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The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Animales , Ratones , Resistencia a Antineoplásicos/genética , Modelos Animales de Enfermedad , Conocimiento , Células Madre Neoplásicas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
Metabolites such as crotonyl-CoA and lactyl-CoA influence gene expression by covalently modifying histones, known as histone lysine crotonylation (Kcr) and lysine lactylation (Kla). However, the existence patterns, dynamic changes, biological functions and associations of these modifications with histone lysine acetylation and gene expression during mammalian development remain largely unknown. Here, we find that histone Kcr and Kla are widely distributed in the brain and undergo global changes during neural development. By profiling the genome-wide dynamics of H3K9ac, H3K9cr and H3K18la in combination with ATAC and RNA sequencing, we reveal that these marks are tightly correlated with chromatin state and gene expression, and extensively involved in transcriptome remodeling to promote cell-fate transitions in the developing telencephalon. Importantly, we demonstrate that global Kcr and Kla levels are not the consequence of transcription and identify the histone deacetylases (HDACs) 1-3 as novel 'erasers' of H3K18la. Using P19 cells as an induced neural differentiation system, we find that HDAC1-3 inhibition by MS-275 pre-activates neuronal transcriptional programs by stimulating multiple histone lysine acylations simultaneously. These findings suggest that histone Kcr and Kla play crucial roles in the epigenetic regulation of neural development.
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Histonas , Lisina , Acetilación , Animales , Epigénesis Genética , Histonas/metabolismo , Lisina/metabolismo , Mamíferos/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
The efficient interconversion of chemicals and electricity through electrocatalytic processes is central to many renewable-energy initiatives. The sluggish kinetics of the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER)1-4 has long posed one of the biggest challenges in this field, and electrocatalysts based on expensive platinum-group metals are often required to improve the activity and durability of these reactions. The use of alloying5-7, surface strain8-11 and optimized coordination environments12 has resulted in platinum-based nanocrystals that enable very high ORR activities in acidic media; however, improving the activity of this reaction in alkaline environments remains challenging because of the difficulty in achieving optimized oxygen binding strength on platinum-group metals in the presence of hydroxide. Here we show that PdMo bimetallene-a palladium-molybdenum alloy in the form of a highly curved and sub-nanometre-thick metal nanosheet-is an efficient and stable electrocatalyst for the ORR and the OER in alkaline electrolytes, and shows promising performance as a cathode in Zn-air and Li-air batteries. The thin-sheet structure of PdMo bimetallene enables a large electrochemically active surface area (138.7 square metres per gram of palladium) as well as high atomic utilization, resulting in a mass activity towards the ORR of 16.37 amperes per milligram of palladium at 0.9 volts versus the reversible hydrogen electrode in alkaline electrolytes. This mass activity is 78 times and 327 times higher than those of commercial Pt/C and Pd/C catalysts, respectively, and shows little decay after 30,000 potential cycles. Density functional theory calculations reveal that the alloying effect, the strain effect due to the curved geometry, and the quantum size effect due to the thinness of the sheets tune the electronic structure of the system for optimized oxygen binding. Given the properties and the structure-activity relationships of PdMo metallene, we suggest that other metallene materials could show great promise in energy electrocatalysis.
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Identification of translocator protein-related genes involved in bensulfuron-methyl (BSM) uptake and transport in rice could facilitate the development of herbicide-tolerant cultivars by inactivating them. This study found that the OsCNGC12 mutants not only reduced BSM uptake but also compromised the Ca2 ⺠efflux caused by BSM in the roots, regulating dynamic equilibrium of Ca2 ⺠inside the cell and conferring non-target-site tolerance to BSM.
