RESUMEN
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
Asunto(s)
Quinasas Ciclina-Dependientes/metabolismo , Neoplasias de la Próstata/patología , Anticuerpos Monoclonales/uso terapéutico , Línea Celular Tumoral , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Reparación del ADN , Regulación Neoplásica de la Expresión Génica , Inestabilidad Genómica , Humanos , Masculino , Mutación Missense , Estadificación de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenotipo , Receptor de Muerte Celular Programada 1/inmunología , Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/inmunología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Linfocitos T/metabolismo , Linfocitos T/patología , Tomografía Computarizada por Rayos XRESUMEN
Bidirectional output oscillating-amplifying integrated fiber laser (B-OAIFL) can achieve the two-ports laser amplification based on a single cavity, showcasing a promising prospect. In order to improve both the laser power and beam quality, we first simulate and optimize the stimulated Raman scattering (SRS) effect in the B-OAIFL. The simulation results show the SRS effect can be suppressed by optimizing the diameter as well as the length of the active fiber at different locations. With the guidance of theoretical and experimental analysis for the combined suppression of SRS and transverse mode instability (TMI), a near-single-mode B-OAIFL with 2 × 4â kW was demonstrated. Based on this foundation, we further devoted ourselves to the pursuit of the optimization of the structure and performance. The necessity of the configuration of side pump, which was initially introduced for its exceptional performance in stabilizing temporal chaos, was reevaluated in detail. With its negative impacts on efficiency improvement and SRS suppression were analyzed and verified, we removed this configuration and finally demonstrated a more simplified design with superior performance. A total bidirectional output of 8105 W was achieved, with an O-O efficiency of 79.6% and a near-single-mode beam quality of M A 2â¼1.36,M B 2â¼1.63. No signs of TMI were observed, and the signal-to-SRS suppression ratio was over 38â dB. The results still demonstrate a promising potential for power scaling based on this configuration and parameters.
RESUMEN
Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ubiquitina-Proteína Ligasas , Factores de Transcripción p300-CBP , Humanos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Factores de Transcripción p300-CBP/metabolismo , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Apoptosis/efectos de los fármacos , Línea Celular TumoralRESUMEN
Previous studies have suggested that exposure to air pollutants may be associated with specific blood indicators or anemia in certain populations. However, there is insufficient epidemiological data and prospective evidence to evaluate the relationship between environmental air pollution and specific types of anemia. We conducted a large-scale prospective cohort study based on the UK Biobank. Annual average concentrations of NO2, PM2.5, PM2.5-10, and PM10 were obtained from the ESCAPE study using the Land Use Regression (LUR) model. The association between atmospheric pollutants and different types of anemia was investigated using the Cox proportional hazards model. Furthermore, restricted cubic splines were used to explore exposure-response relationships for positive associations, followed by stratification and effect modification analyses by gender and age. After adjusting for demographic characteristics, 3-4 of the four types of air pollution were significantly associated with an increased risk of iron deficiency, vitamin B12 deficiency and folate deficiency anemia, while there was no significant association with other defined types of anemia. After full adjustment, we estimated that the hazard ratios (HRs) of iron deficiency anemia associated with each 10 µg/m3 increase in NO2, PM2.5, and PM10 were 1.04 (95%CI: 1.02, 1.07), 2.00 (95%CI: 1.71, 2.33), and 1.10 (95%CI: 1.02, 1.20) respectively. The HRs of folate deficiency anemia with each 10 µg/m3 increase in NO2, PM2.5, PM2.5-10, and PM10 were 1.25 (95%CI: 1.12, 1.40), 4.61 (95%CI: 2.03, 10.47), 2.81 (95%CI: 1.11, 7.08), and 1.99 (95%CI: 1.25, 3.15) respectively. For vitamin B12 deficiency anemia, no significant association with atmospheric pollution was found. Additionally, we estimated almost linear exposure-response curves between air pollution and anemia, and interaction analyses suggested that gender and age did not modify the association between air pollution and anemia. Our research provided reliable evidence for the association between long-term exposure to PM10, PM2.5, PM2.5-10, NO2, and several types of anemia. NO2, PM2.5, and PM10 significantly increased the risk of iron deficiency anemia and folate deficiency anemia. Additionally, we found that the smaller the PM diameter, the higher the risk, and folate deficiency anemia was more susceptible to air pollution than iron deficiency anemia. No association was observed between the four types of air pollution and hemolytic anemia, aplastic anemia, and other types of anemia. Although the mechanisms are not well understood, we emphasize the need to limit the levels of PM and NO2 in the environment to reduce the potential impact of air pollution on folate and iron deficiency anemia.
