphA2.

8.
Acta Biochim Biophys Sin (Shanghai) ; 50(8): 776-781, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29939221

RESUMO

Multiple independent reports have demonstrated pericyte loss in both the hippocampus and cortex in human Alzheimer's disease (AD). The differentiation and recruitment of pericytes are the essential steps in vasculature development. However, the role of amyloid beta (Aß) in pericyte differentiation has not yet been fully elucidated. In this study, we investigated the interaction between Aß and differentiation of mesenchymal stem cells (MSCs) toward pericytes in culture. Our results showed that mice overexpressing Aß-precursor protein (APP/PS1) exhibited the loss of pericytes compared with the control group mice, evidenced by the lack of desmin expression in the cortex of 12-month-old mice. Interestingly, we further found that both Aß40 and Aß42 inhibited the expressions of pericyte markers (α-SMA, desmin, and PDGFRß) in cultured MSCs which can be differentiated into mature pericytes. Mechanistically, the inhibitory effects of Aßs on MSC-pericyte transition is mediated by the activation of the ERK1/2 MAPK signal pathway. These new insights into the roles of Aß in pericyte differentiation may help to develop more effective strategies for the treatment of AD.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Diferenciação Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Pericitos/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Cultivadas , Desmina/genética , Desmina/metabolismo , Expressão Gênica , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pericitos/citologia , Pericitos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo
9.
Acta Pharm Sin B ; 8(2): 165-177, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29719777

RESUMO

Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.

10.
Virol Sin ; 33(1): 74-86, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29520745

RESUMO

Crimean-Congo hemorrhagic fever (CCHF) caused by the CCHF virus (CCHFV) is a tick-borne natural focal disease with a mortality rate of approximately 50%. CCHFV is widely prevalent in Africa, southern Asia, the Middle East, and southeast Europe. CCHF outbreaks have been reported previously in Xinjiang province, China, especially in its southern region. Epidemiological surveys conducted on ticks and animals have revealed the presence of CCHFV strains in ticks, rodents, and infected individuals from cities and counties in southern Xinjiang. Phylogenetic analyses revealed that the Chinese CCHFV strains belong to one genotype, based on complete sequences of the S segments of its negative-stranded RNA genome. The present study reports two new CCHFV strains isolated from Hyalomma asiaticum asiaticum ticks collected from Fukang City and Wujiaqu City in the northern region of Xinjiang. Viral characteristics and their evolutionary relationships were analyzed through metagenomic and reverse-transcription PCR analyses; these analyses indicated that the genotype of both strains was different from that of other Chinese strains. Furthermore, previous reports of CCHFV in Xinjiang were reviewed and phylogenetic analyses were performed. CCHFV was found to prevail in Fukang City in Junggar Basin for more than 20 years, and that Fukang City and Wujiaqu City are considered natural reservoirs of different genotypes of CCHFV strains. Our findings facilitate the understanding of CCHFV distribution in Xinjiang province and provide insights into the evolutionary relationships among Chinese CCHFV strains.


Assuntos
Genótipo , Vírus da Febre Hemorrágica da Crimeia-Congo/classificação , Vírus da Febre Hemorrágica da Crimeia-Congo/isolamento & purificação , Ixodidae/virologia , Filogeografia , Animais , China , Análise por Conglomerados , Vírus da Febre Hemorrágica da Crimeia-Congo/genética , Metagenômica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Homologia de Sequência
11.
Eur J Pharm Biopharm ; 122: 104-112, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29042238

RESUMO

Thymopentin (TP5) is commonly used in the treatment for autoimmune diseases, with a short plasma half-life (30s) and a long treatment period (7 days to 6 months). It is usually administrated by syringe injection, resulting in compromised patient compliance. Dissolving microneedle array (DMNA) offers a superior approach for transdermal delivery of biological macromolecules, as it allows painless penetration through the stratum corneum and generates minimal biohazardous waste after dissolving in the skin. Despite recent advances in DMNA as a novel approach for transdermal drug delivery, problem of insufficient mechanical strength remains to be solved. In this study, TP5-loaded DMNA (TP5-DMNA) was uniquely developed using a modified two-step molding technology. The higher mechanical strength was furnished by employing bovine serum albumin (BSA) as a co-material to fabricate the needles. The obtained TP5-DMNA containing BSA displayed better skin penetration and higher drug loading efficiency than that without BSA. The in vivo pharmacodynamics study demonstrated that TP5-DMNA had comparative effect on immunomodulation to intravenous injection of TP5, in terms of ameliorating the CD4+/CD8+ ratio, SOD activity and MDA value to the basal level. Only mild irritation was observed at the site of administration. These results suggest that the novel TP5-DMNA utilizing BSA provides an alternative approach for convenient and safe transdermal delivery of TP5, which is a promising administration strategy for future clinical application.


