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1.
Artigo em Inglês | MEDLINE | ID: mdl-32078016

RESUMO

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

2.
Cancer Manag Res ; 11: 8977-8989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695490

RESUMO

Purpose: Glioblastoma multiforme (GBM) is a highly malignant tumor of the central nervous system. Although primary GBM patients receive extensive therapies, tumors may recur within months, and there is no objective and scientific method to predict prognosis. Adoptive immunotherapy holds great promise for GBM treatment. However, the expression profiles of the tumor-associated antigens (TAAs) and tumor immune microenvironment (TME) genes used in immunotherapy of GBM patients have not been fully described. The present study aimed to develop a predictive tool to evaluate patient survival based on full analysis of the expression levels of TAAs and TME genes. Methods: Expression profiles of a panel of 87 TAAs and 8 TME genes significantly correlated with poor prognosis were evaluated in 44 GBM patients and 10 normal brain tissues using quantitative real-time polymerase chain reaction (qRT-PCR). A linear formula (the LASSO algorithm based in the R package) weighted by regression coefficients was used to develop a multi-element expression score to predict prognosis; this formula was cross-validated by the leave-one-out method in different GBM cohorts. Results: After analysis of gene expression, clinical features, and overall survival (OS), a total of 8 TAAs (CHI3L1, EZH2, TRIOBP, PCNA, PIK3R1, PRKDC, SART3 and EPCAM), 1 TME gene (FOXP3) and 4 clinical features (neutrophil-to-lymphocyte (NLR), number of basophils (BAS), age and treatment with standard radiotherapy and chemotherapy) were included in the formula. There were significant differences between high and low scoring groups identified using the formula in different GBM cohorts (TCGA (n=732) and GEO databases (n=84)), implying poor and good prognosis, respectively. Conclusion: The multi-element expression score was significantly associated with OS of GBM patients. The improve understanding of TAAs and TMEs and well-defined formula could be implemented in immunotherapy for GBM to provide better care.

3.
Phys Chem Chem Phys ; 21(44): 24620-24628, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31670329

RESUMO

The Janus structure, by combining properties of different transition metal dichalcogenide (TMD) monolayers in a single polar material, has attracted increasing research interest because of its particular structure and potential application in electronics, optoelectronics and piezoelectronics. In this work, Janus SnSSe monolayer is predicted by means of first-principles calculations, and it exhibits dynamic and mechanical stability. By using the generalized gradient approximation (GGA) and spin-orbit coupling (SOC), the Janus SnSSe monolayer is found to be an indirect band-gap semiconductor, whose gap can easily be tuned by strain. High carrier mobilities are obtained for SnSSe monolayer, and the hole mobility is higher than the electron mobility. For SnSSe monolayer, a uniaxial strain in the basal plane can induce both strong in-plane and much weaker out-of-plane piezoelectric polarizations, which reveals the potential as a piezoelectric two-dimensional (2D) material. High absorption coefficients in the visible light region are observed, suggesting a potential photocatalytic application. Calculated results show that SnSSe monolayer has a very high power factor, making it a promising candidate for thermoelectric applications. Our works reveal that the Janus SnSSe structure can be fabricated with unique electronic, optical, piezoelectric and transport properties, and can motivate related experimental works.