Asunto(s)
Contaminantes Atmosféricos , Anemia , Material Particulado , Humanos , Masculino , Femenino , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/efectos adversos , Persona de Mediana Edad , Reino Unido/epidemiología , Material Particulado/análisis , Material Particulado/efectos adversos , Anemia/epidemiología , Anemia/sangre , Estudios Prospectivos , Anciano , Adulto , Dióxido de Nitrógeno/análisis , Dióxido de Nitrógeno/efectos adversos , Modelos de Riesgos Proporcionales , Bancos de Muestras Biológicas , Medición de Riesgo , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Deficiencia de Ácido Fólico/epidemiología , Deficiencia de Ácido Fólico/sangre , Biobanco del Reino UnidoRESUMEN
Photocatalytic organic reactions, harvesting solar energy to produce high value-added organic chemicals, have attracted increasing attention as a sustainable approach to address the global energy crisis and environmental issues. Reticular framework materials, including metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), are widely considered as promising candidates for photocatalysis owing to their high crystallinity, tailorable pore environment and extensive structural diversity. Although the design and synthesis of MOFs and COFs have been intensively developed in the last 20 years, their applications in photocatalytic organic transformations are still in the preliminary stage, making their systematic summary necessary. Thus, this review aims to provide a comprehensive understanding and useful guidelines for the exploration of suitable MOF and COF photocatalysts towards appropriate photocatalytic organic reactions. The commonly used reactions are categorized to facilitate the identification of suitable reaction types. From a practical viewpoint, the fundamentals of experimental design, including active species, performance evaluation and external reaction conditions, are discussed in detail for easy experimentation. Furthermore, the latest advances in photocatalytic organic reactions of MOFs and COFs, including their composites, are comprehensively summarized according to the actual active sites, together with the discussion of their structure-property relationship. We believe that this study will be helpful for researchers to design novel reticular framework photocatalysts for various organic synthetic applications.
RESUMEN
Arsenic contamination in soils poses a critical global challenge, yet the influence of surfactants on arsenic adsorption behavior is often underestimated. This study aims to investigate the effects of three representative surfactants, namely cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS), and polyethylene glycol anhydrous sugar alcohol monooleate (Tween 80), on arsenic adsorption behavior in soils. The adsorption isotherm shifts from a single Temkin model without surfactants to both the Langmuir and Temkin models in the presence of surfactants, indicating the simultaneous occurrence of monolayer and multilayer adsorption for arsenic in soils. Moreover, the surfactants can inhibit the adsorption and hasten the attainment of adsorption equilibrium. SDS displayed the most inhibitory effect on arsenic adsorption, followed by Tween 80 and CTAB, due to the competitive adsorption, electrostatic interaction, and hydrophobic interaction. Variations in zeta potential with different surfactants further elucidate this inhibitory phenomenon. Through orthogonal experiment analyses, pH emerges as a primary factor influencing arsenic adsorption in soils, with surfactant concentration and type identified as secondary factors. Temperature notably affects CTAB, with the adsorption inhibition rate plummeting to a mere 0.88% at 50 °C. Sequential extraction analysis revealed that surfactants enhanced the bioavailability of arsenic. The FTIR, XRD, SEM, and CA analyses further support the mechanism underlying the effect of surfactants on arsenic adsorption in soil. These analyses indicate that surfactants modify the composition and abundance of functional groups, hinder the formation of arsenic-containing substances, and improve soil compactness, smoothness, and hydrophilicity. This study provides valuable insights into the effect of surfactants in arsenic-contaminated soils, which is often ignored in previous work.
