RESUMEN
The codling moth Cydia pomonella is a major pest of global significance impacting pome fruits and walnuts. It threatens the apple industry in the Loess Plateau and Bohai Bay in China. Sterile insect technique (SIT) could overcome the limitations set by environmentally compatible area-wide integrated pest management (AW-IPM) approaches such as mating disruption and attract-kill that are difficult to suppress in a high-density pest population, as well as the development of insecticide resistance. In this study, we investigated the effects of X-ray irradiation (183, 366, 549 Gy) on the fecundity and fertility of a laboratory strain of C. pomonella, using a newly developed irradiator, to evaluate the possibility of X-rays as a replacement for Cobalt60 (60Co-γ) and the expanded future role of this approach in codling moth control. Results show that the 8th-day is the optimal age for irradiation of male pupae. The fecundity decreased significantly as the dosage of radiation increased. The mating ratio and mating number were not influenced. However, treated females were sub-sterile at a radiation dose of 183 Gy (20.93%), and were almost 100% sterile at a radiation dose of 366 Gy or higher. Although exposure to a radiation dose of 366 Gy resulted in a significant reduction in the mating competitiveness of male moths, our radiation biology results suggest that this new generation of X-ray irradiator has potential applications in SIT programs for future codling moth control.
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Infertilidad , Mariposas Nocturnas , Femenino , Masculino , Animales , Rayos X , Rayos gamma , FertilidadRESUMEN
Video watermarking is an important means of video and multimedia copyright protection, but the current watermarking algorithm is difficult to ensure high robustness under various attacks. In this paper, a video watermarking algorithm based on NSCT, pseudo 3D-DCT and NMF has been proposed. Combined with NSCT, 3D-DCT and NMF, the algorithm embeds the encrypted QR code copyright watermark into the NMF base matrix to improve the anti-attack ability of the watermark under the condition of invisibility. The experimental results show that the algorithm ensures the invisibility of the watermark with a high signal-to-noise ratio of the video, and meanwhile has high ability and robustness against common single and combined attacks, such as filtering, noise, compression, shear, rotation and so on. The issue that the video watermarking algorithm has poor resistance to various attacks, especially the shearing attack, has been solved in this paper; thus, it can be used for digital multimedia video copyright protection.
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N-Chloro-α-amino acids formed in the chlorination disinfection treatment of water or wastewater and in living organisms have attracted extensive attention due to the potential toxicities of themselves and their decomposition products. The degradation mechanisms of three N-chloro-α-amino acids, i.e., N-chloro-glycine, N-chloro-alanine, and N-chloro-valine, have been systematically investigated using quantum chemical computations. The results indicate that N-chloro-α-amino acid anions undergo two competitive degradation pathways: a concerted Grob fragmentation (CGF) and ß-elimination (ß-E). Generally, the former predominates over the latter under neutral conditions and finally generates amines and carbonyls, while the latter is preferred under base-promoted conditions and mainly produces the respective α-keto acid anions or nitriles in the end. To gain deeper insights into the substitution effects, in view of the advantages of quantum chemical computations, a number of real or designed N-chloro-α-amino acids with traditional electron-donating groups (EDG) or electron-withdrawing groups (EWG) have been studied. All of the substituted N-chloro-α-amino acids, regardless of the type and position of substituents, are kinetically more favorable than N-monochloro-glycine for degradation via the CGF pathway. Moreover, conjugated EDG substituted on the N-terminal facilitate both CGF and ß-E reactions, whereas conjugated EDG and EWG on the α-carbon are only favorable for the CGF and ß-E reactions, respectively. These results are expected to expand our understanding of organic N-chloramine degradation mechanisms and chlorination reaction characteristics.
