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1.
Mar Environ Res ; 196: 106416, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38394977

RESUMEN

Soil/sediment samples of four different land types were collected from aquaculture land, farmland, industrial land and river bottom sediment in the estuary area of Dagu River. The contents of Cr, Cu, Zn, As, Cd and Pb in 0-30 cm inner surface samples were detected, and the distribution characteristics of heavy metal content in surface soil/sediment of different land use types in the estuary area were analyzed. Local accumulation index method, potential risk index evaluation method and principal component analysis method were used to analyze the pollution status and sources of heavy metals. The results showed that the heavy metal accumulation levels in soil and sediment samples in the study area were As > Cd > Cu > Pb > Zn > Cr, and the heavy metal content exceeded the soil background value in Shandong Province, but the potential risks were all in a low risk state. The main sources of Cr, Zn and As are transportation sources and natural sources, while the main sources of Cd and Pb are agricultural.


Asunto(s)
Monitoreo del Ambiente , Metales Pesados , Ríos , Estuarios , Cadmio/análisis , Plomo/análisis , Medición de Riesgo , Metales Pesados/análisis , Suelo , China
2.
Anal Chem ; 96(5): 1834-1842, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38266381

RESUMEN

Light-absorbing organic aerosols, referred to as brown carbon (BrC), play a vital role in the global climate and air quality. Due to the complexity of BrC chromophores, the identified absorbing substances in the ambient atmosphere are very limited. However, without comprehensive knowledge of the complex absorbing compounds in BrC, our understanding of its sources, formation, and evolution mechanisms remains superficial, leading to great uncertainty in climatic and atmospheric models. To address this gap, we developed a constrained non-negative matrix factorization (NMF) model to resolve the individual ultraviolet-visible spectrum for each substance in dissolved organic aerosols, with the power of ultrahigh-performance liquid chromatography-diode array detector-ultrahigh-resolution mass spectrometry (UHPLC-DAD-UHRMS). The resolved spectra were validated by selected standard substances and validation samples. Approximately 40,000 light-absorbing substances were recognized at the MS1 level. It turns out that BrC is composed of a vast number of substances rather than a few prominent chromophores in the urban atmosphere. Previous understanding of the absorbing feature of BrC based on a few identified compounds could be biased. Weak-absorbing substances missed previously play an important role in BrC absorption when they are integrated due to their overwhelming number. This model brings the property exploration of complex dissolved organic mixtures to a molecular level, laying a foundation for identifying potentially significant compositions and obtaining a comprehensive chemical picture.

4.
Mar Pollut Bull ; 194(Pt B): 115340, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37541140

RESUMEN

Four different types of 0-30 cm soil/sediment samples were collected from aquaculture land, farmland, industrial land and river bottom sediment in the estuary area of Dagu River, and the pollution status and sources of 7 PCB congeners were analyzed. The results showed that the mean values of Σ7PCBs in soil/sediments of different land use types were 5.01 ng g-1 dw for industrial land, 3.6 ng g-1 dw for estuarine sediments, 2.09 ng g-1 dw for farmland soil and 1.78 ng g-1 dw for farming land. All samples were at low pollution levels and pose little ecological risks. PCBs in the samples are mainly comprised of highly chlorinated biphenyls, and their content decreases gradually with increasing sampling depth. Based on the principal component analysis, it is concluded that the main source of PCBs in the study area is shipping activities, in addition to atmospheric transport and sedimentation sources.


Asunto(s)
Bifenilos Policlorados , Contaminantes Químicos del Agua , Bifenilos Policlorados/análisis , Estuarios , Ríos , Sedimentos Geológicos/análisis , Monitoreo del Ambiente/métodos , Contaminantes Químicos del Agua/análisis , Suelo , China , Medición de Riesgo
5.
Medicine (Baltimore) ; 102(25): e34101, 2023 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-37352028