4.
Int J Mol Med ; 44(3): 847-856, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257467

RESUMO

Oxidized low­density lipoprotein (ox­LDL)­mediated endothelial cell injury has an important role in the vascular complications of type 2 diabetes. Astragaloside IV (ASV) is an active component of Radix Astragali, which has been demonstrated to exert protective effects against endothelial damage. The present study explored whether microRNAs (miRNAs) are involved in mediating the protective effects of ASV on ox­LDL­induced damage in human umbilical vein endothelial cells (HUVECs). RNA sequencing and reverse transcription­quantitative PCR analyses revealed that ox­LDL treatment significantly downregulated miR­140­3p expression in HUVECs. miR­140­3p overexpression promoted cell proliferation and inhibited apoptosis in ox­LDL­induced HUVECs. However, inhibition of miR­140­3p expression could reverse the effects of ASV on ox­LDL­induced HUVECs and reactivate ASV­inhibited PI3K/Akt signaling in ox­LDL­induced HUVECs. In addition, Krüppel­like factor 4 (KLF4) was identified as a target of miR­140­3p in ox­LDL­treated HUVECs. Subsequent experiments revealed that KLF4 overexpression partially counteracted the protective effects of miR­140­3p or ASV treatment in ox­LDL­induced HUVECs. Taken together, the current findings demonstrated that the protective effects of ASV on HUVECs were dependent on miR­140­3p upregulation and subsequent inhibition of KLF4 expression, which in turn suppressed the PI3K/Akt signaling pathway. The present results shed light to the molecular mechanism by which ASV alleviated ox­LDL­induced endothelial cell damage.


Assuntos
Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipoproteínas LDL/metabolismo , MicroRNAs/genética , Saponinas/farmacologia , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
BMC Infect Dis ; 19(1): 655, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337339

RESUMO

BACKGROUND: Although significant improvement in efficacy measured by a sustained virological response, the high acquisition costs of direct-acting antivirals limit the access for patients and influence the costs of healthcare resource utilisation in hepatitis C. It is important to have the latest estimates of prevalence, especially in high-risk groups, for cost of illness, cost-effectiveness and budget impact studies. METHODS: Original studies on the estimates of the prevalence among general and high-risk groups in the European Union/European Economic Area (EU/EEA) were retrieved from Medline and Embase for the period from 2015 to 2018. All included studies were evaluated for risk of selection bias and summarised together in a narrative form. Results from previous reviews and updated searches were compared per country among different populations, respectively. RESULTS: Among the 3871 studies identified, 46 studies were included: 20 studies were used for the estimate of the general population; 3 for men who have sex with men (MSM); 6 for prisoners; and 17 for people who inject drugs (PWID). Compared with the results reported in previous systematic reviews, the updated estimates were lower than previously in most available countries. Anti-HCV general population prevalence estimates ranged from 0.54 to 1.50% by country. The highest prevalence of anti-HCV was found among PWID (range of 7.90-82.00%), followed by prisoners (7.00-41.00%), HIV-positive MSM (1.80-7.10%), HIV-negative MSM (0.20-1.80%), pregnant women (0.10-1.32%) and first-time blood donors (0.03-0.09%). CONCLUSIONS: Our study highlights the heterogeneity in anti-HCV prevalence across different population groups in EU/EEA. The prevalence also varies widely between European countries. There are many countries that are not represented in our results, highlighting the need for the development of robust epidemiological studies.


Assuntos
Hepatite C/epidemiologia , Adulto , Doadores de Sangue/estatística & dados numéricos , Europa (Continente)/epidemiologia , União Europeia , Feminino , Anticorpos Anti-Hepatite C/sangue , Homossexualidade Masculina , Humanos , Masculino , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Gestantes , Prevalência , Prisioneiros/estatística & dados numéricos , Minorias Sexuais e de Gênero/estatística & dados numéricos
6.
Iran J Public Health ; 48(4): 722-729, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31110983

RESUMO

Background: In order to generate data on the burden of foodborne diseases in Shandong Province, we aimed to use the case monitoring data of foodborne diseases from 2016 to 2017 to estimate. Methods: Data were obtained from the foodborne disease surveillance reporting system with dates of onset from Jan 1, 2016, to Dec 31, 2017, in Shandong, China. Results: The places of food exposure were categorized by settings as follows: private home, catering facility, collective canteens, retail markets, rural banquets and other. Exposed food is divided into 23 categories. Overall incidence rate and proportions by exposure categories, age, and sex-specific incidence rates were calculated and sex proportions compared. Approximately 75.00% of cases who had at least one exposure settings were in private homes. The most frequently reported exposed food was a variety of food (meaning more than two kinds of food). The two-year average incidence rate was 75.78/100,000, sex-specific incidence rate was much higher for females compared to males (78.23 vs. 74.69 cases per 100,000 population). An age-specific trend was observed in the cases reported (Chi-Square for linear trend, χ2=4.39, P=0.036<0.05). Conclusion: A preliminary estimate of 14 million cases of foodborne diseases in Shandong province each year. Future studies should focus on cross-sectional and cohort studies to facilitate the assessment of the distribution and burden of foodborne disease of the population in Shandong. Considering strengthening the burden of foodborne diseases in foodborne disease surveillance is also a feasible way.

