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1.
Oncogene ; 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34759344

RESUMO

Castration-resistant prostate cancer (CRPC) is a highly malignant type of advanced cancer resistant to androgen deprivation therapy. One of the important mechanisms for the development of CRPC is the persistent imbalanced regulation of AR and AR splice variants (AR/AR-Vs). In this study, we reported KDM4A-AS1, a recently discovered lncRNA, as a tumor promoter that was significantly increased in CRPC cell lines and cancer tissues. Depletion of KDM4A-AS1 significantly reduced cell viability, proliferation, migration in vitro, and tumor growth in vivo. We found that by binding to the NTD domain, KDM4A-AS1 enhances the stability of USP14-AR/AR-Vs complex, and promoted AR/AR-Vs deubiquitination to protect it from MDM2-mediated ubiquitin-proteasome degradation. Moreover, KDM4A-AS1 was found to enhance CRPC drug resistance to enzalutamide by repressing AR/AR-Vs degradation; antisense oligonucleotide drugs targeting KDM4A-AS1 significantly reduced the growth of tumors with enzalutamide resistance. Taken together, our results indicated that KDM4A-AS1 played an important role in the progression of CRPC and enzalutamide resistance by regulating AR/AR-Vs deubiquitination; targeting KDM4A-AS1 has broad clinical application potential.

2.
Chemosphere ; : 132607, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34678341

RESUMO

Microplastic (MP) and nanoplastic (NP) induce neurotoxicity, cytotoxicity, and reproductive system toxicity in mammals. However, the impacts of NPs on the endocrine system are obscure. Here, monodisperse polystyrene nanoplastics (PS-NPs) were prepared by emulsion polymerization and the accumulation of fluorescent PS-NPs in various organs, including the liver, kidney, spleen, and pancreas, was examined. The oral administration of PS-NPs induced visceral organ injury, and the main toxicities were damage to hepatic function and the abnormity of lipid metabolism. Global transcriptome sequencing (RNA-Seq) revealed the impact of PS-NPs on the genes involved in reactive oxygen species (ROS) generation and the PI3K/Akt signaling pathway, which is associated with glucose metabolism in mice. Chronic exposure to PS-NPs significantly increased plasma glucose levels and ROS levels, but did not affect plasma insulin secretion. The phosphorylation of insulin receptor substrate (IRS)-1 at Ser307 was raised, which decreased the phosphorylation of Akt (at Ser473) in the PI3K/Akt pathway. Collectively, these findings suggested that the oral administration of PS-NPs significantly increased ROS, hepatic triglycerides, and cholesterol accumulation. The high levels of ROS disturbed the PI3K/Akt pathway, causing insulin resistance and increased plasma glucose in the mouse liver.

3.
PLoS One ; 16(10): e0252558, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34634047

RESUMO

The identification of antibody variable regions in the heavy (VH) and light (VL) chains from hybridomas is necessary for the production of recombinant, sequence-defined monoclonal antibodies (mAbs) and antibody derivatives. This process has received renewed attention in light of recent reports of hybridomas having unintended specificities due to the production of non-antigen specific heavy and/or light chains for the intended antigen. Here we report a surprising finding and potential pitfall in variable domain sequencing of an anti-human CD63 hybridoma. We amplified multiple VL genes from the hybridoma cDNA, including the well-known aberrant Sp2/0 myeloma VK and a unique, full-length VL. After finding that the unique VL failed to yield a functional antibody, we discovered an additional full-length sequence with surprising similarity (~95% sequence identify) to the non-translated myeloma kappa chain but with a correction of its key frameshift mutation. Expression of the recombinant mAb confirmed that this highly homologous sequence is the antigen-specific light chain. Our results highlight the complexity of PCR-based cloning of antibody genes and strategies useful for identification of correct sequences.