RESUMEN

BACKGROUND: Hyalinising clear cell carcinoma (HCCC) of the lung is a rare tumor, with only 12 reported cases. To improve the differential diagnosis, the aim of this study was to clarify the clinicopathological characteristics, immunophenotype, and molecular characteristics of HCCC of the lung and relate these to prognosis. METHODS: Sections of HCCC of the lung were collected from a patient for pathological observation, immunohistochemistry, histochemistry, and fluorescence in situ hybridization; the clinical, pathological, and molecular characteristics were compared with those reported in the literature. RESULTS: The tumor had a well-demarcated border nodule with a maximal diameter of 2.5 cm. Microscopic findings showed either clear or eosinophilic cytoplasm in the tumor cells. Growth was predominantly in the sheets, nests, and trabeculae in a background of hyalinised, fibrotic stroma, and mucus degeneration. Immunohistochemistry showed that the tumor cells expressed cytokeratin 7, P63, P40, CK5/6, Pan Cytokeratin (PCK), and epithelial membrane antigen, whereas they were negative for thyroid transcription factor-1, napsin A, CD10, vimentin, and smooth muscle actin. The Ki67 proliferation index was 5%. The tumor was positive for both period acid-Schiff (PAS) and Alcian blue-PAS, with a small amount of mucus staining positive for PAS-diastase. Fluorescence in situ hybridization revealed Ewing sarcoma breakpoint region 1 rearrangement and Ewing sarcoma breakpoint region 1-activating transcription factor 1 fusion. CONCLUSIONS: HCCC is a low-grade carcinoma with excellent prognosis. Tumour necrosis may be a potential risk factor for recurrence and metastasis. Our review of reported cases suggests that regional lymph node dissection combined with lobectomy is a safer treatment than only lobectomy for HCCC of the lung.


Asunto(s)
Adenocarcinoma de Células Claras , Sarcoma de Ewing , Humanos , Hibridación Fluorescente in Situ , Queratinas/genética , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/cirugía , Adenocarcinoma de Células Claras/genética , Pulmón/patología , Biomarcadores de Tumor
6.
Sci Total Environ ; 857(Pt 1): 159340, 2023 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-36228803

RESUMEN

An increasing number of people tend to live in cities, where they suffer from serious air pollution from anthropogenic sources. Vehicle exhaust and cooking emission are closely related to daily life of urban residents, and could be defined as "urban-lifestyle sources". The primary emissions of urban-lifestyle sources tend to form abundant secondary organic aerosols (SOA) through complicated atmospheric chemistry processes. The newly formed SOA is a kind of complex mixture and causes considerable health effects with high uncertainty. Most studies focus on formation pathway, mass growth potential and chemical feature of urban-lifestyle SOA under simple laboratory conditions. Few studies have measured the urban-lifestyle SOA in ambient air, let alone verified laboratory findings under complicated atmospheric conditions. In this work, we established a new method that combined laboratory simulation and field observation, which quantified the urban-lifestyle SOA with high time resolution under the real atmospheric condition. The complex SOA was measured and resolved by a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). The multilinear engine model (ME-2) and multilinear correction methods were used to apply laboratory results into ambient SOA apportionment. It was found that the vehicle source dominated the SOA formation during the diurnal photochemical process, and the SOA:POA ratio of vehicle source was about 1.4 times larger than that of cooking source. The vehicle emission may undergo an alcohol/peroxide & carboxylic acid oxidation pathway and form higher oxidized SOA, while the cooking emission may undergo an alcohol/peroxide oxidation pathway and form relatively lower oxidized SOA. The vehicle SOA and cooking SOA contributed 45.6 % and 24.8 % of OA during a local episode in 2021 winter of downtown Beijing. Our findings could not only provide a new way to quantify urban SOA but also demonstrate some laboratory hypotheses, conducing to understand its ambient contributions, chemical features, and environmental effects.


Asunto(s)
Contaminantes Atmosféricos , Emisiones de Vehículos , Humanos , Emisiones de Vehículos/análisis , Contaminantes Atmosféricos/análisis , Aerosoles/análisis , Culinaria , China , Estilo de Vida , Peróxidos , Material Particulado/análisis
7.
Front Psychol ; 13: 1006957, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36304873

RESUMEN

Enterprises do not exist independently of the external environment, so uncertainty affects their earnings volatility and exacerbates the information asymmetry between internal and external stakeholders. As a major manifestation of capital market mispricing, the accrual anomaly is caused by investors' functional fixation on total surplus under information asymmetry. Against this backdrop, taking A-share listed companies in China from 2007 to 2019 as our research objects, this study explores the impact of environmental uncertainty on the accrual anomaly based on the information asymmetry and investor irrationality perspective. We find that environmental uncertainty enterprises facing exacerbates the accrual anomaly in the Chinese stock market, and internal control quality, state ownership and the media coverage will affect this impact. Furthermore, this study shows that there are three factors playing the mediating role in the effect, accounting information quality, investment growth and the investor attention. The results show that environmental uncertainty exacerbates the accrual anomaly driven by information manipulation, empire building and investor irrationality. Improving investor irrationality behavior and restraining the self-interest behavior of managers can help alleviate the mispricing of accruals caused by information asymmetry in psychology.