7.
Hum Mutat ; 40(8): 1039-1045, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30998843

RESUMO

Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases with high degree of genetic, allelic, and phenotypic heterogeneity. CEP250 encodes the C-Nap1 protein and has been associated with various retinal phenotypes. Here, we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP. To gain insights into the molecular pathomechanism underlying CEP250 defects and the functional relevance of CEP250 variants in humans, we conducted a functional characterization of CEP250 variant using a novel Cep250 knockin mouse line. Remarkably, the disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations. The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses. This study not only broadens the spectrum of phenotypes associated with CEP250 mutations, but also, for the first time, elucidates the function of CEP250 in photoreceptors using a newly established animal model.

8.
Environ Toxicol ; 34(4): 505-512, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30675760

RESUMO

Long non-coding RNA (lncRNA) plays a critical role in male germline development. Atrazine (AZ) as an environmental endocrine disrupting chemical (EDCs) can induce male reproductive toxicity in amphibians. Our previous studies demonstrated that AZ can alter gene and circular RNA (circRNA) expression of damaged testes in Xenopus laevis (X. laevis). We furthered to investigate the lncRNA expression profiling in the testis of X. laevis. Over 3559 lncRNAs were detected by lncRNA sequencing. AZ induced 40 upregulated and 46 downregulated differentially expressed lncRNAs. KEGG analysis showed that AZ-affected lncRNAs mainly involve in 19 pathways among which 12 pathways are found in circRNA analysis. This study for the first time demonstrated that AZ can alter lncRNAs which may play a role in testicular degeneration through regulating expressions of functional genes in X. laevis. Our data may provide more insights on the mechanism about male reproductive toxicity of EDCs.


Assuntos
Atrazina/toxicidade , Disruptores Endócrinos/toxicidade , RNA Longo não Codificante/genética , Testículo/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Regulação para Baixo , Perfilação da Expressão Gênica , Masculino , Reprodução , Testículo/metabolismo , Testículo/patologia , Regulação para Cima , Xenopus laevis
9.
Front Cell Dev Biol ; 6: 75, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30050903

RESUMO

Over recent decades, zebrafish has been established as a sophisticated vertebrate model for studying human ocular diseases due to its high fecundity, short generation time and genetic tractability. With the invention of morpholino (MO) technology, it became possible to study the genetic basis and relevant genes of ocular diseases in vivo. Many genes have been shown to be related to ocular diseases. However, the issue of specificity is the major concern in defining gene functions with MO technology. The emergence of the first- and second-generation genetic modification tools zinc-finger nucleases (ZFNs) and TAL effector nucleases (TALENs), respectively, eliminated the potential phenotypic risk induced by MOs. Nevertheless, the efficiency of these nucleases remained relatively low until the third technique, the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, was discovered. This review highlights the application of multiple genome engineering techniques, especially the CRISPR/Cas9 system, in the study of human ocular diseases in zebrafish.

10.
Pestic Biochem Physiol ; 147: 75-82, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29933996

RESUMO

In our previous study on natural products with fungicidal activity, pseudolaric acid B (PAB) isolated from Pseudolarix amabilis was examined to inhibit significantly mango anthracnose (Colletotrichum gloeosporioides) in vivo and in vitro. In the current study, sensitivity of 17 plant pathogenic fungi to PAB was determined. Mycelial growth rate results showed that PAB possessed strong antifungal activities to eleven fungi with median effective concentration (EC50) values ranging from 0.087 to 1.927µg/mL. EC50 of PAB against spore germination was greater than that of mycelium growth inhibition, which suggest that PAB could execute antifungal activity through mycelial growth inhibition. Further action mechanism of PAB against C. gloeosporioides was investigated, in which PAB treatment inhibited mycelia dry weight, decreased the mycelia reducing sugar and soluble protein. Furthermore, PAB induced an increase in membrane permeability, inhibited the biosynthesis of ergosterol, caused the extreme alteration in ultrastructure as indicated by the thickened cell wall and increased vesicles. These results will increase our understanding of action mechanism of PAB against plant pathogenic fungi.


