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1.
Artigo em Inglês | MEDLINE | ID: mdl-34028566

RESUMO

Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling. In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28.6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0.017). In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0.037; HR, 0.208) and overall survival (OS, P = 0.045; HR, 0.185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0.022; HR, 0.290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors. Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle. Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden. Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy.

2.
J Clin Oncol ; 39(7): 748-756, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417481

RESUMO

PURPOSE: Effective interventions to improve prognosis in metastatic esophagogastric cancer (EGC) are urgently needed. We assessed the effect of the early integration of interdisciplinary supportive care for patients with metastatic EGC on overall survival (OS). PATIENTS AND METHODS: An open-label, phase III, randomized, controlled trial was conducted at Peking University Cancer Hospital & Institute. Patients with previously untreated metastatic EGC were enrolled. Patients were randomly assigned (2:1) to either early interdisciplinary supportive care (ESC) integrated into standard oncologic care or standard care (SC). ESC was provided by a team of GI medical oncologists, oncology nurse specialists, dietitians, and psychologists; patients in the SC group received standard oncologic care alone. The primary end point was OS in the intention-to-treat population. RESULTS: Between April 16, 2015, and December 29, 2017, 328 patients were enrolled: 214 in the ESC group and 114 in the SC group. At the data cutoff date of January 26, 2019, 15 (5%) patients were lost to follow-up. The median number of cycles of first-line chemotherapy was five (interquartile range [IQR], 4-7) in the ESC group and four (IQR, 2-6) in the SC group. The median OS was 14.8 months (95% CI, 13.3 to 16.3) in the ESC group and 11.9 months (95% CI, 9.6 to 13.6) in the SC group (hazard ratio, 0.68; 95% CI, 0.51 to 0.9; P = .021). CONCLUSION: The early integration of interdisciplinary supportive care is an effective intervention with survival benefits for patients with metastatic EGC. Further optimization and standardization are warranted.

3.
Immunotherapy ; 13(1): 55-66, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33086925

RESUMO

Biomarkers for immune checkpoint inhibitors (ICIs) are limited in gastrointestinal cancer. Peripheral blood lymphocyte subset and associated dynamic changes were retrospectively analyzed in patients with gastrointestinal cancer treated with ICIs. Cox regression and Kaplan-Meier analyses were conducted for survival. A total of 80 patients were enrolled. Baseline CD4+/CD8+ T cells were lower in patients who experienced tumor progression by 6 months than in patients who did not (1.160 ± 0.652 vs 1.705 ± 0.924, respectively; p = 0.003). In multivariate analyses, decline in CD4+ T cells after the first dose of ICIs (CD4-C1-decline) was an independent prognostic factor for overall survival (hazard ratio: 13.00; 95% CI: 2.24-75.54; p = 0.004). Furthermore, CD4-C1-decline was a preferable indicator for progression in patients with deficient mismatch repair/microsatellite instability-high (p = 0.027). Early change in CD4+ T cell counts in peripheral blood may act as a prognostic biomarker for gastrointestinal cancer patients treated with ICIs.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33272567

RESUMO

The Gretchen Hagen 3 (GH3) family of acyl acid amido synthetases regulate the levels and activities of plant hormones containing carboxyl groups, thereby modulating diverse physiological responses. While structure-function relationships have been elucidated for dicotyledonous GH3s, the catalytic mechanism of monocotyledonous GH3 remains elusive. Rice (Oryza sativa) is a representative monocot, and its yield is controlled by the natural growth hormone IAA (indole-3-acetic acid). OsGH3-8 is a model GH3 enzyme that conjugates excess IAA to amino acids in an ATP-dependent manner, ensuring auxin homeostasis and regulating disease resistance, growth and development. Here, we report the crystal structure of OsGH3-8 protein in complex with AMP to uncover the molecular and structural basis for the activity of monocotyledonous GH3-8. Structural and sequence comparisons with other GH3 proteins reveal that the AMP/ATP binding sites are highly conserved. Molecular docking studies with IAA, the GH3-inhibitor Adenosine-5'-[2-(1H-indol-3-yl)ethyl]phosphate (AIEP), and Aspartate provide important information for substrate binding and selectivity of OsGH3-8. Moreover, the observation that AIEP nearly occupies the entire binding site for AMP, IAA and amino acid, offers a ready explanation for the inhibitory effect of AIEP. Taken together, the present study provides vital insights into the molecular mechanisms of monocot GH3 function, and will help to shape the future designs of effective inhibitors.

