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1.
J Integr Plant Biol ; 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35043580

RESUMO

Although two Enhancer of Polycomb-like proteins, EPL1A and EPL1B (EPL1A/B), are known to be conserved and characteristic subunits of the NuA4-type histone acetyltransferase complex in Arabidopsis thaliana, the biological function of EPL1A/B and the mechanism by which EPL1A/B function in the complex remain unknown. Here, we report that EPL1A/B are required for the histone acetyltransferase activity of the NuA4 complex on the nucleosomal histone H4 in vitro and for the enrichment of histone H4K5 acetylation at thousands of protein-coding genes in vivo. We demonstrate that EPL1A/B are required for linking the NuA4 catalytic subunit HAM1 with accessory subunits in the NuA4 complex. EPL1A/B function redundantly in regulating plant development especially in chlorophyll biosynthesis and de-etiolation. The EPL1A/B-dependent transcription and H4K5Ac are enriched at genes involved in chlorophyll biosynthesis and photosynthesis. We also find that EAF6, another characteristic subunit of the NuA4 complex, contribute to de-etiolation. These results suggest that the Arabidopsis NuA4 complex components function as a whole to mediate histone acetylation and transcriptional activation specifically at light-responsive genes and are critical for photomorphogenesis. This article is protected by copyright. All rights reserved.

3.
Sci Total Environ ; 806(Pt 1): 150411, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34563899

RESUMO

To assess the impacts of regulations and laws enhancing the management of e-waste in China, hair samples of local residents and dismantling workers in a former e-waste area in 2016 and 2019, five and eight years after the implementation of legislation and regulations in this area since 2011, respectively. The temporal changes in levels of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organophosphorus flame retardants (OPFRs) in the hair samples were investigated. Besides, the levels of these organic contaminants in hair samples collected from the same area in 2009, 2011, and 2015 reported in previous studies were used as comparison. The highest median levels of Σ9PCBs (719 ng/g), Σ3Penta-BDEs (16.1 ng/g), and Σ3Octa-BDEs (8.46 ng/g) in hair were found in 2011, with a significant decrease trend was observed from 2011 to 2019 (p < 0.05). As for Deca-BDE, the levels reached the maximum in 2015 (133 ng/g), following by a significant decrease to 2016 (7.46 ng/g) and 2019 (2.61 ng/g) (p < 0.05). The median levels of Σ8OPFRs, also decreased significantly (p < 0.05) from 2015 (357 ng/g) to 2016 (264 ng/g) and 2019 (112 ng/g). Moreover, a significantly increasing trend was observed for the ratios of triphenyl phosphate (TPHP) and tris(2-chloropropyl) phosphate (TCIPP), two predominant OPFRs, to Deca-BDE from 2015 to 2019 (p < 0.01), suggesting a shift of "legacy" to "emerging" contaminants released from e-waste recycling in this area. The temporal changes in hair levels of typical organic contaminants in residents and dismantling workers indicated the effectiveness of the regulations on informal e-waste recycling activities and solid waste in China.


Assuntos
Resíduo Eletrônico , Retardadores de Chama , China , Resíduo Eletrônico/análise , Monitoramento Ambiental , Retardadores de Chama/análise , Éteres Difenil Halogenados/análise , Humanos , Reciclagem
4.
Nucleic Acids Res ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34850113

RESUMO

Mixed lineage leukemia 1 (MLL1) is a histone methyltransferase. Kaposi's sarcoma-associated herpesvirus (KSHV) is a leading cause of malignancy in AIDS. KSHV latently infects tumor cells and its genome is decorated with epigenetic marks. Here, we show that KSHV latency-associated nuclear antigen (LANA) recruits MLL1 to viral DNA where it establishes H3K4me3 modifications at the extensive KSHV terminal repeat elements during primary infection. LANA interacts with MLL1 complex members, including WDR5, integrates into the MLL1 complex, and regulates MLL1 activity. We describe the 1.5-Å crystal structure of N-terminal LANA peptide complexed with MLL1 complex member WDR5, which reveals a potential regulatory mechanism. Disruption of MLL1 expression rendered KSHV latency establishment highly deficient. This deficiency was rescued by MLL1 but not by catalytically inactive MLL1. Therefore, MLL1 is LANA regulable and exerts a central role in virus infection. These results suggest broad potential for MLL1 regulation, including by non-host factors.