Assuntos
Anticorpos Monoclonais/genética , Hibridomas/fisiologia , Cadeias Leves de Imunoglobulina/genética , Mieloma Múltiplo/genética , Sequência de Aminoácidos , Animais , Células CHO , Linhagem Celular , Clonagem Molecular/métodos , Cricetulus , DNA Complementar/genética , Mutação da Fase de Leitura/genética , Genes de Imunoglobulinas/genética , Células HEK293 , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Camundongos , Proteínas Recombinantes/genética , Tetraspanina 30/genética
4.
Cell Death Dis ; 12(9): 825, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475393

RESUMO

Osteoporosis-related fractures, such as femoral neck and vertebral fractures, are common in aged people, resulting in increased disability rate and health-care costs. Thus, it is of great importance to clarify the mechanism of osteoclast-related osteoporosis and find effective ways to avoid its complication. In this study, gene expression profile analysis and real-time polymerase chain reaction revealed that DUSP6 expression was suppressed in human and mice osteoporosis cases. In vitro experiments confirmed that DUSP6 overexpression prevented osteoclastogenesis, whereas inhibition of DUSP6 by small interference RNA or with a chemical inhibitor, (E/Z)-BCI, had the opposite effect. (E/Z)-BCl significantly accelerated the bone loss process in vivo by enhancing osteoclastogenesis. Bioinformatics analyses and in vitro experiments indicated that miR-181a was an upstream regulator of DUSP6. Moreover, miR-181a positively induced the differentiation and negatively regulated the apoptosis of osteoclasts via DUSP6. Furthermore, downstream signals by ERK2 and SMAD2 were also found to be involved in this process. Evaluation of ERK2-deficiency bone marrow-derived macrophages confirmed the role of ERK2 signaling in the DUSP6-mediated osteoclastogenesis. Additionally, immunoprecipitation assays confirmed that DUSP6 directly modified the phosphorylation status of SMAD2 and the subsequent nuclear transportation of NFATC1 to regulate osteoclast differentiation. Altogether, this study demonstrated for the first time the role of miRNA-181a/DUSP6 in the progression of osteoporosis via the ERK2 and SMAD2 signaling pathway. Hence, DUSP6 may represent a novel target for the treatment of osteoclast-related diseases in the future.

5.
Cell Death Dis ; 12(10): 856, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545063

RESUMO

The refractory of castration-resistant prostate cancer (CRPC) is mainly reflected in drug resistance. The current research on the resistance mechanism of CRPC is still in its infancy. In this study, we revealed for the first time the key role of LncRNA PCBP1-AS1 in CRPC drug resistance. Through detailed in vivo and in vitro studies, we found that PCBP1-AS1 may enhance the deubiquitination of AR/AR-V7 by stabilizing the USP22-AR/AR-V7 complex, thereby preventing AR/AR-V7 from being degraded through the ubiquitin-proteasome pathway. Targeting PCBP1-AS1 can significantly restore the drug sensitivity of enzalutamide-resistant tumors in vivo and in vitro. Our research further expands the function of LncRNA in castration-resistant prostate cancer, which may provide new potential for clinical diagnosis and targeted therapy.

6.
Exp Eye Res ; 212: 108763, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34517004

RESUMO

Posterior capsule opacification (PCO) is a common ocular fibrosis disease related to the epithelial-mesenchymal transition (EMT) of human lens epithelial cells (HLECs). However, safe and effective drugs that prevent or treat PCO are lacking. Metformin (Mtf) has been used to treat fibrosis-related diseases affecting many organs and tissues, but its effect on ocular fibrosis-related diseases is unclear. We investigated whether Mtf can inhibit EMT and fibrosis in HLECs to prevent and treat PCO and elucidated the potential molecular mechanism. Here, we established an HLEC model of TGF-ß-induced EMT and found that 400 µM Mtf inhibited vertical and lateral migration and EMT-related gene and protein expression in HLECs. Smad2/3 are downstream molecules of TGF-ß that enter the nucleus to regulate EMT-related gene expression during the occurrence and development of PCO. We revealed that Mtf suppressed TGF-ß-induced Smad2/3 phosphorylation and nuclear translocation. Mtf induces AMP-activated protein kinase (AMPK) phosphorylation. In this study, we found that Mtf induced the activation of AMPK phosphorylation in HLECs. To further explore the mechanism of Mtf, we pretreated HLECs with Compound C (an AMPK inhibitor) to repeat the above experiments and found that Compound C abolished the inhibitory effect of Mtf on HLEC EMT and the TGF-ß/Smad2/3 signalling pathway. Thus, Mtf targets AMPK phosphorylation to inhibit the TGF-ß/Smad2/3 signalling pathway and prevent HLEC EMT. Notably, we first illustrated the AMPK/TGF-ß/Smad2/3 signalling pathway in HLECs, which may provide a new therapeutic strategy for PCO.

