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An array of biologically interesting tri/difluoromethylated chromones and their heteroatom analogues were conveniently synthesized from the reaction of chromones and their heteroatom analogues with CF3SO2Na or HCF2SO2Na in the presence of tert-butyl hydroperoxide under mild conditions. A mechanistic pathway involving the generation of the electrophilic tri/difluoromethyl radical, followed with the radical substitution of chromones and their heteroatom analogues, was postulated.
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The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT- and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing-mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions -156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.
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Neoplasias Mamarias Animales , Neoplasias de la Mama Triple Negativas , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Mamarias Animales/genética , Complejo Mediador/genética , Complejo Mediador/metabolismo , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
A metal-free synthesis of a series of fluoroalkyl-containing oxazoles from ß-monosubstituted enamines was developed. This fluoroacyloxylation/cyclization cascade process was mediated by fluoroalkyl-containing hypervalent iodine(III) species formed in situ from the reaction of phenyliodine(III) diacetate (PIDA) and RCF2CO2H (R = H, Cl, Br, F, CF3, CH3, Ph, SAr, OAr).
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BACKGROUND: Resistance to HER2-targeted therapy is a critical issue in breast cancer that must be addressed immediately. PIK3R1 mutations are more common in Chinese breast cancer patients (17%, 25/147, Fudan University Shanghai Cancer Center FUSCC vs. 1.8%, 87/4602, TCGA all breast cancer studies). However, very limited information is available on the relationship between PIK3R1 mutation status and resistance to HER2-targeted therapies in patients with HER2-positive breast cancer. CASE REPORT: We present a case of a HER2-positive advanced breast cancer patient with the PIK3R1EY451delinsD mutation who developed resistance to HER2-targeted therapy and had a better response to everolimus combined with trastuzumab and carboplatin. CONCLUSIONS: To the best of our knowledge, this is the first study to show that the PIK3R1EY451delinsD mutation confers resistance to anti-HER2 therapy in breast cancer and that combining with everolimus treatment may overcome this resistance mechanism. We hypothesize that the PIK3R1EY451delinsD mutation is associated with the resistance to anti-HER2 therapy, and that this mutation merits further investigation as a clinical biomarker and therapeutic target.
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Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , China , Fosfatidilinositol 3-Quinasa Clase Ia/uso terapéutico , Resistencia a Antineoplásicos/genética , Everolimus/uso terapéutico , Femenino , Humanos , Receptor ErbB-2/genética , Trastuzumab/uso terapéuticoRESUMEN
Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)-MBP87-99[A91, A96], MBP87-99[A91], and MBP87-99[R91, A96]-in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87-99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87-99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87-99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87-99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87-99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune-neural interactions may impact central nervous system function and alter an individual's response to stress.
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Antidepresivos/química , Antidepresivos/inmunología , Depresión/inmunología , Depresión/terapia , Inmunización , Proteína Básica de Mielina/química , Proteína Básica de Mielina/inmunología , Animales , Antidepresivos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Ansiedad/inmunología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Depresión/etiología , Modelos Animales de Enfermedad , Proteína Básica de Mielina/administración & dosificación , Proteína Básica de Mielina/uso terapéutico , Ratas , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/inmunologíaRESUMEN
