Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Heliyon ; 8(12): e12108, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36544816

RESUMEN

Background: LINC02535 has gained much attention for its oncogenicity across several cancers, but the systematic pan-cancer analysis of LINC02535 has not been carried out before. Methods: Herein, we explored the expression level, prognostic value, and hallmark pathways of LINC02535 across multiple cancers using the Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases. Moreover, the expression and biological features of LINC02535 in lung adenocarcinoma (LUAD) were confirmed by qRT-PCR, in vitro and in vivo experiments. Results: LINC02535 is differentially expressed in 10 of 17 human cancers and serves as a favorable or unfavorable biomarker in distinct cancer types. Gene set enrichment analysis (GSEA) indicated that key oncogenic pathways/phenotypes were remarkably activated in most cancers with intratumoral increased LINC02535, whereas these pathways/phenotypes were suppressed in other cancer types (colon adenocarcinoma, kidney renal clear cell carcinoma, rectal adenocarcinoma) with intratumoral decreased LINC02535. Of note, the epithelial-mesenchymal transition (EMT) phenotype was greatly enriched in LUAD patients with elevated LINC02535. Based on the TCGA and CCLE datasets, LINC02535 was positively correlated with the EMT-related gene CD73 (also named as NT5E, an immunosuppressive gene) in almost all cancer types (Spearman R > 0.5, P < 0.001) including LUAD. Most importantly, qRT-PCR confirmed that LINC02535 was upregulated in lung cancer cells or tissues as opposed to human bronchial epithelial cells or paratumor tissues. Knockdown of LINC02535 inhibited proliferation, migration of LUAD cells and retarded xenografted tumor growth. Moreover, silencing of LINC02535 induced apoptosis and cell cycle arrest at G1 phase. Conclusions: The findings from our pan-cancer analysis provide a relatively comprehensive understanding of the potential value of LINC02535 across multiple cancers, and the oncogenic role of LINC02535 in LUAD has been confirmed.

2.
Pharm Biol ; 60(1): 1469-1477, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35938509

RESUMEN

CONTEXT: Paeoniflorin (PF) and calycosin-7-glucoside (CG, Paeonia lactiflora Pall. extract) have demonstrated protective effects in ischaemic stroke. OBJECTIVE: To investigate the synergistic effects of PF + CG on ischaemia/reperfusion injury in vivo and in vitro. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to the middle cerebral artery occlusion/reperfusion (MCAO/R). After MCAO/R for 24 h, rats were randomly subdivided into 5 groups: sham, model (MCAO/R), study treatment (PF + CG, 40 + 20 mg/kg), LY294002 (20 mg/kg), and study treatment + LY294002. Males were given via intragastric administration; the duration of the in vivo experiment was 8 days. Neurologic deficits, cerebral infarction, brain edoema, and protein levels were assessed in vivo. Hippocampal neurons (HT22) were refreshed with glucose-free DMEM and placed in an anaerobic chamber for 8 h. Subsequently, HT22 cells were reoxygenated in a 37 °C incubator with 5% CO2 for 6 h. SOD, MDA, ROS, LDH and protein levels were measured in vitro. RESULTS: PF + CG significantly reduced neurobehavioral outcomes (21%), cerebral infarct volume (44%), brain edoema (1.6%) compared with the MCAO/R group. Moreover, PF + CG increased p-PI3K/PI3K (4.69%, 7.4%), p-AKT/AKT (6.25%, 60.6%) and Bcl-2/BAX (33%, 49%) expression in vivo and in vitro, and reduced GSK-3ß (10.5%, 9.6%) expression. In vitro, PF + CG suppressed apoptosis in HT22 cells and decreased ROS and MDA levels (20%, 50%, respectively). CONCLUSIONS: PF + CG showed a synergistic protective effect against ischaemic brain injury, potentially being a future treatment for ischaemic stroke.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Daño por Reperfusión , Accidente Cerebrovascular , Animales , Isquemia Encefálica/tratamiento farmacológico , Glucósidos/farmacología , Glucógeno Sintasa Quinasa 3 beta , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Isoflavonas , Masculino , Monoterpenos , Fármacos Neuroprotectores/farmacología , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Accidente Cerebrovascular/tratamiento farmacológico
3.
Environ Sci Pollut Res Int ; 28(40): 57183-57191, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34085200

