Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Pediatr Blood Cancer ; 71(9): e31177, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38967594

RESUMO

INTRODUCTION: Thalassemia represents a significant public health challenge globally. However, the global burden of thalassemia and the disparities associated with it remain poorly understood. Our study aims to uncover the long-term spatial and temporal trends in thalassemia at global, regional, and national levels, analyze the impacts of age, time periods, and birth cohorts, and pinpoint the global disparities in thalassemia burden. METHODS: We extracted data on the thalassemia burden from the Global Burden of Disease Study (GBD) 2019. We employed a joinpoint regression model to assess temporal trends in thalassemia burden and an age-period-cohort model to evaluate the effects of age, period, and cohort on thalassemia mortality. RESULTS: From 1990 to 2019, the number of thalassemia incident cases, prevalent cases, mortality cases, and disability-adjusted life years (DALYs) decreased by 20.9%, 3.1%, 38.6%, and 43.1%, respectively. Age-standardized rates of incidence, prevalence, mortality, and DALY declined across regions with high, high-middle, middle, and low-middle sociodemographic index (SDI), yet remained the highest in regions with low SDI and low-middle SDI as well as in Southeast Asia, peaking among children under five years of age. The global prevalence rate was higher in males than in females. The global mortality rate showed a consistent decrease with increasing age. CONCLUSION: The global burden of thalassemia has significantly declined, yet notable disparities exist in terms of gender, age groups, periods, birth cohorts, SDI regions, and GBD regions. Systemic interventions that include early screening, genetic counseling, premarital health examinations, and prenatal diagnosis should be prioritized in regions with low, and low-middle SDI, particularly in Southeast Asia. Future population-based studies should focus specifically on thalassemia subtypes and transfusion requirements, and national registries should enhance data capture through newborn screening.


Assuntos
Carga Global da Doença , Talassemia , Humanos , Talassemia/epidemiologia , Talassemia/mortalidade , Carga Global da Doença/tendências , Masculino , Feminino , Criança , Pré-Escolar , Adolescente , Prevalência , Lactente , Incidência , Adulto , Saúde Global/estatística & dados numéricos , Adulto Jovem , Recém-Nascido , Anos de Vida Ajustados por Deficiência , Efeitos Psicossociais da Doença , Taxa de Sobrevida
2.
Invest Ophthalmol Vis Sci ; 64(7): 2, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37261387

RESUMO

Purpose: The purpose of this study was to investigate the protective effect of low-dose trans-resveratrol (trans-RSV) on diabetes-induced retinal ganglion cell (RGC) degeneration and its possible mechanism. Methods: A streptozotocin-induced diabetic mouse model was established and treated with or without trans-RSV intragastric administration (10 mg/kg body weight/day) for 12 weeks. Oscillatory potentials (Ops) of the dark-adapted electroretinogram (ERG) were recorded. The number of RGCs was detected by Tuj1 and TUNEL staining. The apoptosis markers in the retina were analyzed by Western blot. The cross sections of optic nerves were observed by transmission electron microscopy. In addition, mouse neuroblastoma N2a cells were injured by high-glucose (HG) treatment. Cell viability and apoptosis were measured with or without low-dose trans-RSV treatment. The intracellular localization of tyrosyl transfer-RNA synthetase (TyrRS) was observed in both mouse retinas and N2a cells. The effects of low-dose trans-RSV on the binding of TyrRS to the transcription factor c-Jun and the binding of c-Jun to pro-apoptotic genes were analyzed by co-IP and ChIP assays in HEK 293 cells. Results: Trans-RSV relieved electrophysiological injury of retinas and inhibited RGC apoptosis in diabetic mice. It also protected N2a cells from HG-induced apoptosis. Additionally, it promoted TyrRS nuclear translocation in both diabetic mouse retinas and HG-treated N2a cells. Trans-RSV promoted TyrRS binding to c-Jun, inhibited the phosphorylation of Ser-63 of c-Jun, and downregulated pro-apoptotic gene transcription. Conclusions: Low-dose trans-RSV can ameliorate diabetes-induced RGC degeneration via the TyrRS/c-Jun pathway. It can promote TyrRS nuclear translocation and bind to c-Jun, downregulating c-Jun phosphorylation and downstream pro-apoptotic genes.


