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1.
Environ Sci Technol ; 58(8): 3629-3640, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38354315

RESUMEN

Key stages in people's lives have particular relevance for their health; the life-course approach stresses the importance of these stages. Here, we applied a life-course approach to analyze the health risks associated with PM2.5-bound elements, which were measured at three sites with varying environmental conditions in eastern China. Road traffic was found to be the primary source of PM2.5-bound elements at all three locations, but coal combustion was identified as the most important factor to induce both cancer risk (CR) and noncancer risk (NCR) across all age groups due to the higher toxicity of elements such as As and Pb associated with coal. Nearly half of NCR and over 90% of CR occurred in childhood (1-6 years) and adulthood (>18 years), respectively, and females have slightly higher NCR and lower CR than males. Rural population is found to be subject to the highest health risks. Synthesizing previous relevant studies and nationwide PM2.5 concentration measurements, we reveal ubiquitous and large urban-rural environmental exposure disparities over China.


Asunto(s)
Contaminantes Atmosféricos , Material Particulado , Masculino , Femenino , Humanos , Material Particulado/análisis , Contaminantes Atmosféricos/análisis , Estaciones del Año , Monitoreo del Ambiente , Medición de Riesgo , China/epidemiología , Carbón Mineral/análisis
2.
Environ Sci Technol ; 58(12): 5453-5460, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38477969

RESUMEN

Many types of living plants release gaseous trimethylamine (TMA), making it a potentially important contributor to new particle formation (NPF) in remote areas. However, a panoramic view of the importance of forest biogenic TMA at the regional scale is lacking. Here, we pioneered nationwide mobile measurements of TMA across a transect of contiguous farmland in eastern China and a transect of subtropical forests in southern China. In contrast to the farmland route, TMA concentrations measured during the subtropical forest route correlated significantly with isoprene, suggesting potential TMA emissions from leaves. Our high time-resolved concentrations obtained from a weak photo-oxidizing atmosphere reflected freshly emitted TMA, indicating the highest emission intensity from irrigated dryland (set as the baseline of 10), followed by paddy field (7.1), subtropical evergreen forests (5.9), and subtropical broadleaf and mixed forests (4.3). Extrapolating their proportions roughly to China, subtropical forests alone, which constitute half of the total forest area, account for nearly 70% of the TMA emissions from the nation's total farmland. Our estimates, despite the uncertainties, take the first step toward large-scale assessment of forest biogenic amines, highlighting the need for observational and modeling studies to consider this hitherto overlooked source of TMA.


Asunto(s)
Bosques , Metilaminas , Granjas , China , Suelo
3.
Environ Sci Technol ; 58(24): 10652-10663, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38829825

RESUMEN

Secondary organic aerosol (SOA) formation from gasoline vehicles spanning a wide range of emission types was investigated using an oxidation flow reactor (OFR) by conducting chassis dynamometer tests. Aided by advanced mass spectrometric techniques, SOA precursors, including volatile organic compounds (VOCs) and intermediate/semivolatile organic compounds (I/SVOCs), were comprehensively characterized. The reconstructed SOA produced from the speciated VOCs and I/SVOCs can explain 69% of the SOA measured downstream of an OFR upon 0.5-3 days' OH exposure. While VOCs can only explain 10% of total SOA production, the contribution from I/SVOCs is 59%, with oxygenated I/SVOCs (O-I/SVOCs) taking up 20% of that contribution. O-I/SVOCs (e.g., benzylic or aliphatic aldehydes and ketones), as an obscured source, account for 16% of total nonmethane organic gas (NMOG) emission. More importantly, with the improvement in emission standards, the NMOG is effectively mitigated by 35% from China 4 to China 6, which is predominantly attributed to the decrease of VOCs. Real-time measurements of different NMOG components as well as SOA production further reveal that the current emission control measures, such as advances in engine and three-way catalytic converter (TWC) techniques, are effective in reducing the "light" SOA precursors (i.e., single-ring aromatics) but not for the I/SVOC emissions. Our results also highlight greater effects of O-I/SVOCs to SOA formation than previously observed and the urgent need for further investigation into their origins, i.e., incomplete combustion, lubricating oil, etc., which requires improvements in real-time molecular-level characterization of I/SVOC molecules and in turn will benefit the future design of control measures.