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Herbicidas , Oryza , Herbicidas/farmacología , Plantones/genética , CalcioRESUMEN
BACKGROUND: Although there is a strong correlation between the novel cholesterol-to-lymphocyte ratio (CLR) and tumor survival, its prognostic significance in breast cancer (BC) is unknown. After analyzing the relationship between CLR and the overall survival (OS) of patients with BC, we created a predictive model. METHODS: Following retrospective enrollment, 1316 patients with BC were randomized into two cohorts: validation (n = 392) and training (n = 924). Distinct factors within the training dataset were identified for OS by univariate and multivariate Cox analyses; two-tailed P-value < 0.05 were considered to indicate statistical significance. On this premise, we developed novel signals for survival prediction and utilized the calibration curve, receiver operating characteristic curves, and concordance index (C-index) to validate their efficacy across both datasets. RESULTS: Patients with BC were categorized into two categories with differing prognoses based on the CLR score [hazard ratio = 0.492; 95% confidence interval (CI): 0.286-0.846, P = 0.009]. A prediction nomogram was created based on multivariate analysis, which showed that N stage, postoperative pathological categorization, and CLR score were all independently correlated with OS. In the training [C-index = 0.831 (95% CI: 0.788-0.874)] and validation [C-index = 0.775 (95% CI: 0.694-0.856)] cohorts, the nomogram demonstrated favorable performance in predicting OS. In both the training and validation cohorts, it outperformed the traditional staging system [C-index = 0.702 (95% CI: 0.623-0.782)] and [C-index = 0.709 (95% CI: 0.570-0.847)]. The accurate prediction by the signature was further demonstrated by the time-dependent receiver operating characteristic curves. CONCLUSIONS: The novel immunonutritional marker CLR could function as a simplified, cost-effective, easily accessible, non-invasive, and readily promotive prognostic indicator for patients with early-stage BC and demonstrates superior predictive power than the traditional staging system.
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Neoplasias de la Mama , Colesterol , Linfocitos , Nomogramas , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/sangre , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Pronóstico , Persona de Mediana Edad , Colesterol/sangre , Estudios Retrospectivos , Adulto , Anciano , Curva ROC , Biomarcadores de Tumor/sangre , Recuento de Linfocitos , Estadificación de NeoplasiasRESUMEN
Pneumonia is the most common complication of varicella infections. Although previous studies have tended to focus mainly on immunocompromised patients, varicella pneumonia can also occur in healthy adults. Therefore, in this study, we aimed to assess the progression of varicella pneumonia in immunocompetent hosts. This retrospective study involved immunocompetent adult outpatients with varicella who attended the adult Fever Emergency facility of Peking University Third Hospital from April 1, 2020, to October 31, 2022. Varicella pneumonia was defined as a classic chickenpox-type rash in patients with infiltrates on chest computed tomography. The study included 186 patients, 57 of whom had a contact history of chickenpox exposure. Antiviral pneumonia therapy was administered to 175 patients by treating physicians. Computed tomography identified pneumonia in 132 patients, although no deaths from respiratory failure occurred. Seventy of the discharged patients were subsequently contacted, all of whom reported being well. Follow-up information, including computed tomography findings, was available for 37 patients with pneumonia, among whom 24 reported complete resolution whereas the remaining 13 developed persistent calcifications. Notably, we established that the true incidence of varicella pneumonia is higher than that previously reported, although the prognosis for immunocompetent hosts is generally good.