6.
Mol Med ; 27(1): 95, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34470609

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs), a type of pervasive genes that regulates various biological processes, are differentially expressed in different types of malignant tumors. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we investigated the role of the lncRNA DKFZp434J0226 in PDAC. METHODS: Aberrantly expressed mRNAs and lncRNAs among six PDAC and paired non-tumorous tissues were profiled using microarray analysis. Quantitative real-time polymerase chain reaction was used to evaluate DKFZp434J0226 expression in PDAC tissues. CCK-8 assay, wound-healing assay, soft agar colony formation assay, and transwell assay were performed to assess the invasiveness and proliferation of PDAC cells. Furthermore, RNA pull-down, immunofluorescence, RNA immunoprecipitation, and western blotting assays were performed to investigate the association between DKFZp434J0226 and SF3B6. Tumor xenografts in mice were used to test for tumor formation in vivo. RESULTS: In our study, 222 mRNAs and 128 lncRNAs were aberrantly expressed (≥ twofold change). Of these, 66 mRNAs and 53 lncRNAs were upregulated, while 75 lncRNAs and 156 mRNAs were downregulated. KEGG pathway analysis and the Gene ontology category indicated that these genes were associated with the regulation of mRNA alternative splicing and metabolic balance. Clinical analyses revealed that overexpression of DKFZp434J0226 was associated with worse tumor grading, frequent perineural invasion, advanced tumor-node-metastasis stage, and decreased overall survival and time to progression. Functional assays demonstrated that DKFZp434J0226 promoted PDAC cell migration, invasion, and growth in vitro and accelerated tumor proliferation in vivo. Mechanistically, DKFZp434J0226 interacted with the splicing factor SF3B6 and promoted its phosphorylation, which further regulated the alternative splicing of pre-mRNA. CONCLUSIONS: This study indicates that DKFZp434J0226 regulates alternative splicing through phosphorylation of SF3B6 in PDAC and leads to an oncogenic phenotype in PDAC.

7.
Front Pharmacol ; 12: 705325, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262463

RESUMO

Patients with Crohn's disease (CD) are inclined to have platelet hyperactivity and an increased risk of intestinal micro-thrombosis. However, the mechanisms underlying platelet hyperactivity in CD are not well understood. We investigated the assembly of platelet NLRP3 inflammasome in patients with active CD and its correlation with platelet hyperactivity. In this study, Real-time PCR and western blotting analyses uncovered that ASC, NLRP3, and active caspase-1 were significantly upregulated in platelets from patients with active CD compared with healthy subjects. As revealed by flow cytometry (FCM) and ELISA analyses, the levels of interleukin-1ß in both serum and isolated platelets were elevated in patients with active CD. Co-immunoprecipitation and immunofluorescence experiments revealed an increased assembly of NLRP3 inflammasome in platelets from patients with active CD. In addition, higher levels of intracellular reactive oxygen species (ROS) were observed in these platelets by FCM. Furthermore, elevated levels of platelet P-selectin exposure and fibrinogen binding were demonstrated in patients with active CD by FCM. They were positively correlated with the protein levels of NLRP3 inflammasome components. Collectively, our results indicate that the ROS-NLRP3 inflammasome-interleukin-1ß axis may contribute to platelet hyperactivity in active CD.

8.
Plant Cell ; 33(10): 3250-3271, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34270751

RESUMO

In the INO80 chromatin remodeling complex, all of the accessory subunits are assembled on the following three domains of INO80: N-terminal domain (NTD), HSA domain, and ATPase domain. Although the ATPase and HSA domains and their interacting accessory subunits are known to be responsible for chromatin remodeling, it is largely unknown how the accessory subunits that interact with the INO80 NTD regulate chromatin status. Here, we identify both conserved and nonconserved accessory subunits that interact with the three domains in the INO80 complex in Arabidopsis thaliana. While the accessory subunits that interact with all the three INO80 domains can mediate transcriptional repression, the INO80 NTD and the accessory subunits interact with it can contribute to transcriptional activation even when the ATPase domain is absent, suggesting that INO80 has an ATPase-independent role. A subclass of the COMPASS histone H3K4 methyltransferase complexes interact with the INO80 NTD in the INO80 complex and function together with the other accessory subunits that interact with the INO80 NTD, thereby facilitating H3K4 trimethylation and transcriptional activation. This study suggests that the opposite effects of the INO80 complex on transcription are required for the balance between vegetative growth and flowering under diverse environmental conditions.