5.
J Immunother Cancer ; 8(2)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32792358

RESUMO

BACKGROUND: Despite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer. METHODS: This study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort. RESULTS: In the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well. CONCLUSIONS: Our results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

6.
J Immunother Cancer ; 8(2)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32792359

RESUMO

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of gastrointestinal cancer. However, biomarkers correlated with the efficacy of ICIs in gastrointestinal cancer are still lacking. In this study, we performed 395-plex immune oncology (IO)-related gene target sequencing in tumor samples from 96 patients with metastatic gastrointestinal cancer patients treated with ICIs, and a linear support vector machine learning strategy was applied to construct a predictive model. ResultsAll 96 patients were randomly assigned into the discovery (n=72) and validation (n=24) cohorts. A 24-gene RNA signature (termed the IO-score) was constructed from 395 immune-related gene expression profiling using a machine learning strategy to identify patients who might benefit from ICIs. The durable clinical benefit rate was higher in patients with a high IO-score than in patients with a low IO-score (discovery cohort: 92.0% vs 4.3%, p<0.001; validation cohort: 85.7% vs 17.6%, p=0.004). The IO-score may exhibit a higher predictive value in the discovery (area under the receiver operating characteristic curve (AUC)=0.97)) and validation (AUC=0.74) cohorts compared with the programmed death ligand 1 positivity (AUC=0.52), tumor mutational burden (AUC=0.69) and microsatellite instability status (AUC=0.59) in the combined cohort. Moreover, patients with a high IO-score also exhibited a prolonged overall survival compared with patients with a low IO-score (discovery cohort: HR, 0.29; 95% CI 0.15 to 0.56; p=0.003; validation cohort: HR, 0.32; 95% CI 0.10 to 1.05; p=0.04). Taken together, our results indicated the potential of IO-score as a biomarker for immunotherapy in patients with gastrointestinal cancers.

7.
Nature ; 579(7798): 284-290, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103175

RESUMO

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.


Assuntos
Epigênese Genética , Terapia Genética , Células Supressoras Mieloides/fisiologia , Neoplasias/terapia , Microambiente Tumoral , Animais , Azacitidina/farmacologia , Benzamidas/farmacologia , Diferenciação Celular , Movimento Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Camundongos , Células Supressoras Mieloides/citologia , Metástase Neoplásica/terapia , Neoplasias/cirurgia , Piridinas/farmacologia , Receptores CCR2/genética , Receptores de Interleucina-8B/genética , Microambiente Tumoral/efeitos dos fármacos
8.
Clin Immunol ; 212: 108345, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31953149

RESUMO

BACKGROUND: Biomarkers in non-colorectal gastrointestinal (GI) cancer patients receiving immune checkpoint blockades (ICBs) are still limited. METHODS: Data were prospectively collected from a discovery cohort (n = 53) and a validation cohort (n = 107) in patients with non-colorectal GI cancer receiving ICB, as well as a chemotherapy-only cohort (n = 171). System inflammatory markers and derived neutrophil-to-lymphocyte ratio (dNLR) were determined as biomarkers by univariate and multivariate analyses. RESULTS: A higher level of dNLR (cutoff = 3) was associated with shorter overall survival (OS) in discovery and validation cohorts. In pooled cohort, disease control rate (DCR) (28% vs. 48.1%) was associated with dNLR (p = .017). In univariate analysis, original tumor site, tumor histopathology, number of metastases, and dNLR were correlated with OS. In multivariate analysis, higher dNLR level was correlated with reduced OS (10.43 months vs. 4.20 months, p < .001). In chemotherapy-only cohort, dNLR was also correlated with DCR and OS. CONCLUSION: Higher dNLR level was correlated with worse outcomes, suggesting that dNLR may help risk-group stratification and assist disease management strategies as a prognostic biomarker for non-colorectal GI patients receiving ICB.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Contagem de Linfócitos , Neutrófilos , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Neoplasias do Sistema Digestório/sangue , Neoplasias do Sistema Digestório/tratamento farmacológico , Neoplasias do Sistema Digestório/patologia , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Feminino , Neoplasias da Vesícula Biliar/sangue , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/patologia , Humanos , Contagem de Leucócitos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Adulto Jovem
9.
J Struct Biol ; 208(1): 69-76, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419523