Assuntos
Antifúngicos/farmacologia , Colletotrichum/efeitos dos fármacos , Diterpenos/farmacologia , Doenças das Plantas/prevenção & controle , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colletotrichum/crescimento & desenvolvimento , Colletotrichum/fisiologia , Ergosterol/antagonistas & inibidores , Ergosterol/biossíntese , Hifas/ultraestrutura , Mangifera/microbiologia , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Esporos Fúngicos/efeitos dos fármacos
11.
Exp Mol Med ; 50(4): 53, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29700284

RESUMO

Ocular coloboma is a developmental structural defect of the eye that often occurs as complex ocular anomalies. However, its genetic etiology remains largely unexplored. Here we report the identification of mutation (c.331C>T, p.R111C) in the IPO13 gene in a consanguineous family with ocular coloboma, microphthalmia, and cataract by a combination of whole-exome sequencing and homozygosity mapping. IPO13 encodes an importin-B family protein and has been proven to be associated with the pathogenesis of coloboma and microphthalmia. We found that Ipo13 was expressed in the cornea, sclera, lens, and retina in mice. Additionally, the mRNA expression level of Ipo13 decreased significantly in the patient compared with its expression in a healthy individual. Morpholino-oligonucleotide-induced knockdown of ipo13 in zebrafish caused dose-dependent microphthalmia and coloboma, which is highly similar to the ocular phenotypes in the patient. Moreover, both visual motor response and optokinetic response were impaired severely. Notably, these ocular phenotypes in ipo13-deficient zebrafish could be rescued remarkably by full-length ipo13 mRNA, suggesting that the phenotypes observed in zebrafish were due to insufficient ipo13 function. Altogether, our findings demonstrate, for the first time, a new role of IPO13 in eye morphogenesis and that loss of function of IPO13 could lead to ocular coloboma, microphthalmia, and cataract in humans and zebrafish.

12.
Development ; 144(16): 2940-2950, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28705895

RESUMO

Hypoxia signaling is an ancient pathway by which animals can respond to low oxygen. Malfunction of this pathway disturbs hypoxic acclimation and can result in various diseases, including cancers. The role of hypoxia signaling in early embryogenesis remains unclear. Here, we show that in the blastula of the sea urchin Strongylocentrotus purpuratus, hypoxia-inducible factor α (HIFα), the downstream transcription factor of the hypoxia pathway, is localized and transcriptionally active on the future dorsal side. This asymmetric distribution is attributable to its oxygen-sensing ability. Manipulations of the HIFα level entrained the dorsoventral axis, as the side with the higher level of HIFα tends to develop into the dorsal side. Gene expression analyses revealed that HIFα restricts the expression of nodal to the ventral side and activates several genes encoding transcription factors on the dorsal side. We also observed that intrinsic hypoxic signals in the early embryos formed a gradient, which was disrupted under hypoxic conditions. Our results reveal an unprecedented role of the hypoxia pathway in animal development.