Assuntos
Diabetes Mellitus Experimental , Células Ganglionares da Retina , Camundongos , Humanos , Animais , Células Ganglionares da Retina/metabolismo , Resveratrol/farmacologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Células HEK293 , Retina/metabolismo , Apoptose
3.
World J Gastrointest Surg ; 15(1): 9-18, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36741068

RESUMO

The post-hepatectomy recurrence rate of hepatocellular carcinoma (HCC) is persistently high, affecting the prognosis of patients. An effective therapeutic option is crucial for achieving long-term survival in patients with postoperative recurrences. Local ablative therapy has been established as a treatment option for resectable and unresectable HCCs, and it is also a feasible approach for recurrent HCC (RHCC) due to less trauma, shorter operation times, fewer complications, and faster recovery. This review focused on ablation techniques, description of potential candidates, and therapeutic and prognostic implications of ablation for guiding its application in treating intrahepatic RHCC.

4.
Zool Res ; 43(6): 989-1004, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36257830

RESUMO

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.


Assuntos
Transtorno Depressivo Maior , Ketamina , Doenças dos Roedores , Masculino , Camundongos , Animais , Ketamina/toxicidade , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , Lítio/farmacologia , Mania , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinase/farmacologia , RNA Interferente Pequeno , Serina-Treonina Quinases TOR/genética , Transdução de Sinais , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Sirolimo/farmacologia , Compostos de Lítio/farmacologia , Mamíferos , Doenças dos Roedores/tratamento farmacológico
5.
World J Gastrointest Oncol ; 14(4): 858-871, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35582105

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. HCC-targeted magnetic resonance imaging (MRI) is an effective noninvasive diagnostic method that involves targeting clinically-related HCC biomarkers, such as alpha-fetoprotein (AFP) or glypican-3 (GPC3), with iron oxide nanoparticles. However, in vivo studies of HCC-targeted MRI utilize single-target iron oxide nanoprobes as negative (T2) contrast agents, which might weaken their future clinical applications due to tumor heterogeneity and negative MRI contrast. Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles (approximately 5 nm) are potential optimal positive (T1) contrast agents. We previously verified the efficiency of AFP/GPC3-double-antibody-labeled iron oxide MR molecular probe in vitro. AIM: To validate the effectiveness of a bi-specific probe in vivo for enhancing T1-weighted positive contrast to diagnose the early-stage HCC. METHODS: The single- and double-antibody-conjugated 5-nm USPIO probes, including anti-AFP-USPIO (UA), anti-GPC3-USPIO (UG), and anti-AFP-USPIO-anti-GPC3 (UAG), were synthesized. T1- and T2-weighted MRI were performed on day 10 after establishment of the orthotopic HCC mouse model. Following intravenous injection of U, UA, UG, and UAG probes, T1- and T2-weighted images were obtained at 12, 12, and 32 h post-injection. At the end of scanning, mice were euthanized, and a histologic analysis was performed on tumor samples. RESULTS: T1- and T2-weighted MRI showed that absolute tumor-to-background ratios in UAG-treated HCC mice peaked at 24 h post-injection, with the T1- and T2-weighted signals increasing by 46.7% and decreasing by 11.1%, respectively, relative to pre-injection levels. Additionally, T1-weighted contrast in the UAG-treated group at 24 h post-injection was enhanced 1.52-, 2.64-, and 4.38-fold compared to those observed for single-targeted anti-GPC3-USPIO, anti-AFP-USPIO, and non-targeted USPIO probes, respectively. Comparison of U-, UA-, UG-, and UAG-treated tumor sections revealed that UAG-treated mice exhibited increased stained regions compared to those observed in UG- or UA-treated mice. CONCLUSION: The bi-specific T1-positive contrast-enhanced MRI probe (UAG) for HCC demonstrated increased specificity and sensitivity to diagnose early-stage HCC irrespective of tumor size and/or heterogeneity.