RESUMEN

Pregnancy represents a sensitive susceptibility window to phthalate esters (PAEs). In this study, we develop an intervention strategy for reducing the exposure of pregnant women to phthalates. Thirty-five pregnant women, who initially underwent maternity examination, were recruited from an ongoing longitudinal prospective prenatal cohort study. The intervention strategy integrates diet, lifestyle, and environmental factors. Participants were encouraged to modify their behaviors and habits according to the intervention strategy at three different periods. Urine samples were collected from the participants after antenatal examination every month, for 8 months, to measure ten PAE metabolites. Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-n-butyl phthalate (MnBP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) declined significantly after the 1st intervention, while mono-isobutyl phthalate (MiBP) and mono-methyl phthalate (MMP) noticeably decreased after the 2nd intervention. The sum of the molar concentrations of MEHP, MEHHP, MEOHP, and MECPP reduced by 20 to 40% during subsequent intervention. In addition, the sum of the molar concentrations of MEP, MnBP, MMP, and MiBP as well as the sum of the molar concentrations of the ten metabolites also reduced. Our findings suggest that intervention through written recommendations can effectively reduce the burden of phthalates during pregnancy.


Asunto(s)
Contaminantes Ambientales , Ácidos Ftálicos , Estudios de Cohortes , Exposición a Riesgos Ambientales , Femenino , Humanos , Embarazo , Estudios Prospectivos
4.
Drug Des Devel Ther ; 14: 2877-2888, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32764886

RESUMEN

OBJECTIVE: The aim of our research was to analyze and compare the pharmacokinetics of paeoniflorin, calycosin, calycosin-7-o-ß-d-6-glucoside, and 6-gingerol in the blood and brain tissue of normal and cerebral ischemia-reperfusion injury rats by HPLC-MS/MS method. METHODS: The blood and brain tissue samples of normal and middle cerebral artery occlusion (MCAO) rats were compared. The blood and brain tissue samples were collected by using microdialysis technique. The concentrations of paeoniflorin, calycosin, calycosin-7-o-ß-d-6-glucoside, and 6-gingerol in blood and brain tissues were determined by the HPLC-MS/MS internal standard method. RESULTS: Compared with the normal group, the model group after the administration of the Huangqi Guizhi Wuwu Decoction showed that Cmax blood, AUC0-t blood, and AUC0-inf blood of paeoniflorin were increased, CLblood, t1/2 brain, and Vbrain of paeoniflorin were decreased; Cmaxblood, AUC0-tblood, AUC0-infblood, and average residence time (MRTbrain) of calycosin-7-o-ß-d-6-glucoside were decreased and the CLblood and Cmax brain of calycosin-7-o-ß-d-6-glucoside were increased; Cmax blood of calycosin was decreased, Vblood and Vbrain of calycosin were increased; Cmax blood, AUC0-t blood, AUC0-inf blood, and MRTbrain of 6-gingerol were decreased, CLblood of 6-gingerol was increased. CONCLUSION: This method is simple, rapid, and sensitive. It is suitable for the pharmacokinetic study of Huangqi Guizhi Wuwu Decoction in the blood and brain tissue of rats. Cerebral ischemia-reperfusion injury increased the content of paeoniflorin, calycosin, calycosin-7-o-ß-d-6-glucoside, and 6-gingerol in the blood, affecting the clearance rate of paeoniflorin in the brain, the detention time of calycosin-7-o-ß-d-6-glucoside and the 6-gingerol in the brain. In normal and cerebral ischemia-reperfusion rats, the content of paeoniflorin and 6-gingerol in the blood was higher than that in brain tissue, while the content of calycosin, calycosin-7-o-ß-d-6-glucoside in the brain tissue was higher than that in blood, suggesting that calycosin and calycosin-7-o-ß-d-6-glucoside have brain targeting properties.