Assuntos
Imunomodulação/efeitos dos fármacos , Timopentina/administração & dosagem , Timopentina/sangue , Administração Cutânea , Animais , Sistemas de Liberação de Medicamentos/métodos , Feminino , Agulhas , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Ratos , Ratos Sprague-Dawley , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/química , Pele/metabolismo
12.
Brain Res ; 1676: 69-76, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28842123

RESUMO

MicroRNAs (miRNAs) play a critical role in glioblastoma initiation and progression. PIWIL1, a human homolog of the PIWI family, has a critical effect on glioblastoma progression. In present study, we found that the expression of miR-154-5p was significantly lower in glioblastoma. Our results suggested that the overexpression of miR-154-5p suppressed proliferation and metastasis, induced apoptosis, whereas inhibiting the expression of miR-154-5p significantly promoted proliferation and metastasis of glioblastoma. We further proved that miR-154-5p directly integrated with the 3'-UTR of PIWIL1 and reintroduction of PIWIL1 can rescue the phenotype changes induced by miR-154-5p. Taken together, our study reveals that miR-154-5p can counteract the malignant phenotypes of glioblastoma by targeting PIWIL1, which might be beneficial to reveal new therapeutic targets for glioblastoma.


Assuntos
Proliferação de Células/fisiologia , Glioblastoma/metabolismo , MicroRNAs/metabolismo , Metástase Neoplásica/fisiopatologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/fisiologia , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Encéfalo/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/administração & dosagem , Invasividade Neoplásica/fisiopatologia , Transplante de Neoplasias
13.
Cancer Sci ; 108(1): 61-72, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27862679

RESUMO

Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real-time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase-activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial-mesenchymal transition markers E-cadherin and N-cadherin, which is important given that epithelial-mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.


Assuntos
Movimento Celular , Fatores de Transcrição Forkhead/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Glioma/metabolismo , Glioma/patologia , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Transição Epitelial-Mesenquimal , Feminino , Proteínas Ativadoras de GTPase/deficiência , Proteínas Ativadoras de GTPase/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Urol Int ; 99(2): 237-244, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27027898

RESUMO

PURPOSE: Lactate dehydrogenase A (LDHA), which functions as a crucial enzyme in transforming from pyruvate into lactate, has been reported to be overexpressed in various advanced cancer and its silencing has turned out to be tumor suppressive. Previous studies have showed that the expression of LDHA was higher in renal cell carcinoma (RCC) than that in corresponding normal renal tissue. However, the function of LDHA in RCC, and its possible mechanism in tumor progression, has not been investigated. METHODS: MTT and cell cycle assay were performed to explore the growth of the renal cells. Transwell assay for the migration and invasion and tube formation were conducted to detect the metastatic properties of the renal cancer. RESULTS: Here, we show that siRNA-mediated knockdown of LDHA inhibits cell proliferation by decreasing cell cycle and promoting apoptosis in renal cancer cell lines. Mechanistically, LDHA siRNA treatment altered the expression of cell cycle- and apoptosis-related proteins, including p21, cyclin D1, Bcl-2 and Bax. In addition, LDHA siRNA treatment leads to markedly diminished migratory and invasive ability by reducing the expression of matrix metalloproteinase (MMP)-2 and MMP-9. CONCLUSIONS: These findings are consistent with the view that LDHA, as an oncogene, might be a potential therapeutic target in RCC.


Assuntos
Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , L-Lactato Desidrogenase/metabolismo , Interferência de RNA , Terapêutica com RNAi , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Neoplasias Renais/enzimologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , L-Lactato Desidrogenase/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transfecção
15.
Neurochem Res ; 41(10): 2810-2818, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27386875