7.
Methods Mol Biol ; 2355: 163-173, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386959

RESUMO

Single-chain protein affinity ligands are recombinant polypeptides that recreate the antigen-binding site of parental, monoclonal antibodies (mAbs) or present unique binding surfaces derived from display technologies, computational design, or other approaches. These diverse ligands have several advantages over full-length mAbs as agents for delivery of small molecule, protein, and nanoparticle cargoes to desired sites in the body. However, they present unique challenges for modification and bioconjugation. Fusion of a LPXTGG motif, or "sortag," and a 5-amino acid, flexible linker to the C-terminus of these affinity ligands enables high-efficiency transpeptidation by the bacterial enzyme, Sortase A, and site-specific addition of fluorophores, radiolabels, or functional groups for oriented and stoichiometrically controlled bioconjugation. We describe in detail this method and address several challenges and pitfalls in the purification and characterization of modified single-chain affinity ligands.

8.
Adv Mater ; 33(34): e2101374, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34288156

RESUMO

The organic insulator-metal interface is the most important junction in flexible electronics. The strong band offset of organic insulators over the Fermi level of electrodes should theoretically impart a sufficient impediment for charge injection known as the Schottky barrier. However, defect formation through Anderson localization due to topological disorder in polymers leads to reduced barriers and hence cumbersome devices. A facile nanocoating comprising hundreds of highly oriented organic/inorganic alternating nanolayers is self-coassembled on the surface of polymer films to revive the Schottky barrier. Carrier injection over the enhanced barrier is further shunted by anisotropic 2D conduction. This new interface engineering strategy allows a significant elevation of the operating field for organic insulators by 45% and a 7× improvement in discharge efficiency for Kapton at 150 °C. This superior 2D nanocoating thus provides a defect-tolerant approach for effective reviving of the Schottky barrier, one century after its discovery, broadly applicable for flexible electronics.

9.
Environ Int ; 154: 106672, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34062401

RESUMO

Methylsiloxanes (MSs) are a significant source of indoor environmental pollution due to their high production level and widespread application, and pose a potential health risk. Given the special vulnerability of children to environmental contaminants, assessment of indoor MSs exposure in children is quite essential. In this study, we assessed internal exposure doses and external exposure levels of MSs in children from industrial and residential areas in southwestern China. Indoor air, indoor dust, and personal care product (PCP) samples were collected to evaluate indoor non-dietary MSs exposure in children through various pathways. The concentrations of MSs in indoor environments of industrial areas were approximately one to four orders of magnitude higher than those of residential areas. Sun protection products contained the highest concentrations of MSs. Relatively high levels of cyclic methylsiloxanes (CMSs) were found in plasma of children from industrial areas, which were one to two orders of magnitude higher than those in children from residential areas. The highest MSs levels in plasma were detected in infants (0-1 year), with values of 1.4 × 102 ng/mL and 1.3 × 102 ng/mL for CMSs (D4-D6) and linear methylsiloxanes (LMSs) (L5-L16), respectively. The internal exposure dose of infants in residential areas is driven by major unknown sources of MSs. The average daily doses via inhalation and dust ingestion in children from industrial areas were one to three orders of magnitude higher than in those from residential areas, indicating that these children should be considered a highly exposed population. Inhalation and dust ingestion were both major exposure pathways to MSs for children of all age groups in industrial areas, whereas dermal absorption from PCPs was the predominant exposure pathway for children of all age groups in residential areas (except for infants). Although the exposure risk to D4 and D5 was at an acceptable level for all children studied, the total daily exposure doses of these two cyclic compounds via inhalation for infants in the industrial areas was near the chronic reference dose. Meanwhile, MSs may accumulate in infant plasma within a short period of time (<6 months). Therefore, infants should be the focus of greater attention in future research. As indoor environments may pose high risks for infants in industrial areas, they should be the focus of future research.


