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1.
Sci Total Environ ; 772: 144829, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33578154

RESUMO

This study reports on the first continuous measurements of ambient OH and HO2 radicals at a suburban site in Chengdu, Southwest China, which were collected during 2019 as part of a comprehensive field campaign 'CompreHensive field experiment to explOre the photochemical Ozone formation mechaniSm in summEr - 2019 (CHOOSE-2019)'. The mean concentrations (11:00-15:00) of the observed OH and HO2 radicals were 9.5 × 106 and 9.0 × 108 cm-3, respectively. To investigate the state-of-the-art chemical mechanism of radical, closure experiments were conducted with a box model, in which the RACM2 mechanism updated with the latest isoprene chemistry (RACM2-LIM1) was used. In the base run, OH radicals were underestimated by the model for the low-NO regime, which was likely due to the missing OH recycling. However, good agreement between the observed and modeled OH concentrations was achieved when an additional species X (equivalent to 0.25 ppb of NO mixing ratio) from one new OH regeneration cycle (RO2 + X â†’ HO2, HO2 + X â†’ OH) was added into the model. Additionally, in the base run, the model could reproduce the observed HO2 concentrations. Discrepancies in the observed and modeled HO2 concentrations were found in the sensitivity runs with HO2 heterogeneous uptake, indicating that the impact of the uptake may be less significant in Chengdu because of the relatively low aerosol concentrations. The ROx (= OH + HO2 + RO2) primary source was dominated by photolysis reactions, in which HONO, O3, and HCHO photolysis accounted for 34%, 19%, and 23% during the daytime, respectively. The efficiency of radical cycling was quantified by the radical chain length, which was determined by the NO to NO2 ratio successfully. The parameterization of the radical chain length may be very useful for the further determinations of radical recycling.

2.
Sci Total Environ ; : 144127, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33288267

RESUMO

Photolysis of nitrous acid (HONO) is one of the major sources for atmospheric hydroxyl radicals (OH), playing significant role in initiating tropospheric photochemical reactions for ozone (O3) production. However, scarce field investigations were conducted to elucidate this effect. In this study, a field campaign was conducted at a suburban site in southwest China. The whole observation was classified into three periods based on O3 levels and data coverage: the serious O3 pollution period (Aug 13-18 as P1), the O3 pollution period (Aug 22-28 as P2) and the clean period (Sep 3-12 as P3), with average O3 peak values of 96 ppb, 82 ppb and 44 ppb, respectively. There was no significant difference of the levels of O3 precursors (VOCs and NOx) between P1 and P2, and thus the evident elevation of OH peak values in P1 was suspected to be the most possible explanation for the higher O3 peak values. Considering the larger contribution of HONO photolysis to HOX primary production than photolysis of HCHO, O3 and ozonolysis of Alkenes, sensitivity tests of HONO reduction on O3 production rate in P1 are conducted by a 0-dimension model. Reduced HONO concentration effectively slows the O3 production in the morning, and such effect correlates with the calculated production rate of OH radicals from HONO photolysis. Higher HONO level supplying for OH radical initiation in the early morning might be the main reason for the higher O3 peak values in P1, which explained the correlation (R2 = 0.51) between average O3 value during daytime (10:00-19:00 LT) and average HONO value during early morning (00:00-05:00 LT). For nighttime accumulation, a suitable range of relative humidity that favored NO2 conversion within P1 was assumed to be the reason for the higher HONO concentration in the following early morning which promoted O3 peak values.

3.
Cell Death Discov ; 6(1): 121, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33298855

RESUMO

The PML/RARα fusion protein acts in concert with cooperative genetic events in the development of acute promyelocytic leukemia (APL). However, oncogenic long non-coding RNAs (lncRNAs) cooperating with PML/RARα remain under-explored. Here, we first identified a set of pathogenesis-related lncRNAs, aberrantly expressed in APL using RNA-seq data from a large cohort of acute myeloid leukemia (AML) patients and normal counterparts. Among the pathogenesis-related lncRNAs, one of the evolutionarily conservative lncRNAs CRNDE (Colorectal Neoplasia Differentially Expressed) drew our attention. We found that CRNDE was highly expressed in the disease state but not in the preleukemic stage of APL, suggesting that CRNDE might be a secondary event coordinating with PML/RARα to promote APL development. Functional analysis showed that CRNDE knockdown induced differentiation and inhibited proliferation of APL cells, and prolonged survival of APL mice. Further mechanistic studies showed that CRNDE elicited its oncogenic effects through binding the miR-181 family and thereby regulating NOTCH2. Finally, we found that high CRNDE expression was also significantly correlated with NPM1 mutations and contributed to the differentiation block in NPM1-mutant AML. Collectively, our findings shed light on the importance of oncogenic lncRNAs in the development of AML and provide a promising target for AML therapy.