Drug resistance is the leading cause for rapid progression and relapse in small-cell lung cancer (SCLC) patients. Thus overcoming drug resistance still remains to be urgently resolved during SCLC treatment. Here, we found p62/SQSTM1 was enriched in SCLC spheroids, a subpopulation possessing cancer stem-like properties, which is responsible for cancer relapse and metastasis. Subsequent functional assays in vitro showed that short hairpin RNA (shRNA)-mediated p62 knockdown increased sensitivity of SCLC cell lines to cisplatin (DDP), whereas lentivirus-mediated p62 ectopic overexpression diminished DDP-induced cytotoxicity in both NCI-H446 and NCI-H1688 cell lines. Moreover, ectopic p62 overexpression promoted DDP resistance of NCI-H446 cells-derived tumor xenografts in immunodeficient mice in vivo, as indicated by accelerated tumor growth rate and reduced fluorescent activity of cleaved caspase-3. Gene expression profiling analysis revealed that p62 was positively correlated with neuronal precursor cell-expressed, developmentally downregulated gene 9 (NEDD9) expression level. Consistently, NEDD9 messenger RNA (mRNA) level was decreased upon p62 suppression by small interfering RNA (siRNA) and increased with p62 transient overexpression in SCLC cell lines, suggesting that p62 positively regulated NEDD9 mRNA. Depletion of NEDD9 by siRNA, to a large extent, reversed p62-overexpressed SCLC cells to DDP-induced cytotoxicity, implying NEDD9 might act as a downstream target which was in charge of p62-mediated DDP resistance. Taken together, our findings uncovered a previously unknown role of p62 in the regulation of SCLC drug resistance, assigning p62 as an attractive target for SCLC treatment.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteína Sequestosoma-1/antagonistas & inhibidores , Carcinoma Pulmonar de Células Pequeñas/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , ARN Interferente Pequeño/genética , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The on-purpose-modulated dendritic cells (DCs) have shown charming effects on restoring immune regulatory functions in subjects with immune diseases. OBJECTIVE: This study aims to construct DCs carrying chimerical antigen (Ag) peptides (CAP-DCs) to induce interleukin (IL)-17+ inducible Tregs (iTregs) to alleviate food allergy (FA) in a murine model. METHODS: In this study, we constructed CAP-DCs. The CAP is a fusion protein, consisting of a segment of recombinant scFv of anti-DEC205 antibody and an ovalbumin (OVA) epitope (IC). A murine OVA-FA model was developed to test the effects of CAP-DCs on suppressing the allergic response in the intestine. RESULTS: The CAP-DCs are characterized as that a complex of scFv-IC is presented on the surface of the cells, moderately express CD80 and CD86 as well as IL-6, IL-23, transforming growth factor (TGF)-ß and CCR9. After being passively transferred with CAP-DCs or injection of scFv-IC, Ag-specific IL-17+ Foxp3+ iTregs were induced in the intestinal lamina propria of FA mice. The iTregs showed immune suppressive effects on Ag-specific Th2 response. FA mice were adoptively transferred with the CAP-DCs or scFv-IC injection, which resulted in a significant decrease in the number of Ag-specific Th2 cells and suppression of FA response in an Ag-specific manner. CONCLUSIONS AND CLINICAL RELEVANCE: CAP-DCs can ameliorate FA response by inducing Ag-specific IL-17+ Foxp3+ iTregs and suppressing Ag-specific Th2 response. To generate CAP-DCs has the translational potential in the treatment of FA.
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Antígenos/inmunología , Células Dendríticas , Desensibilización Inmunológica , Epítopos de Linfocito T/inmunología , Hipersensibilidad a los Alimentos , Interleucina-17/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/terapia , RatonesRESUMEN
Breast cancer is the most common cancer in women worldwide, and advanced breast cancer is the leading cause of cancer death in women. In present study, we aim to investigate that role of T-cell lymphoma invasion and metastasis-inducing protein1 (TIAM1) on NVP-BEZ235 resistance to breast cancer MCF7 and MDA-MB-361 cells. Briefly, MCF7 and MDA-MB-361 cells were treated with NVP-BEZ235 and the relative expressions of TIAM1 at both mRNA level and protein level were determined by RT-PCR and western blot. In addition, MCF7 and MDA-MB-361 cells were transfected with TIAM1 knockdown or overexpression vector. Then the IC50 of NVP-BEZ235 on MCF7 and MDA-MB-361 cells were detected by MTT assay. Finally, FGFR/STAT3 pathway protein members were investigated by western blot. Consequently, we found that the mRNA and protein expressions of TIAM1 and FGFR1/3 were dramatically upregulated in NVP-BEZ235-treated group in both MCF7 and MDA-MB-361 cells. Interestingly, TIAM1 knockdown via shRNA decreased the IC50 of NVP-BEZ235 of breast cancer cells, while TIAM1 overexpression increased the IC50 of NVP-BEZ235 of breast cancer cells, which suggested that TIAM1 was one of the contributors for NVP-BEZ235 resistance. In addition, FGFR members including FGFR1/3 showed similar results to TIAM1. Importantly, FGFR inhibitor AZD4547 decreased the IC50 of NVP-BEZ235, which suggested that FGFR downregulation reduced the NVP-BEZ235 resistance to breast cancer cells. In summary, our present study revealed that TIAM1 conferred NVP-BEZ235 resistance to breast cancer cells via activating FGFR/STAT3 pathway.