9.
J Genet Genomics ; 48(5): 369-383, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34144927

RESUMO

The Arabidopsis thaliana RPD3-type histone deacetylases have been known to form conserved SIN3-type histone deacetylase complexes, but whether they form other types of complexes is unknown. Here, we perform affinity purification followed by mass spectrometry and demonstrate that the Arabidopsis RPD3-type histone deacetylases HDA6 and HDA19 interact with several previously uncharacterized proteins, thereby forming three types of plant-specific histone deacetylase complexes, which we named SANT, ESANT, and ARID. RNA-seq indicates that the newly identified components function together with HDA6 and HDA19 and coregulate the expression of a number of genes. HDA6 and HDA19 were previously thought to repress gene transcription by histone deacetylation. We find that the histone deacetylase complexes can repress gene expression via both histone deacetylation-dependent and -independent mechanisms. In the mutants of histone deacetylase complexes, the expression of a number of stress-induced genes is up-regulated, and several mutants of the histone deacetylase complexes show severe retardation in growth. Considering that growth retardation is thought to be a trade-off for an increase in stress tolerance, we infer that the histone deacetylase complexes identified in this study prevent overexpression of stress-induced genes and thereby ensure normal growth of plants under nonstress conditions.

10.
J Genet Genomics ; 48(4): 333-340, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-34039517

RESUMO

Repair of DNA double-strand break (DSB) is critical for the maintenance of genome integrity. A class of DSB-induced small RNAs (diRNAs) has been shown to play an important role in DSB repair. In humans, diRNAs are associated with Ago2 and guide the recruitment of Rad51 to DSB sites to facilitate repair by homologous recombination (HR). Ago2 activity has been reported to be regulated by phosphorylation under normal and hypoxic conditions. However, the role of Ago2 phosphorylation in DNA damage repair is unexplored. Here, we show that S672, S828, T830, and S831 of human Ago2 are phosphorylated in response to ionizing radiation (IR). S672A mutation of Ago2 leads to significant reduction in Rad51 foci formation and HR efficiency. We further show that defective association of Ago2 S672A variant with DSB sites, instead of defects in diRNA and Rad51 binding, may account for decreased Rad51 foci formation and HR efficiency. Our study reveals a novel regulatory mechanism for the function of Ago2 in DNA repair.

11.
Elife ; 102021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34029184

RESUMO

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) normally signals to necroptosis by phosphorylating MLKL. We report here that when the cellular RIPK3 chaperone Hsp90/CDC37 level is low, RIPK3 also signals to apoptosis. The apoptotic function of RIPK3 requires phosphorylation of the serine 165/threonine 166 sites on its kinase activation loop, resulting in inactivation of RIPK3 kinase activity while gaining the ability to recruit RIPK1, FADD, and caspase-8 to form a cytosolic caspase-activating complex, thereby triggering apoptosis. We found that PGF2α induces RIPK3 expression in luteal granulosa cells in the ovary to cause luteal regression through this RIPK3-mediated apoptosis pathway. Mice carrying homozygous phosphorylation-resistant RIPK3 S165A/T166A knockin mutations failed to respond to PGF2α but retained pro-necroptotic function, whereas mice with phospho-mimicking S165D/T166E homozygous knock-in mutation underwent spontaneous apoptosis in multiple RIPK3-expressing tissues and died shortly after birth. Thus, RIPK3 signals to either necroptosis or apoptosis depending on its serine 165/threonine 166 phosphorylation status.


