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1.
Materials (Basel) ; 17(7)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38612147

RESUMO

After the Fukushima nuclear disaster, the nuclear materials community has been vastly investing in accident tolerant fuel (ATF) concepts to modify/replace Zircaloy cladding material. Iron-chromium-aluminum (FeCrAl) alloys are one of the leading contenders in this race. In this study, we investigated FA-SMT (or APMT-2), PM-C26M, and Fe17Cr5.5Al over a time period of 6 months in simulated BWR environments and compared their performance with standard Zirc-2 and SS316 materials. Our results implied that water chemistry along with alloy chemistry has a profound effect on the corrosion rate of FeCrAl alloys. Apart from SS316 and Zirc-2 tube specimens, all FeCrAl alloys showed a mass loss in hydrogen water chemistry (HWC). FA-SMT displayed minimal mass loss compared to PM-C26M and Fe17Cr5.5Al because of its higher Cr content. The mass gain of FeCrAl alloys in normal water chemistry (NWC) is significantly less when compared to Zirc-2.

2.
World J Clin Cases ; 11(33): 7972-7979, 2023 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-38075571

RESUMO

BACKGROUND: Acute myelitis (AM) can lead to sudden sensory, motor and autonomic nervous dysfunction, which negatively affects their daily activities and quality of life, so it is necessary to explore optimization from a therapeutic perspective to curb the progression of the disease. AIM: To investigate the effect of ganglioside (GM) combined with methylprednisolone sodium succinate (MPSS) on the curative effect and neurological function of patients with AM. METHODS: First, we selected 108 AM patients visited between September 2019 and September 2022 and grouped them based on treatment modality, with 52 patients receiving gamma globulin (GG) + MPSS and 56 patients receiving GM + MPSS, assigned to the control group (Con) and observation group (Obs), respectively. The therapeutic effect, neurological function (sensory and motor function scores), adverse events (AEs), recovery (time to sphincter function recovery, time to limb muscle strength recovery above grade 2, and time to ambulation), inflammatory factors (IFs) [interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-α] and other data of the two groups were collected for evaluation and comparison. RESULTS: The Obs had: (1) A significantly higher response rate of treatment than the Con; (2) Higher scores of sensory and motor functions after treatment that were higher than the baseline (before treatment) and higher than the Con levels; (3) Lower incidence rates of skin rash, gastrointestinal discomfort, dyslipidemia, osteoporosis and other AEs; (4) Faster posttreatment recovery of sphincter function, limb muscle strength and ambulation; and (5) Markedly lower posttreatment IL-6, CRP and TNF-α levels than the baseline and the Con levels. CONCLUSION: From the above, it can be seen that GM + MPSS is highly effective in treating AM, with a favorable safety profile comparable to that of GG + MPSS. It can significantly improve patients' neurological function, speed up their recovery and inhibit serum IFs.

3.
Chemosphere ; 340: 139844, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37597626

RESUMO

Exposure to heavy metal(loid)s (HM) through contaminated food chains poses significant health risks to humans. While soil amendments are known to reduce HM bioavailability, their effects on bioaccessibility and health risks in soil-pakchoi-human systems remain unclear. To address this knowledge gap, we conducted a greenhouse pot experiment coupling soil immobilization with bioaccessibility-based health risk assessment for Cd and As exposure from pakchoi consumption. Four amendments (attapulgite, shell powder, nanoscale zero-valent iron, and biochar) were applied to soil, resulting in changes to soil characteristics (pH and organic matter), plant dry weight, and exchangeable fractions of As and Cd. Among the tested amendments, biochar exhibited the highest effectiveness in reducing the risk of Cd and As exposure from pakchoi consumption. The bioaccessibility-based health risk assessment revealed that the application of 5% biochar resulted in the lowest hazard index, significantly decreasing it from 1.36 to 0.33 in contaminated soil. Furthermore, the structural equation model demonstrated that pH played a critical role in influencing remediation efficiency, impacting the exposure of the human body to Cd and As. In conclusion, our study offers a new perspective on mitigating exposure risks of soil HM and promoting safe crop production. The results underscore the importance of considering bioaccessibility in health risk assessment and highlight the potential of biochar as a promising amendment for reducing Cd and As exposure from pakchoi consumption.