Asunto(s)
Aerosoles , Gasolina , Emisiones de Vehículos , Compuestos Orgánicos Volátiles , Contaminantes Atmosféricos/química , Compuestos Orgánicos/química
4.
Environ Res ; 206: 112624, 2022 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-34973195

RESUMEN

China's unprecedented lockdown to contain the spread of the novel coronavirus disease (COVID-19) in early 2020, provided a tragic natural experiment to investigate the responses of atmospheric pollution to emission reduction at regional scale. Primarily driven by primary emissions, particulate trace elements is vitally important due to their disproportionally adverse impacts on human health and ecosystem. Here 14 trace elements in PM2.5 were selected for continuous measurement hourly in urban representative site of Shanghai, for three different phases: pre-control period (1-23 January 2020), control period (24 January-10 February 2020; overlapped with Chinese Lunar New Year holiday) and post control period (11-26 February 2020) the city's lockdown measures. The results show that all meteorological parameters (including temperature, RH, mixing layer height et al.) were generally consistent among different periods. Throughout the study period, the concentrations of most species displayed a "V-shaped" trend, suggesting significant effects by the restriction measures imposed during the lockdown period. While this is not the case for species like K, Cu and Ba, indicating their unusual origins. As a case study, the geographical origins of Cu were explored. Seven major sources, i.e., Vehicle-related emission (including road dust; indicative of Ca, Fe, Ba, Mn, Zn, Cu; accounting for 30.1%), shipping (Ni; 5.0%), coal combustion (As, Pb; 4.2%), Se and Cr industry (24.9%), nonferrous metal smelting (Au, Hg; 7.5%) and fireworks burning (K, Cu, Ba; 28.3%) were successfully pinpointed based on positive matrix factorization (PMF) analysis. Our source apportionment results also highlight fireworks burning was one of the dominant source of trace elements during the Chinese Lunar New Year holiday. It is worth noting that 56% of the total mass vehicular emissions are affiliated with non-exhaust sources (tire wear, brake wear, and road surface abrasion).


Asunto(s)
Contaminantes Atmosféricos , COVID-19 , Oligoelementos , Contaminantes Atmosféricos/análisis , China , Control de Enfermedades Transmisibles , Polvo/análisis , Ecosistema , Monitoreo del Ambiente , Humanos , Material Particulado/análisis , SARS-CoV-2 , Oligoelementos/análisis , Emisiones de Vehículos/análisis
5.
Int J Mol Sci ; 22(10)2021 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-34065633

RESUMEN

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial-mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial-mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.


Asunto(s)
Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Neoplasias del Colon/genética , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Antígenos CD/metabolismo , Cadherinas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Bases de Datos Genéticas , Molécula de Adhesión Celular Epitelial/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Técnicas de Silenciamiento del Gen , Humanos , Queratina-20/metabolismo , Invasividad Neoplásica/genética , Oxaliplatino/farmacología , Transporte de Proteínas , Vimentina/metabolismo , beta Catenina/metabolismo
6.
Geophys Res Lett ; 47(12): e2020GL088533, 2020 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-32836517

RESUMEN

It is a puzzle as to why more severe haze formed during the New Year Holiday in 2020 (NYH-20), when China was in an unprecedented state of shutdown to contain the coronavirus (COVID-19) outbreak, than in 2019 (NYH-19). We performed a comprehensive measurement and modeling analysis of the aerosol chemistry and physics at multiple sites in China (mainly in Shanghai) before, during, and after NYH-19 and NYH-20. Much higher secondary aerosol fraction in PM2.5 were observed during NYH-20 (73%) than during NYH-19 (59%). During NYH-20, PM2.5 levels correlated significantly with the oxidation ratio of nitrogen (r 2 = 0.77, p < 0.01), and aged particles from northern China were found to impede atmospheric new particle formation and growth in Shanghai. A markedly enhanced efficiency of nitrate aerosol formation was observed along the transport pathways during NYH-20, despite the overall low atmospheric NO2 levels.