Asunto(s)
Arsénico , Tensoactivos , Tensoactivos/química , Suelo/química , Polisorbatos , Cetrimonio , Adsorción , Arsénico/química , Monitoreo del AmbienteRESUMEN
Efficient photocatalytic CO2 reduction coupled with the photosynthesis of pure H2O2 is a challenging and significant task. Herein, using classical CO2 photoreduction site iron porphyrinate as the linker, Ag(I) clusters were spatially separated and evenly distributed within a new metal-organic framework (MOF), namely Ag27TPyP-Fe. With water as electron donors, Ag27TPyP-Fe exhibited remarkable performances in artificial photosynthetic overall reaction with CO yield of 36.5 µmol g-1 h-1 and ca. 100% selectivity, as well as H2O2 evolution rate of 35.9 µmol g-1 h-1. Since H2O2 in the liquid phase can be more readily separated from the gaseous products of CO2 photoreduction, high-purity H2O2 with a concentration up to 0.1 mM was obtained. Confirmed by theoretical calculations and the established energy level diagram, the reductive iron(II) porphyrinates and oxidative Ag(I) clusters within an integrated framework functioned synergistically to achieve artificial photosynthesis. Furthermore, photoluminescence spectroscopy and photoelectrochemical measurements revealed that the robust connection of Ag(I) clusters and iron porphyrinate ligands facilitated efficient charge separation and rapid electron transfer, thereby enhancing the photocatalytic activity.
RESUMEN
Supported metal catalysts with appropriate metal-support interactions (MSIs) hold a great promise for heterogeneous catalysis. However, ensuring tight immobilization of metal clusters/nanoparticles on the support while maximizing the exposure of surface active sites remains a huge challenge. Herein, we report an Ir/WO3 catalyst with a new enrooted-type MSI in which Ir clusters are, unprecedentedly, atomically enrooted into the WO3 lattice. The enrooted Ir atoms decrease the electron density of the constructed interface compared to the adhered (root-free) type, thereby achieving appropriate adsorption toward oxygen intermediates, ultimately leading to high activity and stability for oxygen evolution in acidic media. Importantly, this work provides a new enrooted-type supported metal catalyst, which endows suitable MSI and maximizes the exposure of surface active sites in contrast to the conventional adhered, embedded, and encapsulated types.
RESUMEN
Molecular sieving is an ideal separation mechanism, but controlling pore size, restricting framework flexibility, and avoiding strong adsorption are all very challenging. Here, we report a flexible adsorbent showing molecular sieving at ambient temperature and high pressure, even under high humidity. While typical guest-induced transformations are observed, a high transition pressure of 16.6â atm is observed for C2H4 at 298â K because of very weak C2H4 adsorption (~16â kJ mol-1). Also, C2H6 is completely excluded below the pore-opening pressure of 7.7â atm, giving single-component selectivity of ca. 300. Quantitative high-pressure column breakthrough experiments using 1 : 1â C2H4/C2H6 mixtures at 10â atm as input confirm molecular sieving with C2H4 adsorption of 0.73â mmol g-1 or 32â cm3(STP) cm-3 and negligible C2H6 adsorption of 0.001(2) mmol g-1, and the adsorbent can be completely regenerated by inert gas purging. Furthermore, it is highly hydrophobic with negligible water adsorption, and the C2H4/C2H6 separation performance is unaffected at high humidity.
RESUMEN
Considering that CO2 reduction is mostly a multielectron reaction, it is necessary for the photocatalysts to integrate multiple catalytic sites and cooperate synergistically to achieve efficient photocatalytic CO2 reduction to various products, such as C2 hydrocarbons. Herein, through crystal engineering, we designed and constructed a metal-organic framework-derived Zr/Ti bimetallic oxide solid solution support, which was confirmed by X-ray diffraction, electron microscopy and X-ray absorption spectroscopy. After anchoring Au nanoparticles, the composite photocatalyst exhibited excellent performances toward photocatalytic CO2 reduction to syngas (H2 and CO production rates of 271.6 and 260.6â µmol g-1 h-1) and even C2 hydrocarbons (C2H4 and C2H6 production rates of 6.80 and 4.05â µmol g-1 h-1). According to the control experiments and theoretical calculations, the strong interaction between bimetallic oxide solid solution support and Au nanoparticles was found to be beneficial for binding intermediates and reducing CO2 reduction, highlighting the synergy effect of the catalytic system with multiple active sites.