Assuntos
Poluição do Ar em Ambientes Fechados , Poluição do Ar em Ambientes Fechados/análise , Criança , China , Poeira/análise , Exposição Ambiental/análise , Monitoramento Ambiental , Humanos , Lactente , Siloxanas/análise
10.
Environ Sci Pollut Res Int ; 28(36): 50767-50789, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33970422

RESUMO

Industrial restructuring is a significant measure for low-carbon transition. In principle, carbon emissions can be effectively reduced by limiting the output of high-emission sectors; however, the socio-economic effects of the sectors should also be considered. Moreover, owing to the limitations of the method or data, the interactions between households and production sectors have been neglected in the study of industrial restructuring, resulting in an incomplete and potentially biased understanding of the role of households. To fill this gap, we applied a semi-closed input-output model to identify key sectors by economic and emission linkages and measure the employment impacts (direct, indirect, and induced) of reduced carbon emissions. The empirical results for China in 2010-2018 showed that relatively small changes in key emission sectors would significantly affect the economic growth, and reduced carbon emissions reduction would generally lead to high job losses. Promoting labor-intensive sectors, particularly the service sector, is conducive to achieving a "multi-win" situation for economic development, carbon emission reductions, and stable employment. Furthermore, our results highlight the significance of households: expanding consumption and increasing household income can bring multiple benefits, such as economic growth, job creation, and low carbon emissions. These findings can provide useful information for identifying the optimized path of restructuring and helping achieve the sustainable development of the environment, economy, and society.


Assuntos
Carbono , Desenvolvimento Econômico , Carbono/análise , Dióxido de Carbono/análise , China , Emprego , Indústrias
11.
BMC Endocr Disord ; 21(1): 47, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711989

RESUMO

BACKGROUND: NKX6.1 is a transcription factor for insulin, as well as a marker for ß cell maturity. Abnormal NKX6.1 expression in ß cells, such as translocation from the nucleus to cytoplasm or lost expression, has been shown as a marker for ß cell dedifferentiation. METHODS: We obtained pancreatic sections from organ donors and immunofluorescence staining with NKX6.1 and insulin was performed to characterize NKX6.1 expression in subjects with or without type 2 diabetes mellitus (T2DM). RESULTS: Our results showed that cells with insulin expression but no nucleic NKX6.1 expression (NKX6.1Nuc-Ins+), and cells with cytoplasmic NKX6.1 expression but no insulin expression (NKX6.1cytIns-) were significantly increased in T2DM subjects and positively correlated with glycated hemoglobin (HbA1c), indicating the elevated ß cell dedifferentiation with NKX6.1 inactivation in T2DM. To investigate whether ß cell dedifferentiation has initiated in subjects with higher risks for T2DM, we next analyzed the association between ß-cell dedifferentiation level in ND subjects with different ages, body mass index, and HbA1c. The results showed the absolute number and percentage of dedifferentiated ß cells with NKX6.1 inactivation did not significantly change in subjects with advanced aging, obesity, or modest hyperglycemia, indicating that the ß cell dedifferentiation might mainly occur after T2DM was diagnosed. CONCLUSION: Our results suggested that NKX6.1 expression in ß cells was changed in type 2 diabetic subjects, evidenced by significantly increased NKX6.1Nuc-Ins+ and NKX6.1cytIns- cells. This abnormality did not occur more frequently in subjects with a higher risk for T2DM, suggesting that ß cell dedifferentiation might be secondary to the pathological changes in T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/metabolismo , Estado Pré-Diabético/metabolismo , Adulto , Idoso , Autopsia , Estudos de Casos e Controles , Contagem de Células , Diferenciação Celular , Diabetes Mellitus Tipo 2/patologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/patologia , Fatores de Risco
12.
Biochem Biophys Res Commun ; 546: 1-6, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33556637