Asunto(s)
Encéfalo/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Masculino , Microdiálisis , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión , Espectrometría de Masas en Tándem
5.
Artículo en Chino | MEDLINE | ID: mdl-31245949

RESUMEN

OBJECTIVE: To evaluate the effects of 12 weeks high intensity interval training(HIIT) on serum lipids profile in patients with dyslipidemia of different apolipoprotein E(ApoE) genotypes. METHODS: Eighty-eight patients with dyslipidemia were screened by fasting blood lipid as subjects. Apolipoprotein E genotypes were detected in oral mucosa of subjects. Serum lipids before and after 12 weeks high intensity interval training were measured to analysis the effect of high intensity interval training on serum lipids. RESULTS: Five genotypes were detected in 88 cases of dyslipidemia. The distributions were ApoE3/3>ApoE3/4>ApoE2/3>ApoE2/2>ApoE2/4,and allele ε3>ε2=ε4. Before exercise intervention, the level of total cholesterol in patients with ε4 allele was significant higher than those in patients with ε2 and ε3 (P<0.01), low density lipoprotein cholesterol in patients with ε4 was significant higher than that of patients with ε2 (P<0.05), and the other indexes had no significant difference among the groups (P> 0.05). After 12 weeks high intensity interval training, the levels of total cholesterol, triglyceride and low density lipoprotein cholesterol were decreased significantly ,while the level of high density lipoprotein cholesterol was increased in those patients with ε3 genotype. For those individuals with ε4 genotype , their serum levels of total cholesterol and low density lipoprotein cholesterol were reduced after 12 weeks high intensity interval training , but there was no changes in serum levels of triglyceride and high density lipoprotein cholesterol. For those individuals with ε2 genotype, there was no significant improvement in serum lipids after 12 weeks high intensity interval training interventions. CONCLUSION: The polymorphisms of apolipoprotein E gene resulted in different effects of exercise interventions on serum lipids of dyslipidemia. Twelve weeks high intensity interval training can be used as an intervention method to regulate serum lipids of dyslipidemia with ε3 and ε4 alleles.


Asunto(s)
Apolipoproteínas E , Dislipidemias , Entrenamiento de Intervalos de Alta Intensidad , Lípidos , Apolipoproteínas E/genética , Dislipidemias/genética , Dislipidemias/terapia , Genotipo , Humanos , Lípidos/sangre
6.
Am J Physiol Cell Physiol ; 315(6): C839-C849, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30183321

RESUMEN

Glaucoma represents a major cause of blindness, generally associated with elevated intraocular pressure (EIOP). The aim of the present study was to investigate whether microRNA-149 (miR-149) affects retinal ganglion cells (RGCs) and the underlying mechanism based on a mouse model of chronic glaucoma with EIOP. The successfully modeled mice were administered with mimics or inhibitors of miR-149. Next, the number of RGCs, ultrastructural changes of RGCs, and purity of RGCs in the retinal tissues were detected. Moreover, the RGCs were collected and subsequently treated with 60 mmHg pressure and transfected with a series of plasmids aiding in the regulation of the expression of miR-149 and betacellulin (BTC). The levels of miR-149, BTC, phosphatidylinositol 3-kinase (PI3K), and Akt were subsequently determined. Finally, RGC viability and apoptosis were detected accordingly. Dual luciferase reporter gene assay provided validation, highlighting BTC was indeed a target gene of miR-149. The downregulation of miR-149 is accompanied by an increased number of RGCs and decreased ultrastructural RGC alterations. Additionally, downregulated miR-149 was noted to increase the levels of BTC, PI3K, and Akt in both the retinal tissues and RGCs, whereas the silencing of miR-149 was observed to promote the viability of RGC and inhibit RGC apoptosis. Taken together, the results of the current study provided validation suggesting that the downregulation of miR-149 confers protection to RGCs by means of activating the PI3K/Akt signaling pathway via upregulation of BTC in mice with glaucoma. Evidence presented indicated the promise of miR-149 inhibition as a potential therapeutic strategy for glaucoma treatment.