RESUMO

Plant cytokinins (CKs) are essential for many central cellular processes and play important roles in the interaction between bacteria and plants. Perception of CK is executed by the CHASE domain in the histidine kinase sensors of a class of two-component regulatory systems. Despite advances in understanding the structural basis for CK perception by the sensor AHK4 in Arabidopsis, the molecular mechanism of CK binding by other sensors is unclear. Here, we report the crystal structure of the CHASE domain in the histidine kinase PcrK of the bacterial plant pathogen Xanthomonas campestris pathovar campestris, which senses plant CK, determined at 2.55 Šresolution. The structure reveals that the PcrK has an AHK4-like overall topology and assembles into a homodimer. Strikingly, detailed structural analysis unveils two unique features of the PcrK ligand binding pocket: the size of the pocket is restricted for CK binding, and the PcrK applies a positively charged arginine but not a negatively charged aspartate to recognize the ligand. We propose a model to explain how the PcrK accommodates CK-sized compounds through conformational changes, providing a potential mechanistic framework for understanding ligand recognition by the PcrK.


Assuntos
Proteínas de Bactérias/química , Citocininas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Xanthomonas/enzimologia , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Ligação Proteica , Conformação Proteica
10.
Br J Radiol ; 91(1092): 20180580, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30160183

RESUMO

OBJECTIVES:: To investigate the use of shortened contrast injection with late triggering in coronary CT angiography (CCTA) for decreasing contrast dose and maintaining image quality. METHODS:: 106 patients for CCTA on a 16-cm wide-detector CT were prospectively enrolled into groups A (n = 50) and B (n = 56) randomly. Patient weight-dependent contrast medium (Iopamiro, 370 mgI ml-1) at dose rate of 25 mgI/kg/s was used with 8 s and the standard 10 s injection time in groups A and B, respectively. CT values of the aortic sinus (AS), right coronary artery, left anterior descending and left circumflex at the proximal, middle and distal segments were measured and compared. Subjective image quality was evaluated and analyzed with Fisher exact test. Contrast dose, injection rate and enhancement duration (between the start of enhancement in AS and scan finish) were also compared. RESULTS:: There was no difference in the injection rate and enhancement duration between the two groups (p > 0.05), while the total contrast dose in group A (36.2 ± 5.7 ml) was significantly lower than in group B (46.4 ± 6.3 ml) (p < 0.001). There was no difference for CT values in all major coronary vessels between the two groups and no difference in subjective image quality scores (all p > 0.05). CONCLUSION:: It is feasible to shorten contrast injection to 8 s in CCTA on wide-detector CT systems to significantly reduce contrast dosage, maintain adequate enhancement and reduce contrast-related artifacts. ADVANCES IN KNOWLEDGE:: (1) Coronary CT angiography (CCTA) scans with shortened contrast medium injection duration and late triggering are feasible with a 16-cm wide-detector CT system (2) Compared with the conventional CCTA with 10 s contrast injection duration, the new contrast injection protocol of using shortened injection duration (to 8 s) and late triggering reduces contrast dose to 36.2 ml, while maintaining adequate enhancement in vessels and reducing contrast-related artifacts.