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Varicela , Neumonía Viral , Adulto , Humanos , Varicela/complicaciones , Varicela/epidemiología , Estudios Retrospectivos , Prevalencia , Neumonía Viral/complicaciones , Neumonía Viral/epidemiología , Inmunocompetencia , Herpesvirus Humano 3RESUMEN
BACKGROUND & AIMS: Severe alcohol-associated hepatitis (SAH) represents a lethal subset of alcohol-associated liver disease. Although corticosteroids are recommended by guidelines, their efficacy and safety remain questionable and so liver transplantation (LT) has been increasingly utilized. The timing and indication of corticosteroid use, specifically in patients being considered for LT requires further clarification. METHODS: A retrospective analysis was conducted on 256 patients with SAH between 2018 and 2022 at a single US center. RESULTS: Twenty of these patients underwent LT. Of the 256 patients, 38% had what we termed "catastrophic" SAH, defined as a MELD-Na ≥35 and/or discriminant function (DF) ≥100, which carried a mortality of 90% without LT. Compared with 100 matched controls, patients undergoing LT exhibited a one-year survival rate of 100% versus 35% (p < .0005). LT provided an absolute risk reduction of 65%, with a number needed to treat of 1.5. Steroid utilization in the entire cohort was 19% with 60% developing severe complications. Patients administered steroids were younger with lower MELD and DF scores. Only 10% of those prescribed steroids derived a favorable response. Sustained alcohol use post-LT was 20%. CONCLUSIONS: We propose ELFSAH: Expedited LT as First Line Therapy for SAH; challenging the current paradigm with recommendations to defer steroids in patients with "catastrophic" SAH (defined as: MELD-Na ≥35 and/or DF ≥100). Patients should be seen urgently by hepatology, transplant surgery, psychiatry and social work. Patients without an absolute contraindication should be referred for LT as first-line therapy during their index admission.
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Corticoesteroides , Hepatitis Alcohólica , Trasplante de Hígado , Humanos , Masculino , Hepatitis Alcohólica/cirugía , Hepatitis Alcohólica/tratamiento farmacológico , Hepatitis Alcohólica/mortalidad , Hepatitis Alcohólica/complicaciones , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Estudios de Seguimiento , Pronóstico , Corticoesteroides/uso terapéutico , Tasa de Supervivencia , Adulto , Índice de Severidad de la Enfermedad , Factores de Riesgo , Estudios de Casos y ControlesRESUMEN
Understanding how different mechanisms act and interact in shaping communities and ecosystems is essential to better predict their future with global change. Disturbance legacy, abiotic conditions, and biotic interactions can simultaneously influence tree growth, but it remains unclear what are their relative contributions and whether they have additive or interactive effects. We examined the separate and joint effects of disturbance intensity, soil conditions, and neighborhood crowding on tree growth in 10 temperate forests in northeast China. We found that disturbance was the strongest driver of tree growth, followed by neighbors and soil. Specifically, trees grew slower with decreasing initial disturbance intensity, but with increasing neighborhood crowding, soil pH and soil total phosphorus. Interestingly, the decrease in tree growth with increasing soil pH and soil phosphorus was steeper with high initial disturbance intensity. Testing the role of species traits, we showed that fast-growing species exhibited greater maximum tree size, but lower wood density and specific leaf area. Species with lower wood density grew faster with increasing initial disturbance intensity, while species with higher specific leaf area suffered less from neighbors in areas with high initial disturbance intensity. Our study suggests that accounting for both individual and interactive effects of multiple drivers is crucial to better predict forest dynamics.
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Ecosistema , Bosques , Suelo , Árboles , Árboles/crecimiento & desarrollo , ChinaRESUMEN
Abnormalities in the zona pellucida (ZP) adversely affect oocyte maturation, embryo development and pregnancy outcomes. However, the assessment of severity is challenging. To evaluate the effects of different degrees of ZP abnormalities on embryo development and clinical outcomes, in total, 590 retrieval cycles were scored and divided into four categories (control, mild, moderate and severe) based on three parameters: perivitelline space, percentage of immature oocytes and percentage of oocytes with abnormal morphology. As the severity of abnormal ZP increased, both the number of retrieved oocytes and mature oocytes decreased. The fertilization rate did not differ significantly among groups. The rates of embryo cleavage and day-3 high-quality embryos in the mild group and the moderate group did not vary significantly between the two groups but were significantly higher than those in the severe group. The blastulation rates of the abnormal ZP groups were similar; however, they were lower than those of the control group. Moreover, the cycle cancellation rate of the severe abnormal ZP group was as high as 66.20%, which was significantly higher than that of the other three groups. Although the rates of cumulative clinical pregnancy and live births were lower than those in the control group, they were comparable among the abnormal ZP groups. There were no differences in the neonatal outcomes of the different groups. Together, ZP abnormalities show various degrees of severity, and in all patients regardless of the degree of ZP abnormalities who achieve available embryos, there will be an opportunity to eventually give birth.