4.
Dev Biol ; 470: 49-61, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33188738

RESUMO

Mutations in non-muscle myosin 2A (NM2A) encompass a wide spectrum of anomalies collectively known as MYH9-Related Disease (MYH9-RD) in humans that can include macrothrombocytopenia, glomerulosclerosis, deafness, and cataracts. We previously created mouse models of the three mutations most frequently found in humans: R702C, D1424N, and E1841K. While homozygous R702C and D1424N mutations are embryonic lethal, we found homozygous mutant E1841K mice to be viable. However the homozygous male, but not female, mice were infertile. Here, we report that these mice have reduced testis size and defects in actin-associated junctions in Sertoli cells, resulting in inability to form the blood-testis barrier and premature germ cell loss. Moreover, compound double heterozygous (R702C/E1841K and D1424/E1841K) males show the same abnormalities in testes as E1841K homozygous males. Conditional ablation of either NM2A or NM2B alone in Sertoli cells has no effect on fertility and testis size, however deletion of both NM2A and NM2B in Sertoli cells results in infertility. Isolation of mutant E1841K Sertoli cells reveals decreased NM2A and F-actin colocalization and thicker NM2A filaments. Furthermore, AE1841K/AE1841K and double knockout Sertoli cells demonstrate microtubule disorganization and increased tubulin acetylation, suggesting defects in the microtubule cytoskeleton. Together, these results demonstrate that NM2A and 2B paralogs play redundant roles in Sertoli cells and are essential for testes development and normal fertility.

5.
Hum Mol Genet ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030203

RESUMO

Proteus syndrome is a progressive overgrowth disorder with vascular malformations caused by mosaic expression of the AKT1 c.49G > A, p.(E17K) activating variant which was predicted to cause lethality if expressed ubiquitously. To test that hypothesis, we used the ACTB-Cre gene to activate a conditional Akt1 p.(E17K) allele in the mouse. No offspring heterozygous for both Cre and the conditional allele (ßA-Akt1WT/flx) were viable. Fewer than expected numbers of ßA-Akt1WT/flx embryos were seen beginning at E11.5, but a few survived until E17.5. The phenotype ranged from mild to severe but generally ßA-Akt1WT/flx embryos had fewer visible blood vessels and more hemorrhages than their wild type littermates suggestive of a vascular abnormality. Examination of E13.5 limb skin showed a primitive capillary network with increased branching complexity and abnormal patterning compared to wild type skin. By E15.5, wild type skin had undergone angiogenesis and formed a hierarchical network of remodeled vessels, whereas in ßA-Akt1WT/flx embryos, the capillary network failed to remodel. Mural cell coverage of the blood vessels was also reduced in ßA-Akt1WT/flx skin compared to that of wild type. Restricting expression of Akt1E17K to endothelial, cardiac or smooth muscle cells resulted in viable offspring and remodeled vasculature and did not recapitulate the ßA-Akt1WT/flx phenotype. We conclude that ubiquitous expression of Akt1E17K suppresses remodeling and inhibits the formation of a normal skin vasculature. We postulate that this failure prevents proper circulation necessary to support the growing embryo and that it is the result of interactions of multiple cell types with increased AKT signaling.