7.
Philos Trans A Math Phys Eng Sci ; 378(2183): 20190314, 2020 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-32981430

RESUMEN

Air pollution has been recognized as a threat to human health since the time of Hippocrates, ca 400 BC. Successive written accounts of air pollution occur in different countries through the following two millennia until measurements, from the eighteenth century onwards, show the growing scale of poor air quality in urban centres and close to industry, and the chemical characteristics of the gases and particulate matter. The industrial revolution accelerated both the magnitude of emissions of the primary pollutants and the geographical spread of contributing countries as highly polluted cities became the defining issue, culminating with the great smog of London in 1952. Europe and North America dominated emissions and suffered the majority of adverse effects until the latter decades of the twentieth century, by which time the transboundary issues of acid rain, forest decline and ground-level ozone became the main environmental and political air quality issues. As controls on emissions of sulfur and nitrogen oxides (SO2 and NOx) began to take effect in Europe and North America, emissions in East and South Asia grew strongly and dominated global emissions by the early years of the twenty-first century. The effects of air quality on human health had also returned to the top of the priorities by 2000 as new epidemiological evidence emerged. By this time, extensive networks of surface measurements and satellite remote sensing provided global measurements of both primary and secondary pollutants. Global emissions of SO2 and NOx peaked, respectively, in ca 1990 and 2018 and have since declined to 2020 as a result of widespread emission controls. By contrast, with a lack of actions to abate ammonia, global emissions have continued to grow. This article is part of a discussion meeting issue 'Air quality, past present and future'.


Asunto(s)
Contaminación del Aire , Lluvia Ácida , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/historia , Contaminación del Aire/legislación & jurisprudencia , Ciudades , Ecosistema , Monitoreo del Ambiente , Eutrofización , Salud Global/historia , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Historia Antigua , Historia Medieval , Humanos , Ozono/análisis , Material Particulado/análisis , Tecnología de Sensores Remotos
8.
Environ Sci Technol ; 53(4): 1822-1833, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30645946

RESUMEN

Ammonia (NH3) is the predominant alkaline gas in the atmosphere contributing to formation of fine particles-a leading environmental cause of increased morbidity and mortality worldwide. Prior findings suggest that NH3 in the urban atmosphere derives from a complex mixture of agricultural (mainly livestock production and fertilizer application) and nonagricultural (e.g., urban waste, fossil fuel-related emissions) sources; however, a citywide holistic assessment is hitherto lacking. Here we show that NH3 from nonagricultural sources rivals agricultural NH3 source contributions in the Shanghai urban atmosphere. We base our conclusion on four independent approaches: (i) a full-year operation of a passive NH3 monitoring network at 14 locations covering urban, suburban, and rural landscapes; (ii) model-measurement comparison of hourly NH3 concentrations at a pair of urban and rural supersites; (iii) source-specific NH3 measurements from emission sources; and (iv) localized isotopic signatures of NH3 sources integrated in a Bayesian isotope mixing model to make isotope-based source apportionment estimates of ambient NH3. Results indicate that nonagricultural sources and agricultural sources are both important contributors to NH3 in the urban atmosphere. These findings highlight opportunities to limit NH3 emissions from nonagricultural sources to help curb PM2.5 pollution in urban China.