RESUMO

Prostate cancer with high Gleason grade is prone to metastasis, which is one of the factors that seriously threaten the survival of patients, and it is also a treatment difficulty. In this study, we first revealed the potential connection between TPX2 and prostate cancer metastasis. We found that TPX2 is highly expressed in high-grade prostate cancer and is significantly related to poor prognosis. Depletion of TPX2 can significantly inhibit cell activity and migration, and in vivo experiments show that knockdown of TPX2 can significantly inhibit tumor growth. In terms of mechanism, we found that knocking down TPX2 can inhibit the expression of CDK1, repress the phosphorylation of ERK/GSK3ß/SNAIL signaling pathway, and thereby inhibit tumor epithelial-mesenchymal transition. Subsequently, we found that after rescuing TPX2, all related proteins and phenotype changes were restored, and this effect can be inhibited by CDK1 inhibitor, RO-3306. Our findings suggest the potential of TPX2 as an important target in anti-tumor metastasis therapy, which is conducive to precision medicine for prostate cancer.


Assuntos
Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Transição Epitelial-Mesenquimal , Glicogênio Sintase Quinase 3 beta/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Proteína Quinase CDC2/antagonistas & inibidores , Ciclo Celular , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Metástase Neoplásica/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Quinolinas/farmacologia , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Chemosphere ; 273: 129727, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33524747

RESUMO

Thiamethoxam (TMX) is one of the major compounds of neonicotinoids, the most widely used class of insecticides worldwide. Previously, TMX was considered a non-toxic neonicotinoid insecticide to mammals. However, the genotoxicity, cytotoxicity, and hepatotoxicity of TMX in mammals were recently reported. Thus far, the effects of TMX on the mouse liver and its detailed mechanism remain unclear. NNMT, strongly expressed in the liver, plays a critical role in body energy expenditure. To confirm the potential pathogenesis of liver dysfunction induced by TMX, ICR mice were exposed to TMX at a dose of 4 mg/kg and 20 mg/kg by gavage administration for 12 weeks. The data showed that chronic TMX exposure caused dyslipidemia and nonalcoholic fatty liver disease (NAFLD) in mice. Moreover, aggravated oxidative stress, dysfunction, and disorganized structure were also observed in TMX-treated mouse livers. In addition, increases of PPARγ, fatty acid synthase, and NNMT expression, as well as decreases of PPARα and GNMT expression, S-adenosylmethionine deficiency, and methionine metabolism disorder were also observed in TMX-treated mouse livers. These results suggest that chronic TMX exposure induces dyslipidemia and NAFLD in mice. Moreover, inhibition of NNMT in hepatocytes significantly reversed the effects of TMX. The molecular mechanism of TMX-induced NAFLD is mostly through NNMT-mediated methionine metabolism and methyl donor balance, which ultimately regulates PPARα signaling pathway. Inhibition of NNMT could be a potentially novel strategy for blocking the progression of NAFLD induced by TMX.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Fígado , Metionina , Camundongos , Camundongos Endogâmicos ICR , Nicotinamida N-Metiltransferase , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Tiametoxam
14.
Talanta ; 225: 122087, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33592798

RESUMO

Hypersensitive detection of organic pollutions with high toxicity in drinking water always keeps its challenge in electroanalysis due to their low concentration and electrochemical redox inert. In this work, a novel nanomaterial modified electrode for the sensitive detection of nitrobenzene (NB) is presented, based on environmental friendly and cost-effective Ni/Fe layered double hydroxides functionalized with sodium dodecyl sulfate (Ni/Fe(SDS)-LDH). Such 2D layered composites were prepared and used to improve the sensitivity for NB detection, due to its good catalytic activity for NB reduction. Besides, the proposed electrode shows a remarkably promoted sensitivity to NB compared to Ni/Fe-LDHs modified one. It is because that the surface modifier SDS can provide more adsorption sites to significantly improve the adsorption of NB, which has been confirmed by the adsorption experiment and the characterization of Fourier transform infrared spectroscopy (FTIR). As a result, an impressive sensing behaviour is achieved at the proposed Ni/Fe(SDS)-LDHs modified electrode with a sensitivity of 15.79 µA µM-1 cm-2. This work provides a promising way to build more advanced nanomaterials to electrochemical detection of organic pollution based on energetically synergizing of adsorption by surface functionalization engineering.