Assuntos
Embrião não Mamífero/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ouriços-do-Mar/embriologia , Ouriços-do-Mar/metabolismo , Animais , Padronização Corporal/genética , Padronização Corporal/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
13.
Biomed Pharmacother ; 93: 88-94, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28624426

RESUMO

OBJECTIVE: The current study aimed to investigate whether the saponins, bioactive component of effects of D. collettii, could reduce the serum uric acid level in a hyperuricemic mouse via regulation of urate transporters. METHODS: Chronic hyperuricemia model was established by combine administration of adenine (100mg/kg) and ethambutol (250mg/kg). In the model group, the serum uric acid (SUA), urine uric acid (UUA) volume, and 24-h UUA values increased significantly, while the uric acid clearance rate (CUr) and creatinine clearance rate (CCr) values decreased. Further, the model groups showed significantly lower expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) and significantly higher expression of renal tubular urate transporter 1 (URAT1), glucose transporter 9 (GLUT9) and URAT1 mRNA than the normal control group. RESULTS: Saponins administration was found to have a dose-dependent effect, as evidenced by the increase in the 24-h UUA, CUr and CCr values; the decrease in SUA; the decrease in the renal expression of URAT1 mRNA and URAT1 and GLUT9 proteins; and the increase in the renal expression of the OAT1 and OAT3 proteins. CONCLUSION: The saponins extracted from D. collettii rhizomes had an obvious anti-hyperuricemic effect through downregulation of the URAT1 mRNA and the URAT1 and GLUT9 proteins and upregulation of the OAT1 and OAT3 proteins.


Assuntos
Dioscorea/química , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Extratos Vegetais/farmacologia , Rizoma/química , Saponinas/farmacologia , Animais , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos , Ratos Sprague-Dawley , Ácido Úrico/metabolismo
14.
Biotechniques ; 62(3): 115-122, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28298178

RESUMO

Fluorescent immunolabeling and imaging in free-floating thick (50-60 µm) tissue sections is relatively simple in practice and enables design-based non-biased stereology, or 3-D reconstruction and analysis. This method is widely used for 3-D in situ quantitative biology in many areas of biological research. However, the labeling quality and efficiency of standard protocols for fluorescent immunolabeling of these tissue sections are not always satisfactory. Here, we systematically evaluate the effects of raising the conventional antibody incubation temperatures (4°C or 21°C) to mammalian body temperature (37°C) in these protocols. Our modification significantly enhances the quality (labeling sensitivity, specificity, and homogeneity) and efficiency (antibody concentration and antibody incubation duration) of fluorescent immunolabeling of free-floating thick tissue sections.


Assuntos
Anticorpos/metabolismo , Imunofluorescência/métodos , Corantes Fluorescentes/metabolismo , Imuno-Histoquímica/métodos , Animais , Anticorpos/química , Corantes Fluorescentes/química , Temperatura Alta , Masculino , Ratos , Ratos Sprague-Dawley , Pele/química , Medula Espinal/química
15.
Int J Ophthalmol ; 9(8): 1094-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27588261

RESUMO

AIM: To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS: Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE6B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS: We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T604I) in PDE6B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION: We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE6B contribute to the genetic heterogeneity of RP.

16.
Sci Rep ; 6: 31946, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27550826

RESUMO

Klebsiella pneumoniae can cause community-acquired pyogenic liver abscess (PLA). Capsular polysaccharide (CPS) is important for its virulence. Among 79 capsular (K) types discovered thus far, K57 is often associated with PLA. Here, we report the identification of a K57 variant. Cps gene locus sequencing revealed differences between the K57 reference strain 4425/51 (Ref-K57) and a variant, the PLA isolate A1142. While Ref-K57 cps contained orf13 encoding a putative acetyltransferase, the insertion of a putative transposase-encoding gene at this position was detected in A1142. This variation was detected in other K57 clinical strains. Biochemical analyses indicated that A1142 was deficient in CPS acetylation. Genetic replacement and complementation verified that orf13 was responsible for CPS acetylation. Acetylation increased CPS immunoreactivity to antiserum and enhanced K. pneumoniae induction of pro-inflammatory cytokines through JNK and MAPK signaling. While acetylation diminished the serum resistance of bacteria, it promoted adhesion to intestinal epithelial cells possibly via increasing production of type I fimbriae. In conclusion, acetylation-mediated capsular variation in K57 was observed. Capsular acetylation contributed to the variety and antigenic diversity of CPS, influenced its biological activities, and was involved in K. pneumoniae-host interactions. These findings have implications for vaccine design and pathogenicity of K. pneumoniae.