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Fertilización In Vitro , Zona Pelúcida , Embarazo , Femenino , Recién Nacido , Humanos , Oocitos , Resultado del Embarazo , Inyecciones de Esperma IntracitoplasmáticasRESUMEN
OBJECTIVE: To identify tumor-associated macrophages (TAMs) related molecular subtypes and develop a TAMs related prognostic model for prostate cancer (PCa). METHODS: Consensus clustering analysis was used to identify TAMs related molecular clusters. A TAMs related prognostic model was developed using univariate and multivariate Cox analysis. RESULTS: Three TAMs related molecular clusters were identified and were confirmed to be associated with prognosis, clinicopathological characteristics, PD-L1 expression levels and tumor microenvironment. A TAMs related prognostic model was constructed. Patients in low-risk group all showed a more appreciable biochemical recurrence-free survival (BCRFS) than patients in high-risk group in train cohort, test cohort, entire TCGA cohort and validation cohort. SLC26A3 attenuated progression of PCa and prevented macrophage polarizing to TAMs phenotype, which was initially verified. CONCLUSIONS: We successfully identified molecular clusters related to TAMs. Additionally, we developed a prognostic model involving TAMs that exhibits excellent predictive performance for biochemical recurrence-free survival in PCa.
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Neoplasias de la Próstata , Macrófagos Asociados a Tumores , Masculino , Humanos , Pronóstico , Neoplasias de la Próstata/metabolismo , Macrófagos , Fenotipo , Microambiente TumoralRESUMEN
In the context of rapid urban expansion, the interaction between humanity and nature has become more prominent. Urban land and rivers often exist as distinct entities with limited material exchange. However, during rainfall, these two systems interconnect, resulting in the transfer of land-derived pollutants into rivers. Such transfer significantly increases river pollutant levels, adversely affecting water quality. Therefore, developing a water quality simulation and prediction model is crucial. This model should effectively illustrate pollutant movement and dispersion during rain events. This study proposes a comprehensive model that merges the Storm Water Management Model (SWMM) with the Environmental Fluid Dynamics Code (EFDC). This integrated model assesses the spread and dispersion of pollutants, including Ammonia Nitrogen (NH3-N), Total Phosphorus (TP), Total Nitrogen (TN), and Chemical Oxygen Demand (COD), within urban water cycles for various rainfall conditions, thus offering critical theoretical support for managing the water environment. The application of this model under different rainfall intensities (light, moderate and heavy) provides vital insights. During light rainfall, the river's natural purification process can sustain surface water quality at Class IV. Moderate rainfall causes accumulation of pollutants, reducing water quality to Class V. Conversely, heavy rainfall rapidly increases pollutant concentrations due to higher inflow, pushing the river to a degraded Class V status, which is beyond its natural purification capacity, necessitating engineering solutions to reattain Class IV quality. Furthermore, pollutant accumulation in downstream river sections is more influenced by flow rate than by rainfall intensity. In summary, the SWMM-EFDC integrated model proves highly effective in predicting river water quality, thereby significantly aiding urban water pollution control.