Asunto(s)
Contaminantes Atmosféricos , Amoníaco , Teorema de Bayes , China , Monitoreo del Ambiente
9.
Blood ; 128(26): 3137-3145, 2016 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-27737892

RESUMEN

Megakaryocyte polyploidy is characterized by cytokinesis failure resulting from defects in contractile forces at the cleavage furrow. Although immature megakaryocytes express 2 nonmuscle myosin II isoforms (MYH9 [NMIIA] and MYH10 [NMIIB]), only NMIIB localizes at the cleavage furrow, and its subsequent absence contributes to polyploidy. In this study, we tried to understand why the abundant NMIIA does not localize at the furrow by focusing on the RhoA/ROCK pathway that has a low activity in polyploid megakaryocytes. We observed that under low RhoA activity, NMII isoforms presented different activity that determined their localization. Inhibition of RhoA/ROCK signaling abolished the localization of NMIIB, whereas constitutively active RhoA induced NMIIA at the cleavage furrow. Thus, although high RhoA activity favored the localization of both the isoforms, only NMIIB could localize at the furrow at low RhoA activity. This was further confirmed in erythroblasts that have a higher basal RhoA activity than megakaryocytes and express both NMIIA and NMIIB at the cleavage furrow. Decreased RhoA activity in erythroblasts abolished localization of NMIIA but not of NMIIB from the furrow. This differential localization was related to differences in actin turnover. Megakaryocytes had a higher actin turnover compared with erythroblasts. Strikingly, inhibition of actin polymerization was found to be sufficient to recapitulate the effects of inhibition of RhoA/ROCK pathway on NMII isoform localization; thus, cytokinesis failure in megakaryocytes is the consequence of both the absence of NMIIB and a low RhoA activity that impairs NMIIA localization at the cleavage furrow through increased actin turnover.


Asunto(s)
Citocinesis , Megacariocitos/citología , Megacariocitos/metabolismo , Miosina Tipo IIA no Muscular/metabolismo , Miosina Tipo IIB no Muscular/metabolismo , Actinas/metabolismo , Eritrocitos/citología , Humanos , Cadenas Ligeras de Miosina/metabolismo , Fosforilación , Polimerizacion , Isoformas de Proteínas/metabolismo , Transporte de Proteínas , Transducción de Señal , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo
10.
Environ Sci Technol ; 51(14): 7842-7852, 2017 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-28648047

RESUMEN

Source apportionment of organic carbon (OC) and elemental carbon (EC) from PM1 (particulate matter with a diameter equal to or smaller than 1 µm) in Beijing, China was carried out using radiocarbon (14C) measurement. Despite a dominant fossil-fuel contribution to EC due to large emissions from traffic and coal combustion, nonfossil sources are dominant contributors of OC in Beijing throughout the year except during the winter. Primary emission was the most important contributor to fossil-fuel derived OC for all seasons. A clear seasonal trend was found for biomass-burning contribution to OC with the highest in autumn and spring, followed by winter and summer. 14C results were also integrated with those from positive matrix factorization (PMF) of organic aerosols from aerosol mass spectrometer (AMS) measurements during winter and spring. The results suggest that the fossil-derived primary OC was dominated by coal combustion emissions whereas secondary OC was mostly from fossil-fuel emissions. Taken together with previous 14C studies in Asia, Europe and USA, a ubiquity and dominance of nonfossil contribution to OC aerosols is identified not only in rural/background/remote regions but also in urban regions, which may be explained by cooking contributions, regional transportation or local emissions of seasonal-dependent biomass burning emission. In addition, biogenic and biomass burning derived SOA may be further enhanced by unresolved atmospheric processes.


Asunto(s)
Aerosoles , Contaminantes Atmosféricos , Monitoreo del Ambiente , Asia , Beijing , Carbono , China , Europa (Continente) , Material Particulado
11.
Blood ; 124(16): 2564-8, 2014 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-25185263

RESUMEN

Endomitosis is a unique megakaryocyte (MK) differentiation process that is the consequence of a late cytokinesis failure associated with a contractile ring defect. Evidence from in vitro studies has revealed the distinct roles of 2 nonmuscle myosin IIs (NMIIs) on MK endomitosis: only NMII-B (MYH10), but not NMII-A (MYH9), is localized in the MK contractile ring and implicated in mitosis/endomitosis transition. Here, we studied 2 transgenic mouse models in which nonmuscle myosin heavy chain (NMHC) II-A was genetically replaced either by II-B or by a chimeric NMHCII that combined the head domain of II-A with the rod and tail domains of II-B. This study provides in vivo evidence on the specific role of NMII-B on MK polyploidization. It demonstrates that the carboxyl-terminal domain of the heavy chains determines myosin II localization to the MK contractile ring and is responsible for the specific role of NMII-B in MK polyploidization.