RESUMEN
BACKGROUND: Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. METHODS: MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. RESULTS: MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. CONCLUSIONS: We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.
Asunto(s)
Vesículas Extracelulares , Células Madre Mesenquimatosas , MicroARNs , Infarto del Miocardio , Ratas , Animales , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Atorvastatina/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/terapia , Infarto del Miocardio/metabolismo , Vesículas Extracelulares/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Células Madre Mesenquimatosas/metabolismo , Macrófagos/metabolismo , Factor de Transcripción STAT1/metabolismoRESUMEN
Peptide asparaginyl ligases (PALs) are useful tools for precision modifications of proteins and live-cell surfaces by ligating peptides after Asn/Asp (Asx). They share high sequence and structural similarity to plant legumains that are generally known as asparaginyl endopeptidases (AEPs), thus making it challenging to identify PALs from AEPs. In this study, we investigate 875 plant species from algae to seed plants with available sequence data in public databases to identify new PALs. We conducted evolutionary trace analysis on 1500 plant legumains, including eight known PALs, to identify key residues that could differentiate ligases and proteases, followed by recombinant expression and functional validation of 16 novel legumains. Previously, we showed that the substrate-binding sequences flanking the catalytic site can strongly influence the enzymatic direction of a legumain and which we named as ligase-activity determinants (LADs). Here, we show that two conserved substrate-binding Gly residues of LADs are critical, but negative determinants for ligase activity. Our results suggest that specific glycine residues are molecular determinants to identify PALs and AEPs as two different legumain subfamilies, accounting for c. 1% and 88%, respectively.
Asunto(s)
Fabaceae , Proteínas de Plantas , Proteínas de Plantas/metabolismo , Glicina , Cisteína Endopeptidasas/metabolismo , Plantas/metabolismo , Ligasas/metabolismoRESUMEN
Underwater images have the advantage of carrying high information density and are widely used for marine information acquisition. Due to the complex underwater environment, the captured images are often unsatisfactory and often suffer from color distortion, low contrast, and blurred details. Physical model-based methods are often used in relevant studies to obtain clear underwater images; however, water selectively absorbs light, making the use of a priori knowledge-based methods no longer applicable and thus rendering the restoration of underwater images ineffective. Therefore, this paper proposes an underwater image restoration method based on adaptive parameter optimization of the physical model. Firstly, an adaptive color constancy algorithm is designed to estimate the background light value of underwater image, which effectively guarantees the color and brightness of underwater image. Secondly, aiming at the problem of halo and edge blur in underwater images, a smoothness and uniformity transmittance estimation algorithm is proposed to make the estimated transmittance smooth and uniform, and eliminate the halo and blur of the image. Then, in order to further smooth the edge and texture details of the underwater image, a transmittance optimization algorithm for smoothing edge and texture details is proposed to make the obtained scene transmittance more natural. Finally, combined with the underwater image imaging model and histogram equalization algorithm, the image blurring is eliminated and more image details are retained. The qualitative and quantitative evaluation on the underwater image dataset (UIEBD) shows that the proposed method has obvious advantages in color restoration, contrast and comprehensive effect, and has achieved remarkable results in application testing. It shows that the proposed method can effectively restore underwater degraded images and provide a theoretical basis for the construction of underwater imaging models.
RESUMEN
Thermal blooming effect is one of the significant factors affecting the propagation performance of high-power ytterbium-doped fiber lasers (YDFLs) in the atmosphere. In this paper, two 20â kW YDFL systems with typical wavelengths (1070â nm and 1080â nm) are fabricated for propagation comparison experiments, which are used to investigate the thermal blooming effect induced by high-power YDFL propagation through the atmosphere. Under approximately the same laser system parameters (except wavelength) and atmospheric environment, the 1070â nm laser has better propagation characteristics than the 1080â nm laser. Due to the combined effect between the different central wavelengths of the two fiber lasers and the spectral broadening caused by output power scaling, the thermal blooming caused by the different absorptivity of water vapor molecules to the two fiber lasers is the main factor for the variation of the propagation properties. Through theoretical analysis and numerical calculation of factors affecting the thermal blooming effect, and considering the industrial manufacturing difficulty of YDFLs, a reasonable selection of fiber laser parameters can effectively improve atmospheric propagation performance and reduce manufacturing costs.