Assuntos
Arsênio , Cádmio , Disponibilidade Biológica
4.
J Med Virol ; 95(2): e28554, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36738232

RESUMO

Lung cancer is a fatal disease with the highest worldwide morbidity and mortality rates. Despite recent advances in targeted therapy and immune checkpoint inhibitors for cancer, their efficacy remained limited. Therefore, we designed a Newcastle disease virus (NDV)-modified tumor whole-cell vaccine as a therapeutic vaccine and identified its antigen presentation level to develop effective immunotherapy. Then, we calculated the therapeutic and immune-stimulating effects of NDV-modified lung cancer cell vaccine and intratumoral NDV injection combination on tumor-bearing mice. The results showed that the immunogenic cell death (ICD) expression in NDV-modified lung cancer cell vaccine stimulates dendritic cell maturation and T cell activation in vivo and in vitro. Moreover, NDV-modified lung cancer cell vaccine combined with intratumoral NDV injection could significantly inhibit tumor growth and enhance the differentiation of Th1 cells and Inflammatory cell infiltration in vivo, leading to an excellent immunotherapeutic effect. Therefore, our results revealed that NDV-modified lung cancer cell vaccine combined with intratumoral NDV injection could promote antigen presentation and induce a strong antitumor immune response, which provided a promising combined therapy strategy for tumor immunotherapy.


Assuntos
Vacinas Anticâncer , Neoplasias Pulmonares , Animais , Camundongos , Vírus da Doença de Newcastle , Imunoterapia/métodos , Vacinas Anticâncer/metabolismo , Imunidade
5.
J Hazard Mater ; 448: 130887, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36731321

RESUMO

Microplastics (MPs) and cadmium (Cd) are widely distributed in soil ecosystems, posing a potential threat to agricultural production and human health. However, the coupled effects of MPs and Cd in soil-plant systems remain largely unknown, especially on a large scale. In this study, a meta-analysis was conducted to evaluate the influence of MPs on plant growth and Cd accumulation under the Cd contamination conditions. Our results showed that MPs had significantly negative effects on shoot biomass (a decrease of 11.8 %) and root biomass (a decrease of 8.79 %). MPs also significantly increased Cd accumulation in the shoots and roots by 14.6 % and 13.5 %, respectively, revealing that MPs promote plant Cd uptake. Notably, polyethylene displayed a stronger promoting effect (an increase of 29.4 %) on Cd accumulation among these MP types. MPs induced a significantly increase (9.75 %) in concentration of soil available Cd and a slight decrease in soil pH, which may be the main driver promoting plant Cd uptake. MP addition posed physiological toxicity risks to plants by inhibiting photosynthesis and enhancing oxidative damage, directly demonstrating that MPs in combination with Cd can pose synergetic toxicity risks to plants. We further noted that MPs altered microbial diversity, likely influencing Cd bioavailability in soil-plant systems. Overall, our study has important implications for the combined impacts of Cd and MPs on plants and provides new insights into developing guidelines for the sustainable use of MPs in agriculture.


Assuntos
Microplásticos , Poluentes do Solo , Humanos , Microplásticos/toxicidade , Cádmio/toxicidade , Cádmio/análise , Plásticos/toxicidade , Ecossistema , Poluentes do Solo/toxicidade , Poluentes do Solo/análise , Solo
6.
Comput Math Methods Med ; 2022: 1272729, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669369

RESUMO

The loss of nuclear factor I (NFI) function can lead to defects in Muller's glial differentiation, abnormalities of retinal morphology, and changes in retinal neurons numbers, which are highly involved in diabetic retinopathy (DR). In this study, we addressed the roles of NFIA and NFIB gene expression in the development of DR by using diabetes mellitus (DM) rat models. Retinal histologies were examined, and the expression of NFIA and NFIB at mRNA and protein levels was detected. The results showed that retinal edema and disordered cell arrangement frequently occurred in DR rats. The expressions of NFIA and NFIB in retinal tissue were significantly decreased in DM rats with DR complications. After further inhibiting the expression of NFIA gene in DM rats by using RNA-silencing, majority of DM rats occurred retinopathy and lens fibrosis, which indicated the relationship between decreased expression of NFI and occurrence of retinopathy in DM.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Animais , Retinopatia Diabética/genética , Humanos , Fatores de Transcrição NFI/genética , Fatores de Transcrição NFI/metabolismo , Ratos , Retina
7.
Nanomaterials (Basel) ; 12(8)2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35458053