Asunto(s)
Megacariocitos/citología , Cadenas Pesadas de Miosina/análisis , Cadenas Pesadas de Miosina/metabolismo , Miosina Tipo IIB no Muscular/análisis , Miosina Tipo IIB no Muscular/metabolismo , Animales , Diferenciación Celular , Megacariocitos/metabolismo , Ratones , Ratones Transgénicos , Mitosis , Cadenas Pesadas de Miosina/genética , Miosina Tipo IIA no Muscular/química , Miosina Tipo IIA no Muscular/genética , Miosina Tipo IIB no Muscular/genética , Poliploidía , Estructura Terciaria de Proteína
12.
Blood ; 124(26): 3967-77, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25298036

RESUMEN

Megakaryocytes are highly specialized precursor cells that produce platelets via cytoplasmic extensions called proplatelets. Proplatelet formation (PPF) requires profound changes in microtubule and actin organization. In this work, we demonstrated that DIAPH1 (mDia1), a mammalian homolog of Drosophila diaphanous that works as an effector of the small GTPase Rho, negatively regulates PPF by controlling the dynamics of the actin and microtubule cytoskeletons. Moreover, we showed that inhibition of both DIAPH1 and the Rho-associated protein kinase (Rock)/myosin pathway increased PPF via coordination of both cytoskeletons. We provide evidence that 2 major effectors of the Rho GTPase pathway (DIAPH1 and Rock/myosin II) are involved not only in Rho-mediated stress fibers assembly, but also in the regulation of microtubule stability and dynamics during PPF.


Asunto(s)
Actinas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citoesqueleto/metabolismo , Megacariocitos/citología , Microtúbulos/metabolismo , Antígenos CD34/metabolismo , Plaquetas/citología , Plaquetas/metabolismo , Diferenciación Celular , Clonación Molecular , Forminas , GTP Fosfohidrolasas/metabolismo , Humanos , Lentivirus/genética , Miosina Tipo II/metabolismo , ARN Interferente Pequeño/metabolismo , Trombopoyetina/química , Tubulina (Proteína)/química
14.
Environ Sci Technol ; 49(4): 2066-72, 2015 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-25606710

RESUMEN

China is seeking to unlock its shale gas in order to curb its notorious urban air pollution, but robust assessment of the impact on PM2.5 pollution of replacing coal with natural gas for winter heating is lacking. Here, using a whole-city heating energy shift opportunity offered by substantial reductions in coal combustion during the heating periods in Urumqi, northwest China, we conducted a four-year study to reveal the impact of replacing coal with natural gas on the mass concentrations and chemical components of PM2.5. We found a significant decline in PM2.5, major soluble ions and metal elements in PM2.5 in January of 2013 and 2014 compared with the same periods in 2012 and 2011, reflecting the positive effects on air quality of using natural gas as a heating fuel throughout the city. This occurred following complete replacement with natural gas for heating energy in October 2012. The weather conditions during winter did not show any significant variation over the four years of the study. Our results indicate that China and other developing nations will benefit greatly from a change in energy source, that is, increasing the contribution of either natural gas or shale gas to total energy consumption with a concomitant reduction in coal consumption.


Asunto(s)
Contaminación del Aire/prevención & control , Aire/normas , Conservación de los Recursos Energéticos/métodos , Calefacción/métodos , Gas Natural/análisis , Material Particulado/análisis , Contaminación del Aire/análisis , China , Ciudades , Carbón Mineral/análisis , Monitoreo del Ambiente , Metales/análisis , Tamaño de la Partícula , Material Particulado/química , Estaciones del Año , Tiempo (Meteorología)
15.
Blood ; 120(13): 2719-22, 2012 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-22677128