8.
Sci Total Environ ; 847: 157582, 2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-35882337

RESUMEN

Biomass burning emits large quantities of phenols, which readily partition into the atmospheric aqueous phase and subsequently may react to produce aqueous secondary organic aerosol (aqSOA). For the first time, we quantitatively explored the influence of phenols emitted from biomass burning on aqSOA formation in the winter of Beijing. A typical haze episode associated with significant aqSOA formation was captured. During this episode, aqueous-phase processing of biomass burning promoted aqSOA formation was identified. Furthermore, high-resolution mass spectrum analysis provided molecular-level evidence of the phenolic aqSOA tracers. Estimation of aqSOA formation rate (RaqSOA) with compiled laboratory kinetic data indicated that biomass-burning phenols can efficiently produce aqSOA at midday, with RaqSOA of 0.42 µg m-3 h-1 accounting for 15 % of total aqSOA formation rate. The results highlight that aqSOA formation of phenols contributes the haze pollution. This implies the importance of regional joint control of biomass burning to mitigate the heavy haze.


Asunto(s)
Contaminantes Atmosféricos , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Biomasa , Monitoreo del Ambiente , Material Particulado/análisis , Fenoles/análisis , Agua/análisis
9.
Chemosphere ; 287(Pt 1): 131987, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34474385

RESUMEN

As traditional methods of oil shale production emitting high levels of pollutants, in-situ exploitation has aroused great concerns. In order to study the effect of in-situ pyrolysis products on the underground environment, an in-situ oil shale exploitation of underground environment impact laboratory simulation system was designed. Based on the hydrogeological condition of oil shale area in Nong'an City, a physical simulation test was conducted. It was found the temperature of surrounding layers continued to be perturbed after heating of the formation had stopped. The time during which the temperature was perturbed was about 4-5 times the heating period. During the simulation test, stray gas migration through fractures and faults was considered a mechanism for groundwater contamination. In the test, the maximum TOC content in aquifer was the value of 97.0 mg/L. The maximum total petroleum hydrocarbon (TPH) content of the simulated formation was 129 mg/kg after oil pyrolysis.


Asunto(s)
Agua Subterránea , Petróleo , Minerales , Minería , Modelos Teóricos
11.
Environ Pollut ; 290: 118032, 2021 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-34467886

RESUMEN

The annual mean PM2.5 mass concentration has decreased because of the stringent emission controls implemented in Beijing, China in recent years, whereas the nitrate NO3- mass fraction in PM2.5 increases gradually. Low-visibility events occur frequently even though PM2.5 pollution has been mitigated significantly, with the daily mean PM2.5 mass concentration mostly less than 75 µg/m3. In this study, the non-linear relationship was analyzed between atmospheric visibility and PM2.5 based on chemical composition from a two-year field observation. Our results showed that NO3- became the main constituent of PM2.5, especially during the haze pollution episodes. A localized parameterization scheme was proposed between the atmospheric extinction coefficient (σext) and major chemical constituents of PM2.5 by multiple linear regression (MLR). The contribution of NO3- to σext increased with increasing air pollution, and NO3- became the most important contributor for PM2.5 above 75 µg/m3. The visibility decreased with increasing NO3- mass fraction for the same PM2.5 mass concentration when PM2.5 was above 20 µg/m3. The hygroscopicity of PM2.5 increased with increasing mass fraction of hygroscopic NO3-. These results stressed the importance of reducing particulate NO3- and its precursors (for instance, NH3) through effective emission control measures as well as the tightening of PM2.5 standards to further improve air quality and visibility in Beijing.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Beijing , China , Monitoreo del Ambiente , Nitratos , Material Particulado/análisis , Estaciones del Año
12.
Ying Yong Sheng Tai Xue Bao ; 31(3): 814-820, 2020 Mar.
Artículo en Chino | MEDLINE | ID: mdl-32537976