RESUMO

With zinc acetate and butyl titanate as raw materials, pure ZnO and ZnTiO3/ZnO composite photocatalysts were synthesized by a sol-gel method and calcined at 550 °C. The crystal structure, morphology, surface area, optical property, and element valence states of samples were characterized and the photocatalytic activity of the prepared photocatalysts were assessed by the degradation of rhodamine B. Results show that the crystal structure of ZnO is a hexagonal wurtzite phase with a band gap of 3.20 eV. When the Zn/Ti molar ratio reaches 0.2, ZnTiO3 phase appears and ZnTiO3/ZnO composite forms, which advances the transfer of photogenerated charges. ZnTiO3/ZnO (Ti/Zn = 0.2) exhibits the highest photocatalytic activity, and the degradation degree of RhB reaches 99% after 60 min, which is higher than that of pure ZnO (90%). An exorbitant Ti/Zn molar ratio will reduce the crystallinity and form more amorphous components, which is not conducive to photocatalytic performance. Therefore, when the Ti/Zn molar ratio exceeds 0.2, the photocatalytic activities of ZnTiO3/ZnO composites decrease.

8.
Nanomaterials (Basel) ; 12(5)2022 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-35269361

RESUMO

The anatase/rutile mixed crystal TiO2 was prepared and modified with Ag decoration and SnO2 coupling to construct a Ag@SnO2/anatase/rutile composite photocatalytic material. The crystal structure, morphology, element valence, optical properties and surface area were characterized, and the effects of Ag decoration and SnO2 coupling on the structure and photocatalytic properties of TiO2 were studied. Ag decoration and SnO2 coupling are beneficial to reduce the recombination of photogenerated electrons and holes. When the two modification are combined, a synergistic effect is produced in suppressing the photogenerated charge recombination, making Ag@SnO2/TiO2 exhibits the highest quantum utilization. After 30 min of illumination, the degradation degree of tetracycline hydrochloride (TC) by pure TiO2 increased from 63.3% to 83.1% with Ag@SnO2/TiO2.

9.
J Magn Reson ; 295: 72-79, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30144687

RESUMO

Test disk electrodes were fabricated from carbon nanotubes (CNT) using the Carbon Nanotube Templated Microfabrication (CNT-M) technique. The CNT-M process uses patterned growth of carbon nanotube forests from surfaces to form complex patterns, enabling electrode sizing and shaping. The additional carbon infiltration process stabilizes these structures for further processing and handling. At a macroscopic scale, the electrochemical, electrical and magnetic properties, and magnetic resonance imaging (MRI) characteristics of the disk electrodes were investigated; their microstructure was also assessed. CNT disk electrodes showed electrical resistivity around 1â€¯Ω·cm, charge storage capacity between 3.4 and 38.4 mC/cm2, low electrochemical impedance and magnetic susceptibility of -5.9 to -8.1 ppm, closely matched to that of tissue (∼-9 ppm). Phantom MR imaging experiments showed almost no distortion caused by these electrodes compared with Cu and Pt-Ir reference electrodes, indicating the potential for significant improvement in accurate tip visualization.

10.
Front Physiol ; 9: 325, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670541

RESUMO

In recent years, automatic change detection for real-time monitoring of electroencephalogram (EEG) signals has attracted widespread interest with a large number of clinical applications. However, it is still a challenging problem. This paper presents a novel framework for this task where joint time-domain features are firstly computed to extract temporal fluctuations of a given EEG data stream; and then, an auto-regressive (AR) linear model is adopted to model the data and temporal anomalies are subsequently calculated from that model to reflect the possibilities that a change occurs; a non-parametric statistical test based on Randomized Power Martingale (RPM) is last performed for making change decision from the resulting anomaly scores. We conducted experiments on the publicly-available Bern-Barcelona EEG database where promising results for terms of detection precision (96.97%), detection recall (97.66%) as well as computational efficiency have been achieved. Meanwhile, we also evaluated the proposed method for real detection of seizures occurrence for a monitoring epilepsy patient. The results of experiments by using both the testing database and real application demonstrated the effectiveness and feasibility of the method for the purpose of change detection in EEG signals. The proposed framework has two additional properties: (1) it uses a pre-defined AR model for modeling of the past observed data so that it can be operated in an unsupervised manner, and (2) it uses an adjustable threshold to achieve a scalable decision making so that a coarse-to-fine detection strategy can be developed for quick detection or further analysis purposes.