RESUMEN

RUNX1 gene alterations are associated with acquired and inherited hematologic malignancies that include familial platelet disorder/acute myeloid leukemia, primary or secondary acute myeloid leukemia, and chronic myelomonocytic leukemia. Recently, we reported that RUNX1-mediated silencing of nonmuscle myosin heavy chain IIB (MYH10) was required for megakaryocyte ploidization and maturation. Here we demonstrate that runx1 deletion in mice induces the persistence of MYH10 in platelets, and a similar persistence was observed in platelets of patients with constitutional (familial platelet disorder/acute myeloid leukemia) or acquired (chronic myelomonocytic leukemia) RUNX1 mutations. MYH10 was also detected in platelets of patients with the Paris-Trousseau syndrome, a thrombocytopenia related to the deletion of the transcription factor FLI1 that forms a complex with RUNX1 to regulate megakaryopoiesis, whereas MYH10 persistence was not observed in other inherited forms of thrombocytopenia. We propose MYH10 detection as a new and simple tool to identify inherited platelet disorders and myeloid neoplasms with abnormalities in RUNX1 and its associated proteins.


Asunto(s)
Biomarcadores/metabolismo , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Plaquetas/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/fisiología , Cadenas Pesadas de Miosina/genética , Miosina Tipo IIB no Muscular/genética , Proteína Proto-Oncogénica c-fli-1/genética , Animales , Trastornos de las Plaquetas Sanguíneas/genética , Trastornos de las Plaquetas Sanguíneas/metabolismo , Plaquetas/patología , Estudios de Casos y Controles , Hibridación Genómica Comparativa , Femenino , Predisposición Genética a la Enfermedad , Humanos , Immunoblotting , Síndrome de Deleción Distal 11q de Jacobsen/diagnóstico , Síndrome de Deleción Distal 11q de Jacobsen/genética , Síndrome de Deleción Distal 11q de Jacobsen/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/metabolismo , Masculino , Megacariocitos/patología , Ratones , Cadenas Pesadas de Miosina/metabolismo , Miosina Tipo IIB no Muscular/metabolismo , Linaje , Ploidias , Pronóstico , Proteína Proto-Oncogénica c-fli-1/metabolismo , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/metabolismo
16.
EMBO Mol Med ; 16(6): 1404-1426, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38684864

RESUMEN

As an important immune stimulator and modulator, IFNγ is crucial for gut homeostasis and its dysregulation links to diverse colon pathologies, such as colitis and colorectal cancer (CRC). Here, we demonstrated that the epigenetic regulator, CBX3 (also known as HP1γ) antagonizes IFNγ signaling in the colon epithelium by transcriptionally repressing two critical IFNγ-responsive genes: STAT1 and CD274 (encoding Programmed death-ligand 1, PD-L1). Accordingly, CBX3 deletion resulted in chronic mouse colon inflammation, accompanied by upregulated STAT1 and CD274 expressions. Chromatin immunoprecipitation indicated that CBX3 tethers to STAT1 and CD274 promoters to inhibit their expression. Reversely, IFNγ significantly reduces CBX3 binding to these promoters and primes gene expression. This antagonist effect between CBX3 and IFNγ on STAT1/PD-L1 expression was also observed in CRC. Strikingly, CBX3 deletion heightened CRC cells sensitivity to IFNγ, which ultimately enhanced their chemosensitivity under IFNγ stimulation in vitro with CRC cells and in vivo with a syngeneic mouse tumor model. Overall, this work reveals that by negatively tuning IFNγ-stimulated immune genes' transcription, CBX3 participates in modulating colon inflammatory response and CRC chemo-resistance.


Asunto(s)
Antígeno B7-H1 , Proteínas Cromosómicas no Histona , Neoplasias Colorrectales , Interferón gamma , Factor de Transcripción STAT1 , Animales , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Interferón gamma/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Humanos , Ratones , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Colitis/metabolismo , Colitis/patología , Ratones Endogámicos C57BL , Transducción de Señal , Línea Celular Tumoral
17.
Cancers (Basel) ; 16(1)2023 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-38201582

RESUMEN

(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.