6.
World J Gastroenterol ; 27(32): 5341-5350, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34539136

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor in China. Preoperative diagnosis of HCC is challenging because of atypical imaging manifestations and the diversity of focal liver lesions. Artificial intelligence (AI), such as machine learning (ML) and deep learning, has recently gained attention for its capability to reveal quantitative information on images. Currently, AI is used throughout the entire radiomics process and plays a critical role in multiple fields of medicine. This review summarizes the applications of AI in various aspects of preoperative imaging of HCC, including segmentation, differential diagnosis, prediction of histopathology, early detection of recurrence after curative treatment, and evaluation of treatment response. We also review the limitations of previous studies and discuss future directions for diagnostic imaging of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Inteligência Artificial , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Diagnóstico por Imagem , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia
7.
Front Psychiatry ; 12: 609458, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33584384

RESUMO

Background: Alcohol dependence (AD) is a chronic recurrent brain disease that causes a heavy disease burden worldwide, partly due to high relapse rates after detoxification. Verified biomarkers are not available for AD and its relapse, although the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) may play important roles in the mechanism of addiction. This study investigated AD- and relapse-associated functional connectivity (FC) of the NAc and mPFC with other brain regions during early abstinence. Methods: Sixty-eight hospitalized early-abstinence AD male patients and 68 age- and education-matched healthy controls (HCs) underwent resting-functional magnetic resonance imaging (r-fMRI). Using the NAc and mPFC as seeds, we calculated changes in FC between the seeds and other brain regions. Over a follow-up period of 6 months, patients were measured with the Alcohol Use Disorder Identification Test (AUDIT) scale to identify relapse outcomes (AUDIT ≥ 8). Results: Thirty-five (52.24%) of the AD patients relapsed during the follow-up period. AD displayed lower FC of the left fusiform, bilateral temporal superior and right postcentral regions with the NAc and lower FC of the right temporal inferior, bilateral temporal superior, and left cingulate anterior regions with the mPFC compared to controls. Among these FC changes, lower FC between the NAc and left fusiform, lower FC between the mPFC and left cingulate anterior cortex, and smoking status were independently associated with AD. Subjects in relapse exhibited lower FC of the right cingulate anterior cortex with NAc and of the left calcarine sulcus with mPFC compared to non-relapsed subjects; both of these reductions in FC independently predicted relapse. Additionally, FC between the mPFC and right frontal superior gyrus, as well as years of education, independently predicted relapse severity. Conclusion: This study found that values of FC between selected seeds (i.e., the NAc and the mPFC) and some other reward- and/or impulse-control-related brain regions were associated with AD and relapse; these FC values could be potential biomarkers of AD or for prediction of relapse. These findings may help to guide further research on the neurobiology of AD and other addictive disorders.