Assuntos
Angiografia por Tomografia Computadorizada/métodos , Meios de Contraste/administração & dosagem , Angiografia Coronária/métodos , Vasos Coronários/diagnóstico por imagem , Iopamidol/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Artefatos , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
11.
World J Gastroenterol ; 24(2): 266-273, 2018 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-29375212

RESUMO

AIM: To investigate predictive and prognostic value of serum alpha-fetoprotein (AFP) level and its dynamic changes in patients with advanced gastric cancer with elevated serum AFP (AFPAGC). METHODS: One hundred and five patients with AFPAGC were enrolled in the study, and all of them underwent at least one cycle of systemic chemotherapy at our institute and had serum AFP ≥ 20 ng/mL at diagnosis or recurrence. Clinicopathologic features, serum AFP level at diagnosis and changes during treatment, first-line chemotherapy regimens, efficacy and toxicity, and survival information were collected. A Person's χ2 or Fisher's exact test was used to measure the differences between variables. Survival prognostic factors were investigated using the Kaplan-Meier method and Cox regression. RESULTS: Median serum AFP level was 161.7 ng/mL (range, 22.9-2557110 ng/mL). Objective response rates (ORR) was significantly lower in the AFP ≥ 160 ng/mL group than in the AFP < 160 ng/mL group (30.4% vs 68.3%, P < 0.001). ORR to doublet regimens was significantly lower in the AFP ≥ 160 ng/mL group, whereas ORR to triplet regimens was similar between the two groups. Liver metastasis rate was significantly higher in the AFP ≥ 160 ng/mL group than in the AFP < 160 ng/mL (69.8% vs 50.0%, P < 0.001). Overall survival (OS) in the two cohorts did not show any significant difference (P = 0.712). Dynamic changes of AFP were consistent with response to chemotherapy, and median OS of patients with a serum AFP decline ≥ 50% and those with a serum AFP decline < 50% was 17.5 m and 10.0 m, respectively (P = 0.003). Hepatic (P = 0.005), peritoneal (P < 0.001), non-regional lymph node metastasis (P < 0.001), and portal vein tumor thrombus (PVTT) (P = 0.042) were identified as independent prognostic factors for AFPAGC. CONCLUSION: Real-time examination of AFP has great predictive and prognostic value for managing AFPAGC. For those with markedly elevated AFP, triplet regimens may be a better choice.


Assuntos
Adenocarcinoma/sangue , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/tratamento farmacológico , alfa-Fetoproteínas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Distribuição de Qui-Quadrado , Tomada de Decisão Clínica , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Seleção de Pacientes , Neoplasias Peritoneais/secundário , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
12.
J Mot Behav ; 50(3): 343-352, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28915098

RESUMO

The authors' aim was to find the features of balance, proprioception, and gross motor development of Chinese children 3-6 years old and their correlations, provide theoretical support for promoting children's motor development, and enrich the world theoretical system of motor development. This study used a Tekscan foot pressure measurement instrument (Tekscan, Inc., Boston, MA), walking on a balance beam, Xsens 3-dimensional positional measuring system (Xsens Technologies, Enschede, the Netherlands), and Test of Gross Motor Development-2 to assess static balance, dynamic balance, knee proprioception, and levels of gross motor development (GMD) of 3- to 6-year-old children (n = 60) in Beijing. The results are as follows: children had significant age differences in static balance, dynamic balance, proprioception, and levels of GMD; children had significant gender differences in static balance, proprioception, and levels of GMD; children's static balance, dynamic balance, and proprioception had a very significant positive correlation with GMD (p < .01), but no significant correlation with body mass index.


Assuntos
Desenvolvimento Infantil/fisiologia , Equilíbrio Postural/fisiologia , Propriocepção/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Joelho , Masculino , Caracteres Sexuais , Caminhada
13.
Biochem Biophys Res Commun ; 477(4): 548-555, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27297106

RESUMO

Vascular endothelial dysfunction, a central hallmark of diabetes, predisposes diabetic patients to numerous cardiovascular complications. The POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1), is an important transcriptional regulatory factor and regulates divergent pathways depending on the cellular context, but its role in endothelial cells remains poorly understood. Herein, we report for the first time that endothelial PATZ1 expression was abnormally upregulated in diabetic endothelial cells (ECs) regardless of diabetes classification. This stimulatory effect was further confirmed in the high glucose-treated human umbilical vein endothelial cells (HUVECs). From a functional standpoint, transgenic overexpression of PATZ1 in endothelial colony forming cells (ECFCs) blunted angiogenesis in vivo and rendered endothelial cells unresponsive to established angiogenic factors. Mechanistically, PATZ1 acted as a potent transcriptional corepressor of fatty acid-binding protein 4 (FABP4), an essential convergence point for angiogenic and metabolic signaling pathways in ECs. Taken together, endothelial PATZ1 thus potently inhibits endothelial function and angiogenesis via inhibition of FABP4 expression, and abnormal induction of endothelial PATZ1 may contribute to multiple aspects of vascular dysfunction in diabetes.