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Aminoácidos , Purificación del Agua , Desinfección , Halogenación , AguaRESUMEN
Microproteins and endogenous peptides in the brain contain important substances that have critical roles in diverse biological processes, contributing to signal transduction and intercellular signaling. However, variability in their physical or chemical characteristics, such as molecule size, hydrophobicity, and charge states, complicate the simultaneous analysis of these compounds, although this would be highly beneficial for the field of neuroscience research. Here, we present a top-down analytical method for simultaneous analysis of microproteins and endogenous peptides using high-resolution nanocapillary LC-MS/MS. This method is detergent-free and digestion-free, which allows for extracting and preserving intact microproteins and peptides for direct LC-MS analysis. Both higher energy collision dissociation and electron-transfer dissociation fragmentations were used in the LC-MS analysis to increase the identification rate, and bioinformatics tools ProteinGoggle and PEAKS Studio software were utilized for database search. In total, we identified 471 microproteins containing 736 proteoforms, including brain-derived neurotrophic factor and a number of fibroblast growth factors. In addition, we identified 599 peptides containing 151 known or potential neuropeptides such as somatostatin-28 and neuropeptide Y. Our approach bridges the gap for the characterization of brain microproteins and peptides, which permits quantification of a diversity of signaling molecules for biomarker discovery or therapy diagnosis in the future.
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Química Encefálica , Cromatografía Liquida/métodos , Nanotecnología/métodos , Proteínas/análisis , Espectrometría de Masas en Tándem/métodos , Animales , Encéfalo/metabolismo , Biología Computacional/métodos , Ratones , Neuropéptidos/aislamiento & purificación , Neuropéptidos/metabolismo , Proteínas/metabolismo , Proteoma/análisis , Proteómica/métodosRESUMEN
In Wireless Sensor Networks (WSNs), unlicensed users, that is, sensor nodes, have excessively exploited the unlicensed radio spectrum. Through Cognitive Radio (CR), licensed radio spectra, which are owned by licensed users, can be partly or entirely shared with unlicensed users. This paper proposes a strategic bargaining spectrum-sharing scheme, considering a CR-based heterogeneous WSN (HWSN). The sensors of HWSNs are discrepant and exist in different wireless environments, which leads to various signal-to-noise ratios (SNRs) for the same or different licensed users. Unlicensed users bargain with licensed users regarding the spectrum price. In each round of bargaining, licensed users are allowed to adaptively adjust their spectrum price to the best for maximizing their profits. . Then, each unlicensed user makes their best response and informs licensed users of "bargaining" and "warning". Through finite rounds of bargaining, this scheme can obtain a Nash bargaining solution (NBS), which makes all licensed and unlicensed users reach an agreement. The simulation results demonstrate that the proposed scheme can quickly find a NBS and all players in the game prefer to be honest. The proposed scheme outperforms existing schemes, within a certain range, in terms of fairness and trade success probability.
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Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl-cholanthrene-induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell-dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27.
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Células Dendríticas/inmunología , Interleucinas/fisiología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/prevención & control , Células T Asesinas Naturales/inmunología , Animales , Diferenciación Celular/inmunología , Línea Celular Tumoral , Células Dendríticas/metabolismo , Tolerancia Inmunológica , Células Asesinas Naturales/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Noqueados , Células T Asesinas Naturales/metabolismoRESUMEN
Oxidative stress promotes several diseases, including liver disease. We have isolated several stilbenoids from Rheum undulatum to investigate their hepatoprotective activities and mechanism. Stilbenoids from R. undulatum protects hepatocytes against arachidonic acid + iron (AA + Fe) induced oxidative stress. Pterostilbene (compound 5) shows stronger activity than the others. Trimethoxystilbenoid (compound 6) shows best activity on protection of HepG2 cells from AA + Fe-induced oxidative stress, and trans-stilbenoid (compound 7) shows weak activity. These stilbenoids suppress ROS generation in AA + Fe-treated HepG2 cells and also suppress AA + Fe-induced MMP disruption. Their protective effects on AA + Fe-induced MMP disruption were abrogated by treatment of AMP-activated protein kinase (AMPK) inhibitor, compound C or transfection of dominant negative form of AMPK. Taken together, stilbenoids from R. undulatum protect hepatocytes against AA + Fe-induced oxidative stress through AMPK activation. And the methoxy groups in the aryl groups are important for their cytoprotective activity.