8.
World J Gastroenterol ; 25(24): 3030-3043, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31293339

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) ranks second in terms of cancer mortality worldwide. Molecular magnetic resonance imaging (MRI) targeting HCC biomarkers such as alpha-fetoprotein (AFP) or glypican-3 (GPC3) offers new strategies to enhance specificity and help early diagnosis of HCC. However, the existing iron oxide nanoparticle-based MR molecular probes singly target AFP or GPC3, which may hinder their efficiency to detect heterogeneous micro malignant HCC tumors < 1 cm (MHCC). We hypothesized that the strategy of double antibody-conjugated iron oxide nanoparticles which simultaneously target AFP and GPC3 antigens may potentially be used to overcome the tumor heterogeneity and enhance the detection rate for MRI-based MHCC diagnosis. AIM: To synthesize an AFP/GPC3 double antibody-labeled iron oxide MRI molecular probe and to assess its impact on MRI specificity and sensitivity at the cellular level. METHODS: A double antigen-targeted MRI probe for MHCC anti-AFP-USPIO-anti-GPC3 (UAG) was developed by simultaneously conjugating AFP andGPC3 antibodies to a 5 nm ultra-small superparamagnetic iron oxide nanoparticle (USPIO). At the same time, the singly labeled probes of anti-AFP-USPIO (UA) and anti-GPC3-USPIO (UG) and non-targeted USPIO (U) were also prepared for comparison. The physical characterization including morphology (transmission electron microscopy), hydrodynamic size, and zeta potential (dynamic light scattering) was conducted for each of the probes. The antigen targeting and MRI ability for these four kinds of USPIO probes were studied in the GPC3-expressing murine hepatoma cell line Hepa1-6/GPC3. First, AFP and GPC3 antigen expression in Hepa1-6/GPC3 cells was confirmed by flow cytometry and immunocytochemistry. Then, the cellular uptake of USPIO probes was investigated by Prussian blue staining assay and in vitro MRI (T2-weighted and T2-map) with a 3.0 Tesla clinical MR scanner. RESULTS: Our data showed that the double antibody-conjugated probe UAG had the best specificity in targeting Hepa1-6/GPC3 cells expressing AFP and GPC3 antigens compared with single antibody-conjugated and unconjugated USPIO probes. The iron Prussian blue staining and quantitative T2-map MRI analysis showed that, compared with UA, UG, and U, the uptake of double antigen-targeted UAG probe demonstrated a 23.3% (vs UA), 15.4% (vs UG), and 57.3% (vs U) increased Prussian stained cell percentage and a 14.93% (vs UA), 9.38% (vs UG), and 15.3% (vs U) reduction of T2 relaxation time, respectively. Such bi-specific probe might have the potential to overcome tumor heterogeneity. Meanwhile, the coupling of two antibodies did not influence the magnetic performance of USPIO, and the relatively small hydrodynamic size (59.60 ± 1.87 nm) of double antibody-conjugated USPIO probe makes it a viable candidate for use in MHCC MRI in vivo, as they are slowly phagocytosed by macrophages. CONCLUSION: The bi-specific probe presents enhanced targeting efficiency and MRI sensitivity to HCC cells than singly- or non-targeted USPIO, paving the way for in vivo translation to further evaluate its clinical potential.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Sondas Moleculares/administração & dosagem , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Dextranos/administração & dosagem , Dextranos/química , Glipicanas/metabolismo , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Neoplasias Hepáticas/patologia , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/química , Camundongos , Sondas Moleculares/química
9.
Oncol Lett ; 18(1): 720-732, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31289547

RESUMO

The purpose of the present study was to investigate the value of contrast-enhanced magnetic resonance imaging (CE-MRI) texture analysis for preoperatively predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). Accordingly, a retrospective study of 142 patients with pathologically confirmed HCC was performed. The patients were divided into two cohorts: The training cohort (n=99) and the validation cohort (n=43), including the MVI-positive group (n=53) and MVI-negative group (n=89). On the basis of three-dimensional texture analysis, 58 features were extracted from the preoperative CE-MR images of arterial-phase (AP) and portal-venous-phase (PP). The t-test or Kruskal-Wallis test, univariate logistic regression analysis and Pearson correlation were applied for feature reduction. Clinical-radiological features were also analyzed. Multivariate logistic regression analysis was used to build the texture model and combined model with clinical-radiological features. The MVI-predictive performance of the models was evaluated using receiver operating characteristic (ROC) analysis and presented using nomogram. Among the clinical features, a significant difference was found in maximum tumor diameter (P=0.002), tumor differentiation (P=0.026) and α-fetoprotein level (P=0.025) between the two groups in the training cohort. Four MR texture features in AP and five in PP images were identified through feature reduction. On ROC analysis, the AP texture model showed better diagnostic performance than did the PP model in the validation cohort, with an area under the curve (AUC) of 0.773 vs. 0.623, sensitivity of 0.750 vs. 0.500, and specificity of 0.815 vs. 0.926. Together with the clinical features, the combined model of AP improved the AUC, sensitivity and specificity to 0.810, 0.811 and 0.790, respectively, which was demonstrated in nomogram. To conclude, model-based texture analysis of CE-MRI could predict MVI in HCC preoperatively and noninvasively, and the AP image shows better predictive efficiency than PP image. The combined model of AP with clinical-radiological features could improve MVI prediction ability.