6.
Exp Eye Res ; : 108300, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33065089

RESUMO

Diabetic retinopathy (DR) is the leading cause of visual impairment and acquired blindness among adults worldwide. Retinal microvascular pericyte deficiency is one of the earliest pathological changes associated with DR, and long noncoding RNA myocardial infarction-associated transcript (MIAT) has been implicated as a crucial regulator of microvascular dysfunction in DR. Pyroptosis is a caspase-1-dependent proinflammatory form of cell death, and in the present study, we investigated the potential pyroptosis of primary human retinal pericytes (HRPCs) and the mechanism by which MIAT is involved in this process. We applied advanced glycation end product modified bovine serum albumin (AGE-BSA) to simulate the DR environment. The results suggested that AGE-BSA induced the active cleavage of caspase-1 and gasdermin D, the release of IL-1ß, IL-18 and LDH, and reduced cell viability, which was prevented by the inhibition of caspase-1, indicating the occurrence of caspase-1-mediated pyroptosis in HRPCs. Immunofluorescence images revealed the phenotypic characteristics of pyroptosis, including pyknosis, swelling and hyperpermeability in plasmolemma. MIAT and CASP1 expression were substantially increased, while that of miR-342-3p was decreased in AGE-BSA-treated HRPCs. MIAT knockdown inhibited pyroptosis in HRPCs, which was reinforced by cotreatment with miR-342-3p mimic but relieved by cotreatment with miR-342-3p inhibitor. Furthermore, HRPC pyroptosis was inhibited by treatment with the miR-342-3p mimic alone but enhanced by the miR-342-3p inhibitor. Luciferase reporter assay results demonstrated binding between MIAT and miR-342-3p, as well as between miR-342-3p and CASP1. MIAT antagonized the effect of miR-342-3p on the depression of its target CASP1 and promoted AGE-BSA-induced pericyte pyroptosis. These findings may promote a better understanding of retinal pericyte depletion pathogenesis and the development of new therapeutic strategies for the treatment of diabetic retinopathy.

7.
Environ Sci Technol ; 54(15): 9243-9253, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32589840

RESUMO

Particulate nitrate (pNO3-) has often been found to be the major component of fine particles in urban air-sheds in China, the United States, and Europe during winter haze episodes in recent years. However, there is a lack of knowledge regarding the experimentally determined contribution of different chemical pathways to the formation of pNO3-. Here, for the first time, we combine ground and tall-tower observations to quantify the chemical formation of pNO3- using observationally constrained model approach based on direct observations of OH and N2O5 for the urban air-shed. We find that the gas-phase oxidation pathway (OH+NO2) during the daytime is the dominant channel over the nocturnal uptake of N2O5 during pollution episodes, with percentages of 74% in urban areas and 76% in suburban areas. This is quite different from previous studies in some regions of the US, in which the uptake of N2O5 was concluded to account for a larger contribution in winter. These results indicate that the driving factor of nitrate pollution in Beijing and different regions of the US is different, as are the mitigation strategies for particulate nitrate.


Assuntos
Poluentes Atmosféricos , Material Particulado , Poluentes Atmosféricos/análise , Pequim , China , Monitoramento Ambiental , Europa (Continente) , Material Particulado/análise , Estações do Ano
8.
Mol Biol Cell ; 31(18): 1974-1987, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32583739

RESUMO

Among the three nonmuscle myosin 2 (NM2) paralogs, NM 2A and 2B, but not 2C, are detected in endothelial cells. To study the role of NM2 in vascular formation, we ablate NM2 in endothelial cells in mice. Ablating NM2A, but not NM2B, results in reduced blood vessel coverage and increased vascular branching in the developing mouse skin and coronary vasculature. NM2B becomes essential for vascular formation when NM2A expression is limited. Mice ablated for NM2B and one allele of NM2A develop vascular abnormalities similar to those in NM2A ablated mice. Using the embryoid body angiogenic sprouting assay in collagen gels reveals that NM2A is required for persistent angiogenic sprouting by stabilizing the endothelial cell cortex, and thereby preventing excessive branching and ensuring persistent migration of the endothelial sprouts. Mechanistically, NM2 promotes focal adhesion formation and cortical protrusion retraction during angiogenic sprouting. Further studies demonstrate the critical role of Rho kinase-activated NM2 signaling in the regulation of angiogenic sprouting in vitro and in vivo.

9.
World Neurosurg ; 138: 608-618, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31953096

RESUMO

This paper used magnetic resonance diffusion kurtosis imaging to observe the acute cerebral infarction model of mice, and studied the imaging changes of ischemic penumbra after perfusion of model for rat middle cerebral artery occlusion experiment, and combined with the physiologic changes of mice. The damage of neurons was evaluated by the evolution of N-methyl-D-aspartate receptors to provide a corresponding imaging basis for the diagnosis and treatment of ischemic penumbra. The research shows that the diffusivity value decreases with time, and the diffusion kurtosis increases with time. The difference in diffusivity between different parts of the same time point and the same part of the same point (except the edge relative to the normal area) is statistically different. Learning significance was set at P < 0.05. The expression of N-methyl-D-aspartate receptor 2A in tissue homogenate increased overall, and expression in synaptic membrane, synaptic membrane, and light membrane decreased. The expression of N-methyl-D-aspartate acid receptor 2B in tissue homogenate, synaptic membrane, and light cell membrane decreased, and it increased first and then decreased in the synaptic membrane. The studies confirmed that magnetic resonance imaging has a certain clinical diagnostic value for the penumbra evolution mechanism and neuronal injury of acute cerebral infarction, which deserves further study.