RESUMEN

The mineralization of soil carbon (C) and nitrogen (N) is a critical process in the cycling of C and N in terrestrial ecosystems, which is strongly controlled by water availability. In this study, we collected soil samples in a 3-year extreme drought experiment in a meadow steppe in Inner Mongolia, freeze-dried these samples, and measured the potential C and N mineralization rates and water sensitivity of soil microorganism by incubating soils under soil water contents (SWC) of 3%, 8%, 13%, 18%, 25% and 35%. The results showed that averaged across different SWC, the extreme drought treatment of reducing 66% precipitation in growing season significantly increased potential N mineralization rate by 14.2%, but did not affect the potential C mineralization. Extreme drought significantly increased soil microbial biomass N and soil dissolved organic C by 26.8% and 26.9%, respectively. In both the control (natural rainfall) and extreme drought treatment, the potential C and N mineralization and microbial biomass C and N increased with SWC in the incubation, which was possibly caused by the enhanced substrate diffusion. Extreme drought also promoted the initial pulse response of C mineralization, implying the enhanced microbial response to water availability. Extreme drought significantly reduced the ratio of the potential soil C mineralization to the potential N mineralization, suggesting that extreme drought might weak the coupling of soil C and N. Extreme drought could cause different responses to soil water availability between soil C and N cycling. Extreme drought could enhance microbial response to increasing water availability, weak coupling between soil C and N, with consequences on nutrient cycling and primary productivity in the meadow steppe of northern China.


Asunto(s)
Nitrógeno , Suelo , Carbono , China , Sequías , Ecosistema , Microbiología del Suelo
13.
Am J Cancer Res ; 10(12): 4198-4210, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33414995

RESUMEN

Vasculogenic Mimicry (VM) is the main source of blood supply in the early stage of tumor growth. Carcinoma-associated fibroblasts (CAFs) are one of the most important host cells in the tumor microenvironment. Some studies have found that CAFs can promote tumor angiogenesis, but there are few reports on the relationship between CAFs and VM. Tissue samples were collected from 60 cases of hepatocellular carcinoma (HCC) and 10 persons with normal liver function. The relationship between VM expression and clinicopathologic features was analyzed. Furthermore, the relationship between VM expression and vimentin or α-SMA expression was analyzed. Primary culture of hepatocellular CAFs and the collection of conditioned media were carried out. The effects of hepatocellular CAF conditioned medium on the formation of VM and the levels of VM-related proteins and genes in MHCC-97H cells were studied. The positive rate of VM was 35.0% in HCC tissues. There was no VM expression in normal liver tissues. VM expression was related to tumor diameter, Edmondson grade, clinical stage, and liver cirrhosis. The expression of vimentin and α-SMA in VM-positive patients was higher than in VM-negative patients. Different concentrations of hepatocellular CAF conditioned medium could promote the formation of VM and increase the expression of VM-related genes and proteins (MMP2 and EphA2) in MHCC-97H cells. The results show that there was a significant correlation between VM formation and the expression of vimentin or α-SMA in HCC tissues. The conditioned medium of hepatocellular CAFs may promote VM formation and the expression of VM-related genes and proteins (MMP2 and EphA2) in hepatoma cell line MHCC-97H.

14.
Chemosphere ; 228: 384-389, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31042612

RESUMEN

Oil shale samples were obtained from Nong'an oil shale ore-bearing area which was located in the southeastern uplift of Songliao basin, China. The XRD test for oil shale identified the minerals in it and a series of water-rock interaction experiment between oil shale-water and oil shale ash-water were carried out to the study the release of organic matter from groundwater during oil shale in-situ exploitation. The content of phenol, BTEX, TOC and TPH in oil shale and oil shale ash aqueous solution were determined. The phenol and TOC in oil shale aqueous solution were higher than that of oil shale ash aqueous solution, conversely, more BTEX and TPH were existed in oil shale ash aqueous solution. The reaction temperature had significant influence on phenol, TOC and TPH in oil shale aqueous solution, which was not obvious in oil shale ash aqueous solution. Besides, the TOC average content in oil shale aqueous solution gradually increased along with the reaction time. The results show that not only oil shale in situ mining process make groundwater organic pollution aggravate but also continuous pollution of groundwater caused by the residual oil shale ash still exist.


Asunto(s)
Agua Subterránea/química , Minerales/química , Minería/métodos , Yacimiento de Petróleo y Gas/química
15.
Ecotoxicol Environ Saf ; 172: 303-307, 2019 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-30716665

RESUMEN

The levels and distribution of synthetic musks (ADBI, AHMI, ATII, HHCB, AHTN, MX and MK) were investigated in farmland soils from the Three Northeast Provinces of China. The total concentrations of SMs ranged from 2.40 ng/g to 12.2 ng/g (dry weight). HHCB and AHTN were the main pollutants that were detected in all samples, accounting for 99.35% of the total SMs. The hazard quotients were 0.0700 and 0.102 for AHTN and HHCB, respectively. Although the results indicate there is no serious environmental impact, the detection frequency of SMs in the farmland soil is high, which demonstrated that SMs are widely used in the Three Northeast Provinces of China. Therefore, more attention should be given to synthetic musks during environment monitoring and risk assessments for their bioaccumulation, lipophilicity and persistence.