Assuntos
Cápsulas Bacterianas/genética , Cápsulas Bacterianas/metabolismo , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/metabolismo , Abscesso Hepático Piogênico/microbiologia , Acetilação , Aderência Bacteriana , Cápsulas Bacterianas/imunologia , Citocinas/metabolismo , Variação Genética , Humanos , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/imunologia , Klebsiella pneumoniae/patogenicidade , Abscesso Hepático Piogênico/imunologia , Sistema de Sinalização das MAP Quinases , Fases de Leitura Aberta
17.
Int J Nanomedicine ; 10: 5171-84, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26316748

RESUMO

The aim of this research is to provide proof of principle by applying the fiber-optic triggered release of photo-thermally responsive liposomes embedded with gold nanoparticles (AuNPs) using a 200 µm fiber with 65 mW and 532 nm excitation for topical release in vivo. The tunable delivery function can be paired with an apoptosis biosensor based on the same fiber-optic configuration for providing real-time evaluation of chemotherapy efficacy in vivo to perform as a personalized chemotherapy system. The pattern of topical release triggered by laser excitation conveyed through optical fibers was monitored by the increase in fluorescence resulting from the dilution of self-quenching (75 mM) fluorescein encapsulated in liposomes. In in vitro studies (in 37°C phosphate buffer saline), the AuNP-embedded liposomes showed a more efficient triggered release (74.53%±1.63% in 40 minutes) than traditional temperature-responsive liposomes without AuNPs (14.53%±3.17%) or AuNP-liposomes without excitation (21.92%±2.08%) by spectroscopic measurements. Using the mouse xenograft studies, we first demonstrated that the encapsulation of fluorescein in liposomes resulted in a more substantial content retention (81%) in the tumor than for free fluorophores (14%) at 120 minutes after administration from in vivo fluorescence imaging. Furthermore, the preliminary results also suggested the tunable release capability of the system by demonstrating consecutive triggered releases with fiber-optic guided laser excitation.


Assuntos
Antineoplásicos/química , Tecnologia de Fibra Óptica , Ouro/química , Lipossomos/química , Neoplasias/tratamento farmacológico , Animais , Sistemas de Liberação de Medicamentos , Fluoresceína/química , Corantes Fluorescentes/química , Temperatura Alta , Humanos , Lasers , Luz , Masculino , Nanopartículas Metálicas/química , Camundongos , Camundongos Nus , Fibras Ópticas , Solventes/química , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Chin Med J (Engl) ; 128(11): 1510-5, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-26021509

RESUMO

BACKGROUND: Sevoflurane and propofol are widely used anesthetics for surgery. Studies on the mechanisms of general anesthesia have focused on changes in protein expression properties and membrane lipid. MicroRNAs (miRNAs) regulate neural function by altering protein expression. We hypothesize that sevoflurane and propofol affect miRNA expression profiles in the brain, expect to understand the mechanism of anesthetic agents. METHODS: Rats were randomly assigned to a 2% sevoflurane group, 600 µg·kg - 1·min - 1 propofol group, and a control group without anesthesia (n = 4, respectively). Treatment group was under anesthesia for 6 h, and all rats breathed spontaneously with continuous monitoring of respiration and blood gases. Changes in rat cortex miRNA expression profiles were analyzed by miRNA microarrays and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Differential expression of miRNA using qRT-PCR among the control, sevoflurane, and propofol groups were compared using one-way analysis of variance (ANOVA). RESULTS: Of 677 preloaded rat miRNAs, the microarray detected the expression of 277 miRNAs in rat cortex (40.9%), of which 9 were regulated by propofol and (or) sevoflurane. Expression levels of three miRNAs (rno-miR-339-3p, rno-miR-448, rno-miR-466b-1FNx01) were significantly increased following sevoflurane and six (rno-miR-339-3p, rno-miR-347, rno-miR-378FNx01, rno-miR-412FNx01, rno-miR-702-3p, and rno-miR-7a-2FNx01) following propofol. Three miRNAs (rno-miR-466b-1FNx01, rno-miR-3584-5p and rno-miR-702-3p) were differentially expressed by the two anesthetic treatment groups. CONCLUSIONS: Sevoflurane and propofol anesthesia induced distinct changes in brain miRNA expression patterns, suggesting differential regulation of protein expression. Determining the targets of these differentially expressed miRNAs may help reveal both the common and agent-specific actions of anesthetics on neurological and physiological function.