Assuntos
Infarto Cerebral/terapia , Imagem por Ressonância Magnética/métodos , Técnicas de Sonda Molecular , Células-Tronco Neurais/transplante , Paralisia/terapia , Células-Tronco Pluripotentes/transplante , Animais , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/patologia , Membro Posterior/diagnóstico por imagem , Membro Posterior/patologia , Sondas Moleculares , Paralisia/diagnóstico por imagem , Ratos
10.
Eur J Pharmacol ; 864: 172715, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593687

RESUMO

Non-alcoholic steatohepatitis (NASH) is a key step in the progression of non-alcoholic fatty liver disease (NAFLD), which causes serious health problems worldwide. The nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor-containing pyrin domain 3 (NLRP3) inflammasome and pyroptosis play crucial roles in the progression of NASH. Our team has provided clinical evidence of the effects of glucagon-like peptide-1 (GLP-1) on the improvement in liver function and histological resolution of NAFLD. Preliminary work has demonstrated that GLP-1 inhibited NLRP3 inflammasome activation in a mouse model of NAFLD. We further explored the potential molecular mechanisms underlying the anti-inflammatory effect of liraglutide, a long-acting GLP-1 analog, in the treatment of NASH. We established a HepG2 cell model of NASH using double stimulation with palmitic acid and lipopolysaccharide to assess NLRP3 inflammasome and pyroptotic cell activity and to evaluate mitochondrial function and mitophagy. Liraglutide reduced lipid accumulation, inhibited NLRP3 inflammasome and pyroptosis activation, attenuated mitochondrial dysfunction and reactive oxygen species generation, augmented mitophagy in hepatocytes. Mitophagy inhibition with 3-methyladenine/PINK1-directed siRNA weakened the liraglutide-mediated suppression of inflammatory injury. We propose that liraglutide suppresses NLRP3 inflammasome-induced hepatocyte pyroptosis via mitophagy to slow the progression of NASH.


Assuntos
Inflamassomos/metabolismo , Liraglutida/farmacologia , Mitofagia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Piroptose/efeitos dos fármacos , Progressão da Doença , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Liraglutida/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1696-1700, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607334

RESUMO

Abstract  The promyelocytic leukemia (PML) gene encoded PML protein as a tumor suppressor protein, plays important roles in the occurrence and development of various cancers including acute promyelocytic leukemia. Recent studies have indicated that there are a variety of post-translational modifications of the PML protein, such as SUMOylation, ubiquitination, phosphorylation, and acetylation in cells. These modifications of the PML protein can directly affect the formation of PML nuclear bodies (PML-NBs), repair DNA damage, and modulate cell apoptosis. Furthermore, the abnormal modifications of PML not only result in the occurrence of hematopoietic tumors, but also are closely related to the drug-resistance of cancer. Therefore, investigating the post-translational modifications of PML is significant to uncover the mechanism of formation and functions of PML-NBs, thus contributing to the prevention and treatment of related hematopoietic tumors. In this review, the characteristics of the post-translational modifications of PML protein and the relationship between these modifications and functions of PML-NBs are summarized so as to provide the potential targets for the treatment of related cancers.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Corpos de Inclusão Intranuclear , Proteínas Nucleares , Proteína da Leucemia Promielocítica , Processamento de Proteína Pós-Traducional
12.
Environ Sci Technol ; 53(18): 10676-10684, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31418557