RESUMEN
Bidirectional output oscillating-amplifying integrated fiber laser (B-OAIFL) is a newly developed configuration with many advantages like compactness and good reliability. In this work, a B-OAIFL with a low time-stabilized threshold was constructed by employing a pair of side pump/signal combiner in the oscillating section, which demonstrates smooth temporal characteristics with no pulse detected by the photodetector at the output power level of only a few of tens Watts. We investigated the effect of side pumping on the Raman Stokes light and verified its contribution to mitigating the temporal-chaos-induced stimulated Raman scattering (SRS). The phenomenon of co-SRS caused by the mutual excitation of backward Stokes light from two amplifying sections under bidirectional pumping was first reported and studied. A pair of chirped and tilted fiber Bragg gratings (CTFBGs) were applied between the oscillating and amplifying sections to suppress the co-SRS, and the effect of the number of CTFBGs on the suppression of co-SRS was studied in detail experimentally. Finally, we successfully suppressed the co-SRS, and achieved a 3kW × 2 ports laser output, with a near-single-mode beam quality of M A 2â¼1.3,M B 2â¼1.4. In contrast, without the use of CTFBG, only a 2â kW-level output was obtained from each port, limited by co-SRS (with an SRS suppression ratio of less than 15â dB). The maximum output power of end A and end B is 3133 W and 3213 W, with the SRS suppression ratio of about 27.6â dB and 28.1â dB, respectively. No TMI features were observed under bidirectional pumping. The results demonstrate a significant potential for further power scaling based on this configuration. To the best of our knowledge, it is the highest output power achieved based on the B-OAIFL.
RESUMEN
Nosocomial infections with the opportunistic bacterium Acinetobacter baumannii pose a severe challenge to clinical treatment, which is aggravated by the increasing occurrence of multi-drug resistance, especially resistance to carbapenems. The use of phage therapy as an alternative and supplement to the current antibiotics has become an important research topic in the post-antibiotic era. This review summarizes in vivo and in vitro studies on phage therapy against multi-drug-resistant A. baumannii infection that have used different approaches, including treatment with a single phage, combination with other phages or non-phage agents, and administration of phage-derived enzymes. We also briefly discuss the current challenges of phage-based therapy as well as promising approaches for the treatment of A. baumannii infection in the future.
Asunto(s)
Acinetobacter baumannii , Bacteriófagos , Bacteriófagos/genética , Antibacterianos/uso terapéutico , Carbapenémicos/uso terapéuticoRESUMEN
BACKGROUND: Runt-related transcription factor-2 (Runx2) has been considered an inducer to improve bone repair ability of mesenchymal stem cells (MSCs). METHODS AND RESULTS: Twenty-four rabbits were used to establish Osteonecrosis of the femoral head (ONFH) and randomly devided into four groups: Adenovirus Runx2 (Ad-Runx2) group, Runx2-siRNA group, MSCs group and Model group. At 1 week after model establishment, the Ad-Runx2 group was treated with 5 × 107 MSCs transfected through Ad-Runx2, the Runx2-siRNA group was treated with 5 × 107 MSCs transfected through Runx2-siRNA, the MSCs group was injected with 5 × 107 untreated MSCs, and the Model group was treated with saline. The injection was administered at 1 week and 3 weeks after model establishment. The expression of bone morphogenetic protein 2 (BMP-2), Runx2 and Osterix from the femoral head was detected at 3 and 6 weeks after MSCs being injected, and Masson Trichrome Staining, Gross Morphology, X-ray and CT images observation were used to evaluate the repair effect of ONFH. The data revealed that the expression of BMP-2, Runx2 and Osterix in the Runx2-siRNA group was reduced at 3 weeks compared with the MSCs group, and then the expression further reduced at 6 weeks, but was still higher than the Model group besides Osterix; The expression of these three genes in the Ad-Runx2 group was higher than in the MSCs group. Masson Trichrome Staining, Gross Morphology and X-ray and CT images observation revealed that necrotic femoral head of the MSCs group was more regular and smooth than the Runx2-siRNA group, which has a collapsed and irregular femoral head. In the Ad-Runx2 group, necrotic femoral head was basically completely repaired and covered by rich cartilage and bone tissue. CONCLUSIONS: Overexpression of Runx2 can improve osteoblastic phenotype maintenance of MSCs and promote necrotic bone repair of ONFH.