Asunto(s)
Apoptosis/genética , Betacelulina/genética , Glaucoma/genética , MicroARNs/genética , Animales , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Glaucoma/patología , Humanos , Hipertensión Intracraneal/genética , Hipertensión Intracraneal/patología , Ratones , Proteína Oncogénica v-akt/genética , Fosfatidilinositol 3-Quinasas/genética , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Transducción de Señal/genética
7.
Mar Pollut Bull ; 120(1-2): 184-191, 2017 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-28511941

RESUMEN

Ocean acidification (OA) resulting from increasing atmospheric CO2 strongly influences marine ecosystems, particularly in the polar ocean due to greater CO2 solubility. Here, we grew the Antarctic sea ice diatom Nitzschia sp. ICE-H in a semicontinuous culture under low (~400ppm) and high (1000ppm) CO2 levels. Elevated CO2 resulted in a stimulated physiological response including increased growth rates, chlorophyll a contents, and nitrogen and phosphorus uptake rates. Furthermore, high CO2 enhanced cellular particulate organic carbon production rates, indicating a greater shift from inorganic to organic carbon. However, the cultures grown in high CO2 conditions exhibited a decrease in both extracellular and intracellular carbonic anhydrase activity, suggesting that the carbon concentrating mechanisms of Nitzschia sp. ICE-H may be suppressed by elevated CO2. Our results revealed that OA would be beneficial to the survival of this sea ice diatom strain, with broad implications for global carbon cycles in the future ocean.


Asunto(s)
Carbono , Clorofila/análisis , Diatomeas , Cubierta de Hielo , Regiones Antárticas , Dióxido de Carbono , Clorofila A , Océanos y Mares
8.
Curr Microbiol ; 74(8): 921-929, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28516199

RESUMEN

Calmodulin (CaM) is a Ca2+-binding protein that plays a role in several Ca2+ signaling pathways, which dynamically regulates the activities of hundreds of proteins. The ice alga Chlamydomonas sp. ICE-L, which has the ability to adapt to extreme polar conditions, is a crucial primary producer in Antarctic ecosystem. This study hypothesized that Cam helps the ICE-L to adapt to the fluctuating conditions in the polar environment. It first verified the overall length of Cam, through RT-PCR and RACE-PCR, based on partial Cam transcriptome library of ICE-L. Then, the nucleotide and predicted amino acid sequences were, respectively, analyzed by various bioinformatics approaches to gain more insights into the computed physicochemical properties of the CaM. Potential involvements of Cam in responding to certain stimuli (i.e., UVB radiation, high salinity, and temperature) were investigated by differential expression, measuring its transcription levels by means of quantitative RT-PCR. Results showed that CaM was indeed inducible and regulated by high UVB radiation, high salinity, and nonoptimal temperature conditions. Different conditions had different expression tendencies, which provided an important basis for investigating the adaptation mechanism of Cam in ICE-L.


Asunto(s)
Calmodulina/análisis , Calmodulina/genética , Chlamydomonas/enzimología , Perfilación de la Expresión Génica , Regiones Antárticas , Calmodulina/química , Chlamydomonas/efectos de los fármacos , Chlamydomonas/genética , Chlamydomonas/efectos de la radiación , Clonación Molecular , Biología Computacional , Presión Osmótica , Reacción en Cadena de la Polimerasa , Salinidad , Temperatura , Rayos Ultravioleta
9.
J Org Chem ; 82(5): 2462-2471, 2017 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-28155278

RESUMEN

A substrate-controlled regioselective arylation of 2-indolylmethanols with indoles has been established, which efficiently afforded bis(indolyl)methane and 3,3'-bisindole derivatives in high yields and with a broad substrate scope (up to 98% yield, 36 examples). This approach will not only provide an important strategy for the diversified synthesis of bis(indolyl)methane and 3,3'-bisindole derivatives but also serve as a good example for substrate-controlled regioselective reactions.