Asunto(s)
Ácidos Grasos Monoinsaturados/análisis , Contaminantes del Suelo/análisis , Tetrahidronaftalenos/análisis , China , Monitoreo del Ambiente , Granjas
16.
Oncogene ; 38(13): 2364-2379, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30518875

RESUMEN

DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the biosynthesis of deoxyribonucleoside triphosphates (dNTPs) that are essential for DNA replication and DNA damage repair. Gemcitabine, a nucleotide analog that inhibits RNR, has been used to treat various cancers. However, patients often develop resistance to this drug during treatment. Thus, new drugs that inhibit RNR are needed to be developed. In this study, we identified a synthetic analog of resveratrol (3,5,4'-trihydroxy-trans-stilbene), termed DHS (trans-4,4'-dihydroxystilbene), that acts as a potent inhibitor of DNA replication. Molecular docking analysis identified the RRM2 (ribonucleotide reductase regulatory subunit M2) of RNR as a direct target of DHS. At the molecular level, DHS induced cyclin F-mediated down-regulation of RRM2 by the proteasome. Thus, treatment of cells with DHS reduced RNR activity and consequently decreased synthesis of dNTPs with concomitant inhibition of DNA replication, arrest of cells at S-phase, DNA damage, and finally apoptosis. In mouse models of tumor xenografts, DHS was efficacious against pancreatic, ovarian, and colorectal cancer cells. Moreover, DHS overcame both gemcitabine resistance in pancreatic cancer and cisplatin resistance in ovarian cancer. Thus, DHS is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest cancer development.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Neoplasias/patología , Ribonucleótido Reductasas/antagonistas & inhibidores , Estilbenos/farmacología , Animales , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Subunidades de Proteína/efectos de los fármacos , Ribonucleótido Reductasas/química , Ribonucleótido Reductasas/metabolismo , Estilbenos/química , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Nucleic Acids Res ; 46(13): 6806-6822, 2018 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-29718312

RESUMEN

It has been reported that the two major types of RNA interference triggers, the classical Dicer-generated small RNAs (siRNAs), which function with all members of the Argonaute (Ago) protein family in mammals, and the Ago2-sliced small RNAs (sli-siRNAs), which function solely through Ago2, have similar potency in target cleavage and repression. Here, we show that sli-siRNAs are generally more potent than siRNAs in silencing mismatched targets. This phenomenon is usually more apparent in targets that have mismatched nucleotides in the 3' supplementary region than in targets with mismatches in the seed region. We demonstrate that Ago2 slicer activity is a major factor contributing to the greater silencing efficiency of sli-siRNA against mismatched targets and that participation of non-slicing Agos in silencing mismatched siRNA targets may dilute the slicing ability of Ago2. The difference in length of the mature guide RNA used in sli-RISCs and si-RISCs may also contribute to the observed difference in knockdown efficiency. Our data suggest that a sli-siRNA guide strand is likely to have substantially stronger off-target effects than a guide strand with the same sequence in a classical siRNA and that Dicer and non-slicing Agos may play pivotal roles in controlling siRNA target specificity.


Asunto(s)
Disparidad de Par Base , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Animales , Proteínas Argonautas/metabolismo , Línea Celular Tumoral , Células Cultivadas , Células HEK293 , Humanos , Ratones , MicroARNs/química , MicroARNs/metabolismo , Procesamiento Postranscripcional del ARN , ARN Interferente Pequeño/química , Complejo Silenciador Inducido por ARN/metabolismo , Ribonucleasa III/metabolismo
18.
J Colloid Interface Sci ; 495: 191-199, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28208080