10.
Autophagy ; 13(12): 2056-2071, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28981387

RESUMO

Lysosomal autophagy inhibitors (LAI) such as hydroxychloroquine (HCQ) have significant activity in a subset of cancer cell lines. LAIs are being evaluated in cancer clinical trials, but genetic determinants of sensitivity to LAIs are unknown, making it difficult to predict which tumors would be most susceptible. Here we characterize differentially expressed genes in HCQ-sensitive (-S) and -resistant (-R) cancer cells. Notably, expression of canonical macroautophagy/autophagy genes was not associated with sensitivity to HCQ. Expression patterns of ALDH1A1 (aldehyde dehydrogenase 1 family member A1) and HLTF (helicase like transcription factor) identified HCQ-S (ALDH1A1high HLTFlow; ALDH1A1low HLTFlow) and HCQ-R (ALDH1A1low HLTFhigh) cells. ALDH1A1 overexpression was found to enhance LAI cell entry and cytotoxicity without directly affecting lysosome function or autophagic flux. Expression of HLTF allows repair of DNA damage caused by LAI-induced reactive oxygen species, leading to HCQ resistance. Sensitivity to HCQ is increased in cells where HLTF is silenced by promoter methylation. HLTF overexpression blunted the antitumor efficacy of chloroquine derivatives in vitro and in vivo. Analysis of tumor RNA sequencing data from >700 patients in the Cancer Genome Atlas identified cancers including colon cancer, renal cell carcinoma, and gastric cancers, that were enriched for the HCQ-S or HCQ-R signature. These results provide mechanistic insights into LAI efficacy, and guidance for LAI clinical development.


Assuntos
Aldeído Desidrogenase/metabolismo , Autofagia , Proteínas de Ligação a DNA/metabolismo , Lisossomos/metabolismo , Fatores de Transcrição/metabolismo , Família Aldeído Desidrogenase 1 , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cloroquina/farmacologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidroxicloroquina/farmacologia , Lisossomos/efeitos dos fármacos , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Retinal Desidrogenase
11.
Comput Biol Chem ; 66: 63-68, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27923202

RESUMO

The PTP non-receptor type 4 (PTPN4) is an important regulator protein in learning, spatial memory and cerebellar synaptic plasticity; targeting the PDZ domain of PTPN4 has become as attractive therapeutic strategy for human neuroglioma. Here, we systematically examined the complex crystal structures of PTPN4 PDZ domain with its known peptide ligands; a number of charged amino acid residues were identified in these ligands and in the peptide-binding pocket of PDZ domain, which can constitute a complicated salt-bridge network across the complex interface. Molecular dynamics (MD) simulations, binding free energy calculations and continuum model analysis revealed that the electrostatic effect plays a predominant role in domain-peptide binding, while other noncovalent interactions such as hydrogen bonds and hydrophobic forces are also responsible for the binding. The computational findings were then used to guide structure-based optimization of the interfacial salt-bridge network. Consequently, five peptides were rationally designed using the high-affinity binder Cyto8-RETEV (RETEV-COOH) as template, including four single-point mutants (i.e. Cyto8-mtxe0: RETEE-COOH, Cyto8-mtxd-1: RETDV-COOH, Cyto8-mtxd-3: RDTEV-COOH and Cyto8-mtxk-4: KETEV-COOH) and one double-point mutant (i.e. Cyto8-mtxd-1k-4: KETDV-COOH). Binding assays confirmed that three (Cyto8-mtxd-1, Cyto8-mtxk-4 and Cyto8-mtxd-1k-4) out of the five designed peptides exhibit moderately or considerably increased affinity as compared to the native peptide Cyto8-RETEV.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Peptídeos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 4/metabolismo , Neoplasias Encefálicas/patologia , Glioma/patologia , Ligantes , Modelos Moleculares , Domínios PDZ , Peptídeos/química , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 4/química , Eletricidade Estática , Termodinâmica
12.
Environ Sci Pollut Res Int ; 23(8): 7890-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26762933