10.
Chemistry ; 22(49): 17526-17532, 2016 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-27734551

RESUMEN

The first catalytic asymmetric cycloaddition using 2-indolylmethanols as 3C building blocks has been established by a chiral phosphoric acid-catalyzed enantioselective and regioselective [3+3] cycloaddition of 2-indolylmethanols with azomethine ylides, which constructed biologically important tetrahydro-γ-carboline frameworks in high yields and excellent enantioselectivities (up to 83 % yield, 99:1 e.r.). This reaction not only represents the first application of 2-indolylmethanols as 3C building blocks in catalytic asymmetric cycloadditions, but also has established an abnormal regioselectivity in indolylmethanol-involved transformations.


Asunto(s)
Reacción de Cicloadición , Indoles/química , Catálisis , Estructura Molecular , Estereoisomerismo
11.
Biosci Biotechnol Biochem ; 80(3): 584-90, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26442995

RESUMEN

Administration of macromolecule compositions in medicine and cosmetics always exhibited low bioavailability due to the limitation of transmembrane transport. Here, human epidermal growth factor (hEGF) was fused with glutathione S-transferase (GST) and Pep-1, the first commercial cell-penetrating peptide, in Escherichia coli. The fusion protein was firstly purified with the affinity chromatography, and then the GST tag was released by TEV protease. Final purification was achieved by the ion exchange chromatography. The biological activities and the transmembrane ability of the obtained products were determined using scratch wound-healing assay, MTT analysis, and immunofluorescence assay. The results showed that both rhEGF and Pep-1-fused hEGF were soluble expressed in E. coli. The fusion of Pep-1 could markedly increase the transmembrane ability of EGF, whereas it did not interfere with the growth-stimulating and migration-promoting functions of hEGF on fibroblasts. This research provided a novel strategy for the transmembrane transport of protein-derived cosmetics or drugs.


Asunto(s)
Membrana Celular/metabolismo , Cisteamina/análogos & derivados , Factor de Crecimiento Epidérmico/metabolismo , Péptidos/química , Animales , Células COS , Chlorocebus aethiops , Cromatografía por Intercambio Iónico , Cisteamina/química , Humanos
12.
Biotechnol Lett ; 36(5): 975-83, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24375235

RESUMEN

Genes coding for bile salt hydrolase of Lactobacillus plantarum CGMCC 8198, a novel probiotic strain isolated from silage, were identified, analyzed and cloned. L. plantarum strongly resisted the inhibitory effects of bile salts and also decreased serum cholesterol levels by 20% in mice with hypercholesterolemia. Using RT-PCR analysis, bsh2, bsh3 and bsh4 were upregulated by bile salts in a dose-dependent manner. All three bsh genes had high similarity with those of other Lactobacillus strains. All three recombinant BSHs had high activities for the hydrolysis of glycodeoxycholic acids and taurodeoxycholic acids.


Asunto(s)
Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Proteínas Bacterianas/genética , Lactobacillus plantarum/enzimología , Lactobacillus plantarum/genética , Amidohidrolasas/química , Secuencia de Aminoácidos , Animales , Anticolesterolemiantes/química , Anticolesterolemiantes/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Ácidos Cólicos/farmacología , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Hipercolesterolemia/metabolismo , Lactobacillus plantarum/metabolismo , Ratones , Datos de Secuencia Molecular , Análisis de Secuencia
13.
Pharmacol Biochem Behav ; 99(4): 738-42, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21722663

RESUMEN

Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB(1) receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB(1) receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0mg/kg) and saline. Rimonabant at a dose of 3.0mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB(1) receptors play a role in nicotine reward memory, suggesting that CB(1) receptor antagonists may be a potential target for managing nicotine addiction.