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Contaminantes Ambientales , Contaminantes Químicos del Agua , Monitoreo del Ambiente/métodos , Contaminantes Ambientales/análisis , Contaminantes Químicos del Agua/análisis , Calidad del Agua , Fósforo/análisis , Lluvia , Nitrógeno/análisis , ChinaRESUMEN
Bacterial species within the Acinetobacter baumannii-calcoaceticus (Acb) complex are very similar and are difficult to discriminate. Misidentification of these species in human infection may lead to severe consequences in clinical settings. Therefore, it is important to accurately discriminate these pathogens within the Acb complex. Raman spectroscopy is a simple method that has been widely studied for bacterial identification with high similarities. In this study, we combined surfaced-enhanced Raman spectroscopy (SERS) with a set of machine learning algorithms for identifying species within the Acb complex. According to the results, the support vector machine (SVM) model achieved the best prediction accuracy at 98.33% with a fivefold cross-validation rate of 96.73%. Taken together, this study confirms that the SERS-SVM method provides a convenient way to discriminate between A. baumannii, Acinetobacter pittii, and Acinetobacter nosocomialis in the Acb complex, which shows an application potential for species identification of Acinetobacter baumannii-calcoaceticus complex in clinical settings in near future.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Acinetobacter , Humanos , Espectrometría Raman , Infecciones por Acinetobacter/microbiologíaRESUMEN
Spinal cord injury (SCI) is a devastating traumatic disease seriously impairing the quality of life in patients. Expectations to allow the hopeless central nervous system to repair itself after injury are unfeasible. Developing new approaches to regenerate the central nervous system is still the priority. Exosomes derived from mesenchymal stem cells (MSC-Exo) have been proven to robustly quench the inflammatory response or oxidative stress and curb neuronal apoptosis and autophagy following SCI, which are the key processes to rescue damaged spinal cord neurons and restore their functions. Nonetheless, MSC-Exo in SCI received scant attention. In this review, we reviewed our previous work and other studies to summarize the roles of MSC-Exo in SCI and its underlying mechanisms. Furthermore, we also focus on the application of exosomes as drug carrier in SCI. In particular, it combs the advantages of exosomes as a drug carrier for SCI, imaging advantages, drug types, loading methods, etc., which provides the latest progress for exosomes in the treatment of SCI, especially drug carrier.
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Portadores de Fármacos , Exosomas , Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/terapia , Humanos , Células Madre Mesenquimatosas/metabolismo , Animales , Apoptosis , Trasplante de Células Madre Mesenquimatosas/métodosRESUMEN
Surrounded by the Shandong Peninsula, the Bohai Sea and Yellow Sea possess vast marine energy resources. An analysis of actual meteorological data from these regions indicates significant seasonality and intra-day uncertainty in wind and photovoltaic power generation. The challenge of scheduling to leverage the complementary characteristics of various renewable energy sources for maintaining grid stability is substantial. In response, we have integrated wave energy with offshore photovoltaic and wind power generation and propose a day-ahead and intra-day multi-time-scale rolling optimization scheduling strategy for the complementary dispatch of these three energy sources. Using real meteorological data from this maritime area, we employed a CNN-LSTM neural network to predict the power generation and load demand of the area on both day-ahead 24 h and intra-day 1 h time scales, with the DDPG algorithm applied for refined electricity management through rolling optimization scheduling of the forecast data. Simulation results demonstrate that the proposed strategy effectively meets load demands through complementary scheduling of wave power, wind power, and photovoltaic power generation based on the climatic characteristics of the Bohai and Yellow Sea regions, reducing the negative impacts of the seasonality and intra-day uncertainty of these three energy sources on the grid. Additionally, compared to the day-ahead scheduling strategy alone, the day-ahead and intra-day rolling optimization scheduling strategy achieved a reduction in system costs by 16.1% and 22% for a typical winter day and a typical summer day, respectively.