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Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Imidazoles/farmacología , Proteínas de Neoplasias/biosíntesis , Quinolinas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T/biosíntesis , Regulación hacia Arriba , Femenino , Humanos , Células MCF-7 , Proteínas de Neoplasias/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Factor de Transcripción STAT3/genética , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T/genéticaRESUMEN
Oxidative stress refers to an imbalance between oxidative and antioxidative systems due to environmental factors. Although oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD), its precise role is not yet understood. We aimed to investigate the pathogenic mechanisms of the oxidative stress by using in vitro cultured neurons and in vivo AD models of PS1V97L-transgenic (Tg) mice. Our results showed that when oxidative stress became increasingly evident, the endogenous protective pathway of nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) decreased in 10-month-old PS1V97L-Tg mice. Activating the Nrf2/ARE pathway suppressed oxidative stress, decreased amyloid-ß (Aß), and improved the cognitive function of the PS1V97L-Tg mice. In contrast, blocking the Nrf2/ARE pathway augmented oxidative injury and decreased the cell viability of PS1V97L-Tg neurons. Our results highlight the role of the Nrf2/ARE pathway in regulating oxidative stress of the PS1V97L-Tg mice and may indicate a potential therapeutic avenue for AD treatment.
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Enfermedad de Alzheimer/metabolismo , Elementos de Respuesta Antioxidante , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Supervivencia Celular/genética , Cognición , Disfunción Cognitiva , Hemo-Oxigenasa 1/metabolismo , Aprendizaje por Laberinto , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/deficiencia , Neuronas/metabolismo , Proteínas con Repetición de beta-TransducinaRESUMEN
The signalling adaptor p62 is frequently overexpressed in numerous cancer types. Here, we found that p62 expression was elevated in metastatic breast cancer and its overexpression correlated with reduced metastasis- and relapse-free survival times. Analysis of p62 expression in breast cancer cell lines demonstrated that high p62 expression was associated with the invasive phenotypes of breast cancer. Indeed, silencing p62 expression attenuated the invasive phenotypes of highly metastatic cells, whereas overexpressing p62 promoted the invasion of non-metastatic cells in in vitro microfluidic model. Moreover, MDA-MB-231 cells with p62 depletion which were grown in a three-dimensional culture system exhibited a loss of invasive protrusions. Consistently, genetic ablation of p62 suppressed breast cancer metastasis in both zebrafish embryo and immunodeficient mouse models, as well as decreased tumourigenicity in vivo. To explore the molecular mechanism by which p62 promotes breast cancer invasion, we performed a co-immunoprecipitation-mass spectrometry analysis and revealed that p62 interacted with vimentin, which mediated the function of p62 in promoting breast cancer invasion. Vimentin protein expression was downregulated upon p62 suppression and upregulated with p62 overexpression in breast cancer cells. Linear regression analysis of clinical breast cancer specimens showed a positive correlation between p62 and vimentin protein expression. Together, our findings provide strong evidence that p62 functions as a tumour metastasis promoter by binding vimentin and promoting its expression. This finding might help to develop novel molecular therapeutic strategies for breast cancer metastasis treatment.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Metástasis de la Neoplasia/patología , Proteína Sequestosoma-1/genética , Vimentina/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/fisiología , Regulación hacia Abajo/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Células HEK293 , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Regulación hacia Arriba/fisiología , Pez CebraRESUMEN
BACKGROUND/AIMS: Cancer stem cells (CSCs) are considered to be responsible for tumor relapse and metastasis, which serve as a potential therapeutic target for cancer. Aspirin has been shown to reduce cancer risk and mortality, particularly in colorectal cancer. However, the CSCs-suppressing effect of aspirin and its relevant mechanisms in colorectal cancer remain unclear. METHODS: CCK8 assay was employed to detect the cell viability. Sphere formation assay, colony formation assay, and ALDH1 assay were performed to identify the effects of aspirin on CSC properties. Western blotting was performed to detect the expression of the stemness factors. Xenograft model was employed to identify the anti-cancer effects of aspirin in vivo. Unpaired Student t test, ANOVA test and Kruskal-Wallis test were used for the statistical comparisons. RESULTS: Aspirin attenuated colonosphere formation and decreased the ALDH1 positive cell population of colorectal cancer cells. Aspirin inhibited xenograft tumor growth and reduced tumor cells stemness in nude mice. Consistently, aspirin decreased the protein expression of stemness-related transcription factors, including c-Myc, OCT4 and NANOG. Suppression of NANOG blocked the effect of aspirin on sphere formation. Conversely, ectopic expression of NANOG rescued the aspirin-repressed sphere formation, suggesting that NANOG is a key downstream target. Moreover, we found that aspirin repressed NANOG expression in protein level by decreasing its stability. CONCLUSION: We have provided new evidence that aspirin attenuates CSC properties through down-regulation of NANOG, suggesting aspirin as a promising therapeutic agent for colorectal cancer treatment.