Assuntos
Éteres Metílicos/farmacologia , MicroRNAs/genética , Propofol/farmacologia , Anestesia Geral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Sevoflurano
19.
Chin Med J (Engl) ; 128(7): 919-27, 2015 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-25836613

RESUMO

BACKGROUND: Collapsin response mediator protein-2 (CRMP2), a multifunctional cytosolic protein highly expressed in the brain, is degraded by calpain following traumatic brain injury (TBI), possibly inhibiting posttraumatic neurite regeneration. Lipid peroxidation (LP) is involved in triggering postinjury CRMP2 proteolysis. We examined the hypothesis that propofol could attenuate LP, calpain-induced CRMP2 degradation, and brain injury after TBI. METHODS: A unilateral moderate controlled cortical impact injury was induced in adult male Sprague-Dawley rats. The animals were randomly divided into seven groups: Sham control group, TBI group, TBI + propofol groups (including propofol 1 h, 2 h, and 4 h groups), TBI + U83836E group and TBI + fat emulsion group. The LP inhibitor U83836E was used as a control to identify that antioxidation partially accounts for the potential neuroprotective effects of propofol. The solvent of propofol, fat emulsion, was used as the vehicle control. Ipsilateral cortex tissues were harvested at 24 h post-TBI. Immunofluorescent staining, Western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling were used to evaluate LP, calpain activity, CRMP2 proteolysis and programmed cell death. The data were statistically analyzed using one-way analysis of variance and a paired t-test. RESULTS: Propofol and U83836E significantly ameliorated the CRMP2 proteolysis. In addition, both propofol and U83836E significantly decreased the ratio of 145-kDa αII-spectrin breakdown products to intact 270-kDa spectrin, the 4-hydroxynonenal expression and programmed cell death in the pericontusional cortex at 24 h after TBI. There was no difference between the TBI group and the fat emulsion group. CONCLUSIONS: These results demonstrate that propofol postconditioning alleviates calpain-mediated CRMP2 proteolysis and provides neuroprotective effects following moderate TBI potentially by counteracting LP and reducing calpain activation.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Calpaína/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Propofol/uso terapêutico , Proteólise/efeitos dos fármacos , Animais , Western Blotting , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
20.
Cancer Biol Med ; 12(1): 33-40, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25859409

RESUMO

OBJECTIVE: The expression of tumor biomarkers may change after chemotherapy. However, whether secreted protein acidic and rich in cysteine (SPARC) expression changes after chemotherapy in gastric cancer (GC) is unclear. This study investigated the influence of chemotherapy on SPARC expression in GC. METHODS: Immunohistochemistry was used to analyze SPARC expression in 132 GC cases (including 54 cases with preoperative chemotherapy and 78 cases without preoperative chemotherapy). SPARC expression of postoperative specimens with and without preoperative chemotherapy was assessed to analyze the influence of chemotherapy on SPARC expression. RESULTS: SPARC was highly expressed in GC compared with the desmoplastic stroma surrounding tumor cells and noncancerous tissues. High SPARC expression was correlated with invasion depth, lymph node, and TNM stage. After chemotherapy, a lower proportion of high SPARC expression was observed in patients with preoperative chemotherapy than in the controls. For 54 patients with preoperative chemotherapy, gross type, histology, depth of invasion, lymph node, TNM stage, and SPARC expression were related to overall survival. Further multivariate analysis showed that lymph node, histology, and SPARC expression after chemotherapy were independent prognostic factors. CONCLUSION: SPARC expression may change after chemotherapy in GC. SPARC expression should be reassessed for patients with GC after chemotherapy.

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