Asunto(s)
Memoria/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Recompensa , Animales , Reacción de Prevención/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Rimonabant
14.
Zhonghua Xue Ye Xue Za Zhi ; 32(6): 388-91, 2011 Jun.
Artículo en Chino | MEDLINE | ID: mdl-21781496

RESUMEN

OBJECTIVE: To investigate the effect of heme oxygenase-1 (HO-1) expression on cell growth and apoptosis in imatinib resistant chronic myeloid leukemia (CML) cells (K562/A02-IM), and explore the relationship between HO-1 gene and CML. METHODS: The expression of HO-1 in 20 drug-resistant CML patients was detected by RT-PCR. Different concentrations of hemin were used to induce HO-1 expression of K562/A02-IM, HO-1 expression at different time was detected by RT-PCR and Western blot analysis. Cell apoptosis was detected by Annexin V/PI staining, and MTT assay was used to detect viability of K562/A02-IM cells after induction or inhibition of HO-1 gene by hemin and zinc protoporphyrin (ZPP). RESULTS: RT-PCR showed that HO-1 was expressed in the bone marrow mononuclear cells (BMMNCs). When treated with hemin at different concentrations (0, 10, 20, 40 µmol/L) for 16 h, the expression of HO-1 in K562/A02-IM was increased in a dose-dependent manner, and peaked at 20 µmol/L of hemin for 16 h. The apoptosis rates were (17.61 ± 0.01)%, (12.13 ± 0.11)%, (7.94 ± 0.03)% and (4.62 ± 0.15)% at 0,10, 20 and 40 µmol/L of hemin respectively for 16 h and were (14.7 ± 0.05)%, (8.1 ± 0.07)% and (16.3 ± 0.13)% at 20 µmol/L of hemin treatment for 8,16, and 24 h respectively. Hemin induced apoptosis of K562/A02-IM cells in a dose-dependent manner. The expression of HO-1 was induced in K562/A02-IM cells in a dose-dependent manner, and the survival of K562/A02-IM cells was significantly increased as compared to that of control group. When HO-1 was inhibited by ZPP, the cells survival was sharply decreased compared to that of the control group (P < 0.05). CONCLUSION: HO-1 was expressed in the BMMNCs. It is a kind of molecules whose expression can be induced and can promote the growth of drug-resistant cells. Inhibition of HO-1 expression probably be used for the treatment of drug-resistant CML.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/genética , Hemo-Oxigenasa 1/genética , Piperazinas/farmacología , Pirimidinas/farmacología , Benzamidas , Ciclo Celular , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Mesilato de Imatinib , Células K562
15.
Neuropsychopharmacology ; 36(10): 1972-81, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21633338

RESUMEN

The intense associative memories that develop between drug-paired contextual cues and rewarding stimuli or the drug withdrawal-associated aversive feeling have been suggested to contribute to the high rate of relapse. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories, but how this mechanism is maintained is unknown. Protein kinase M ζ (PKMζ) was recently shown to be necessary and sufficient for long-term potentiation maintenance and memory storage. In the present study, we used conditioned place preference (CPP) and aversion (CPA) to examine whether PKMζ maintains both morphine-associated reward memory and morphine withdrawal-associated aversive memory in the basolateral amygdala (BLA). We also investigate the role of PKMζ in the infralimbic cortex in the extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. We found that intra-BLA but not central nucleus of the amygdala injection of the selective PKMζ inhibitor ZIP 1 day after CPP and CPA training impaired the expression of CPP and CPA 1 day later, and the effect of ZIP on memory lasted at least 2 weeks. Inhibiting PKMζ activity in the infralimbic cortex, but not prelimbic cortex, disrupted the expression of the extinction memory of CPP and CPA. These results indicate that PKMζ in the BLA is required for the maintenance of associative morphine reward memory and morphine withdrawal-associated aversion memory, and PKMζ in the infralimbic cortex is required for the maintenance of extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues.