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Aspirina/toxicidad , Proliferación Celular/efectos de los fármacos , Proteína Homeótica Nanog/metabolismo , Animales , Aspirina/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Homeótica Nanog/antagonistas & inhibidores , Proteína Homeótica Nanog/genética , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Estabilidad Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factores de Transcripción SOXB1/metabolismo , Trasplante HeterólogoRESUMEN
Background: Morinda officinalis oligosaccharides have been reported to exert neuroprotective and antidepressant-like effects in the forced swim test in mice. However, the mechanisms that underlie the antidepressant-like effects of Morinda officinalis oligosaccharides are unclear. Methods: Chronic unpredictable stress and forced swim test were used to explore the antidepressant-like effects of Morinda officinalis oligosaccharides and resilience to stress in rats. The phosphoinositide-3 kinase inhibitor LY294002 was microinjected in the medial prefrontal cortex to explore the role of glycogen synthase kinase-3ß in the antidepressant-like effects of Morinda officinalis oligosaccharides. The expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase 3ß, ß-catenin, and synaptic proteins was determined in the medial prefrontal cortex and the orbitofrontal cortex by western blot. Results: We found that Morinda officinalis oligosaccharides effectively ameliorated chronic unpredictable stress-induced depression-like behaviors in the sucrose preference test and forced swim test. The Morinda officinalis oligosaccharides also significantly rescued chronic unpredictable stress-induced abnormalities in the brain-derived neurotrophic factor-glycogen synthase kinase-3ß-ß-catenin pathway and synaptic protein deficits in the medial prefrontal cortex but not orbitofrontal cortex. The activation of glycogen synthase kinase-3ß by the phosphoinositide-3 kinase inhibitor LY294002 abolished the antidepressant-like effects of Morinda officinalis oligosaccharides in the forced swim test. Naïve rats that were treated with Morinda officinalis oligosaccharides exhibited resilience to chronic unpredictable stress, accompanied by increases in the expression of brain-derived neurotrophic factor, phosphorylated-Ser9-glycogen synthase kinase-3ß, and ß-catenin in the medial prefrontal cortex. Conclusion: Our findings indicate that the brain-derived neurotrophic factor-glycogen synthase kinase-3ß-ß-catenin pathway in the medial prefrontal cortex may underlie the antidepressant-like effect of Morinda officinalis oligosaccharides and resilience to stress.
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Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Oligosacáridos/farmacología , Corteza Prefrontal/efectos de los fármacos , beta Catenina/metabolismo , Animales , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Masculino , Morinda , Corteza Prefrontal/metabolismo , Ratas Sprague-Dawley , Resiliencia Psicológica/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismoRESUMEN
The Aurora kinase family is comprised of three serine/threonine kinases, Aurora-A, Aurora-B, and Aurora-C. Among these, Aurora-A and Aurora-B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases has been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis. Aurora kinases therefore represent promising targets for anticancer therapeutics. A number of Aurora kinase inhibitors (AKIs) have been generated; some of which are currently undergoing clinical evaluation. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in promoting tumorigenesis, the recent preclinical and clinical AKI data, and potential alternative routes for Aurora-A kinase inhibition.
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Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Aurora Quinasa A/metabolismo , Humanos , Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/genética , Oncogenes , Inhibidores de Proteínas Quinasas/administración & dosificaciónRESUMEN
Restoration of the antigen (Ag)-specific immune tolerance in an allergic environment is refractory. B cells are involved in immune regulation. Whether B cells facilitate the generation of Ag-specific immune tolerance in an allergic environment requires further investigation. This paper aims to elucidate the mechanism by which B cells restore the Ag-specific immune tolerance in an allergic environment. In this study, a B cell-deficient mouse model was created by injecting an anti-CD20 antibody. The frequency of tolerogenic dendritic cell (TolDC) was assessed by flow cytometry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The expression of thrombospondin-1 (TSP1) was assessed by quantitative real-time RT-PCR, Western blotting, and methylation-specific PCR. The results showed that B cells were required in the generation of the TGF-ß-producing TolDCs in mice. B cell-derived TSP1 converted the latent TGF-ß to the active TGF-ß in DCs, which generated TGF-ß-producing TolDCs. Exposure to IL-13 inhibited the expression of TSP1 in B cells by enhancing the TSP1 gene DNA methylation. Treating food allergy mice with Ag-specific immunotherapy and IL-13 antagonists restored the generation of TolDCs and enhanced the effect of specific immunotherapy. In conclusion, B cells play a critical role in the restoration of specific immune tolerance in an allergic environment. Blocking IL-13 in an allergic environment facilitated the generation of TolDCs and enhanced the therapeutic effect of immunotherapy.