RESUMO

Detoxification by chemical oxidation of polychlorinated biphenyls (PCBs) in contaminated soils is very difficult and inefficient because PCBs typically associate with the solid phase or exist as non-aqueous-phase liquids due to their low solubility and slow desorption rates, and thus, they are difficult to remove from soils by using traditional, water-based elution techniques. Surfactant can enhance washing efficiency of PCBs from contaminated soils. This study used Brij 58, Brij 30, Tween 80, and 2-hydroxypropyl-ß-cyclodextrin (HPCD) to solubilize 2,4,4'-trichlorodiphenyl (PCB28) from soil contaminated with capacitor oil into solution. The feasibility of PCB28 oxidation in soil washing wastewater through a Fe(3+)-catalyzed Fenton-like reaction was subsequently examined. Washing with 10 g L(-1) Brij 58 solution showed the highest extraction efficiency (up to 61.5 %) compared with that of the three other surfactants. The total concentration of PCB28 in contaminated soil at 25 °C after 48-h extraction was 286 mg L(-1). In contrast to conditions in which no washing agent was added, addition of the four washing agents decreased the efficiency of PCB28 degradation by the Fenton-like reaction, with the decrease due to addition of 10 g L(-1) Brij 58 solution being the smallest. The optimal concentration of H2O2 for preventing its useless decomposition was found to be 50 mM. The efficiency of PCB28 removal was lower when the initial concentration of PCB28 treated in the Fenton-like reaction was higher. The degradation efficiencies of PCB28 at initial concentrations of 0.1, 10, and 176 mg L(-1) in 10 g L(-1) Brij 58 solution at 25 °C and pH 3.0 and 9 h of reaction using 50 mM H2O2 were 64.1, 42.0, and 34.6 %, respectively. This result indicates that soil washing combined with Fenton-like oxidation may be a practical approach for the remediation of PCB-contaminated soil.


Assuntos
Peróxido de Hidrogênio/química , Ferro/química , Óleos/química , Bifenilos Policlorados/química , Bifenilos Policlorados/isolamento & purificação , Poluentes do Solo/química , Poluentes do Solo/isolamento & purificação , Solo/química , 2-Hidroxipropil-beta-Ciclodextrina , Capacitância Elétrica , Oxirredução , Polidocanol , Polietilenoglicóis/química , Polissorbatos/química , Soluções , Tensoativos/química , beta-Ciclodextrinas/química
13.
Mol Neurobiol ; 53(7): 4883-92, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26362309

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease, with increasing incidence all over the world. Amyloid-ß (Aß) was considered to be the original cause to AD, and many reported pathogenic or risk genes for AD were located in the Aß generation and degradation pathways. Neprilysin (NEP), insulin-degrading enzyme (IDE), and matrix metalloprotease-9 (MMP-9) are the most important Aß-degrading proteases. Accumulating genetic evidence suggested that single nucleotide polymorphisms (SNPs) of these genes confer susceptibility to AD in Caucasian populations. In this study, we screened eight SNPs within these three Aß-degrading protease genes in 1475 individuals of two independent Han Chinese case-control cohorts. SNP rs1816558 of NEP was found to be significantly associated with AD after adjustment for ε4 allele of the apolipoprotein E gene (APOEε4) and the Bonferroni correction. The remaining variants were not associated with risk of AD in Han Chinese sample set. Further data mining revealed that messenger RNA (mRNA) level of NEP substantially increased during the development of AD and was positively correlated with APP expression. The combined results indicated that NEP confers genetic susceptibility to AD in Han Chinese populations.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Povo Asiático/genética , Predisposição Genética para Doença/genética , Neprilisina/genética , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Mineração de Dados/métodos , Predisposição Genética para Doença/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único/genética , Domínios e Motivos de Interação entre Proteínas/genética
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 45(1): 19-23, 2014 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-24527575

RESUMO

OBJECTIVE: To investigate the effects of Jianpi Qinghua Decoctions on the inflammation injury mediated by the cellular immunity in the focal segmental glomurular Sclerosis (FSGS) nephropathy rats. METHODS: The FSGS nephropathy rat model was established by the method of intravenous injection of Adriamycin after the removal of one kidney. After the treatment of Jianpi Qinghua Decoctions, the blood, spleen and kidney samples of each rat were collected for the detection of splenocytes CD4+/CD8+ ratio, renal tubulointerstitial fibronectin (FN) mRNA, Col III mRNA, and the expression levels of TNF-alpha and IL6. RESULTS: The treatment of Jianpi Qinghua Decoctions decreased the levels of CD4+/CD8+, tubulointerstitial FN mRNA, Col III mRNA, TNF-alpha and IL6 significantly in FSGS nephropathy rats. CONCLUSION: Jianpi Qinghua Decoctions could improve renal FSGS damage in adriamycin-induced nephropathy rats.