Asunto(s)
Necrosis de la Cabeza Femoral , Células Madre Mesenquimatosas , Animales , Conejos , Necrosis de la Cabeza Femoral/genética , Necrosis de la Cabeza Femoral/terapia , Necrosis de la Cabeza Femoral/metabolismo , Cabeza Femoral , Células Madre Mesenquimatosas/metabolismo , ARN Interferente Pequeño/farmacologíaRESUMEN
PURPOSE: Mammary gland tumors are the most common neoplastic diseases in elderly female dogs, about 50% of which are considered to be malignant. Canine mammary tumors are similar to human breast cancers in many respects, so canine mammary tumors are frequently studied alongside human breast cancer. This article mentioned KI-67, HER-2, COX-2, BRCA1, BRCA2, P53, CA15-3, MicroRNA, Top2α and so on. All these markers are expected to have an important role in the clinic. METHODS: Existing markers of canine mammary carcinoma are reviewed, and the expression of each marker and its diagnostic role for this tumor are described in detail. RESULTS: This article introduced several effective markers of canine mammary tumors, among them, antigen KI-67 (KI-67), human epidermal growth factor receptor 2 (HER-2), cyclooxygenase 2 (COX-2) are promising and can be detected in both serum and tissue samples. Breast cancer caused by mutations in the breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) is also a hot topic of research. In addition to the above symbols, tumor protein p53 (p53), cancer antigen15-3 (CA15-3), MicroRNA (miRNA), topoisomerase πα (Top2α), proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR) and E-cadherin will also be involved in this paper. We will also mention Mammaglobin, which has been rarely reported so far.
Asunto(s)
Neoplasias de la Mama , Carcinoma , Enfermedades de los Perros , Neoplasias Mamarias Animales , MicroARNs , Humanos , Animales , Perros , Femenino , Anciano , Antígeno Ki-67/metabolismo , Proteína p53 Supresora de Tumor/genética , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/metabolismo , Carcinoma/genética , Neoplasias de la Mama/genética , MicroARNs/genética , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/genética , Enfermedades de los Perros/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Disruption of bone homeostasis is the pathological basis of bone diseases. Multiple cells work together to maintain homeostasis and bone health. As a natural flavonoid compound, Naringin (NG) can positively affect the maintenance of bone homeostasis by acting on different types of cells. In this review, we discuss the direct and indirect osteoprotective effects of NG as well as the underlying mechanisms, and we provide a critical perspective on its clinical translation.
Asunto(s)
Flavanonas , Flavanonas/farmacología , Flavonoides , HomeostasisRESUMEN
The mammalian target of rapamycin (mTOR) has been proved to be an effective target for cancer therapy. Two kinds of mTOR inhibitors, the rapalogs and mTOR kinase inhibitors (TORKi), have been developed and clinically validated in several types of malignancies. Compared with rapalogs, TORKi can exert better antitumor activity by inhibiting both mTORC1 and mTORC2, but the clinical development of current TORKi candidates has been relative slow, more TORKi with novel scaffold need to be developed to expand the current pipelines. In this study, a series of 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives were designed, synthesized and biological evaluation. Most of these compounds exhibited good mTOR kinase inhibitory activity and selectivity over PI3Kα. Subsequent antiproliferative assay allowed us to identify the lead compound 15i, which display nanomolar to low micromolar IC50s against six human cancer cell lines. 15i could induce cell cycle arrest of MCF-7, PC-3 and A549 cells at the G0/G1 phase and suppress the migration and invasion of these cancer cells by suppressing the phosphorylation of AKT and P70S6 kinase. It could also regulate autophagy-related proteins to induce autophagy. Therefore, 15i would be a starting point for the development of new TORKi as anticancer drug.