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Linfocitos B/inmunología , Metilación de ADN/efectos de los fármacos , Desensibilización Inmunológica , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Hipersensibilidad a los Alimentos/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Trombospondina 1/inmunología , Animales , Linfocitos B/patología , Metilación de ADN/inmunología , Células Dendríticas/inmunología , Células Dendríticas/patología , Hipersensibilidad a los Alimentos/genética , Hipersensibilidad a los Alimentos/patología , Tolerancia Inmunológica/genética , Interleucina-13/genética , Interleucina-13/inmunología , Masculino , Ratones , Trombospondina 1/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
Environmental stress (ES) is commonly used in producing chronic unpredictable mild stress to study pathogenesis of depression, including the regulatory role of circadian system on depression. However, the direct effect of ES on the circadian system has been rarely explored. The present study was aimed to investigate the effect of ES on depression-like behaviors and diurnal rhythm of plasma hormone/peptide levels in male rats. Rats were allocated into control group (CON group), low frequency ES group (LF group) and high frequency ES group (HF group). Sucrose preference test (SPT), open field test (OFT), weight gain, food and water intake were conducted to assess depression- and anxiety-like behaviors. A total of 7 times of the tail venous blood was collected with an interval of 4 h during 24 h from other rats who subjected to the same procedures of ES but not the behavioral tests. The alterations of diurnal rhythm of peripheral plasma corticosterone (CORT) and melatonin, and changes of the cholecystokinin (CCK), neuropeptide Y and leptin levels at zeitgeber time (ZT) 0 were detected by using enzyme-linked immunosorbent assay (ELISA). We found that ES led to a disturbance of diurnal rhythm of CORT and melatonin in the plasma. Besides, it also increased plasma leptin level and decreased body weight gain, but it did not produce depression- and anxiety-like behaviors compared with those rats in the control group. In short, our findings indicated that the ES could induce a disturbance of diurnal rhythm of plasma CORT and melatonin in male rats.
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Ritmo Circadiano , Trastorno Depresivo , Estrés Fisiológico , Animales , Ansiedad , Conducta Animal , Corticosterona , Depresión , Leptina , Masculino , Melatonina , Neuropéptido Y , RatasRESUMEN
Extinction therapy has been suggested to suppress the conditioned motivational effect of drug cues to prevent relapse. However, extinction forms a new inhibiting memory rather than erasing the original memory trace and drug memories invariably return. Perineuronal nets (PNNs) are a specialized extracellular matrix around interneurons in the brain that have been suggested to be a permissive factor that allows synaptic plasticity in the adolescent brain. The degradation of PNNs caused by chondroitinase ABC (ChABC) may generate induced juvenile-like plasticity (iPlasticity) and promote experience-dependent plasticity in the adult brain. In the present study, we investigated the effect of removing PNNs in the amygdala of rat on the extinction of drug memories. We found that extinction combined with intra-amygdala injections of ChABC (0.01 U/side) prevented the subsequent priming-induced reinstatement of morphine-induced and cocaine-induced, but not food -induced, conditioned place preference (CPP). Intra-amygdala injections of ChABC alone had no effect on the retention, retrieval, or relearning of morphine-induced CPP and storage of acquired food-induced CPP. Moreover, we found that the procedure facilitated the extinction of heroin- and cocaine-seeking behavior and prevented the spontaneous recovery and drug-induced reinstatement of heroin- and cocaine-seeking behavior. We also found that the effect of PNNs degradation combined with extinction may be mediated by the potentiation of several plasticity-related proteins in the amygdala. Altogether, our findings demonstrate that a combination of extinction training with PNNs degradation in the amygdala erases drug memories and suggest that ChABC may be an attractive candidate for the prevention of relapse.
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Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Memoria , Red Nerviosa/fisiología , Trastornos Relacionados con Sustancias/psicología , Animales , Western Blotting , Condroitina ABC Liasa/administración & dosificación , Condroitina ABC Liasa/farmacología , Trastornos Relacionados con Cocaína/psicología , Condicionamiento Operante , Extinción Psicológica , Alimentos , Dependencia de Heroína/psicología , Masculino , Microinyecciones , Dependencia de Morfina/psicología , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Prevención SecundariaRESUMEN
BACKGROUND: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies. METHODS: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. RESULTS: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. CONCLUSION: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.