Assuntos
Apoptose , Corpo Lúteo/enzimologia , Dinoprosta/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Chaperoninas/genética , Chaperoninas/metabolismo , Corpo Lúteo/patologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Feminino , Células HEK293 , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutação , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais
12.
Cancer Sci ; 112(7): 2625-2641, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33931921

RESUMO

Bladder cancer (BLCA) remains the leading cause of cancer-related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2-box (CAGGTG) of PARD3 promoter-proximal. Inhibition of GSK-3ß promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936-1356 aa) and ZO-1 (1372-1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK-3ß/Snail/Par3/ZO-1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Neoplasias Pulmonares/secundário , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Núcleo Celular/metabolismo , Polaridade Celular/fisiologia , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fenótipo , Fosforilação , Prognóstico , Distribuição Aleatória , Fatores de Transcrição da Família Snail/genética , Junções Íntimas/fisiologia , Proteína da Zônula de Oclusão-1/metabolismo
13.
J Biol Chem ; 296: 100730, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33933448

RESUMO

Proper dendrite morphogenesis and synapse formation are essential for neuronal development and function. Dasm1, a member of the immunoglobulin superfamily, is known to promote dendrite outgrowth and excitatory synapse maturation in vitro. However, the in vivo function of Dasm1 in neuronal development and the underlying mechanisms are not well understood. To learn more, Dasm1 knockout mice were constructed and employed to confirm that Dasm1 regulates dendrite arborization and spine formation in vivo. We performed a yeast two-hybrid screen using Dasm1, revealing MRCKß as a putative partner; additional lines of evidence confirmed this interaction and identified cytoplasmic proline-rich region (823-947 aa) of Dasm1 and MRCKß self-activated kinase domain (CC1, 410-744 aa) as necessary and sufficient for binding. Using co-immunoprecipitation assay, autophosphorylation assay, and BS3 cross-linking assay, we show that Dasm1 binding triggers a change in MRCKß's conformation and subsequent dimerization, resulting in autophosphorylation and activation. Activated MRCKß in turn phosphorylates a class 2 regulatory myosin light chain, which leads to enhanced actin rearrangement, causing the dendrite outgrowth and spine formation observed before. Removal of Dasm1 in mice leads to behavioral abnormalities. Together, these results reveal a crucial molecular pathway mediating cell surface and intracellular signaling communication to regulate actin dynamics and neuronal development in the mammalian brain.


Assuntos
Actinas/metabolismo , Dendritos/metabolismo , Imunoglobulinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Espinhas Dendríticas/metabolismo , Imunoglobulinas/química , Camundongos , Proteínas do Tecido Nervoso/química , Ligação Proteica , Domínios Proteicos
14.
Biochem Biophys Res Commun ; 561: 172-179, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34023783

RESUMO

Loss of polarity protein Par3 promotes breast cancer tumorigenesis and metastasis. The underlying molecular mechanisms of Par3 down-regulation and related prognostic significance in breast cancer remain unclear. Here, we discovered that Par3 down-regulation was associated with shorter relapse-free survival in Luminal A subtype of breast cancer. Par3 knockdown promoted breast cancer cells migration and invasion. Importantly, we identified that transcription factor Sp1 bound to PARD3 promoter region and induced Par3 expression. Breast cancer patients with low Sp1 showed significantly worse RFS and low expression level of Par3. Par3 over-expression partially reversed Sp1 knockdown induced migration and invasion. Together, decreased Sp1 level mediates Par3 down-regulation, which correlated with poor prognosis of ER + breast cancer patients, via reduced binding with PARD3 promoter.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Recidiva Local de Neoplasia/patologia , Regiões Promotoras Genéticas , Fator de Transcrição Sp1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Polaridade Celular/fisiologia , Feminino , Humanos , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Taxa de Sobrevida
15.
Nucleic Acids Res ; 49(10): 5502-5519, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33963860