RESUMO

In contrast to summer smog, the contribution of photochemistry to the formation of winter haze in northern mid-to-high latitude is generally assumed to be minor due to reduced solar UV and water vapor concentrations. Our comprehensive observations of atmospheric radicals and relevant parameters during several haze events in winter 2016 Beijing, however, reveal surprisingly high hydroxyl radical oxidation rates up to 15 ppbv/h, which is comparable to the high values reported in summer photochemical smog and is two to three times larger than those determined in previous observations during winter in Birmingham (Heard et al. Geophys. Res. Lett. 2004, 31, (18)), Tokyo (Kanaya et al. J. Geophys. Res.: Atmos. 2007, 112, (D21)), and New York (Ren et al. Atmos. Environ. 2006, 40, 252-263). The active photochemistry facilitates the production of secondary pollutants. It is mainly initiated by the photolysis of nitrous acid and ozonolysis of olefins and maintained by an extremely efficiently radical cycling process driven by nitric oxide. This boosted radical recycling generates fast photochemical ozone production rates that are again comparable to those during summer photochemical smog. The formation of ozone, however, is currently masked by its efficient chemical removal by nitrogen oxides contributing to the high level of wintertime particles. The future emission regulations, such as the reduction of nitrogen oxide emissions, therefore are facing the challenge of reducing haze and avoiding an increase in ozone pollution at the same time. Efficient control strategies to mitigate winter haze in Beijing may require measures similar as implemented to avoid photochemical smog in summer.


Assuntos
Poluentes Atmosféricos , Ozônio , Pequim , New York , Fotoquímica , Smog
13.
Mol Biol Cell ; 30(16): 1961-1973, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31318315

RESUMO

Contact guidance refers to the ability of cells to sense the geometrical features of the microenvironment and respond by changing their shape and adopting the appropriate orientation. Inhibition and ablation of nonmuscle myosin 2 (NM2) paralogues have demonstrated their importance for contact guidance. However, the specific roles of the NM2 paralogues have not been systematically studied. In this work we use micropatterned substrates to examine the roles of NM2A and NM2B and to elucidate the relationship of the microenvironment, actomyosin, and microtubules in contact guidance. We show that contact guidance is preserved following loss of NM2B and that expression of NM2A alone is sufficient to establish an appropriate orientation of the cells. Loss of NM2B and overexpression of NM2A result in a prominent cell polarization that is found to be linked to the increased alignment of microtubules with the actomyosin scaffold. Suppression of actomyosin with blebbistatin reduces cell polarity on a flat surface, but not on a surface with contact guidance cues. This indicates that the lost microtubule-actomyosin interactions are compensated for by microtubule-microenvironment interactions, which are sufficient to establish cell polarity through contact guidance.


Assuntos
Comunicação Celular , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Actomiosina/metabolismo , Animais , Polaridade Celular , Forma Celular , Fibroblastos/metabolismo , Camundongos , Microtúbulos/metabolismo , Fibras de Estresse/metabolismo
14.
Sci Total Environ ; 685: 85-95, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174126

RESUMO

A field campaign was conducted from November to December 2017 at the campus of Peking University (PKU) to investigate the formation mechanism of the winter air pollution in Beijing with the measurement of hydroxyl and hydroperoxyl radical (OH and HO2) with the support from comprehensive observation of trace gases compounds. The extent of air pollution depends on meteorological conditions. The daily maximum OH radical concentrations are on average 2.0 × 106 cm-3 and 1.5 × 106 cm-3 during the clean and polluted episodes, respectively. The daily maximum HO2 radical concentrations are on average 0.4 × 108 cm-3 and 0.3 × 108 cm-3 during the clean and polluted episodes, respectively (diurnal averaged for one hour bin). A box model based on RACM2-LIM1 mechanism can reproduce the OH concentrations but underestimate the HO2 concentrations by 50% during the clean episode. The OH and HO2 concentrations are underestimated by 50% and 12 folds during the polluted episode, respectively. Strong dependence on nitric oxide (NO) concentration is found for both observed and modeled HO2 concentrations, with the modeled HO2 decreasing more rapidly than observed HO2, leading to severe HO2 underestimation at higher NO concentrations. The OH reactivity is calculated from measured and modeled species and inorganic compounds (carbon monoxide (CO), NO, and nitrogen dioxide (NO2)) make up 69%-76% of the calculated OH reactivity. The photochemical oxidation rate denoted by the OH loss rate increases by 3 times from the clean to polluted episodes, indicating the strong oxidation capacity in polluted conditions. The comparison between measurements at PKU site and a suburban site from one previous study shows that chemical conditions are similar in both urban and suburban areas. Hence, the strong oxidation capacity and its potential contribution to the pollution bursts are relatively homogeneous over the whole Beijing city and its surrounding areas.

