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1.
Chemosphere ; 283: 131278, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34467945

RESUMO

Production of MCFAs (Medium-chain fatty acids) from simple substrate (i.e., ethanol and acetate) and WAS with chain elongation microbiome was investigated in this study. The results showed that rapid production of MCFAs was observed when simple substrate was utilized. 1889 mg/L of caproate and 3434 mg/L of butyrate were achieved after 10 d's reaction. H2 proportion in the headspace could reach as high as 10.1% on day 8 and then declined quickly. However, when WAS was used, the bacterial consortia was not able to hydrolyze WAS efficiently, which resulted in poor MCFAs production performance. Presence of ethanol could improve the hydrolysis process to a limited degree, which resulted in solubilization of a small fraction of protein and carbohydrate. Around 33.8% and 36.9% of the total detected electrons on day 6 in the 50 mM and 100 mM tests were extracted from WAS respectively. Those results indicate that the chain elongation microbial consortia tended to receive electrons form ethanol directly other than the complex WAS.


Assuntos
Etanol , Esgotos , Elétrons , Ácidos Graxos , Fermentação
2.
Nat Cancer ; 2(4): 429-443, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34568836

RESUMO

CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

3.
Cancer Discov ; 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301793

RESUMO

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K/PTEN pathway lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation but not kinase inhibition profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced G2/M arrest and hyperploidy. PI3K activated AKT phosphorylation of AURKB on threonine 73, which protected it from proteasome degradation. A mutant of AURKB (T73E) that mimics phosphorylation and blocks degradation rescued cells from growth inhibition. Degrader resistant lines were associated with low AKT phosphorylation, wild type PI3K/PTEN status, and mutation of KRAS/BRAF. Pan-cancer analysis identified that 19% of cases have PI3K/PTEN pathway mutation without RAS pathway mutation, suggesting that these cancer patients could benefit from AKT degrader therapy that leads to loss of AURKB.

4.
Bioresour Technol ; 337: 125452, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34186332

RESUMO

This first-attempt study illustrated the microbial cooperative interactions related to bioelectricity generation from the mixture of sludge fermentation liquid (SFL) and fruit waste extracts (FWEs) via microbial fuel cells (MFCs). The optimal output voltages of 0.65 V for SFL-MFCs, 0.51 V for FWEs-MFCs and 0.75 V for mixture-MFCs associated with bioelectricity conversion efficiencies of 1.061, 0.718 and 1.391 kWh/kg COD were reached, respectively. FWEs addition for substrates C/N ratio optimization contributed considerably to increase SFL-fed MFCs performance via triggering a higher microbial diversity, larger relatively abundance of functional genes and microbial synergistic interactions with genera enrichment of Clostridium, Alicycliphilus, Thermomonas, Geobacter, Paludibaculum, Pseudomonas, Taibaiella and Comamonas. Furthermore, a conceptual illustration of co-locating scenario of wastewater treatment plant(s), waste sludge in situ acidogenic fermentation, fruit waste collection/crushing station and MFC plant was proposed for the first time, which provided new thinking for future waste sludge treatment toward maximizing solid reduction and power recovery.


Assuntos
Fontes de Energia Bioelétrica , Eletricidade , Eletrodos , Fermentação , Frutas , Extratos Vegetais , Esgotos , Águas Residuárias
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 193-197, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554818

RESUMO

OBJECTIVE: To investigate the relationship between umbilical cord blood erythrocyte index and thalasse-mia, and reveal its clinical value in the screening of thalassemia in neonates. METHODS: 2 919 cases of umbilical cord blood from neonatal who were born in Boai Hospital of Zhongshan Affiliated with Southern Medical University from July 2017 to December 2018 were collected, the routine blood tests were preformed to detect the umbilical cord blood. Thalassemia gene in peripheral blood of neonates was collected. The cut-off values of cord blood indexes were determined, and the sensitivity, specificity and other evaluation indexs were calculated. RESULTS: Among the cord blood in 2 919 neonates, 314 cases were detected out as thalassemia(positive rate: 10.76%). The average level of RBC and RDW in 2 605 children with non-thalassemia was lower than those with 314 children with thalassemia. The levels of Hb, MCV, MCH, MCHC, HCT, Hb/RBC and MCV/RBC in children with non-thalassemia were higher than those with thalassemia, and there were significant differences in the neonates between the two groups. The RBC and RDW levels of neonates in the α-thalassemia group were higher than those in the non-thalassemia group, while the levels of Hb, MCV, MCH, MCHC, HCT, Hb/RBC and MCV/RBC of neonates were lower than those in the non-thalassemia group. The levels of MCV, MCH and Hb/RBC of neonates in the ß-thalassaemia group were lower than those in the non-thalassaemia group. The levels of MCV, MCH, Hb/RBC, and MCV/RBC of neonates in the complex thalassemia group were lower than those in the non-thalassemia group. When the cut-off value of MCV was set to 106.05 fl, the sensitivity was 0.548, and the specificity was 0.907, the specificity was the highest among all indexes. The area under the ROC curve of the combined diagnosis of MCH+MCV/RBC was the largest(0.807), the sensitivity was 0.710, the specificity was 0.841, the positive predictive value was 0.348, and the negative predictive value was 0.960. CONCLUSION: The single indicator of umbilical cord blood red blood cells has advantages and disadvantages for the screening of thalassemia, but the combination of MCH+MCV/RBC can improve the accuracy of the screening or diagnosis of thalassemia, it also has a positive effect to the reduction of the birth rate of children with thalassemia major, which showed a high popularization value in primary hospitals.


Assuntos
Talassemia alfa , Talassemia beta , Criança , Índices de Eritrócitos , Sangue Fetal , Humanos , Recém-Nascido , Programas de Rastreamento , Talassemia alfa/diagnóstico
6.
Cancer Discov ; 11(7): 1716-1735, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33568355

RESUMO

Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF) but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Molecular dynamic simulations reveal restriction of the movement of the BRAF αC-helix as the basis of inhibitor selectivity. Combination of inhibitors based on their conformation selectivity (mBRAF- plus dBRAF-selective plus the most potent BRAF-MEK disruptor MEK inhibitor) promoted suppression of tumor growth in BRAFV600E therapy-resistant models. Strikingly, the triple combination showed no toxicities, whereas dBRAF-selective plus MEK inhibitor treatment caused weight loss in mice. Finally, the triple combination achieved durable response and improved clinical well-being in a patient with stage IV colorectal cancer. Thus, exploiting allosteric properties of RAF and MEK inhibitors enables the design of effective and well-tolerated therapies for BRAFV600E tumors. SIGNIFICANCE: This work identifies a new class of RAFi that are selective for dBRAF over mBRAF and determines the basis of their selectivity. A rationally designed combination of RAF and MEK inhibitors based on their conformation selectivity achieved increased efficacy and a high therapeutic index when used to target BRAFV600E tumors.See related commentary by Zhang and Bollag, p. 1620.This article is highlighted in the In This Issue feature, p. 1601.

7.
Zhongguo Yi Liao Qi Xie Za Zhi ; 44(6): 499-502, 2020 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-33314857

RESUMO

A kind of adjustable external fixation device for lower extremity is designed. The circuit is mainly composed of TEC1-00703 semiconductor refrigeration chip, HZC-30A pressure sensor, STC89C52RC single chip microcomputer and other electrical components. It can realize the timing intelligent temperature control and meet the local fixed-point refrigeration. The design of adjustable structure and the application of intelligent air cushion can satisfy the full fixation of lower limbs of different individuals. Its operation does not need much medical knowledge. It can solve the problem of emergency transportation and follow-up treatment of lower limb injury in ice and snow sports. It has a good application prospect and universality.


Assuntos
Fixadores Externos , Extremidade Inferior , Refrigeração , Semicondutores , Fixação de Fratura , Humanos
8.
Bioresour Technol ; 302: 122859, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32018085

RESUMO

This paper investigated the effects of citric acid (CA) on extracellular polymer destruction and cell lysis in sludge at different initial pH by measuring capillary suction time (CST), extracellular polymeric substances (EPS) and intracellular bound water. The results indicated that under CA concentration at 0.05 g/g suspended solids (SS) and initial pH 4, the CST value decreased from 175.5 s to 112.3 s, slime extracellular polymeric substances (S-EPS) and loosely bound EPS (LB-EPS) content respectively to increase from 4.92 to 41.43, 2.27 to 5.49 mg/g volatile suspended solids (Vss), while tightly bound EPS (TB-EPS) content to decrease from 12.35 to 5.01 mg/g (Vss), which suggested CA could disrupt outer EPS effectively. Intracellular bound water content decreased from 1.23 g/g to 0.41 g/g dry solid (DS). As a result, CA could release intracellular bound water effectively, thereby improving sludge dewatering degree.


Assuntos
Esgotos , Eliminação de Resíduos Líquidos , Ácido Cítrico , Matriz Extracelular de Substâncias Poliméricas , Concentração de Íons de Hidrogênio , Água
9.
Nat Prod Res ; 34(9): 1256-1263, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30663372

RESUMO

Phytochemical studies on the leaves of Epimedium koreanum Nakai have resulted in the discovery of two new flavonol glycosides, koreanoside F (1) and koreanoside G (2), along with six known flavonoids. Their structures were elucidated on the basis of HRESIMS, UV, IR, 1 D NMR and 2 D NMR data. Absolute configurations of 1 and 2 was further determined by 13C-NMR spectra with gate decoupling (GD). All of the compounds were evaluated for cytotoxic activities by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide (MTT) assay. The results indicated that compounds 3, 5, 6, 7 and 8 inhibited the proliferation of A549 and NCI-292 cells with IC50 values of 5.7-23.5 µM. Real-time monitoring in three kinds of lung cancer cells and a kind of human bronchial epithelial cells treated with compound 6 was also assessed.


Assuntos
Antineoplásicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Epimedium/química , Flavonoides/isolamento & purificação , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Flavonoides/química , Flavonoides/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Estrutura Molecular , Extratos Vegetais/química , Folhas de Planta/química
10.
Huan Jing Ke Xue ; 40(11): 4810-4823, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854546

RESUMO

Northeastern China experiences severe atmospheric pollution, with an increasing occurrence of heavy haze episodes. Based on ground monitoring data, satellite products and meteorological products of atmospheric pollutants in northeast China from 2013 to 2017, the characteristics of spatial and temporal distribution of air quality and the causes of heavy haze events in northeast China were discussed. It was found that the "Shenyang-Changchun-Harbin" city belt was the most polluted area in the region on an annual scale. The spatial distribution of air quality index (AQI) values had a clear seasonality, with the worst pollution occurring in winter, an approximately oval-shaped polluted area around western Jilin Province in spring, and the best air quality occurring in summer and most of autumn. The three periods that typically experienced intense haze events were Period I from late-October to early-November (i. e., late autumn and early winter), Period Ⅱ from late-December to January (i. e., the coldest time in winter), and Period Ⅲ from April to mid-May (i. e., spring). During Period I, strong PM2.5 emissions from seasonal crop residue burning and coal burning for winter heating were the dominant reasons for the occurrence of extreme haze events (AQI>300). Period Ⅱ had frequent heavy haze events (200 < AQI < 300) in the coldest months of January and February(200 < AQI < 300), which were due to high PM2.5 emissions from coal burning and vehicle fuel consumption, a lower atmospheric boundary layer, and stagnant atmospheric conditions. Haze events in Period Ⅲ, with high PM10 concentrations, were primarily caused by the regional transportation of windblown dust from degraded grassland in central Inner Mongolia and bare soil in western Jilin Province. Local agricultural tilling could also release PM10 and enhance the levels of windblown dust from tilled soil.

11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 776-782, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750817

RESUMO

Objective To prepare inducible lupus model mice and investigate the effect of nuclear autoantigenic sperm protein (NASP) gene mutation on the autoimmune response of mice with induced systemic lupus erythematosus (SLE). Methods The 3-month wild-type B6 (B6-WT) mice were used as a control group and the NASP mutant B6 (B6-NASPM) mice as an experimental group. Mouse spleen lymphocytes were activated with concanavalin A (ConA), and the DNA was extracted as autoantigen. B6-WT mice and B6-NASPM mice were immunized three times. Serum anti-double stranded DNA (dsDNA) IgG levels were detected by ELISA. Renal lesions were detected by HE staining. Immunohistochemical staining was performed to detect the deposition of IgG and complement C3 in the renal tissues. Flow cytometry was applied to compare the spleen lymphocyte subsets in B6-WT and B6-NASPM mice and to explore the mechanism of NASP gene mutation affecting the immune response in mice. Results Compared with B6-WT mice, B6-NASPM mice showed no significant changes in body weight, kidney index and spleen index; serum anti-dsDNA IgG levels significantly increased; glomerular cell proliferation was obvious and the deposition of IgG and C3 in the renal tissues increased. The proportion of spleen CD3+ T cells and natural killer (NK) cells decreased, while the proportion of CD19+ B cells and regulatory B cells (Breg) increased. Conclusion Mutation in the NASP gene can increase the levels of anti-dsDNA IgG antibodies, promote cell proliferation in the glomerulus of the kidney, deposition of IgG antibodies and complement C3, alter the proportion of immune cells in the spleen and aggravate the autoimmune response in lupus model mice.


Assuntos
Autoantígenos/genética , Autoimunidade , Lúpus Eritematoso Sistêmico/genética , Proteínas Nucleares/genética , Animais , Anticorpos Antinucleares/sangue , Proteínas de Ciclo Celular , Complemento C3/imunologia , Modelos Animais de Doenças , Glomérulos Renais/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Mutação , Baço/imunologia
12.
Sci Rep ; 9(1): 10865, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350469

RESUMO

Small molecule inhibitors of BRAF and MEK have proven effective at inhibiting tumor growth in melanoma patients, however this efficacy is limited due to the almost universal development of drug resistance. To provide advanced insight into the signaling responses that occur following kinase inhibition we have performed quantitative (phospho)-proteomics of human melanoma cells treated with either dabrafenib, a BRAF inhibitor; trametinib, a MEK inhibitor or SCH772984, an ERK inhibitor. Over nine experiments we identified 7827 class I phosphorylation sites on 4960 proteins. This included 54 phosphorylation sites that were significantly down-modulated after exposure to all three inhibitors, 34 of which have not been previously reported. Functional analysis of these novel ERK targets identified roles for them in GTPase activity and regulation, apoptosis and cell-cell adhesion. Comparison of the results presented here with previously reported phosphorylation sites downstream of ERK showed a limited degree of overlap suggesting that ERK signaling responses may be highly cell line and cue specific. In addition we identified 26 phosphorylation sites that were only responsive to dabrafenib. We provide further orthogonal experimental evidence for 3 of these sites in human embryonic kidney cells over-expressing BRAF as well as further computational insights using KinomeXplorer. The validated phosphorylation sites were found to be involved in actin regulation, which has been proposed as a novel mechanism for inhibiting resistance development. These results would suggest that the linearity of the BRAF-MEK-ERK module is at least context dependent.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Imidazóis/farmacologia , Indazóis/farmacologia , Melanoma/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Oximas/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridonas/farmacologia , Pirimidinonas/farmacologia , Neoplasias Cutâneas/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Proteoma , Proteômica/métodos , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/patologia
13.
J Cell Biol ; 218(7): 2388-2402, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171630

RESUMO

Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-ß cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-ß1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL-ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.


Assuntos
Padronização Corporal/genética , Morfogênese/genética , Proteína Nodal/genética , Trombospondinas/genética , Ativinas/genética , Animais , Proteína Morfogenética Óssea 4/genética , Embrião de Galinha , Regulação da Expressão Gênica no Desenvolvimento/genética , Células HEK293 , Células HeLa , Humanos , Hibridização In Situ , Mesoderma/crescimento & desenvolvimento , Mesoderma/metabolismo , Camundongos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética , Xenopus laevis/genética , Xenopus laevis/crescimento & desenvolvimento
14.
Ecotoxicol Environ Saf ; 179: 71-78, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31026752

RESUMO

Bioconcentration factors and median lethal concentrations (LC50s) are important when assessing risks posed by organic pollutants to aquatic ecosystems. Various quantitative structure-activity relationship models have been developed to predict bioconcentration factors and classify acute toxicity. In the study, we developed a regression model using Recursive Feature Elimination (RFE) method combined with the Support Vector Machine (SVM) algorithm. We calculated 2D molecular descriptors from a dataset containing 450 diverse chemicals in our regression model. Then we built three ensemble models using three machine learning algorithms and calculated 12 molecular fingerprints from a dataset containing 400 diverse chemicals in our classification models. In the regression model, the R2 and Rpred2 for the regression model were 0.860 and 0.757, respectively. Other parameters indicated that the regression model made good predictions and could efficiently predict a new set of compounds following standards set by Golbraikh, Tropsha, and Roy. In the classification models, the ensemble-SVM classification model gave an overall accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of 92.2, 95.1, 86.0, and 0.965, respectively, in a five-fold cross-validation and of 87.3, 92.6, 76.0, and 0.940, respectively, in an external validation. These parameters indicated that our ensemble-SVM model was more stable and gave more accurate predictions than previous models. The model could therefore be used to effectively predict aquatic toxicity and assess risks posed to aquatic ecosystems. We identified several structures most relevant to acute aquatic toxicity through predictions made by the two types of models, and this information may be important to aquatic toxicology experiments and aquatic system management.


Assuntos
Organismos Aquáticos , Compostos Orgânicos/toxicidade , Poluentes Químicos da Água/toxicidade , Algoritmos , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/metabolismo , Aprendizado de Máquina , Compostos Orgânicos/química , Compostos Orgânicos/metabolismo , Relação Quantitativa Estrutura-Atividade , Máquina de Vetores de Suporte , Poluentes Químicos da Água/química , Poluentes Químicos da Água/metabolismo
15.
Brain Res Bull ; 148: 34-45, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30902575

RESUMO

Neurofibrillary tangles consisting of hyperphosphorylated tau (P-tau) are the neuropathological hallmark of Alzheimer's disease (AD), and olfaction disorder is an early symptom of AD. However, the link between P-tau aggregation and olfaction disorder remains unclear. In this study, the expression of P-tau in the olfactory bulb (OB), particularly in the mitral cell layer (MCL), external plexiform layer (EPL), and granule cell layer (GCL), of AD patients was found to be significantly higher than that in the OB of normal aging subjects, which suggested that these layers in the OB were susceptible to P-tau. The P301S tau transgenic mice (P301S mice) exhibit AD-like features, which can be characterized by olfactory dysfunction that precedes cognitive disorder. Importantly, the excessive P-tau expression in the OB of P301S mice, particularly in MCs, was associated with MC loss at 9 months of age, and decreased MC firing activities started to be observed at 2 months of age. Our results revealed that MCs might contribute to olfactory dysfunction in P301S mice. Furthermore, we described an aberrant dendro-dendritic synaptic structure between granule cells (GCs) and MCs and abnormal gamma oscillations in the EPL of the OB, and these findings indicated that P-tau might disrupt the regulation of MCs by GCs in P301S mice starting at 5 months of age. These data showed that the reduction in the MC firing frequency at 2 months of age might not be caused by GC suppression. Based on these findings, we speculated that MCs are a putative target for the treatment of P-tau-induced early olfactory dysfunction, and thus, an exploration of the specific causes and mechanisms of MC functional changes in P301S mice is crucial.


Assuntos
Transtornos do Olfato/fisiopatologia , Bulbo Olfatório/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Dendritos/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Emaranhados Neurofibrilares/patologia , Neurônios/metabolismo , Bulbo Olfatório/citologia , Fosforilação , Olfato/fisiologia
16.
Metab Brain Dis ; 34(2): 545-555, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30746596

RESUMO

Oxidative stress has been suggested to play an important role in neuronal injury. Ethyl gallate (EG) is the ethyl ester of gallic acid which has been acknowledged as an antioxidant. We previously demonstrated that EG effectively inhibited H2O2-induced cytotoxicity and decreased the ROS levels in PC12 cells, while the relevant mechanisms of action of this compound remain largely uncharacterized. The present study was carried out in an attempt to clarify the underlying mechanisms of EG against H2O2-induced neurotoxicity in PC12 cells. EG pretreatment attenuated H2O2-induced mitochondrial dysfunction as indicated by the decreased caspase-9/-3 activation, PARP cleavage, mitochondrial membrane potential (MMP) depletion, Bax/Bcl-2 ratio, cytochrome c release and ROS overproduction. Furthermore, EG treatment resulted in nuclear translocation of Nrf2 along with increased expression of ARE-dependent cytoprotective genes, such as γ-GCS and NQO1, which indicated EG as an Nrf2 pathway activator. Silencing of Nrf2 signaling by siRNA abrogated the protective effects offered by EG on H2O2-induced PC12 cells injury, which suggested the important role of Nrf2 pathway in the protection of EG against oxidative stress induced PC12 cell apoptosis. These results taken together indicated that EG protects PC12 cells against H2O2-induced cell mitochondrial dysfunction possibly through activation of Nrf2 pathway. EG might be a potential candidate for further preclinical study aimed at the prevention and treatment of neurodegenerative diseases.


Assuntos
Ácido Gálico/análogos & derivados , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Ácido Gálico/farmacologia , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Front Aging Neurosci ; 11: 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740049

RESUMO

Olfactory dysfunction is an early event in Alzheimer's disease (AD). However, the mechanism underlying the AD-related changes in the olfactory bulb (OB) remains unknown. Granule cells (GCs) in the OB regulate the activity of mitral cells (MCs) through reciprocal dendrodendritic synapses, which is crucial for olfactory signal processing and odor discrimination. Nevertheless, the relationships between the morphological and functional changes of dendrodendritic synapses, particularly the local field potentials (LFPs) as a consequence of olfactory disorders in patients with AD have not been investigated. Here, we studied the morphological and functional changes induced by dendrodendritic inhibition in GCs onto MCs in the OB of amyloid precursor protein (APP)/PS1 mice and age-matched control mice during aging, particular, we focused on the effects of olfactory disorder in the dendrodendritic synaptic structures and the LFPs. We found that olfactory disorder was associated with increased amyloid-ß (Aß) deposits in the OB of APP/PS1 mice, and those mice also exhibited abnormal changes in the morphology of GCs and MCs, a decreased density of GC dendritic spines and impairments in the synaptic interface of dendrodendritic synapses between GCs and MCs. In addition, the aberrant enhancements in the γ oscillations and firing rates of MCs in the OB of APP/PS1 mice were recorded by multi-electrode arrays (MEAs). The local application of a GABAAR agonist nearly abolished the aberrant increase in γ oscillations in the external plexiform layer (EPL) at advanced stages of AD, whereas a GABAAR antagonist aggravated the γ oscillations. Based on our findings, we concluded that the altered morphologies of the synaptic structures of GCs, the dysfunction of reciprocal dendrodendritic synapses between MCs and GCs, and the abnormal γ oscillations in the EPL might contribute to olfactory dysfunction in AD.

18.
Cell Rep ; 26(1): 65-78.e5, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605687

RESUMO

Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Neoplasias do Colo , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Células HEK293 , Células HT29 , Células HeLa , Humanos , Camundongos , Camundongos Nus , Piperidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/farmacologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Opt Express ; 27(2): 1479-1487, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30696212

RESUMO

Molecular vibration-plasmon couplings in a hybrid structure, which are composed of a silver grating filled with polymethyl methacrylate (PMMA) molecules (SG-PMMA), have been investigated theoretically. It is found that the interaction between the vibrational transitions and plasmons can transform from weak coupling into strong coupling by reducing the distance between the elements. When the space between grating elements is large, the localized surface plasmon resonance (LSP) of the silver elements greatly enhances the absorption of the PMMA molecules. As the gap between elements becomes small, the plasmonic nanocavity (NC) mode emerges and couples strongly with the molecular vibrational mode of PMMA. The strong coupling results in two new hybridized modes and the Rabi splitting energy is about 15 meV. Our work provides an effective way to alter the coupling strength of the molecular vibration-plasmon hybrid system and may be beneficial to the further biochemical and biophysical applications.

20.
Oncogene ; 38(1): 47-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30076411

RESUMO

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.


Assuntos
Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/antagonistas & inibidores , Proteína 11 Semelhante a Bcl-2/agonistas , Estradiol , Receptor alfa de Estrogênio/fisiologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neuropeptídeos/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Sulfonamidas/farmacologia , Tiazóis/farmacologia , Compostos de Anilina/administração & dosagem , Animais , Antineoplásicos Hormonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína 11 Semelhante a Bcl-2/biossíntese , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/fisiologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Cocarcinogênese , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Estradiol/toxicidade , Receptor alfa de Estrogênio/efeitos dos fármacos , Feminino , Fulvestranto/administração & dosagem , Fulvestranto/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Introdução de Genes , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Mutação de Sentido Incorreto , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Hormônio-Dependentes/induzido quimicamente , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/fisiologia , Sulfonamidas/administração & dosagem , Tiazóis/administração & dosagem
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