11.
J Drug Target ; 25(6): 471-484, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28135859

RESUMO

This review focuses on recent investigations that used Pluronic P123 (P123) as pharmaceutical ingredients in vesicle, micelle, mixed micelle, in situ gel, tablet and emulsion. The main results from these studies show that P123 can significantly increase the stability of incorporated hydrophobic drugs with enhanced in vitro cytotoxicity and cellular uptake of anticancer drugs. Moreover, modified forms of P123 with RGD, folate or other targeted marker have shown its therapeutic potentials in various types of tumors and cancers. Furthermore, modified forms of P123 alone and/or mixed with other copolymers have less toxic effects and more tumor-specific delivery of anticancer drugs. They are promising materials as a nanoplatform for the drug delivery. Finally, the future perspectives of the field are briefly discussed.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Poloxaleno/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Estabilidade de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Oligopeptídeos/administração & dosagem , Poloxaleno/efeitos adversos , Poloxaleno/química
12.
Brain Res ; 1657: 312-322, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28034722

RESUMO

High fructose consumption in the Western diet correlates with disease states such as obesity and metabolic syndrome complications, including type II diabetes, chronic kidney disease, and non-alcoholic fatty acid liver disease. Liver and kidneys are responsible for metabolism of 40-60% of ingested fructose, while the physiological fate of the remaining fructose remains poorly understood. The primary metabolic pathway for fructose includes the fructose-transporting solute-like carrier transport proteins 2a (SLC2a or GLUT), including GLUT5 and GLUT9, ketohexokinase (KHK), and aldolase. Bioinformatic analysis of gene expression encoding these proteins (glut5, glut9, khk, and aldoC, respectively) identifies other organs capable of this fructose metabolism. This analysis predicts brain, lymphoreticular tissue, placenta, and reproductive tissues as possible additional organs for fructose metabolism. While expression of these genes is highest in liver, the brain is predicted to have expression levels of these genes similar to kidney. RNA in situ hybridization of coronal slices of adult mouse brains validate the in silico expression of glut5, glut9, khk, and aldoC, and show expression across many regions of the brain, with the most notable expression in the cerebellum, hippocampus, cortex, and olfactory bulb. Dissected samples of these brain regions show KHK and aldolase enzyme activity 5-10 times the concentration of that in liver. Furthermore, rates of fructose oxidation in these brain regions are 15-150 times that of liver slices, confirming the bioinformatics prediction and in situ hybridization data. This suggests that previously unappreciated regions across the brain can use fructose, in addition to glucose, for energy production.


Assuntos
Encéfalo/metabolismo , Frutose/metabolismo , Análise de Variância , Animais , Western Blotting , Biologia Computacional , Frutoquinases/metabolismo , Frutose-Bifosfato Aldolase/metabolismo , Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 5 , Hexoquinase/metabolismo , Hibridização In Situ , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Oxirredução
13.
Clin Biochem ; 46(7-8): 694-7, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23195138

RESUMO

OBJECTIVES: Determinations of cerebrospinal fluid (CSF) lactate and pyruvate concentrations and CSF lactate:pyruvate (L/P) ratios are important in several clinical settings, yet published normative data have significant limitations. We sought to determine a large dataset of stringently-defined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios. DESIGN AND METHODS: We evaluated data from 627 patients who had determinations of CSF lactate and/or CSF pyruvate from 2001 to 2011 at the Cleveland Clinic. Inclusion in the normal reference population required normal CSF cell counts, glucose and protein and routine serum chemistries and absence of progressive brain disorder, epilepsy, or seizure within 24h. Brain MRI, if done, showed no evidence of tumor, acute changes or basal ganglia abnormality. CSF cytology, CSF alanine and immunoglobulin levels, and oligoclonal band analysis were required to be normal, if done. Various inclusion/exclusion criteria were compared. RESULTS: 92 patients fulfilled inclusion/exclusion criteria for a reference population. The 95% central intervals (2.5%-97.5%) for CSF lactate and pyruvate levels were 1.01-2.09mM and 0.03-0.15mM, respectively, and 9.05-26.37 for CSF L/P. There were no significant gender-related differences of CSF lactate or pyruvate concentrations or of CSF L/P. Weak positive correlations between the concentration of CSF lactate or pyruvate and age were noted. CONCLUSIONS: Using stringent inclusion/exclusion criteria, we determined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios in a large, well-characterized reference population. Normalcy of routine CSF and blood analytes are the most important parameters in determining reference intervals for CSF lactate and pyruvate.