Asunto(s)
Amígdala del Cerebelo/enzimología , Extinción Psicológica/fisiología , Memoria/fisiología , Morfina/administración & dosificación , Proteína Quinasa C/fisiología , Recompensa , Amígdala del Cerebelo/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Extinción Psicológica/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Sistema Límbico/enzimología , Masculino , Memoria/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/enzimología , Síndrome de Abstinencia a Sustancias/psicología
16.
J Neurosci ; 31(14): 5436-46, 2011 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-21471379

RESUMEN

During abstinence, memories of drug-associated cues persist for many months, and exposure to these cues often provokes relapse to drug use. The mechanisms underlying the maintenance of these memories are unknown. A constitutively active atypical protein kinase C (PKC) isozyme, protein kinase M ζ (PKMζ), is required for maintenance of spatial memory, conditioned taste aversion, and other memory forms. We used conditioned place preference (CPP) and conditioned place aversion (CPA) procedures to study the role of nucleus accumbens PKMζ in the maintenance of drug reward and aversion memories in rats. Morphine CPP training (10 mg/kg, 4 pairings) increased PKMζ levels in accumbens core but not shell. Injections of the PKMζ inhibitor ζ inhibitory peptide (ZIP) into accumbens core but not shell after CPP training blocked morphine CPP expression for up to 14 d after injections. This effect was mimicked by the PKC inhibitor chelerythrine, which inhibits PKMζ, but not by the conventional and novel PKC inhibitor staurosporine, which does not effectively inhibit PKMζ. ZIP injections into accumbens core after training also blocked the expression of cocaine (10 mg/kg) and high-fat food CPP but had no effect on CPA induced by naloxone-precipitated morphine withdrawal. Accumbens core injections of Tat-GluR2(3Y), which inhibits GluR2-dependent AMPA receptor endocytosis, prevented the impairment in morphine CPP induced by local ZIP injections, indicating that the persistent effect of PKMζ is on GluR2-containing AMPA receptors. Results indicate that PKMζ activity in accumbens core is a critical cellular substrate for the maintenance of memories of relapse-provoking reward cues during prolonged abstinence periods.


Asunto(s)
Condicionamiento Operante/fisiología , Memoria/fisiología , Núcleo Accumbens/enzimología , Proteína Quinasa C/antagonistas & inhibidores , Recompensa , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Endocitosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Memoria/efectos de los fármacos , Morfina/efectos adversos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/efectos adversos , Núcleo Accumbens/efectos de los fármacos , Oligopéptidos/farmacología , Organofosfonatos/farmacología , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinencia a Sustancias/enzimología , Síndrome de Abstinencia a Sustancias/fisiopatología , Factores de Tiempo , Valina/análogos & derivados , Valina/farmacología
17.
J Neurosci ; 30(38): 12632-41, 2010 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-20861369

RESUMEN

Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and survival by controlling translation in response to nutrients and growth factors, has been demonstrated to be involved in neuronal adaptations that underlie drug addiction and learning and memory. We investigated the potential role of the mTOR signaling pathway in relapse to cocaine seeking by using the cue-induced reinstatement model in self-administering rats. We found that exposure to a cocaine-related cue induced reinstatement to cocaine seeking and increased phosphorylation of p70s6 kinase (p70s6k) and ribosomal protein s6 (rps6), measures of mTOR activity, in the nucleus accumbens (NAc) core but not shell. Furthermore, inhibition of NAc core but not shell p70s6k and rps6 phosphorylation by rapamycin decreased cue-induced reinstatement of cocaine seeking. Finally, stimulation of NAc core p70s6k and rps6 phosphorylation by NMDA enhanced cue-induced reinstatement, an effect reversed by rapamycin pretreatment. Additionally, rapamycin infusion into the NAc core or shell did not alter ongoing cocaine self-administration or cue-induced reinstatement of sucrose seeking. These findings indicate that cue-induced reinstatement of cocaine seeking is mediated by activation of the mTOR signaling pathway in the NAc core.