Assuntos
Doxorrubicina/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Nefropatias/patologia , Animais , Relação CD4-CD8 , Fibronectinas/metabolismo , Interleucina-6/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/induzido quimicamente , RNA Mensageiro , Ratos , Fator de Necrose Tumoral alfa/metabolismo
15.
J Clin Invest ; 124(3): 1406-17, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24569374

RESUMO

Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAF(V600E) melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAF(V600E) melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Indóis/farmacologia , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Humanos , Sistema de Sinalização das MAP Quinases , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Nus , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Vemurafenib , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Proc Natl Acad Sci U S A ; 109(21): 8253-8, 2012 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-22566612

RESUMO

Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Lisossomos/efeitos dos fármacos , Poliaminas/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Aminoquinolinas/síntese química , Aminoquinolinas/toxicidade , Animais , Antimaláricos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Autofagia/genética , Proteínas Relacionadas à Autofagia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas de Transporte/genética , Morte Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/genética , Glioblastoma/patologia , Células HT29 , Humanos , Hidroxicloroquina/farmacologia , Obstrução Intestinal/induzido quimicamente , Obstrução Intestinal/genética , Camundongos , Camundongos Nus , Poliaminas/síntese química , Poliaminas/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Clin Cancer Res ; 17(10): 3478-89, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21325076

RESUMO

PURPOSE: Autophagy consists of lysosome-dependent degradation of cytoplasmic contents sequestered by autophagic vesicles (AV). The role of autophagy in determining tumor aggressiveness and response to therapy in melanoma was investigated in this study. EXPERIMENTAL DESIGN: Autophagy was measured in tumor biopsies obtained from metastatic melanoma patients enrolled on a phase II trial of temozolomide and sorafenib and correlated to clinical outcome. These results were compared with autophagy measurements in aggressive and indolent melanoma cells grown in two- and three-dimensional (3D) culture and as xenograft tumors. The effects of autophagy inhibition with either hydroxychloroquine or inducible shRNA (short hairpin RNA) against the autophagy gene ATG5 were assessed in three-dimensional spheroids. RESULTS: Patients whose tumors had a high autophagic index were less likely to respond to treatment and had a shorter survival compared with those with a low autophagic index. Differences in autophagy were less evident in aggressive and indolent melanoma cells grown in monolayer culture. In contrast, autophagy was increased in aggressive compared with indolent melanoma xenograft tumors. This difference was recapitulated when aggressive and indolent melanoma cells were grown as spheroids. Autophagy inhibition with either hydroxychloroquine or inducible shRNA against ATG5 resulted in cell death in aggressive melanoma spheroids, and significantly augmented temozolomide-induced cell death. CONCLUSIONS: Autophagy is a potential prognostic factor and therapeutic target in melanoma. Three dimensional culture mimics the tumor microenvironment better than monolayer culture and is an appropriate model for studying therapeutic combinations involving autophagy modulators. Autophagy inhibition should be tested clinically in patients with melanoma.


Assuntos
Autofagia/fisiologia , Resistencia a Medicamentos Antineoplásicos , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenossulfonatos/administração & dosagem , Contagem de Células , Ensaios Clínicos Fase II como Assunto , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica , Niacinamida/análogos & derivados , Compostos de Fenilureia , Prognóstico , Piridinas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Sorafenibe , Análise de Sobrevida , Temozolomida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Artigo em Chinês | MEDLINE | ID: mdl-20848848

RESUMO

OBJECTIVE: To research serum level of interleukin-17 (IL-17) associated with the progression of hepatic injury in the chronic patients with hepatitis B. METHODS: The serum level of IL-17 was measured by ELISA and the serum levels of IL-6, IL-8 were measured by RIA in patient groups and healthy group, the patient groups including 42 mild patients, 37 moderate patients and 38 severe patients. RESULTS: IL-17,IL-6 and IL-8 levels in patient patients were significantly higher than those in healthy people (P < 0.01). There is no significant difference among mild patients and moderate patients. Compared with mild patients and moderate patients,the cytokines lever were significantly higher in severe patients (P < 0.01). CONCLUSION: IL-17 as a new cytokine probably play a multiple role as immune factor and inflammation element in the progression of the chronic hepatitis B disease. Maybe, it can provide a new approach to the therapy of the chronic hepatitis B.