Assuntos
Ácido Láctico/líquido cefalorraquidiano , Ácido Pirúvico/líquido cefalorraquidiano , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valores de Referência
16.
Biochim Biophys Acta ; 1818(1): 55-63, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21996039

RESUMO

Inactivation of potassium channels plays an important role in shaping the electrical signaling properties of nerve and muscle cells. The rapid inactivation of Kv1.4 has been assumed to be controlled by a "ball and chain" inactivation mechanism. Besides hydrophobic interaction between inactivation ball and the channel's inner pore, the electrostatic interaction has also been proved to participate in the "ball and chain" inactivation process of Kv1.4 channel. Based on the crystal structure of Kv1.2 channel, the acidic T1-S1 linker is indicated to be a candidate interacting with the positively charged hydrophilic region of the inactivation domain. In this study, through mutating the charged residues to amino acids of opposite polar, we identified the electrostatic interaction between the inactivation ball and the T1-S1 linker region of Kv1.4 channel. Inserting negatively charged peptide at the amino terminal of Kv1.4 channel further confirmed the electrostatic interaction between the two regions.


Assuntos
Canal de Potássio Kv1.4/metabolismo , Potenciais da Membrana/fisiologia , Peptídeos/metabolismo , Eletricidade Estática , Sequência de Aminoácidos , Animais , Células CHO , Clonagem Molecular , Cricetinae , Interações Hidrofóbicas e Hidrofílicas , Ativação do Canal Iônico , Canal de Potássio Kv1.4/química , Canal de Potássio Kv1.4/genética , Mamíferos , Dados de Sequência Molecular , Mutação , Neurônios/fisiologia , Técnicas de Patch-Clamp , Peptídeos/química , Peptídeos/genética , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
17.
J Control Release ; 140(3): 301-5, 2009 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-19508879

RESUMO

Previously we reported that plasma kallikrein and high molecular weight kininogen attach to the surface of dextran-coated superparamagnetic iron oxide nanoparticles (SPION) through the incompletely covered iron oxide core (Simberg et al., Biomaterials, 2009). Here we show that SPION also activate kallikrein-kinin system in vitro and in vivo. The serine protease activity of kallikrein was stably associated with SPION and could be detected on the nanoparticles even after extensive washing steps. The enzymatic activity was not detectable in kininogen-deficient and Factor XII-deficient plasma. The enzymatic activation could be blocked by precoating SPION with histidine-rich Domain 5 (D5) of kininogen. Importantly, the kallikrein activity was detectable in plasma of SPION-injected, but not of D5/SPION-injected mice. Tumor-targeted SPION when injected into kininogen-deficient and control mice, produced high levels of vascular clotting in tumors, suggesting that kallikrein activation is not responsible for the nanoparticle-induced thrombosis. These data could help in understanding the toxicity of nanomaterials and could be used in designing nanoparticles with controlled enzymatic activity.


Assuntos
Compostos Férricos , Sistema Calicreína-Cinina/fisiologia , Sistema Calicreína-Cinina/efeitos da radiação , Animais , Proteínas Sanguíneas/química , Dextranos , Sistemas de Liberação de Medicamentos , Ativação Enzimática , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Magnetismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Peso Molecular , Nanopartículas , Trombose/induzido quimicamente
18.
Biomaterials ; 30(23-24): 3926-33, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19394687

RESUMO

In order to understand the role of plasma proteins in the rapid liver clearance of dextran-coated superparamagnetic iron oxide (SPIO) in vivo, we analyzed the full repertoire of SPIO-binding blood proteins using novel two-dimensional differential mass spectrometry approach. The identified proteins showed specificity for surface domains of the nanoparticles: mannan-binding lectins bound to the dextran coating, histidine-rich glycoprotein and kininogen bound to the iron oxide part, and the complement lectin and contact clotting factors were secondary binders. Nanoparticle clearance studies in knockout mice suggested that these proteins, as well as several previously identified opsonins, do not play a significant role in the SPIO clearance. However, both the dextran coat and the iron oxide core remained accessible to specific probes after incubation of SPIO in plasma, suggesting that the nanoparticle surface could be available for recognition by macrophages, regardless of protein coating. These data provide guidance to rational design of bioinert, long-circulating nanoparticles.