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This study aims to examine the effect of salidroside(SAL) on the phenotypic switching of human aortic smooth muscle cells(HASMC) induced by the platelet-derived growth factor-BB(PDGF-BB) and investigate the pharmacological mechanism. Firstly, the safe concentration of SAL was screened by the lactate dehydrogenase release assay. HASMC were divided into control, model, and SAL groups, and the cells in other groups except the control group were treated with PDGF-BB for the modeling of phenotypic switching. Cell proliferation and migration were detected by the cell-counting kit(CCK-8) assay and Transwell assay, respectively. The cytoskeletal structure was observed by F-actin staining with fluorescently labeled phalloidine. The protein levels of proliferating cell nuclear antigen(PCNA), migration-related protein matrix metalloprotein 9(MMP-9), fibronectin, α-smooth muscle actin(α-SMA), and osteopontin(OPN) were determined by Western blot. To further investigate the pharmacological mechanism of SAL, this study determined the expression of protein kinase B(Akt) and mammalian target of rapamycin(mTOR), as well as the upstream proteins phosphatase and tensin homologue(PTEN) and platelet-derived growth factor receptor ß(PDGFR-ß) and the downstream protein hypoxia-inducible factor-1α(HIF-1α) of the Akt/mTOR signaling pathway. The results showed that the HASMCs in the model group presented significantly increased proliferation and migration, the switching from a contractile phenotype to a secretory phenotype, and cytoskeletal disarrangement. Compared with the model group, SAL weakened the proliferation and migration of HASMC, promoted the expression of α-SMA(a contractile phenotype marker), inhibited the expression of OPN(a secretory phenotype marker), and repaired the cytoskeletal disarrangement. Furthermore, compared with the control group, the modeling up-regulated the levels of phosphorylated Akt and mTOR and the relative expression of PTEN, HIF-1α, and PDGFR-ß. Compared with the model group, SAL down-regulated the protein levels of phosphorylated Akt and mTOR, PTEN, PDGFR-ß, and HIF-1α. In conclusion, SAL exerts a protective effect on the HASMCs exposed to PDGF-BB by regulating the PDGFR-ß/Akt/mTOR/HIF-1α signaling pathway.
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Movimiento Celular , Proliferación Celular , Glucósidos , Miocitos del Músculo Liso , Fenoles , Proliferación Celular/efectos de los fármacos , Glucósidos/farmacología , Movimiento Celular/efectos de los fármacos , Fenoles/farmacología , Humanos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/citología , Transducción de Señal/efectos de los fármacos , Fenotipo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Células Cultivadas , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Becaplermina/farmacología , Aorta/efectos de los fármacos , Aorta/citología , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Osteopontina/metabolismo , Osteopontina/genéticaRESUMEN
Exploitation of key protected wild plant resources makes great sense, but their limited populations become the major barrier. A particular strategy for breaking this barrier was inspired by the exploration of a resource-saving fungal endophyte Penicillium sp. DG23, which inhabits the key protected wild plant Schisandra macrocarpa. Chemical studies on the cultures of this strain afforded eight novel indole diterpenoids, schipenindolenes A-H (1-8), belonging to six diverse skeleton types. Importantly, semisyntheses suggested some key nonenzymatic reactions constructing these molecules and provided targeted compounds, in particular schipenindolene A (Spidâ A, 1) with low natural abundance. Remarkably, Spidâ A was the most potent HMG-CoA reductase (HMGCR) degrader among the indole diterpenoid family. It degraded statin-induced accumulation of HMGCR protein, decreased cholesterol levels and acted synergistically with statin to further lower cholesterol. Mechanistically, transcriptomic and proteomic profiling suggested that Spidâ A potentially activated the endoplasmic reticulum-associated degradation (ERAD) pathway to enhance the degradation of HMGCR, while simultaneously inhibiting the statin-activated expression of many key enzymes in the cholesterol and fatty acid synthesis pathways, thereby strengthening the efficacy of statins and potentially reducing the side effects of statins. Collectively, this study suggests the potential of Spidâ A for treating cardiovascular disease.