Assuntos
Hepatite B Crônica/sangue , Interleucina-17/sangue , Interleucina-6/sangue , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Hepatite B Crônica/patologia , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade
19.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 41(3): 490-3, 2010 May.
Artigo em Chinês | MEDLINE | ID: mdl-20629329

RESUMO

OBJECTIVE: To explore the effect of genetic and environmental factors on externalizing behaviors of children. METHODS: A total of 168 twin pairs aged 6-16 years were recruited. Their parents completed Achenbach Child Behavior Checklist (CBCL) to evaluate the children's externalizing behaviors. The parents also completed FACESII-CV and GHQ-12 to assess their family environment. Structural equation modeling was performed to evaluate the effects of additive genetic factors (A), common environmental factors (C) and individual-specific environmental factors (E) on the externalizing behaviors. RESULTS: The effect of A, C, and E on externalizing behaviors were 0.39 (95% CI: 0.22-0.62), 0.51 (95% CI: 0.28-0.67), and 0.10 (95% Cl: 0.07-0.15), respectively. Significant correlations were found between the children's externalizing behaviors and the total GHQ-12 scores of their fathers and mothers (r = 0.24, P < 0.05; r = 0.30, P < 0.05). The externalizing behaviors were also correlated with family adaptability (r = 0.27, P< 0.01). The logistic regression identified mother's habits, such as smoking and drinking as risk factors of their children's externalizing behaviors. CONCLUSION: Externalizing behaviors are mainly affected by shared environmental factors. Externalizing behaviors are related to general mental health of fathers and mothers and the family adaptability.


Assuntos
Transtornos do Comportamento Infantil/epidemiologia , Transtornos do Comportamento Infantil/genética , Comportamento Infantil , Família , Adolescente , Criança , China/epidemiologia , Meio Ambiente , Feminino , Humanos , Masculino , Inquéritos e Questionários
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 25(3): 311-4, 2008 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-18543224

RESUMO

OBJECTIVE: To investigate the expression of Toll-like receptors (TLRs) in thymus of myasthenia gravis (MG) patients and the relationship with clinical features. METHODS: Thymic specimens of 36 patients received extended thymectomy for MG were divided into three groups by pathological type: 13 thymoma tissues (thymoma group) and 13 thymic tissues adjacent to thymomas (parathymoma group) from 13 cases of MG patients with thymomas, and 23 thymic tissues from MG patients without thymomas (MG nonthymoma group). Twenty-one normal thymic specimens from cardiac surgery were used as controls. The levels of TLR2-4 mRNA were examined by RT-PCR, then the levels of TLR4 mRNA were assayed by real time RT-PCR and their relationship with clinical features were analyzed. RESULTS: The levels of TLR4 mRNA among the different groups had significant differences, while there was no difference in TLR2 and TLR3 levels. The real time RT-PCR showed that the level of TLR4 mRNA in nonthymoma group was significantly higher than that in control group(0.8544+/- 0.1200 vs 0.6851+/- 0.1524, P=0.018). And so is parathymoma group compared with the thymoma group (0.8214+/- 0.1019 vs 0.7101+/- 0.0916, P=0.005). No significant difference of TLR4 mRNA level was found between the parathymoma and nonthymoma groups. Nevertheless, the expression of TLR4 in both groups was increased compared with control group. The levels of TLR4 mRNA had positive correlation with Osserman type(R=0.609; P=0.004) . CONCLUSION: TLR4 may play a key role in the pathogenesis of MG. It was the thymic tissues adjacent to thymomas but not thymomas themselves participated in the onset of MG.


Assuntos
Regulação da Expressão Gênica , Miastenia Gravis/genética , Timo/metabolismo , Receptores Toll-Like/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 2 Toll-Like/genética , Receptor 3 Toll-Like/genética , Receptor 4 Toll-Like/genética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA