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Interleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) and AlphaFold modeling to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα (domains 1-2) with GP130 (domains 1-3) to initiate signaling. While both receptors contact the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα and Domain 1 of GP130. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.
Assuntos
Receptor gp130 de Citocina , Interleucina-27 , Receptores de Interleucina , Receptor gp130 de Citocina/química , Humanos , Interleucina-12 , Interleucina-27/química , Interleucina-6 , Interleucinas , Receptores de Interleucina/químicaRESUMO
Systemic lupus erythematosus (SLE) is a chronic, devastating autoimmune disorder associated with severe organ damage. The roles of Toll-like receptor 9 (TLR9) and NETosis in SLE have been described, suggesting the involvement of NETosis signaling in the development of SLE. Shaoyao-Gancao Decoction (SGT) is a potential medication for the treatment of SLE; however, its potential therapeutic mechanism remains unexplored. To determine the function of SGT in SLE, we treated MRL/lpr female mice with SGT, the main components of which were paeoniflorin (56.949 µg·mL-1) and glycyrrhizin (459.393 µg·mL-1). We found that SGT treatment relieved lymphadenectasis and splenomegaly, reduced urine protein and anti-dsDNA antibody concentrations, and relieved kidney pathology in MRL/lpr mice. SGT could also effectively regulate the oxidation/antioxidant balance, significantly reduce malondialdehyde (MDA) and nitric oxide (NO) contents and significantly increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in MRL/lpr mice. The neutrophil extracellular trap (NET) content of MRL/lpr mice also decreased to a certain extent after SGT treatment. All these results suggested that SGT might improve the inflammatory damage to tissues caused by oxygen free radicals, thereby regulating the NETosis process mediated by TLR9 and exerting a good therapeutic effect on SLE.
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Lúpus Eritematoso Sistêmico , Receptor Toll-Like 9 , Animais , Camundongos , Feminino , Camundongos Endogâmicos MRL lpr , Rim/patologiaRESUMO
OBJECTIVE: To accelerate the onset of systemic lupus erythematosus in C57BL/6 mice by injecting cadmium chloride nanoemulsion and shorten the traditional modeling time. METHODS: Pristane cadmium chloride nanoemulsion was prepared, and 66 C57BL/6 mice were randomly divided into four groups. The pristane group was intraperitoneally injected with 0.6 mL of pristane blank nanoemulsion, the model group was injected with 0.6 mL of pristane cadmium chloride nanoemulsion, the Cadmium chloride control group was injected with 0.6 mL of cadmium chloride nanoemulsion, and the control group was injected with the same amount of 0.9% sodium chloride solution. Urine protein content, anti-dsDNA antibody content, Th1 cell/Th2 cell ratio, and kidney staining were detected in each group. RESULTS: The model group began to develop disease in the 4th week, the anti-dsDNA antibody level reached 566.71 ± 1.44 ng/L, and the proteinuria reached 245.38 ± 30.54 ng/mL. The model group showed an onset at least 5 weeks earlier than that in the pristane group. There was no significant difference in anti-dsDNA antibody content between Cadmium chloride control group and blank group. At the 12th week, the Th1/Th2 cell ratio in the model group significantly decreased, and the pathological changes in the kidneys were consistent with the typical manifestations of lupus in mouse models. CONCLUSION: These results suggest that cadmium chloride promotes earlier onset of pristane-induced systemic lupus erythematosus in a C57BL/6 mouse model.
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Lúpus Eritematoso Sistêmico , Camundongos , Animais , Cloreto de Cádmio/toxicidade , Camundongos Endogâmicos C57BL , Terpenos/efeitos adversos , Modelos Animais de Doenças , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Inflammation may mediate the co-pathogenesis of rheumatoid arthritis (RA) and depression because inflammatory cytokines are associated with RA and depression. However, traditional observational research was not able to address problems with residual confusion and reverse causality. METHODS: We summarized and retrieved 28 inflammatory cytokines associated with RA, depression, or RA with depression through a literature search. The summary statistics from genome-wide association studies for RA, inflammatory biomarkers, broad depression, and major depression disease phenotypes were used. Mendelian randomization was performed to assess the causal association between RA and inflammatory biomarkers, as well as the effects of inflammatory biomarkers on depression. Bonferroni correction was used to reduce the possibility of false positive results. RESULTS: The study found that evidence for associations of genetically predicted RA was associated with higher levels of interleukin (IL)-9 (OR = 1.035, 95%CI = 1.002-1.068, P = 0.027), IL-12 (OR = 1.045, 95%CI = 1.045-1.014, P = 0.004), IL-13 (OR = 1.060, 95%CI = 1.028-1.092, P = 0.0001), IL-20 (OR = 1.037, 95%CI = 1.001-1.074, P = 0.047), and IL-27 (OR = 1.017, 95%CI = 1.003-1.032, P = 0.021). The level of IL-7 (OR = 1.029, 95%CI = 1.018-1.436, P = 0.030) was significantly related to RA. Only the analysis results between RA and IL-13 were satisfied with the statistical significance threshold corrected by Bonferroni (P < 0.002). However, a causal effect was not found between inflammatory biomarkers and depression. CONCLUSIONS: In the current study the inflammatory cytokines associated with RA comorbid depression may not be the mediators that directly lead to the co-pathogenesis of RA and depression.
Assuntos
Artrite Reumatoide , Estudo de Associação Genômica Ampla , Humanos , Depressão/genética , Interleucina-13 , Análise da Randomização Mendeliana/métodos , Artrite Reumatoide/genética , Biomarcadores , Citocinas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The aggregation of the amyloid-beta (Aß) peptides into toxic ß-sheet-rich oligomers, protofibrils and mature fibrils is the major pathological hallmark of Alzheimer's disease (AD). Inhibiting the ß-sheet formation and fibrillization of Aß peptides is considered an important treatment strategy for AD. Graphene oxide (GO) has attracted particular interest in the anti-aggregation of amyloid proteins due to its good ability of crossing the blood-brain barrier (BBB), low cytotoxicity and good biocompatibility. Recent experiments reported that GO nanosheets could strongly inhibit the fibril formation of Aß1-42 and reduce its cytotoxicity. However, the mechanism of suppressing Aß1-42 fibrillization by GO nanosheets is not well understood. Aß1-42 dimer is the smallest toxic oligomer of Aß1-42 aggregation. As a starting step to understand the inhibitory effect of GO nanosheets towards Aß1-42 aggregation, we investigated the conformational distribution of the Aß1-42 dimer with or without GO nanosheets by performing explicit-solvent replica exchange molecular dynamics simulations. Our simulations showed that Aß1-42 peptides could form diverse ß-sheet rich dimeric conformations, whereas those conformations were significantly inhibited after the addition of GO nanosheets. We found that GO suppressed the ß-sheet formation of Aß1-42 mostly by weakening inter-peptide interactions mostly via salt bridge, hydrogen bonding and cation-π interactions with charged residues D1, E3, R5, D7, E11, K16, E22, K28 and A42. The π-π and hydrophobic interactions between GO and Aß1-42 also play a role in the inhibition of Aß aggregation. This study provides mechanistic insights into Aß1-42 aggregation and amyloid inhibition by GO nanosheets, which may provide new clues for the development of therapeutic candidates against AD.
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Alzheimer's disease (AD) is associated with the aggregation of amyloid-ß (Aß) peptides into toxic fibrillar aggregates. Finding effective inhibitors of Aß aggregation is a crucial step for the development of drugs against AD. Recent experiments reported that dihydrochalcone (Dih), a compound extracted from the daemonorops draco tree, could effectively inhibit Aß fibrillization and reduce Aß cytotoxicity. However, the influence of Dih molecules on preformed Aß fibrils and the atomic-level details of interactions between Dih and Aß fibrils are largely unknown. In this work, we performed multiple molecular dynamics (MD) simulations for 1.2 µs in total on the Aß17-42 protofibrils with and without Dih molecules. We found that Dih molecules mostly bind to three different sites of the protofibril: the exterior central hydrophobic core (CHC) spanning residues 17LVFFA21 in the ß1 region, the protofibril cavity and the C-terminal hydrophobic-groove spanning residues 31IIGLM35 in the ß2 region. Binding to the C-terminal hydrophobic-groove slightly affects the structures of Aß17-42 protofibrils, while binding to the exterior CHC and the cavity strongly destabilizes the protofibrils by mostly disrupting the D23-K28 salt bridges and the inter-peptide ß-sheet in the ß1 region. The dynamic process of Dih molecules entering the cavity of Aß17-42 protofibrils is also investigated. We also examined the effect of Dih molecules on both U-shaped Aß40/Aß42 protofibrils and S-shaped Aß42 protofibrils by carrying out multiple MD simulations. Our simulations show that Dih molecules can destabilize both U-shaped and S-shaped Aß protofibrils by binding to the protofibril cavity. This study reveals the mechanism by which Dih molecules disrupt Aß protofibrils, which may offer new clues for the development of drug candidates for the treatment of AD.
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Peptídeos beta-Amiloides/química , Amiloide/química , Chalconas/química , Simulação de Dinâmica Molecular , Sítios de Ligação , Fenômenos Biofísicos , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Fragmentos de Peptídeos/química , Ligação Proteica , Conformação Proteica , Conformação Proteica em Folha beta , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
Two-dimensional (2D) layered transition metal dichalcogenides (TMDs) have been recently proposed as appealing candidate materials for spintronic applications owing to their distinctive atomic crystal structure and exotic physical properties arising from the large bonding anisotropy. Here we introduce the first MoS2-based spin-valves that employ monolayer MoS2 as the nonmagnetic spacer. In contrast with what is expected from the semiconducting band-structure of MoS2, the vertically sandwiched-MoS2 layers exhibit metallic behavior. This originates from their strong hybridization with the Ni and Fe atoms of the Permalloy (Py) electrode. The spin-valve effect is observed up to 240 K, with the highest magnetoresistance (MR) up to 0.73% at low temperatures. The experimental work is accompanied by the first principle electron transport calculations, which reveal an MR of â¼9% for an ideal Py/MoS2/Py junction. Our results clearly identify TMDs as a promising spacer compound in magnetic tunnel junctions and may open a new avenue for the TMDs-based spintronic applications.
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In the traditional measurement of blood oxygen, amended Lambert-Beer Law is used to calculate the oxygen percentage in the blood. On the one hand, results will be acquired slowly because of the divide operation. On the other hand, amount of precision will be lost because of the error by using ratio, wich leads to the low accuracy results. In order to solve this problem, multiple regression analysis is used in this paper to measure and evaluate the oxygen percentage in the blood. Results show that, compared to the ratio, the new method has an obvious advantage and can be realized by hardware more easily.
Assuntos
Oxigênio/sangue , Análise de RegressãoRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE.
Assuntos
Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Análise da Randomização Mendeliana , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/sangue , Feminino , Folistatina/genética , Folistatina/sangue , Menarca , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Fatores de Risco , Risco , Testosterona/sangue , Reprodução/genética , Menopausa , Estradiol/sangueRESUMO
IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.
Assuntos
Interleucina-11 , Interleucina-6 , Humanos , Interleucina-11/genética , Interleucina-6/metabolismo , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Transdução de Sinais , Receptores de Interleucina-6/genéticaRESUMO
A correlation between mental illness and systemic rheumatoid arthritis (RA) has been observed in several prior investigations. However, little is known about the causative relationship between them. The present study aimed to systematically investigate the potential association between genetically determined mental illness and RA. Two-sample bidirectional Mendelian randomization (MR) analysis was performed using publicly released genome-wide association studies (GWAS). We selected independent genetic variants associated with four mental illnesses (bipolar disorder, broad depression, major depression, and anxiety) as instrumental variables. The inverse variance weighted (IVW) method was used as the primary analysis to assess the causal relationship between mental illness and RA. Results of the IVW analysis suggested that genetic predisposition to bipolar disorder was associated with a decreased risk of RA (odds ratio [OR] = 0.825, 95% CI = 0.716 to 0.95, p = 0.007). Furthermore, we did not find a significant causal effect of RA on bipolar disorder in the reverse MR analysis (p > 0.05). In addition, our study found no evidence of a bidirectional causal relationship between genetically predicted broad depression, major depression, anxiety, and RA (p > 0.05). The genetically proxied bipolar disorder population has a lower RA risk, which may indicate that there is a hidden mechanism for inhibiting the pathogenesis of RA in bipolar disorder. However, results do not support a causal connection between depression, anxiety, and RA.
RESUMO
BACKGROUND: The correlation between dietary inflammation index (DII) and rheumatoid arthritis (RA) has been found, but the effect of confounding factors is not considered. This study aims to further explore the association between DII and RA risk by taking the Americans as the research object. METHODS: The data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES) database included 1819 self-reported RA individuals and 8602 non-RA individuals. The analytical methods include logistic regression, additive model, smooth curve fitting, and the recursive algorithm. RESULTS: There was a positive correlation between DII and RA in Americans (ß = 1.068, 95% CI = 1.026 to 1.111, P = 0.001). This result was still presented in the subgroup analysis, including age less than 50 years, female, other Hispanics, BMI ≥ 25, and federal poverty rate > 185%, and it was more pronounced in smokers. The results show that the superposition of DII and other risk factors would increase the risk of RA (ß > 1.068). In addition, individuals with RA are inadequate in intake of anti-inflammatory foods, in line with the Mediterranean diet. CONCLUSIONS: The inflammatory potential of the diet is positively correlated with the risk of RA, and has a superimposed effect with other risk factors, increasing the probability of the risk of disease. These results emphasize that reducing the intake of pro-inflammatory foods may be an effective measure to prevent the onset of rheumatoid arthritis. However, eating anti-inflammatory foods exclusively is not the best option. Intaking some pro-inflammatory foods like protein, energy, and total saturated acids may be necessary to maintain the physiological function of the human body. Key Points ⢠Dietary inflammation index (DII) is positively correlated with RA risk. ⢠When DII and other risk factors appear at the same time, the effects of the two will be superimposed on each other, increasing the risk of RA. ⢠When the DII is the same, Hispanic has a higher incidence of RA. ⢠Among the pro-inflammatory foods, the intake of protein, energy, and saturated fatty acids is still required by RA patients.
Assuntos
Artrite Reumatoide , Dieta Mediterrânea , Artrite Reumatoide/epidemiologia , Dieta/efeitos adversos , Feminino , Humanos , Inflamação/diagnóstico , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fatores de RiscoRESUMO
OBJECTIVE: Recent studies reported that SLE is characterised by altered interactions between the microbiome and immune system. We performed a meta-analysis of publications on this topic. METHODS: Case-control studies that compared patients with SLE and healthy controls (HCs) and determined the diversity of the gut microbiota and the abundance of different microbes were examined. Stata/MP V.16 was used for the meta-analysis. A Bonferroni correction for multiple tests was used to reduce the likelihood of false-positive results. RESULTS: We included 11 case-control studies that examined 373 patients with SLE and 1288 HCs. These studies were performed in five countries and nine cities. Compared with HCs, patients with SLE had gut microbiota with lower Shannon-Wiener diversity index (weighted mean difference=-0.22, 95% CI -0.32 to -0.13, p<0.001) and lower Chao1 richness (standardised mean difference (SMD)=-0.62, 95% CI -1.04 to -0.21, p=0.003). Patients with SLE had lower abundance of Ruminococcaceae (SMD = -0.49, 95% CI -0.84 to -0.15,p=0.005), but greater abundance of Enterobacteriaceae (SMD=0.45, 95% CI 0.01 to 0.89, p=0.045) and Enterococcaceae (SMD=0.53, 95% CI 0.05 to 1.01, p=0.03). However, only the results for Ruminococcaceae passed the Bonferroni correction (p=0.0071). The two groups had no significant differences in Lachnospiraceae and Bacteroides (both p>0.05). Patients with SLE who used high doses of glucocorticoids had altered gut microbiota based on the Chao1 species diversity estimator, and hydroxychloroquine use appeared to reduce the abundance of Enterobacteriaceae. CONCLUSIONS: Patients with SLE have imbalanced gut microbiota, with a decrease in beneficial bacteria and an increase in harmful bacteria. Drugs used to treat SLE may also alter the gut microbiota of these patients.
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Microbioma Gastrointestinal , Lúpus Eritematoso Sistêmico , Estudos de Casos e Controles , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológicoRESUMO
Esophageal cancer has always been associated with poor prognosis and a low five-year survival rate. Chalcone, a flavonoid family member, has shown anti-tumor property in several types of cancer. However, few studies reported the potency and mechanisms of action of synthetic Chalcone derivatives against esophageal squamous cell carcinoma. In this study, we designed and synthesized a series of novel chalcone analogs and Ch-19 was selected for its superior anti-tumor potency. Results indicated that Ch-19 shows a dose- and time-dependent anti-tumor activity in both KYSE-450 and Eca-109 esophageal cancer cells. Moreover, treatment of Ch-19 resulted in the regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the effective anti-tumor effects of Ch-19. As a result, we observed that Ch-19 treatment promoted ROS accumulation and caused G2/M phase arrest in both Eca-109 and KYSE-450 cancer cell lines, thereby resulting in cell apoptosis. Taken together, our study provided a novel synthetic chalcone derivative as a potential anti-tumor therapeutic candidate for treating esophageal cancer.
Assuntos
Antineoplásicos , Chalcona , Chalconas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Camundongos , Animais , Humanos , Chalcona/farmacologia , Chalcona/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Chalconas/farmacologia , Chalconas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Camundongos Nus , Linhagem Celular Tumoral , Transdução de Sinais , Apoptose , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
The apple rootstock Malus prunifolia (Willd.) Borkh. is widely used for apple production. Because polyploid plants are often more tolerant to abiotic stress than diploids, we wondered whether polyploidy induction in M. prunifolia might improve its stress tolerance, particularly to high salinity. We used a combination of colchicine and dimethyl sulfoxide (DMSO) to induce chromosome doubling in M. prunifolia and identified the resulting polyploids by stomatal observations and flow cytometry. We found the best way to induce polyploidy in M. prunifolia was to use 2% DMSO and 0.05% colchicine for 2 days for leaves or 0.02% colchicine for stem segments. The results of hydroponic salt treatment showed that polyploid plants were more salt tolerant and had greater photosynthetic efficiency, thicker leaf epidermis and palisade tissues, and shorter but denser root systems than diploids. During salt stress, the polyploid leaves and roots accumulated less Na+, showed upregulated expression of three salt overly sensitive (SOS) pathway genes, and produced fewer reactive oxygen species. The polyploid plants also had considerably higher ABA and jasmonic acid levels than diploid plants under salt stress. Under normal growth conditions, gibberellins (GAs) levels were much lower in polyploid leaves than in diploid leaves; however, after salt treatment, polyploid leaves showed upregulation of essential GAs synthesis genes. In summary, we developed a system for the induction of polyploidy in M. prunifolia and response to salt stress of the resulting polyploids, as reflected in leaf and root morphology, changes in Na+ accumulation, antioxidant capacity and plant hormone levels.
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Malus , Tolerância ao Sal , Antioxidantes/metabolismo , Colchicina/metabolismo , Dimetil Sulfóxido/metabolismo , Giberelinas/metabolismo , Malus/genética , Reguladores de Crescimento de Plantas , Folhas de Planta/fisiologia , Raízes de Plantas , Poliploidia , Espécies Reativas de Oxigênio/metabolismo , Tolerância ao Sal/genéticaRESUMO
The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers.
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Tyrosine is decarboxylated to tyramine by TYDC (Tyrosine decarboxylase) and then hydroxylated to dopamine, which is involved in plant response to abiotic stress. However, little is known about the function of MdTyDc in response to alkaline stress in plants. In our study, it was found that the expression of MdTyDc was induced by alkaline stress. Therefore, the apple plants overexpressing MdTyDc was treated with alkali stress, and we found that MdTyDc played an important role in apple plants' resistance to alkali stress. Our results showed that the restriction on the growth, the decrease of membrane permeability and the accumulation of Na+ were alleviated to various degrees in MdTyDc transgenic plants under alkali stress. In addition, overexpression of MdTyDc enhanced the root activity and photosynthetic capacity, and improved the enzyme activity related to N metabolism, thus promoting N absorption. It is noteworthy that the dopamine content of these three transgenic lines is significantly higher than that of WT. In summary, these findings indicated that MdTyDc may enhance alkaline tolerance of apples by mediating dopamine content, mainly by maintaining high photosynthetic capacity, normal ion homeostasis and strong nitrogen absorption capacity.
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Signals arising from bacterial infections are detected by pathogen recognition receptors (PRRs) and are transduced by specialized adapter proteins in mammalian cells. The Receptor-interacting-serine/threonine-protein kinase 2 (RIPK2 or RIP2) is such an adapter protein that is critical for signal propagation of the Nucleotide-binding-oligomerization-domain-containing proteins 1/2 (NOD1 and NOD2). Dysregulation of this signaling pathway leads to defects in bacterial detection and in some cases autoimmune diseases. Here, we show that the Caspase-activation-and-recruitment-domain (CARD) of RIP2 (RIP2-CARD) forms oligomeric structures upon stimulation by either NOD1-CARD or NOD2-2CARD. We reconstitute this complex, termed the RIPosome in vitro and solve the cryo-EM filament structure of the active RIP2-CARD complex at 4.1 Å resolution. The structure suggests potential mechanisms by which CARD domains from NOD1 and NOD2 initiate the oligomerization process of RIP2-CARD. Together with structure guided mutagenesis experiments at the CARD-CARD interfaces, we demonstrate molecular mechanisms how RIP2 is activated and self-propagating such signal.
Assuntos
Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Proteínas Adaptadoras de Sinalização CARD/química , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Microscopia Crioeletrônica , Células HEK293 , Humanos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Multimerização Proteica , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/ultraestrutura , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Graphene/two-dimensional (2D) semiconductor heterostructures have been demonstrated to possess many advantages for electronic and optoelectronic devices. However, there are few reports about the utilization of a 2D semiconductor monolayer to tune the properties of graphene. Here, we report the fabrication and characterization of graphene p-n junctions based on graphene/MoS2 hybrid interfaces. Monolayered graphene across the monolayered MoS2 boundary is divided into n-type regions on the MoS2 and p-type regions on the SiO2 substrate. Such van der Waals heterostructure based graphene p-n junctions show good photoelectric properties. The photocurrent modulation of such devices by a single back gate is also demonstrated for the first time, which shows that the graphene on and off MoS2 regions have different responses to the gate voltage. Our results suggest that the atomic thin hybrid structure can remarkably extend the device applications.
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Charge-trap memory with high-κ dielectric materials is considered to be a promising candidate for next-generation memory devices. Ultrathin layered two-dimensional (2D) materials like graphene and MoS2 have been receiving much attention because of their fantastic physical properties and potential applications in electronic devices. Here, we report on a dual-gate charge-trap memory device composed of a few-layer MoS2 channel and a three-dimensional (3D) Al2O3/HfO2/Al2O3 charge-trap gate stack. Because of the extraordinary trapping ability of both electrons and holes in HfO2, the MoS2 memory device exhibits an unprecedented memory window exceeding 20 V. Importantly, with a back gate the window size can be effectively tuned from 15.6 to 21 V; the program/erase current ratio can reach up to 10(4), allowing for multibit information storage. Moreover, the device shows a high endurance of hundreds of cycles and a stable retention of â¼ 28% charge loss after 10 years, which is drastically lower than ever reported MoS2 flash memory. The combination of 2D materials with traditional high-κ charge-trap gate stacks opens up an exciting field of nonvolatile memory devices.