18.
Cells ; 12(17)2023 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-37681908

RESUMEN

(1) Background: Breast cancer is a frequent heterogeneous disorder diagnosed in women and causes a high number of mortality among this population due to rapid metastasis and disease recurrence. Ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy, and inhibit distant metastases, potentially impacting the tumor microenvironment. (2) Methods: Through data mining, the ferroptosis/extracellular matrix remodeling literature text-mining results were integrated into the breast cancer transcriptome cohort, taking into account patients with distant relapse-free survival (DRFS) under adjuvant therapy (anthracyclin + taxanes) with validation in an independent METABRIC cohort, along with the MDA-MB-231 and HCC338 transcriptome functional experiments with ferroptosis activations (GSE173905). (3) Results: Ferroptosis/extracellular matrix remodeling text-mining identified 910 associated genes. Univariate Cox analyses focused on breast cancer (GSE25066) selected 252 individual significant genes, of which 170 were found to have an adverse expression. Functional enrichment of these 170 adverse genes predicted basal breast cancer signatures. Through text-mining, some ferroptosis-significant adverse-selected genes shared citations in the domain of ECM remodeling, such as TNF, IL6, SET, CDKN2A, EGFR, HMGB1, KRAS, MET, LCN2, HIF1A, and TLR4. A molecular score based on the expression of the eleven genes was found predictive of the worst prognosis breast cancer at the univariate level: basal subtype, short DRFS, high-grade values 3 and 4, and estrogen and progesterone receptor negative and nodal stages 2 and 3. This eleven-gene signature was validated as regulated by ferroptosis inductors (erastin and RSL3) in the triple-negative breast cancer cellular model MDA-MB-231. (4) Conclusions: The crosstalk between ECM remodeling-ferroptosis functionalities allowed for defining a molecular score, which has been characterized as an independent adverse parameter in the prognosis of breast cancer patients. The gene signature of this molecular score has been validated to be regulated by erastin/RSL3 ferroptosis activators. This molecular score could be promising to evaluate the ECM-related impact of ferroptosis target therapies in breast cancer.


Asunto(s)
Ferroptosis , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Ferroptosis/genética , Recurrencia Local de Neoplasia , Fenómenos Fisiológicos Celulares , Neoplasias de la Mama Triple Negativas/genética , Estrógenos , Microambiente Tumoral/genética
19.
Cell Death Dis ; 14(11): 744, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37968262

RESUMEN

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment.


Asunto(s)
Neoplasias de la Mama , Ferroptosis , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Hierro/metabolismo , Células Madre Neoplásicas/metabolismo
20.
Sci Bull (Beijing) ; 68(13): 1447-1455, 2023 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-37328366

RESUMEN

Gas-phase dimethylamine (DMA) has recently been identified as one of the most important vapors to initiate new particle formation (NPF), even in China's polluted atmosphere. Nevertheless, there remains a fundamental need for understanding the atmospheric life cycle of DMA, particularly in urban areas. Here we pioneered large-scale mobile observations of the DMA concentrations within cities and across two pan-region transects of north-to-south (∼700 km) and west-to-east (∼2000 km) in China. Unexpectedly, DMA concentrations (mean ± 1σ) in South China with scattered croplands (0.018 ± 0.010 ppbv, 1 ppbv=10-9 L/L) were over three times higher than those in the north with contiguous croplands (0.005 ± 0.001 ppbv), suggesting that nonagricultural activities may be an important source of DMA. Particularly in non-rural regions, incidental pulsed industrial emissions led to some of the highest DMA concentration levels in the world (>2.3 ppbv). Besides, in highly urbanized areas of Shanghai, supported by direct source-emission measurements, the spatial pattern of DMA was generally correlated with population (R2 = 0.31) due to associated residential emissions rather than vehicular emissions. Chemical transport simulations further show that in the most populated regions of Shanghai, residential DMA emissions can contribute for up to 78% of particle number concentrations. Shanghai is a case study for populous megacities, and the impacts of nonagricultural emissions on local DMA concentration and nucleation are likely similar for other major urban regions globally.

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