15.
Front Med ; 13(3): 330-343, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29808251

RESUMO

Alternative splicing is a tightly regulated process that contributes to cancer development. CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers. However, whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain unclear. In this study, we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic malignancies. The investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific manner. Further comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies, including 3 reported and 8 unreported, and also implicated that the overexpressed isoforms differed in various cancer types. Furthermore, anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples, and even had different impacts on the expression of CRNDE isoforms. Finally, experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer types. Collectively, our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms, and may provide promising targets for cancer diagnosis and therapy.


Assuntos
Processamento Alternativo/genética , Carcinogênese/genética , Neoplasias/genética , RNA Longo não Codificante/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Neoplasias/metabolismo , RNA Longo não Codificante/efeitos dos fármacos
16.
Nat Commun ; 9(1): 4600, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389913

RESUMO

Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is downregulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.


Assuntos
Matriz Extracelular/metabolismo , Pneumopatias/metabolismo , Cadeias Pesadas de Miosina/deficiência , Miosina não Muscular Tipo IIB/deficiência , Sequência de Aminoácidos , Animais , Regulação para Baixo/genética , Enfisema/patologia , Etilnitrosoureia , Feminino , Pneumopatias/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Mesoderma/metabolismo , Camundongos Endogâmicos C57BL , Mutagênese/genética , Mutação de Sentido Incorreto/genética , Cadeias Pesadas de Miosina/química , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Miosina não Muscular Tipo IIB/química , Miosina não Muscular Tipo IIB/genética , Miosina não Muscular Tipo IIB/metabolismo , Organogênese , Fenótipo , Alvéolos Pulmonares/embriologia , Alvéolos Pulmonares/metabolismo , Regulação para Cima/genética
17.
Mol Biol Cell ; 29(19): 2326-2335, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30044719

RESUMO

Three paralogues of nonmuscle myosin 2 (NM 2A, 2B, and 2C) are expressed in mammals, and the heavy chains are the products of three different genes (Myh9, Myh10, and Myh14, respectively). NM 2A and 2B are essential for mouse development, while 2C is not. Studies on NM 2C are limited and the in vivo function of this paralogue is not clear. Using homologous recombination, cDNA encoding nonmuscle myosin heavy chain 2C1 fused with GFP was introduced into the first coding exon of Myh9, replacing NM 2A expression with NM 2C1 expression in mice. In contrast to A-/A- embryos, which die by embryonic day (E) 6.5, AC1*gfp/AC1*gfp embryos survive through E8.5, demonstrating that NM 2C1 can support mouse development beyond gastrulation. At E9.5 and E10.5, however, AC1*gfp/AC1*gfp embryos are developmentally delayed, with abnormalities in placental vascular formation. The defect in vascular formation is confirmed in allantois explants from AC1*gfp/AC1*gfp embryos. Thus, NM 2C1 cannot support normal placental vascular formation. In addition, AC1*gfp/AC1*gfp mouse embryonic fibroblasts (MEFs) migrate rapidly but with impaired persistence and develop smaller, less mature focal adhesions than A+/A+ MEFs. This is attributed to enhanced NM 2C1 actomyosin stability and different NM 2C1 subcellular localization than in NM 2A.


Assuntos
Gastrulação , Miosina Tipo II/metabolismo , Neovascularização Fisiológica , Miosina não Muscular Tipo IIA/metabolismo , Placenta/irrigação sanguínea , Actomiosina/metabolismo , Alantoide , Animais , Movimento Celular , Perda do Embrião/patologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Fibroblastos/citologia , Recuperação de Fluorescência Após Fotodegradação , Camundongos , Gravidez , Fibras de Estresse/metabolismo
18.
Gastroenterol Res Pract ; 2018: 1864307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849583

RESUMO

Objective: This study is aimed at investigating whether exenatide (Exe) delays the progression of nonalcoholic fatty liver disease (NAFLD) in C57BL/6 mice by targeting the NLRP3 inflammasome through the autophagy/mitophagy pathway. Methods: Thirty male C57BL/6 mice were randomly divided into three groups: control group (n = 10), model group (n = 10), and Exe (exenatide) group (n = 10). Mouse models of NAFLD and diabetes were established using a high-fat diet and streptozocin. Results: The levels of fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) in the serum were significantly reduced after Exe treatment. The body weight, liver weight/body weight, and number of lipid droplets in the liver significantly decreased in Exe-treated mice. Treatment with Exe markedly reduced the levels of liver lipids, malondialdehyde (MDA), and alanine aminotransferase (ALT) in serum and livers. The number of autophagosomes increased significantly in the Exe group. The expression of LC3A/B-II/I, Beclin-1, Parkin, and BNIP3L increased significantly, whereas NLRP3 and IL-1ß proteins were suppressed after Exe treatment. Conclusion: We successfully established a mouse model of NAFLD and diabetes. Exe may reduce oxidative stress injury and inhibit the NLRP3 inflammasome by enhancing the autophagy/mitophagy pathway in liver, which has a protective effect on the liver in NAFLD and diabetes in C57BL/6 mice.