RESUMO

Tacrolimus (FK506), an immunophilin ligand, has been widely shown to be neuroprotective in a posttraumatic period. The nuclear factor of activated T cells (NFATc1) pathway plays an important role in regenerating neurological function following traumatic brain injury (TBI), but the precise mechanism underlying FK506-induced repair of neurological functions remains unclear. In the present study, a total of 210 SD rats were enrolled and randomly divided into sham group, TBI group and FK506 group. The rats in the TBI and FK506 groups were inflicted with moderate TBI left lateral fluid percussion impact. A modified neurological severity score (mNSS) system was used to evaluate the severity of effects on nerve function. mNSS levels were significantly lower in the FK506 group than in the TBI group. The zaccumulation of cerebral water content was lower, cerebral Aquaporin 4 (AQP4) mRNA level was lower, the number of growth-associated protein-43 (GAP-43)-positive cells was higher, and the distribution of vesicles containing excitatory neurotransmitters was altered in the injured cortex in the FK506 group. Moreover, the cortical mRNA and serum protein expression levels of interleukin-2 (IL-2) and interferon-γ (IFN-γ) were decreased in FK506 group, especially at 6 h and at 1 day after TBI. At days 1-28 after TBI, the expression of cleaved-caspase 3, which indicates apoptosis, was lower in the FK506 group than in the TBI group. Mechanistically, FK506 significantly down-regulated the mRNA and protein levels of calcium-regulated phosphatase (calcineurin, CaN) and inhibited the activation of NFATc1. These results demonstrate that FK506 relieved inflammatory responses by regulating the NFATc1 signaling pathway and promoting the synaptic reconstruction of neurons and glial cells by regulating cell apoptosis, thereby facilitated improvements in neurological function.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tacrolimo/farmacologia , Animais , Lesões Encefálicas Traumáticas/metabolismo , Calcineurina/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Interferon gama/metabolismo , Masculino , Fatores de Transcrição NFATC/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos Sprague-Dawley
16.
Amino Acids ; 48(9): 2169-77, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27156064

RESUMO

In mammalian tissues, taurine is an important natural component and the most abundant free amino acid in the heart, retina, skeletal muscle, brain, and leukocytes. This study is to examine the taurine's protective effects on neuronal ultrastructure, the function of the mitochondrial respiratory chain complex, and on cerebral blood flow (CBF). The model of traumatic brain injury (TBI) was made for SD rats by a fluid percussion device, with taurine (200 mg/kg) administered by tail intravenous injection once daily for 7 days after TBI. It was found that CBF was improved for both left and right brain at 30 min and 7 days post-injury by taurine. Reaction time was prolonged relative to the TBI-only group. Neuronal damage was prevented by 7 days taurine. Mitochondrial electron transport chain complexes I and II showed greater activity with the taurine group. The improvement by taurine of CBF may alleviate edema and elevation in intracranial pressure. Importantly taurine improved the hypercoagulable state.


Assuntos
Edema Encefálico/prevenção & controle , Lesões Encefálicas Traumáticas/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Mitocôndrias/metabolismo , Taurina/farmacologia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Masculino , Mitocôndrias/patologia , Ratos , Ratos Sprague-Dawley
17.
Chin Med J (Engl) ; 129(7): 831-7, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-26996480

RESUMO

BACKGROUND: The interaction between activated microglia and T lymphocytes can yield abundant pro-inflammatory cytokines. Our previous study proved that thymus immune tolerance could alleviate the inflammatory response. This study aimed to investigate whether intrathymic injection of myelin basic protein (MBP) in mice could suppress the inflammatory response after co-culture of T lymphocytes and BV-2 microglia cells. METHODS: Totally, 72 male C57BL/6 mice were randomly assigned to three groups (n = 24 in each): Group A: intrathymic injection of 100 µl MBP (1 mg/ml); Group B: intrathymic injection of 100 µl phosphate-buffered saline (PBS); and Group C: sham operation group. Every eight mice in each group were sacrificed to obtain the spleen at postoperative days 3, 7, and 14, respectively. T lymphocytes those were extracted and purified from the spleens were then co-cultured with activated BV-2 microglia cells at a proportion of 1:2 in the medium containing MBP for 3 days. After identified the T lymphocytes by CD3, surface antigens of T lymphocytes (CD4, CD8, CD152, and CD154) and BV-2 microglia cells (CD45 and CD54) were detected by flow cytometry. The expressions of pro-inflammatory factors of BV-2 microglia cells (interleukin [IL]-1ß, tumor necrosis factor-α [TNF-α], and inducible nitric oxide synthase [iNOS]) were detected by quantitative real-time polymerase chain reaction (PCR). One-way analysis of variance (ANOVA) and the least significant difference test were used for data analysis. RESULTS: The levels of CD152 in Group A showed an upward trend from the 3rd to 7th day, with a downward trend from the 7th to 14th day (20.12 ± 0.71%, 30.71 ± 1.14%, 13.50 ± 0.71% at postoperative days 3, 7, and 14, respectively, P < 0.05). The levels of CD154 in Group A showed a downward trend from the 3rd to 7th day, with an upward trend from the 7th to 14th day (10.00 ± 0.23%, 5.28 ± 0.69%, 14.67 ± 2.71% at postoperative days 3, 7, and 14, respectively, P < 0.05). The ratio of CD4+/CD8 + T in Group A showed a downward trend from the 3rd to 7th day, with the minimum at postoperative day 7, then an upward trend from the 7th to 14th day (P < 0.05). Meanwhile, the levels of CD45 and CD54 in Group A were found as the same trend as the ratio of CD4+/CD8 + T (CD45: 83.39 ± 2.56%, 82.74 ± 2.09%, 87.56 ± 2.11%; CD54: 3.80 ± 0.24%, 0.94 ± 0.40%, 3.41 ± 0.33% at postoperative days 3, 7, and 14, respectively, P < 0.05). The expressions of TNF-α, IL-1ß, and iNOS in Group A were significantly lower than those in Groups B and C, and the values at postoperative day 7 were the lowest compared with those at postoperative days 3 and 14 (P < 0.05). No significant difference was found between Groups B and C. CONCLUSIONS: Intrathymic injection of MBP could suppress the immune reaction that might reduce the secondary immune injury of brain tissue induced by an inflammatory response.