Asunto(s)
Cocaína/administración & dosificación , Condicionamiento Operante/fisiología , Conducta Exploratoria/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Núcleo Accumbens/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Análisis de Varianza , Animales , Western Blotting , Señales (Psicología) , Extinción Psicológica/fisiología , Masculino , Núcleo Accumbens/efectos de los fármacos , Fosforilación , Ratas , Ratas Sprague-Dawley , Autoadministración , Serina-Treonina Quinasas TOR
18.
J Neurosci ; 30(31): 10351-9, 2010 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-20685978

RESUMEN

Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor beta-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine-context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala beta-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral beta-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Aprendizaje por Asociación/fisiología , Cocaína/administración & dosificación , Quinasa 5 Dependiente de la Ciclina/metabolismo , Memoria/fisiología , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Análisis de Varianza , Animales , Aprendizaje por Asociación/efectos de los fármacos , Western Blotting , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Señales (Psicología) , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
19.
Toxicon ; 52(2): 341-7, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18625262

RESUMEN

In vertebrates, non-lens betagamma-crystallins are widely expressed in various tissues but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive. betagamma-CAT, which is responsible for the potent hemolytic activity and lethal toxicity on mice of frog Bombina maxima skin secretions, is the first example of a non-lens betagamma-crystallin and trefoil factor complex. Its alpha- and beta-subunits show significant sequence homology to human Absent In Melanoma 1 and trefoil factors, respectively. Here, we showed that betagamma-CAT triggered two types of cellular responses in human melanoma cells. On one hand, the protein (25-200 pM) was able to stimulate cell migration in melanoma A375 cells. On the other hand, it inhibited cell proliferation by delaying S-G2/M cell phase transition. Blockade of the cell cycle was associated with increased p21/WAF1 expression, and reduced amounts of Cdc2 and Cdc25C. betagamma-CAT also reduced Cdc2 function by increasing the level of inactivated phospho-Cdc2. In addition, the expression of JunB, a well-known cell proliferation inhibitor, was significantly up-regulated. These results provide the first evidence of an anti-proliferative role for a non-lens betagamma-crystallin member and action mechanism via association with a trefoil factor.


Asunto(s)
Anuros/fisiología , Cristalinas/toxicidad , Melanoma/tratamiento farmacológico , Péptidos/toxicidad , Piel/química , Animales , Proteína Quinasa CDC2 , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina B/genética , Ciclina B/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Humanos , Melanoma/metabolismo , Melanoma/patología , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Factor Trefoil-2 , Regulación hacia Arriba , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismo
20.
Toxicon ; 52(1): 22-31, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18588908

RESUMEN

In vertebrates, non-lens betagamma-crystallins are widely expressed in various tissues, but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive. betagamma-CAT is the first example of a naturally existing multifunctional protein complex of a non-lens betagamma-crystallin and a trefoil factor from frog Bombina maxima skin secretions. Here we report the investigation of its in vivo toxic effects on mice and rabbits. The LD(50) values of betagamma-CAT on mice were determined to be 0.4 mg/kg and 20 microg/kg under intraperitoneal (i.p.) and intravenous (i.v.) injection, respectively. The mice subcutaneously injected with betagamma-CAT (6 microg/g body weight) showed strong hyperaemia of subcutaneous capillary vessel, but no hemorrhagic spots were observed. Intravenous injection of betagamma-CAT in rabbits (8-22 microg/kg body weight) caused a rapidly hypotensive effect and followed with cardiovascular collapse. Injection with betagamma-CAT (22 microg/kg, i.v.) significantly decreased hematocrit (P<0.05) and mean corpuscular volume (P<0.05) of the rabbits in 5 min. At the same time, the counts of platelets and white blood cells were significantly decreased (P<0.05), while the blood levels of glucose, lactate dehydrogenase and serum glutamic-oxaloacetic transaminase were significantly increased (P<0.05). Furthermore, serials of tissues edema and damages were also observed. These results indicate that betagamma-CAT rapidly caused several in vivo toxic effects on mammals and its lethal toxic potency was mainly contributed by hypotension and cardiovascular collapse, providing new clues for the understanding of the patho-physiological roles of non-lens betagamma-crystallins and trefoil factors.


Asunto(s)
Anuros/metabolismo , Cristalinas/toxicidad , Péptidos/toxicidad , Piel/metabolismo , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Citocinas/genética , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Dosificación Letal Mediana , Recuento de Leucocitos , Masculino , Ratones , Datos de Secuencia Molecular , Conejos , Factor Trefoil-2
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...