RESUMEN

Adsorption removal of bisphenol-AF (BPAF) from aqueous solutions by synthesized activated carbon-alginate beads (AC-AB) with cetyltrimethyl ammonium bromide (CTAB) has been studied using two ways. The traditional method (two-step) first synthesized CTAB-modified AC-AB (AC-AB-CTAB), then used it to remove BPAF by adsorption. And one-step method dispersed AC-AB and CTAB in wastewater, followed by the removal of BPAF accompanied with the synthesis of AC-AB-CTAB. The one-step method showed a better performance than the two-step method, achieving a maximum removal of BPAF with 284.6mg/g. Kinetic studies and adsorption isotherms indicated that adsorption process of BPAF on AC-AB by the one-step method could be expressed by a pseudo-second-order model and a Dubinin-Ashtakhov (D-A) isotherm, respectively. The effects of pH, ionic strength, and inorganic ions on BPAF adsorption were also investigated. Furthermore, hydrophobic interactions, hydrogen bonds, and π-π electron donor-acceptor (EDA) interactions were discussed to explain the enhanced adsorption behavior of BPAF on AC-AB with CTAB. The findings verified the effectiveness of AC-AB for the removal of BPAF from wastewater and its high stability within five regeneration cycles.

19.
Sci Rep ; 6: 18846, 2016 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-26733354

RESUMEN

Ribonucleotide reductase small subunit B (RRM2B) is a stress response protein that protects normal human fibroblasts from oxidative stress. However, the underlying mechanism that governs this function is not entirely understood. To identify factors that interact with RRM2B and mediate anti-oxidation function, large-scale purification of human Flag-tagged RRM2B complexes was performed. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1, PYCR2) were identified by mass spectrometry analysis as components of RRM2B complexes. Silencing of both PYCR1 and PYCR2 by expressing short hairpin RNAs induced defects in cell proliferation, partial fragmentation of the mitochondrial network, and hypersensitivity to oxidative stress in hTERT-immortalized human foreskin fibroblasts (HFF-hTERT). Moderate overexpression of RRM2B, comparable to stress-induced level, protected cells from oxidative stress. Silencing of both PYCR1 and PYCR2 completely abolished anti-oxidation activity of RRM2B, demonstrating a functional collaboration of these metabolic enzymes in response to oxidative stress.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Estrés Oxidativo , Pirrolina Carboxilato Reductasas/metabolismo , Ribonucleótido Reductasas/metabolismo , Animales , Antioxidantes/metabolismo , Puntos de Control del Ciclo Celular , Proteínas de Ciclo Celular/genética , Línea Celular , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Isoenzimas , Espectrometría de Masas/métodos , Mitocondrias/genética , Mitocondrias/metabolismo , Complejos Multiproteicos/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Transporte de Proteínas , Pirrolina Carboxilato Reductasas/genética , Proteínas Recombinantes de Fusión , Ribonucleótido Reductasas/genética , Transducción de Señal , Telomerasa/genética , Telomerasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Pez Cebra , delta-1-Pirrolina-5-Carboxilato Reductasa
20.
Oncotarget ; 7(2): 1984-99, 2016 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-26675256

RESUMEN

Macroautophagy can promote cellular survival or death depending on the cellular context and its extent. We hypothesized that autophagy induction would synergize with a therapeutic agent targeting the autophagic cargo. To test this hypothesis, we treated breast cancer MDA-MB-231 cells with tamoxifen (TMX), which induces autophagy through an estrogen receptor-independent pathway. Induction of autophagy reduced cellular levels of RRM2, a subunit of ribonucleotide reductase (RR), the rate limiting enzyme in the production of deoxyribonucleotide triphosphates (dNTPs). This autophagy inducer was combined with COH29, an inhibitor developed in our laboratory that targets RR through a novel mechanism. The combination therapy showed synergistic effects on cytotoxicity in vitro and in an in vivo xenograft model. This cytotoxicity was blocked by knockdown of the autophagy protein ATG5 or addition of chloroquine, an autophagy inhibitor. The combined therapy also induced dNTP depletion and massive genomic instability, leading us to hypothesize that combining autophagy induction with RR inhibition can lead to mitotic catastrophe in rapidly dividing cells. We propose that this TMX + COH29 combined therapy may have clinical benefit. Furthermore, autophagy induction may be a general mechanism for augmenting the effects of chemotherapeutic agents.


Asunto(s)
Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ribonucleósido Difosfato Reductasa/antagonistas & inhibidores , Tamoxifeno/farmacología , Animales , Antimaláricos/farmacología , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Western Blotting , Neoplasias de la Mama/enzimología , Proliferación Celular/efectos de los fármacos , Cloroquina/farmacología , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Técnicas para Inmunoenzimas , Ratones , Ratones Endogámicos NOD , Ratones SCID , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleósido Difosfato Reductasa/genética , Ribonucleósido Difosfato Reductasa/metabolismo , Tiazoles/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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