Assuntos
Anti-Inflamatórios/farmacologia , Microglia/imunologia , Proteína Básica da Mielina/farmacologia , Linfócitos T/imunologia , Animais , Antígenos de Superfície/análise , Lesões Encefálicas Traumáticas/tratamento farmacológico , Relação CD4-CD8 , Técnicas de Cocultura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/administração & dosagem
18.
Colloids Surf B Biointerfaces ; 141: 476-482, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26896653

RESUMO

Mesoporous silica Santa Barbara amorphous-15 (SBA-15), derived from supermolecular assemblies of surfactant Pluronic(®) P123 with well-ordered 2-D hexagonal pores, was investigated as a reservoir to construct a novel solid self-emulsifying matrix for enhancing the oral bioavailability of fenofibrate (FNB). The emulsification rate and droplet size of a liquid self-emulsifying delivery system (SEDDS) were analyzed for optimization. SBA-15 was then added to the ethanol solution containing liquid SEDDS, and the obtained suspension changed into solid SEDDS matrix via solvent evaporation. The characterizations by SEM and XRD revealed that the solid matrix consisted of particles with smooth surface and FNB was completely transformed into molecular or amorphous state in the formulation. When introduced to aqueous media under gentle agitation, the solid matrix exhibited excellent self-emulsification properties and formed a uniform microemulsion with mean diameter of 117.35 ± 2.33 nm. The solid SEDDS matrix showed faster in vitro release rate than the raw powder and commercial capsule. The absorption of FNB delivered by solid SEDDS matrix was significantly improved in beagle dogs, and its Cmax and AUC values were about 8- and 4-fold greater than those of commercial products, respectively. In conclusion, SBA-15 emerged as a promising reservoir for SEDDS to enhance the bioavailability of poorly water-soluble drugs, which may provide a new strategy for advanced therapies.


Assuntos
Emulsificantes/química , Emulsões/química , Fenofibrato/farmacocinética , Dióxido de Silício/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Cães , Liberação Controlada de Fármacos , Fenofibrato/administração & dosagem , Fenofibrato/química , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Taxa de Depuração Metabólica , Microscopia Eletrônica de Varredura , Porosidade , Difração de Raios X
19.
Oncol Lett ; 12(6): 5080-5084, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28105214

RESUMO

To investigate the detection value of tumor cells in cerebrospinal fluid (CSF) in the adjuvant diagnosis of meningeal metastasis from lung cancer by immunofluorescence in situ hybridization (immuno-FISH) technology. The circulating tumor cells (CTCs) in the CSF of 16 patients with meningeal metastasis from lung cancer and 8 with non-tumor diseases in the brain were detected using immuno-FISH technology. The diagnosis of meningeal metastasis from lung cancer was based on neurological symptoms, enhanced magnetic resonance imaging (MRI) scans and CSF cytological examination. The number of CTCs in the patients with meningeal metastasis from lung cancer was significantly higher than those with non-tumor diseases in the brain (P<0.01). The critical point of the maximum correct diagnostic index (Youden index) was regarded as the judging criterion for positive tumor cells in CSF according to the receiver operating characteristic curve. When there was one tumor cell in 7.5 ml CSF, the area under curve was 0.875 (95% confidence interval, 0.705~1.000). The diagnostic sensitivity, specificity, effectiveness, positive and negative predictive values were 75.0, 100.0, 83.3, 100.0 and 66.7%, respectively. There may be great clinical value in the detection of CTCs in CSF for the diagnosis of meningeal metastasis from lung cancer by immuno-FISH technology.

20.
Int J Oncol ; 48(2): 559-68, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26648123

RESUMO

The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC50) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/análogos & derivados , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Isotiocianatos/farmacologia , NF-kappa B/genética , Proteínas Supressoras de Tumor/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Dacarbazina/farmacologia , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Glioblastoma/genética , Humanos , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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