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Hepatocitos/efectos de los fármacos , Estrés Oxidativo , Rheum , Estilbenos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Ácido Araquidónico/metabolismo , Células Hep G2 , Humanos , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Sustancias Protectoras/farmacologíaRESUMEN
The codling moth, Cydia pomonella (L.), is an invasive agricultural pest of pome fruits and walnuts in China that threatens the apple industry in the Loess Plateau and Bohai Bay; it has developed resistance to many insecticides. Sterile insect technique (SIT) combined with area-wide integrated pest management (AW-IPM) can reduce the risk of resistance to insecticides and effectively control some insect pest species. Our previous laboratory experiment found that irradiation with 366 Gy of X-ray caused the males of the codling moth to become sterile. However, the sterility and adaptability of males after being irradiated with 366 Gy X-ray in the field are still unclear. In this study, we investigated the effect of X-ray irradiation on the fitness of male adults that emerged from pupae irradiated with 366 Gy to explore their adaptability and mating competitiveness, and to examine the effect of releasing sterile male insects in orchards in northeast China on the fruit infestation rate of the Nanguo pear. The results showed that 366 Gy of X-ray irradiation significantly reduced the mating competitiveness of males and the hatching rate of the eggs laid by females pairing with sterile males. Meanwhile, the lifespan of the sterile male moths was significantly shorter than that of the normal ones in the field. A pilot test showed that the release twice of sterile male moths in the orchards had no significant effect on the fruit infestation rate. Our field experiments provide a scientific basis for the further optimization of the SIT technology program for controlling C. pomonella.
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Spodoptera litura is an omnivorous pest that has spread globally. Because irradiation sterilization technology has a great potential for control of S. litura, the effect of 25-150 Gy doses of X-rays on pupal survival, flight and reproductive variables of adult moths were analyzed in this research. The X-ray irradiation with the dose of 25-150 Gy significantly affected the reproductive ability of females. Irradiating male pupae with 25-150 Gy doses of X-rays had no effect on mating, life span, or flight ability of adult moths, but significantly reduced survival and fecundity of their offspring, and the sterility rate of the F1 generation was 52.65%-99.9%. The results of logistic curve fitting showed that the sterility impact was 84% at the most appropriate irradiation dose (71.26 Gy). The sterility control was 91% in an indoor mating competition experiment when the release ratio of irradiated males (75 Gy) to nonirradiated males reached 12.6:1. The effects of X-ray irradiation doses on biological variables of S. litura and the most effective release ratio determined here provide a theoretical foundation for using radiation sterilization technology to control S. litura.
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BACKGROUND: Spodoptera frugiperda has spread to Africa, Asia, and Oceania, posing a serious threat to global agriculture. We estimated the appropriate dose of X-ray sterilization for S. frugiperda using an X-ray irradiation instrument to investigate environmentally acceptable control techniques, laying the framework for future applications of sterile insect technology (SIT) to manage the pest environmentally-friendly. RESULTS: This study is the first to investigate the effects of X-ray irradiation on the growth, development, survival, reproduction, and flight of S. frugiperda. The results showed that irradiation with 50-400 Gy had no significant effect on pupal eclosion, but females were more sensitive than males in terms of reproductive parameters, especially when doses of radiation were > 350 Gy. After irradiation with a sub-sterilizing dose of 250 Gy, the parental sterility rate was > 85%, and the sterility traits could be passed on to their offspring, resulting in a continuous decrease in the population of F1 and F2 generations. CONCLUSION: Our laboratory experiments theoretically confirmed the feasibility of SIT for controlling S. frugiperda in the field using X-ray radiation. This study provides a theoretical basis for future regional pest management strategies. © 2022 Society of Chemical Industry.