RESUMO

The histone chaperone facilitates chromatin transactions (FACT) functions in various DNA transactions. How FACT performs these multiple functions remains largely unknown. Here, we found, for the first time, that the N-terminal domain of its Spt16 subunit interacts with the Set3 histone deacetylase complex (Set3C) and that FACT and Set3C function in the same pathway to regulate gene expression in some settings. We observed that Spt16-G132D mutant proteins show defects in binding to Set3C but not other reported FACT interactors. At the permissive temperature, induction of the GAL1 and GAL10 genes is reduced in both spt16-G132D and set3Δ cells, whereas transient upregulation of GAL10 noncoding RNA (ncRNA), which is transcribed from the 3' end of the GAL10 gene, is elevated. Mutations that inhibit GAL10 ncRNA transcription reverse the GAL1 and GAL10 induction defects in spt16-G132D and set3Δ mutant cells. Mechanistically, set3Δ and FACT (spt16-G132D) mutants show reduced histone acetylation and increased nucleosome occupancy at the GAL1 promoter under inducing conditions and inhibition of GAL10 ncRNA transcription also partially reverses these chromatin changes. These results indicate that FACT interacts with Set3C, which in turn prevents uncontrolled GAL10 ncRNA expression and fine-tunes the expression of GAL genes upon a change in carbon source.


Assuntos
Cromatina/metabolismo , Galactoquinase/metabolismo , Regulação Fúngica da Expressão Gênica , Histona Desacetilases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Transcrição Genética , RNA não Traduzido/metabolismo , Transativadores , Ativação Transcricional
16.
Environ Pollut ; 284: 117208, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33930779

RESUMO

Organophosphate esters (OPEs) are ubiquitous contaminants in the environment, whereas their atmospheric processes and fate are poorly understood. The present study revealed the spatial heterogeneity and seasonal variations of traditional and novel OPEs in PM2.5 (particulate matter with diameters < 2.5 µm) across a megacity (including residential areas and potential source sites) in South China. Potential influencing factors on the contamination levels of OPEs were addressed. The total concentrations of 11 traditional OPEs ranging from 262 to 42,194 pg/m3 (median = 1872 pg/m3) were substantially higher than those of 10 novel OPEs (33.5-3835 pg/m3, median = 318 pg/m3). Significant spatial and temporal variations in the concentrations of most OPEs were observed. The overall district-specific contamination levels in this city showed dependence on the secondary industry sector for non-predominant OPEs and on the tertiary industry for predominant OPEs. The seasonal variations of the OPE concentrations suggest difference in their sources or influence of meteorological conditions. The correlations between the individual OPEs in PM2.5 are determined largely by either their applications or physicochemical properties (in particular vapor pressure). The correlations between OPE concentrations and each meteorological factor (temperature, relative humidity, wind speed, and surface solar radiation) were inconsistent (positive and negative). Wind speed had the greatest effect on the OPE levels; While most OPEs bound to PM2.5 were not efficiently scavenged by below-cloud rainfall. The results suggest that atmospheric half-life and Henry's Law Constant of OPEs are also determining factors for the wind speed and rainfall influence, respectively. However, mechanisms underlying the influence of meteorological conditions on atmospheric OPEs still need further research.


Assuntos
Retardadores de Chama , China , Cidades , Monitoramento Ambiental , Ésteres/análise , Retardadores de Chama/análise , Organofosfatos/análise , Material Particulado/análise
17.
Thromb J ; 19(1): 27, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910580

RESUMO

BACKGROUND: Sphingomyelin (SM) is an essential component of biological lipid rafts, and it plays an indispensable role in maintaining plasma membrane stability and in mediating signal transduction. The ultimate biosynthesis of SM is catalyzed by two sphingomyelin synthases (SMSs) namely SMS1 and SMS2, which are selectively distributed in the trans-Golgi apparatus and the plasma membrane. It has been demonstrated that SMS2 acts as an irreplaceable molecule in the regulation of transmembrane signaling, and loss of SMS2 has been reported to worsen atherosclerosis and liver steatosis. However, the function of SMS2 in platelet activation and its association with the pathological process of thrombosis in acute coronary syndrome (ACS) and portal hypertension (PH) remain unclear. METHODS: In this study, we tested the role of SMS2 in platelet activation and thrombosis using SMS2 knockout (SMS2 -/-) mice and SMS2-specific inhibitor, D609. Furthermore, we detected SMS2 expression in patients with ACS and PH. RESULTS: SMS2 -/- platelets showed significant reduction in platelet aggregation, spreading, clot retraction and in vivo thrombosis. Similar inhibitory effects on platelet activation were detected in D609-treated wild-type platelets. PLCγ/PI3K/Akt signaling pathway was inhibited in SMS2 -/- platelets and D609-treated wild-type platelets. In addition, we discovered that platelet SMS2 expression was remarkably increased in patients with ACS and PH, compared with healthy subjects. CONCLUSIONS: Our study indicates that SMS2 acts as a positive regulator of platelet activation and thrombosis, and provides a theoretical basis for the potential use of D609 in anti-thrombosis treatment.