19.
Cell Death Dis ; 9(6): 651, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29844435

RESUMO

Circular RNAs (circRNAs) are a novel class of powerful regulators in gene expression and participate in the pathogenesis of many diseases, including cancer. However, little is known about the roles of circRNAs in the development and treatment of acute promyelocytic leukemia (APL). Here we report the expression profiling and function of circRNAs in APL, including their dynamic regulation during all-trans retinoic acid (ATRA)-induced differentiation. We performed two independent ribosomal RNA-minus RNA-sequencing (Ribo-minus RNA-seq) experiments with and without RNase R treatment on APL patient-derived NB4 cells and identified a total of 4313 circRNAs, including 1098 newly identified circRNAs. Detailed analysis showed that circRNAs expressed in APL cells were mostly exon-derived, not by-products during splicing, and could be distinguished from hematopoietic stem cells, neutrophils and lymphocytes. The true presence and stability of circRNAs were verified both in NB4 cells and primary APL patient samples. Moreover, we conducted a time-series analysis of circRNAs on ATRA-treated NB4 cells and uncovered 508 circRNAs with dynamic expression during ATRA treatment, including 246 upregulated and 262 downregulated. Further evidence demonstrated that the majority of circRNAs were regulated independently of their host linear mRNAs. Detailed functional experiments demonstrated that circ-HIPK2, one of the differentially expressed circRNAs, significantly influenced ATRA-induced differentiation of APL cells. Further mechanistic studies revealed that circ-HIPK2 was located in cytoplasm and served as a sponge for differentiation-associated miR-124-3p. Finally, circ-HIPK2 expression in APL patients was significantly lower than that in normal peripheral mononuclear cells and other subtypes of AML, indicating its potential role as an APL biomarker. Our study indicates the biological functions of circRNAs in the development and treatment of APL, and provides a comprehensive circRNA resource for future studies.


Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Promielocítica Aguda/genética , RNA Circular/genética , Tretinoína/farmacologia , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Genoma Humano , Células HEK293 , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
20.
Peptides ; 105: 7-13, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29746877

RESUMO

Retinal pericyte migration represents a novel mechanism of pericyte loss in diabetic retinopathy (DR), which plays a crucial role in the early impairment of the blood-retinal barrier (BRB). Glucagon-like peptide-1 (GLP-1) has been shown to protect the diabetic retina in the early stage of DR; however, the relationship between GLP-1 and retinal pericytes has not been discussed. In this study, advanced glycation end products (AGEs) significantly increased the migration of primary bovine retinal pericytes without influencing cell viability. AGEs also significantly enhanced phosphatidylinositol 3-kinase (PI3K)/Akt activation, and changed the expressions of migration-related proteins, including phosphorylated focal adhesion kinase (p-FAK), matrix metalloproteinase (MMP)-2 and vinculin. PI3K inhibition significantly attenuated the AGEs-induced migration of retinal pericytes and reversed the overexpression of MMP-2. Glucagon-like peptide-1 receptor (Glp1r) was expressed in retinal pericytes, and liraglutide, a GLP-1 analog, significantly attenuated the migration of pericytes by Glp1r and reversed the changes in p-Akt/Akt, p-FAK/FAK, vinculin and MMP-2 levels induced by AGEs, indicating that the protective effect of liraglutide was associated with the PI3K/Akt pathway. These results provided new insights into the mechanism underlying retinal pericyte migration. The early use of liraglutide exerts a potential bebefical effect on regulating pericyte migration, which might contribute to mechanisms that maintain the integrity of vascular barrier and delay the development of DR.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Produtos Finais de Glicação Avançada/metabolismo , Pericitos/metabolismo , Retina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Barreira Hematorretiniana/metabolismo , Bovinos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Quinase 1 de Adesão Focal/metabolismo , Peptídeo 1 Semelhante ao Glucagon/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Liraglutida/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Pericitos/efeitos dos fármacos , Retina/patologia
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