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Infertilidad , Especies Introducidas , Spodoptera , Animales , Femenino , Control de Insectos/métodos , Larva/efectos de la radiación , Masculino , Pupa/efectos de la radiación , Spodoptera/efectos de la radiación , Rayos XRESUMEN
The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and proliferation, supporting anabolic reactions and inhibiting catabolic pathways like autophagy. Its hyperactivation is a frequent event in cancer promoting tumor cell proliferation. Several intracellular membrane-associated mTORC1 pools have been identified, linking its function to distinct subcellular localizations. Here, we characterize the N-terminal kinase-like protein SCYL1 as a Golgi-localized target through which mTORC1 controls organelle distribution and extracellular vesicle secretion in breast cancer cells. Under growth conditions, SCYL1 is phosphorylated by mTORC1 on Ser754, supporting Golgi localization. Upon mTORC1 inhibition, Ser754 dephosphorylation leads to SCYL1 displacement to endosomes. Peripheral, dephosphorylated SCYL1 causes Golgi enlargement, redistribution of early and late endosomes and increased extracellular vesicle release. Thus, the mTORC1-controlled phosphorylation status of SCYL1 is an important determinant regulating subcellular distribution and function of endolysosomal compartments. It may also explain the pathophysiology underlying human genetic diseases such as CALFAN syndrome, which is caused by loss-of-function of SCYL1.
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Aparato de Golgi , Lisosomas , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas de Unión al ADN/metabolismo , Aparato de Golgi/metabolismo , Humanos , Membranas Intracelulares/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , FosforilaciónRESUMEN
Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) has attracted much attention for the detection of small molecules such as neurotransmitters due to its softness, high sensitivity, extensive compatibility and diverse mass analyzers. However, it has been really a difficult challenge to develop a highly specific organic compound as a matrix for the rapid, sensitive and selective detection of neurotransmitters. Herein, we report tris(triphenylphosphine)gold oxonium tetrafluoroborate ([Ph3PAu]3O+BF4-) for the first time as an efficient matrix for the rapid and simultaneous MALDI-MS detection of neurotransmitters. [Ph3PAu]3O+BF4- facilitates the in situ derivatization of gold nanoclusters (Au NCLs) during the interaction with neurotransmitters, which increases their ionization energy by absorbing more ultra-violet (UV) radiation during MALDI-TOF-MS detection. The results show that this [Ph3PAu]3O+BF4- matrix can exhibit a 10-fold faster response time compared to previously reported pyrylium matrices. In addition, [Ph3PAu]3O+BF4- can also provide the simultaneous derivatization of various neurotransmitters, including dopamine (DA), noradrenaline (NAd), serotonin (5-HT), γ-aminobutyric acid (GABA), histamine (H) and tyramine (TY), in mice brain tissue extracts, which can be detected in the MALDI-TOF-MS spectra.
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Química Encefálica , Encéfalo/metabolismo , Neurotransmisores/análisis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Extractos de Tejidos/química , Animales , Masculino , Ratones , Compuestos Orgánicos de Oro/química , Compuestos Organofosforados/químicaRESUMEN
PURPOSE: Alpha-synuclein (α-syn) dopaminylation can lead to the death of dopaminergic neurons in the brain and is a risk factor of Parkinson's disease (PD). This study aims to examine whether such a posttranslational modification (PTM) is presented in human blood plasma. EXPERIMENTAL DESIGN: In vitro reaction simulation between α-syn and dopamine (DA) is conducted to study the biochemical mechanism. Then α-syn from human blood plasma samples is detected by using immunoprecipitation-mass spectrometry (IP-MS). Lastly the levels of endogenous α-syn and α-syn dopaminylation in 88 blood plasma samples from patients with PD, major depressive disorder (MDD), and healthy control (HC) are compared. RESULTS: DA modifies α-syn with the addition of dopamine-quinone (DAQ) into lysine sites of α-syn in vitro and the addition of DAQ and 3,4-dihydroxyphenylacetaldehyde (DOPAL) in plasma samples. The unmodified α-syn between the PD and HC groups showed similar levels. The levels of two peptides, one with lysine 34 (34 K) DAQ modification and the other with lysine 23 (23 K) ubiquitination, are significantly higher in PD and MDD compared with HC. CONCLUSIONS AND CLINICAL RELEVANCE: Thus, α-syn dopaminylation is measurable and might be used to indicatethe presence and progression of neurological disorders.