18.
Environ Res ; 196: 110953, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667474

RESUMO

Air pollution by airborne particles is a serious health problem worldwide. The present study was aimed at investigating the concentrations and composition of total suspended particles (TSPs) and PM2.5 at various industrial/commercial sites of Guangzhou, a megacity of Southern China. Major and trace elements, ions and carbonaceous fraction were determined and main components were calculated. In addition, in order to assess the potential toxic on the respiratory system of these PM, cytotoxicity of size-fractionated particles (PM10-5.6, PM5.6-3.3, PM3.3-1.1, PM1.1-0.43) for a human lung cancer cell line (A549) was also investigated. Correlations between PM constituents and toxicity were assessed. Median levels of TSPs and PM2.5 in industrial/commercial sites were 206 and 57.7 µg/m3, respectively. Nickel, Cu, Mo, Mn, Pb, and Ti were the most abundant metals in TSPs and PM2.5. Industrial activities and coal combustion were the most important sources of carbonaceous particles in the zone. MTT assays showed that PM10-5.6 and PM1.1-0.43 had the highest and the lowest cytotoxicity to A549 cell lines, respectively. Inhalable particles around the manufacturing of metal facilities and formal waste treatment plants showed a high cytotoxicity to A549 cell lines. In general terms, no significant correlations were found between main components of PM and toxicity. However, W showed a significant correlation with cell viability.


Assuntos
Poluentes Atmosféricos , Neoplasias Pulmonares , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Linhagem Celular , China , Monitoramento Ambiental , Humanos , Tamanho da Partícula , Material Particulado/análise , Material Particulado/toxicidade
19.
EMBO Rep ; 22(4): e51606, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33655635

RESUMO

Reduction of mitochondrial membrane potential (Δψm ) is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain Δψm , which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here, we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA, respectively, exhibit activated stress responses and progressive reduction of Δψm . Extensive omics analyses of these mutants show that these mutants progressively activate adaptive responses, including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits, Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis, Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis, and transcriptional upregulation of cytoplasmic chaperones. These adaptations disinhibit mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain Δψm , ISC biosynthesis, and cell proliferation.


Assuntos
Mitocôndrias , Fosforilação Oxidativa , DNA Mitocondrial , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Biogênese de Organelas
20.
Mol Plant ; 14(7): 1071-1087, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33737195

RESUMO

The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an evolutionarily conserved histone acetyltransferase complex that has a critical role in histone acetylation, gene expression, and various developmental processes in eukaryotes. However, little is known about the composition and function of the SAGA complex in plants. In this study, we found that the SAGA complex in Arabidopsis thaliana contains not only conserved subunits but also four plant-specific subunits: three functionally redundant paralogs, SCS1, SCS2A, and SCS2B (SCS1/2A/2B), and a TAF-like subunit, TAFL. Mutations in SCS1/2A/2B lead to defective phenotypes similar to those caused by mutations in the genes encoding conserved SAGA subunits HAG1 and ADA2B, including delayed juvenile-to-adult phase transition, late flowering, and increased trichome density. Furthermore, we demonstrated that SCS1/2A/2B are required for the function of the SAGA complex in histone acetylation, thereby promoting the transcription of development-related genes. These results together suggest that SCS1/2A/2B are core subunits of the SAGA complex in Arabidopsis. Compared with SAGA complexes in other eukaryotes, the SAGA complexes in plants have evolved unique features that are necessary for normal growth and development.

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