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Acilcoenzima A , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Degradación Asociada con el Retículo Endoplásmico , Proteómica , Colesterol/metabolismo , IndolesRESUMEN
Water transport through water channels, aquaporins (AQPs), is vital for many physiological processes including epithelial fluid secretion, cell migration and adipocyte metabolism. Water flux through AQPs is driven by the osmotic gradient that results from concentration differences of solutes including ions. Here, we developed a novel optogenetic toolkit that combines the light-gated anion channel GtACR1 either with the light-gated K+ channel HcKCR1 or the new Na+ channelrhodopsin HcNCR1 with high Na+ permeability, to manipulate water transport in Xenopus oocytes non-invasively. Water efflux through AQP was achieved by light-activating K+ and Cl- efflux through HcKCR1 and GtACR1. Contrarily, when GtACR1 was co-expressed with HcNCR1, inward movement of Na+ and Cl- was light-triggered, and the resulting osmotic gradient led to water influx through AQP1. In sum, we demonstrate a novel optogenetic strategy to manipulate water movement into or out of Xenopus oocytes non-invasively. This approach provides a new avenue to interfere with water homeostasis as a means to study related biological phenomena across cell types and organisms.
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Acuaporinas , Agua , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Agua/metabolismo , Acuaporinas/genética , Acuaporinas/metabolismo , Transporte Biológico , Permeabilidad , Oocitos/metabolismoRESUMEN
Recent breakthroughs in the generation of polar-functionalized and more sustainable degradable polyethylenes have been enabled by advanced phosphinephenolato Ni(II) catalysts. A key has been to overcome this type of catalysts' propensity for extensive chain transfer to enable formation of high-molecular-weight polyethylene chains. We elucidate the mechanistic origin of this paradigm shift by a combined experimental and theoretical study. Single-crystal X-ray structural analysis and cyclic voltammetry of a set of six different catalysts with variable electronics and sterics, combined with extensive pressure reactor polymerization studies, suggest that an attractive Ni-aryl interaction of a P-[2-(aryl)phenyl] is responsible for the suppression of chain transfer. This differs from the established picture of steric shielding found for other prominent late transition metal catalysts. Extensive density functional theory studies identify the relevant pathways of chain growth and chain transfer and show how this attractive interaction suppresses chain transfer.
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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
BACKGROUND: ND630 is believed to be a new therapy pharmacologic molecule in targeting the expression of ACACA and regulating the lipid metabolism. However, the function of ND630 in prostate cancer remains unknown. KIF18B, as an oncogene, plays a vital role in prostate cancer progression. circKIF18B_003 was derived from oncogene KIF18B and was markedly overexpressed in prostate cancer tissues. We speculated that oncoprotein KIF18B-derived circRNA circKIF18B_003 might have roles in prostate cancer promotion. The aim of this study was to validate whether ND630 could control ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. METHODS: RT-qPCR was used to analyze the expression of circKIF18B_003 in prostate cancer cell lines and prostate cancer samples. circKIF18B_003 expression was modulated in prostate cancer cells using circKIF18B_003 interference or overexpression plasmid. We examined the function and effects of circKIF18B_003 in prostate cancer cells using CCK-8, colony formation, wound healing, and Transwell invasion assays and xenograft models. Fluorescence in situ hybridization (FISH) was performed to evaluate the localization of circKIF18B_003. RNA immunoprecipitation (RIP), RNA pull down, and luciferase reporter assay were performed to explore the potential mechanism of circKIF18B_003. RESULTS: The function of ND630 was determined in this study. circKIF18B_003 was overexpressed in prostate cancer tissues, and overexpression of circKIF18B_003 was associated with poor survival outcome of prostate cancer patients. The proliferation, migration, and invasion of prostate cancer cells were enhanced after up-regulation of circKIF18B_003. circKIF18B_003 is mainly located in the cytoplasm of prostate cancer cells, and the RIP and RNA pull down assays confirmed that circKIF18B_003 could act as a sponge for miR-370-3p. Further study demonstrated that up-regulation of circKIF18B_003 increased the expression of ACACA by sponging miR-370-3p. The malignant ability of prostate cancer cells enhanced by overexpression of circKIF18B_003 was reversed by the down-regulation of ACACA. We found that overexpression of circKIF18B_003 was associated with lipid metabolism, and a combination of ND-630 and docetaxel markedly attenuated tumor growth. CONCLUSION: ND630 could control ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. ND630 and circKIF18B_003 may represent a novel target for prostate cancer.