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Dopamina/metabolismo , Enfermedad de Parkinson/sangre , alfa-Sinucleína/sangre , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Enfermedad de Parkinson/metabolismo , Factores de Riesgo , alfa-Sinucleína/metabolismoRESUMEN
Chloropicrin (TCNM) as one of the most frequently detected nitrogenous disinfection byproducts (N-DBPs) has attracted extensive attention due to its high toxicity. Although much research work on TCNM has been done, its formation mechanism during chlorination has not been known clearly yet. In this study, TCNM formation mechanisms from methylamine (MA) during chlorination, including N-chlorination of MA by hypochlorous acid to generate dichloromethylamine (DCMA) first and then oxidation of DCMA to form nitromethane (NM) and chloronitromethane (CNM), and finally TCNM formation from C-chlorination of NM and CNM, were investigated by using the DFT method. The calculated results show that in N-chlorination of MA, 2-3 water molecules involved in the reaction facilitate Cl+ and proton transfer with the activation free energies (ΔG≠) for the first and second chlorination in the range of 4-7 and 14-17 kcal mol-1, respectively, which are in good agreement with the experimental results. Formation of NM and CNM proceeds through a series of elimination, addition, and oxidation reactions with ΔG≠ of the rate-limiting steps being around 34-37 kcal mol-1, and the subsequent C-chlorination of methyl in NM and CNM by hypochlorous acid is a rapid process with ΔG≠ below 7 kcal mol-1. This infers that the TCNM formation mechanism from DCMA is more likely to undergo first N-oxidation and then C-chlorination. These results can explain the experimental findings that the molar yield of TCNM from MA during chlorination is low (<0.1%) whereas that from NM is rather high (â¼45%). This work will be helpful to elucidate formation mechanisms of all the halonitromethanes during chlorination.
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Hidrocarburos Clorados/síntesis química , Metilaminas/química , Cloraminas , Teoría Funcional de la Densidad , Desinfección/métodos , Halogenación , Contaminantes Químicos del Agua/análisis , Purificación del Agua/métodosRESUMEN
The plasma of Parkinson's disease (PD) patients may contain various altered metabolites associated with the risk or progression of the disease. Characterization of the abnormal metabolic pattern in PD plasma is therefore critical for the search for potential PD biomarkers. We collected blood plasma samples from PD patients and used an LC-MS based metabolomics approach to identify 17 metabolites with significantly altered levels. Metabolic network analysis was performed to place the metabolites linked to different pathways. The metabolic pathways involved were associated with tyrosine biosynthesis, glycerol phospholipid metabolism, carnitine metabolism and bile acid biosynthesis, within which carnitine and bile acid metabolites as potential biomarkers are first time reported. These abnormal metabolic changes in the plasma of patients with PD were mainly related to lipid metabolism and mitochondrial function.
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Biomarcadores/sangre , Metabolómica , Enfermedad de Parkinson/metabolismo , Anciano , Biomarcadores/metabolismo , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Análisis por Conglomerados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Pancreatic cancer is one of the leading causes of cancer, and it has the lowest 5-year survival rates. It is necessary to develop more potent anti-pancreatic cancer drugs to overcome the fast metastasis and resistance to surgery, radiotherapy, chemotherapy, and combinations of these. We have identified several diarylheptanoids as anti-pancreatic cancer agents from Alpinia officinarum (lesser galangal) and Alnus japonica. These diarylheptanoids suppressed cell proliferation and induced the cell cycle arrest of pancreatic cancer cells (PANC-1). Among them, the most potent compounds 1 and 7 inhibited the shh-Gli-FoxM1 pathway and their target gene expression in PANC-1 cells. Furthermore, they suppressed the expression of the cell cycle associated genes that were rescued by the overexpression of exogenous FoxM1. Taken together, (E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one (1) from Alpinia officinarum (lesser galangal) and platyphyllenone (7) from Alnus japonica inhibit PANC-1 cell proliferation by suppressing the shh-Gli-FoxM1 pathway, and they can be potential candidates for anti-pancreatic cancer drug development.
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Alpinia/química , Antineoplásicos Fitogénicos/farmacología , Diarilheptanoides/farmacología , Proteína Forkhead Box M1/antagonistas & inhibidores , Proteínas Hedgehog/antagonistas & inhibidores , Proteína con Dedos de Zinc GLI1/antagonistas & inhibidores , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Diarilheptanoides/química , Diarilheptanoides/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Proteína Forkhead Box M1/metabolismo , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Estructura Molecular , Relación Estructura-Actividad , Proteína con Dedos de Zinc GLI1/metabolismoRESUMEN
Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and TGFß signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.