Asunto(s)
Anticuerpos/administración & dosificación , Conducta Animal/efectos de los fármacos , Dopamina/sangre , Morfina/inmunología , Vacunas Conjugadas/administración & dosificación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Animales , Anticuerpos/farmacología , Cromatografía Líquida de Alta Presión , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Heroína/administración & dosificación , Heroína/efectos adversos , Locomoción/efectos de los fármacos , Masculino , Morfina/administración & dosificación , Morfina/efectos adversos , Derivados de la Morfina/administración & dosificación , Derivados de la Morfina/efectos adversos , Derivados de la Morfina/inmunología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Autoadministración , Resultado del Tratamiento , Vacunas Conjugadas/farmacologíaRESUMEN
INTRODUCTION: Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations. Nonetheless, research findings on VEGF in Alzheimer's disease (AD) and vascular dementia (VaD) are inconsistent across various studies. METHODS: We conducted a meta-analysis to elucidate relationships between VEGF and AD/VaD. RESULTS: Twenty-four studies were included. Pooled data showed that both blood and cerebrospinal fluid (CSF) VEGF levels were higher in VaD patients, whereas no significant difference was found between AD patients and healthy controls. However, the correlation between blood VEGF and AD was found among studies with AD pathology verification. And blood VEGF levels were higher in AD patients than controls in "age difference < 5 years" subgroup and CSF samples for European cohorts. DISCUSSION: This study highlights that VEGF is more effective for the diagnosis of VaD and vascular factors are also an important contributor in AD. Highlights: Vascular endothelial growth factor (VEGF) levels were higher in the vascular dementia group, but not in the overall Alzheimer's disease (AD) group.Correlation between VEGF and AD was found among studies with clear AD pathological verification.Elevated VEGF in the cerebrospinal fluid might be a diagnostic marker for AD in European populations.
RESUMEN
Bone marrow metastasis (BMM) of solid tumors refers to a group of diseases that originate from non-hematopoietic malignant tumor cells invading the bone marrow (BM) through complex metastatic patterns. If BMM identification is delayed, the disease will rapidly develop into disseminated carcinogenesis of the BM, which manifests as a series of hematological disorders and microangiopathic hemolytic anemia, leading to serious life-threatening conditions. Although the study of solid tumor BMM is receiving increasing attention, study remains limited, and most descriptions are derived from case reports. Currently, clinicians have insufficient understanding of BMM, and BMM occurrence is often not recognized early or treated effectively, resulting in high mortality rates. In this article, we review the epidemiology, molecular mechanisms, clinical diagnosis, treatment, and prognosis of solid tumor BMM.
Asunto(s)
Neoplasias de la Médula Ósea , Neoplasias Óseas , Humanos , Médula Ósea/patología , Pronóstico , Neoplasias de la Médula Ósea/diagnóstico , Neoplasias de la Médula Ósea/terapia , Neoplasias Óseas/patologíaRESUMEN
Chronic inflammation is the pathological feature of inflammatory bowel diseases (IBD), but its etiology is unknown. Macrophages are one of the major immune cell fractions in the colon. The objectives of this study are to characterize the immune regulatory functions of macrophages in the colon of patients with ulcerative colitis (UC). UC patients (n = 30) were recruited into this study. Colon lavage fluid (CLF) was collected. Macrophages are isolated from the cellular components of CLF. The immune suppressive functions of macrophages were assessed using immunological approaches. We observed that macrophages occupied about half of the proportions of the cellular components in CLF. Lower amounts of IL10 mRNA and proteins were detected in macrophages of the UC group than the normal control (NC) group. The expression of IL10 in CLF macrophages was positively correlated with the UC-associated cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, IFN-γ, eosinophil-derived mediators, in CLF. The immune suppressive functions of CLF macrophages in UC patients were impaired. The inducibility of IL10 expression of UC M0 cells was defective as compared with NC M0 cells. Exposure to CpG restored the inducibility of IL10 expression in UC M0 cells, and gain the potential to acquire the immune suppressive functions. To sum up, the immune suppressive functions of UC macrophages are impaired. The inducibility of IL10 expression of M0 cells is impaired, which can be restored by the treatment with CpG.