Assuntos
Ferro/metabolismo , Nanopartículas/química , Óxidos/metabolismo , Proteômica/métodos , Animais , Células Cultivadas , Dextranos , Óxido Ferroso-Férrico , Ferro/química , Células de Kupffer/metabolismo , Nanopartículas de Magnetita , Camundongos , Óxidos/química , Plasma/metabolismo , Ligação Proteica , Proteínas/metabolismo
19.
Zhong Yao Cai ; 32(11): 1746-8, 2009 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-20218300

RESUMO

OBJECTIVE: To study the optimal extraction process of chaihushugan powder by orthogonal design. METHODS: RP-HPLC method was developed for the determination of saikosaponin a, ferulic acid, hesperidin and paeoniflorin in chaihushugan powder. The contents of the components and the extraction yield were selected as assessment indices. Four factors were study by L9 (3(4)), including the alcohol concentration, amount of alcohol, duration of extraction and times of extraction. RESULTS: The optimal extracting condition was 80% alcohol consumed as 10 times of crude herb amount, and extracting two times for 90 min each time. CONCLUSION: This study supplies theoretical base for the development of chaihushugan powder formulation.


Assuntos
Bupleurum/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Ácido Oleanólico/análogos & derivados , Plantas Medicinais/química , Saponinas/análise , Tecnologia Farmacêutica/métodos , Benzoatos/análise , Benzoatos/isolamento & purificação , Hidrocarbonetos Aromáticos com Pontes/análise , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Ácidos Cumáricos/análise , Ácidos Cumáricos/isolamento & purificação , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/química , Etanol/química , Glucosídeos/análise , Glucosídeos/isolamento & purificação , Hesperidina/análise , Hesperidina/isolamento & purificação , Temperatura Alta , Monoterpenos , Ácido Oleanólico/análise , Ácido Oleanólico/isolamento & purificação , Pós , Controle de Qualidade , Saponinas/isolamento & purificação , Solubilidade , Fatores de Tempo
20.
J Biol Chem ; 284(2): 913-20, 2009 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-19008228

RESUMO

Mutations in SHP-2 phosphatase (PTPN11) that cause hyperactivation of its catalytic activity have been identified in Noonan syndrome and various childhood leukemias. Recent studies suggest that the gain-of-function (GOF) mutations of SHP-2 play a causal role in the pathogenesis of these diseases. However, the molecular mechanisms by which GOF mutations of SHP-2 induce these phenotypes are not fully understood. Here, we show that GOF mutations in SHP-2, such as E76K and D61G, drastically increase spreading and migration of various cell types, including hematopoietic cells, endothelial cells, and fibroblasts. More importantly, in vivo angiogenesis in SHP-2 D61G knock-in mice is also enhanced. Mechanistic studies suggest that the increased cell migration is attributed to the enhanced beta1 integrin outside-in signaling. In response to beta1 integrin cross-linking or fibronectin stimulation, activation of ERK and Akt kinases is greatly increased by SHP-2 GOF mutations. Also, integrin-induced activation of RhoA and Rac1 GTPases is elevated. Interestingly, mutant cells with the SHP-2 GOF mutation (D61G) are more sensitive than wild-type cells to the suppression of cell motility by inhibition of these pathways. Collectively, these studies reaffirm the positive role of SHP-2 phosphatase in cell motility and suggest a new mechanism by which SHP-2 GOF mutations contribute to diseases.


Assuntos
Movimento Celular/genética , Leucemia/enzimologia , Leucemia/patologia , Neovascularização Patológica/enzimologia , Síndrome de Noonan/enzimologia , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Enzimológica da Expressão Gênica/genética , Leucemia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Transdução de Sinais
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