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Disulfuros/farmacología , Ajo , Glioblastoma/tratamiento farmacológico , Inhibidores de Crecimiento/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Resistencia a Antineoplásicos , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Glioblastoma/patología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Terapia Molecular Dirigida , Células Madre Neoplásicas/patología , Proteína Oncogénica v-akt/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Sulfóxidos , Factor de Crecimiento Transformador beta1/metabolismo , Células Tumorales Cultivadas , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMEN
Tregs (Foxp3+CD4+) are enriched in tumors to foster a tolerant microenvironment that inhibits antitumor immune response. IL-27 is reported to regulate the development and function of Tregs in vitro and in vivo; however, the effects of endogenous IL-27 on Tregs in the tumor microenvironment remain elusive. We demonstrated that in the absence of DC-derived IL-27, Tregs were decreased significantly in transplanted B16 melanoma, transplanted EL-4 lymphoma, and MCA-induced fibrosarcoma by using IL-27p28 conditional KO mice. Further studies revealed that IL-27 promoted the expression of CCL22, which is established to mediate the recruitment of peripheral Tregs into tumors. Tumor-associated DCs were identified as the major source of CCL22 in tumor sites, and IL-27 could induce CCL22 expression in an IL-27R-dependent manner. Intratumoral reconstitution of rmCCL22 or rmIL-27, but not rmIL-27p28, significantly restored the tumor infiltration of Tregs in IL-27p28 KO mice. Correlated with a decreased number of Tregs, tumor-infiltrating CD4 T cells were found to produce much more IFN-γ in IL-27p28 KO mice, which highlighted the physiological importance of Tregs in suppressing an antitumor immune response. Overall, our results identified a novel mechanism of action of IL-27 on Tregs in the context of cancers.
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Movimiento Celular/inmunología , Células Dendríticas/inmunología , Interleucinas/inmunología , Linfoma/inmunología , Melanoma/inmunología , Proteínas de Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Movimiento Celular/genética , Quimiocina CCL22/genética , Quimiocina CCL22/inmunología , Células Dendríticas/patología , Regulación Neoplásica de la Expresión Génica/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Interleucinas/genética , Linfoma/genética , Linfoma/patología , Melanoma/genética , Melanoma/patología , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Linfocitos T Reguladores/patologíaRESUMEN
Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 45 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-κB (NF-κB), which revealed that SPA0355 suppressed the nuclear translocation and DNA binding of NF-κB subunits. Concomitantly, the expression of NF-κB target genes such as IL-1ß, IL-6, TNF-α and iNOS was significantly downregulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase and glutathione were upregulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.
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Antiinflamatorios/uso terapéutico , Benzoxazinas/uso terapéutico , Hígado/efectos de los fármacos , Hígado/lesiones , Daño por Reperfusión/tratamiento farmacológico , Tiourea/análogos & derivados , Animales , Hígado/inmunología , Hígado/patología , Masculino , Ratones Endogámicos C57BL , FN-kappa B/inmunología , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Tiourea/uso terapéuticoRESUMEN
CD8(+) T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL-10-producing CD8(+) T cells that were induced by IL-4. These IL-10(+)CD8(+) T cells possessed a strong inhibitory effect on the CD4(+) T cell proliferation in an IL-10-dependent and cell contact-dependent fashion. In comparison with IL-10(-)CD8(+) T cells, IL-10(+)CD8(+) T cells expressed an array of Th2-like cytokines (IL-4, IL-5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL-4-induced IL-10 production significantly. Furthermore, CD8(+) T cells from Cdkn2a(-/-) mice produced a significantly lower amount of IL-10, and the effect was limited to CD8(+) T cells but not observed in CD4(+) T cells and APCs. Finally, IL-10(+)CD8(+) T cells played a protective role in the TNBS-induced murine colitis model, indicating a critical role of this population of CD8(+) T cells in regulatory immune responses. Taken together, we have defined a population of IL-10-producing CD8(+) Tregs induced by IL-4 and mediated by Cdkn2a.