Assuntos
Proteínas de Ligação a Ácido Graxo/metabolismo , Hiperglicemia/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Animais , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Glucose/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Sheng Li Ke Xue Jin Zhan ; 46(3): 170-4, 2015 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-26521480

RESUMO

Neurotrophic factor is a kind of protein family that plays an important role in the nutrition, support and differentiation to central neurons as well as synaptic plasticity. Growing evidences have revealed that pro-forms of various neurotrophic factors, which are generated in process of protein synthesis and might exert opposite roles involving in inducement of neuronal apoptosis and implication in pathogenesis of neurodegenerative diseases. This paper reviews "Yin/Yang" features of neurotrophic factors in the anabolism, receptor regulation, functional aspects, and their related role in pathogenesis of neurodegenerative diseases. It is hopefully to provide new idea on understanding and investigation of the neurotrophic factors regarding on their functional, pathological and potential therapeutic significance.


Assuntos
Neurônios , Apoptose , Humanos , Fatores de Crescimento Neural , Doenças Neurodegenerativas , Plasticidade Neuronal
15.
Stem Cell Res ; 9(2): 156-66, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22771389

RESUMO

Recent studies demonstrated that mature atrocytes have the capacity for de-differentiating into neural stem/progenitor cells (NSPCs) in vitro and in vivo. However, it is still unknown what signals endow astroglial cells with a de-differentiation potential. Furthermore, the signaling molecules and underlying mechanism that confer astrocytes with the competence of NSPC phenotypes have not been completely elucidated. Here, we found that sonic hedgehog (Shh) production in astrocytes following mechanical injury was significantly elevated, and that incubation of astrocyes with the injured astrocyte conditioned medium (ACM) causes astrocytes to gradually lose their immunophenotypical profiles, and acquire NSPC characteristics, as demonstrated by down-regulation of typical astrocytic markers (GFAP and S100) and up-regulation of markers that are generally expressed in NSCs, (nestin, Sox2, and CD133). ACM treated astrocytes exhibit self-renewal capacity and multipotency similar to NSPCs. Concomitantly, in addition to Ptc, there was a significant up-regulation of the Shh downstream signal components Gli2 and Cyclin D1 which are involved in cell proliferation, dramatic changes in cell morphology, and the disruption of cell-cycle G1 arrest. Conversely, the depletion of Shh by administration of its neutralizing antibody (Shh n-Ab) effectively inhibited the de-differentiation process. Strikingly, Shh alone had little effect on astrocyte de-differentiation to NSPCs. These data above suggest that Shh is a key instructive molecule while other molecules secreted from insulted astrocytes may synergistically promote the de-differentiation event.


Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Desdiferenciação Celular , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Animais , Astrócitos/efeitos dos fármacos , Biomarcadores/metabolismo , Desdiferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Ciclina D1/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Receptores Patched , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Estresse Mecânico , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína Gli2 com Dedos de Zinco
16.
Neurochem Int ; 61(2): 175-86, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22561407

RESUMO

It has long been promulgated that microglial cells serve beneficial roles in the central nervous system (CNS). The beneficial role of microglial cells is considered to be linked with microglial activation and consequent up-regulation of various trophic factors. However, what triggers microglial activation and consequent elevated level of trophic factors, especially brain-derived neurotrophic factor (BDNF), following traumatic CNS injury has become a crucial but elusive issue. Furthermore, an effort still remains in understanding of the cellular and molecular mechanisms underlying the endogenous neuroprotection of activated microglial cells. In this study, we demonstrated that mechanically-injured astrocyte conditioned medium (ACM) could provoke beneficial activation of microglial cells and thus promote the transcription, synthesis and release of BDNF in cultured microglial cells. The microglia-derived BDNF can exerted a demonstrable biological role in promoting neurite outgrowth and intimate terminal contacts of dorsal root ganglion (DRG) neurons co-cultured with microglial cells. Moreover, ACM induced remarkable p38MAPK phosphorylation in cultured microglial cells that preceded the burst of BDNF. Activating p38-MAPK by anisomycin resulted in salutary effects similar to those seen with ACM, whereas specific inhibition of the p38MAPK by SB203580 abrogated all the positive effects of ACM, including BDNF promotion and subsequent neurite outgrowth of DRG neurite outgrowth of DRG neurons and their intimate terminal contacts with microglial cells. Together, our results indicated that the neuroprotection of the microglial source is mainly caused by micro-environmental soluble molecules released from injured astrocytes, and ACM-induced BDNF production and release from microglial cells may be mediated through p38-MAPK signaling pathway. Therefore, these findings may lay a foundation to further investigations on the microglial beneficial activation role in the repair of traumatic CNS injury and neurodegenerative diseases.


Assuntos
Astrócitos/fisiologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Ativação de Macrófagos/fisiologia , Microglia/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , Animais , Western Blotting , Células Cultivadas , Imunofluorescência , Gânglios Espinais/crescimento & desenvolvimento , Gânglios Espinais/fisiologia , Microglia/fisiologia , Neuritos/fisiologia , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Medula Espinal/citologia , Estresse Mecânico , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
17.
Restor Neurol Neurosci ; 30(4): 335-43, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22614954

RESUMO

PURPOSE: To compare neuroprotection and therapeutic time windows of two diazepam regimens on retinal ganglion cells (RGCs) after rat optic nerve transection (ONT). METHODS: Adult rats received initial intraperitoneal diazepam injections 30 minutes before left ONT, followed by daily diazepam (regimen-A) or every 8 hours for 3 days (regimen-B) until they were killed at day 7 or 14. Initial diazepam in regimen-A and regimen-B was delayed to 3, 6, 7, 9, 10, 12 and 6, 7, 8, 9, 10, 12 hours after ONT and these animals survived for 7 days. The effect of daily combinational uses of diazepam and bicuculline was assayed at 7 days. RESULTS: Regimen-A induced higher RGC densities than those in control and regimen-B groups at day 7, but lower density than regimen-B did at day 14. When initial diazepam was delayed beyond 6 or 8 hours after ONT with regimen-A and regimen-B, the promoting effects of diazepam on RGC densities disappeared. Bicuculline completely inhibited the protection of diazepam. CONCLUSIONS: Prolonged neuroprotection on RGCs at day 14 and extended therapeutic time window for 8 hours can be achieved by regimen-B, while regimen-A induces a stronger neuroprotection at day 7. Diazepam neuroprotection is mediated through GABAA receptor.


Assuntos
Diazepam/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos do Nervo Óptico/tratamento farmacológico , Células Ganglionares da Retina/efeitos dos fármacos , Envelhecimento , Animais , Axotomia/efeitos adversos , Contagem de Células/métodos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Injeções Intraperitoneais/métodos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
18.
Neurochem Res ; 36(10): 1759-66, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21562748

RESUMO

Tyrosine kinase receptors TrkB and TrkC mediate neuroprotective effects of the brain-derived neurotrophic factor (BDNF) and neurotrophins in the dopaminergic nigro-striatal system, but it is obscure about their responses or expression changes in the injured substantia nigra under Parkinson's disease. In present study, immunofluorescence, Fluoro-Jade staining and laser scanning confocal microscopy were applied to investigate distribution and changes of TrkB and TrkC in the dopamine neurons of the substantia nigra by comparison of control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. It revealed that TrkB and TrkC-immunoreactivities were substantially localized in cytoplasm and cell membrane of the substantia nigra neurons of control adults. While neurons double-labeled with tyrosine hydroxylase (TH)/TrkB, or TH/TrkC were distributed in a large numbers in the substantia nigra of controls, they apparently went down at 36.2-65.7% of normal level, respectively following MPTP insult. In MPTP model, cell apoptosis or degeneration of nigral neurons were confirmed by caspase-3 and Fluoro-Jade staining. More interestingly, TH/TrkB-positive neurons survived more in cell numbers in comparison with that of TH/TrkC-positive ones in the MPTP model. This study has indicated that TrkB-containing dopamine neurons are less sensitive in the substantia nigra of MPTP mouse model, suggesting that specific organization of Trks may be involved in neuronal vulnerability to MPTP insult, and BDNF-TrkB signaling may play more important role in protecting dopamine neurons and exhibit therapeutic potential for Parkinson's disease.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Dopaminérgicos/toxicidade , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Neurotoxinas/toxicidade , Receptor trkB/metabolismo , Receptor trkC/metabolismo , Substância Negra/patologia , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Humanos , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Distribuição Aleatória , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
19.
Cell Transplant ; 19(2): 159-66, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20350358

RESUMO

Intraorbital transection of the optic nerve (ON) always induces ultimate apoptosis of retinal ganglion cells (RGCs) and consequently irreversible defects of vision function. It was demonstrated that transplanted olfactory ensheathing cells (OECs) in partially injured spinal cord have a distant in vivo neuroprotective effect on descending cortical and brain stem neurons. However, this study gave no answers to the question whether OECs can protect the central sensitive neurons with a closer axonal injury because different neurons respond variously to similar axonal injury and the distance between the neuronal soma and axonal injury site has a definite effect on the severity of neuronal response and apoptosis. In the present study, we investigated the effect of transplanted OECs on RGCs after intraorbital ON transection in adult rats. Green fluorescent protein (GFP)-OECs were injected into the ocular stumps of transected ON and a significantly higher number of surviving RGCs was found together with a consistent marked increase in the mRNA and protein levels of BDNF in the ON stump and retina in the OEC-treated group at 7 days, but not 2 and 14 days, time point when compared to the control group. Our findings suggest that OEC transplantation induces the expression of BDNF in the ocular ON stump and retina and delays the death of axotomized RGCs at a certain survival period.


Assuntos
Axotomia , Morte Celular/fisiologia , Neuroglia/transplante , Condutos Olfatórios/citologia , Traumatismos do Nervo Óptico/cirurgia , Células Ganglionares da Retina/fisiologia , Animais , Sobrevivência Celular , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neuroglia/citologia , Neuroglia/fisiologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Células Ganglionares da Retina/citologia
20.
Cell Mol Neurobiol ; 30(1): 149-60, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19688260

RESUMO

Thymosin-beta4 (Tbeta4) is a major actin monomer-binding peptide in mammalian tissues and plays a crucial role in the nervous system in synaptogenesis, neuronal survival and migration, axonal growth, and plastic changes of dendritic spines. However, it is unknown whether Tbeta4 is also involved in challenges with external stress such as ethanol-induced neurotoxicity. In the present study, we investigated the effects of Tbeta4 on ethanol-induced neurotoxicity in cultured cerebral cortical astrocytes and the underlying mechanisms. Primarily cultured astrocytes were treated with 1 microg/ml Tbeta4 2 h prior to administration of 100 mM ethanol for 0.5, 1, 3 and 6 days, respectively. The results showed that ethanol caused neurotoxicity in cultured astrocytes, as shown by declined cell viability, distinct astroglial apoptosis and increased intracellular peroxidation. Tbeta4 markedly promoted cell viability, ameliorated the injury of intracellular glial fibrillary acidic protein-immunopositive cytoskeletal structures, reduced the percentage of apoptotic astrocyte and cellular DNA fragmentation, suppressed caspase-3 activity and upregulated Bcl-2 expression, inhibited the accumulation of reactive oxygen species and production of malondialdehyde in ethanol-treated astrocytes in a time-dependent manner. These data indicated that Tbeta4 attenuates ethanol-induced neurotoxicity in cultured cortical astrocytes through inhibition of apoptosis signaling, and one of the mechanisms underlying the capacity of Tbeta4 to suppress apoptosis may in part be due to its effect of anti-peroxidation.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Córtex Cerebral/patologia , Síndromes Neurotóxicas/patologia , Timosina/farmacologia , Animais , Astrócitos/enzimologia , Caspase 3/metabolismo , Contagem de Células , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Etanol , Proteína Glial Fibrilar Ácida/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
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