15.
Rev Sci Instrum ; 91(11): 114702, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33261459

RESUMO

Power sources play an important role in the characteristics and the applications of the electrothermal (ET) plasma as an edge localized mode (ELM) heat flux simulator. A repetitive high current ET plasma source with the capability of working at a 10 Hz repetition rate and peak current 7.5 kA is presented in this paper. By controlling the sequence of discharge of ten pulse power modules, a repetitive high heat flux plasma jet can be generated. A two-stage capillary structure is presented, and its repetitive trigger driving circuit based on surface flashover ignition is designed to achieve reliable and repetitive discharge. The topology of the inductive and capacitive (LC) series resonant circuit is applied to the charging system of the pulsed power source. The charging current is limited to 500 A with a charging time of 3.5 ms, and the ratio of the charging voltage to the operating voltage is 1.85. A diode and a power resistor in series are used to suppress the negative overvoltage, which is helpful to increase the thyristors' operating reliability. Using the designed repetitive ET plasma source, the characteristics of the ET plasma jet are investigated by measuring the voltages and currents and by obtaining images of the discharges. Experimental results show that the repetitive ET plasma generator can be used as an appropriate way to simulate the ELM-like heat flux plasma.

16.
Aging (Albany NY) ; 12(22): 23017-23028, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197887

RESUMO

Human papillomavirus type 11 (HPV11) is one of the main causes of condyloma acuminatum, a widespread sexually transmitted disease. During infection of its primary target cell, keratinocytes, it is likely to encounter the autophagy pathway, which is an intracellular maintenance process that is also able to target invading pathogens. It is currently unknown whether HPV11 is targeted by autophagy or whether it is able to escape autophagy-mediated killing. Here, we investigated the autophagy response during HPV11 pseudovirion (PsV) entry in human keratinocytes. Transmission electron microscopy showed that intracellular PsVs were sequestered in lumen of double-membrane autophagosomes that subsequently appeared to fuse with lysosomes, while confocal microscopy showed induction LC3 puncta, the hallmark of induced autophagy activity. Furthermore, quantitative infection assays showed that high autophagy activity resulted in reduced HPV11 PsV infectivity. Therefore, the autophagy pathway seemed to actively target invading HPV11 PsVs for destruction in the autolysosome. Western analysis on the phosphorylation state of autophagy regulators and upstream pathways indicated that autophagy was activated through interplay between Erk and Akt signaling. In conclusion, autophagy functions as a cellular protection mechanism against intracellular HPV11 and therefore therapies that stimulate autophagy may prevent recurrent condyloma acuminatum by helping eliminate latent HPV11 infections.


Assuntos
Autofagia , Papillomavirus Humano 11/patogenicidade , Queratinócitos/virologia , Infecções por Papillomavirus/virologia , Vírion/patogenicidade , Internalização do Vírus , Proteínas Relacionadas à Autofagia/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HaCaT , Interações Hospedeiro-Patógeno , Papillomavirus Humano 11/ultraestrutura , Humanos , Queratinócitos/metabolismo , Queratinócitos/ultraestrutura , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Vírion/ultraestrutura
17.
Int J Biol Sci ; 16(15): 2924-2937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061806

RESUMO

Human papillomavirus (HPV) is a DNA virus that causes sexually transmitted infections. The HPV oncoprotein E7 plays a critical role in the regulation of host immunity to promote the immune escape of HPV and the occurrence of cervical cancer or genital warts. Pyroptosis, a highly inflammatory form of programmed cell death, can be induced by inflammasomes and acts as a defense against pathogenic infection. However, whether HPV E7 can regulate cell pyroptosis to evade immune surveillance has not been determined. In this study, we found that HPV E7 could inhibit cell pyroptosis induced by transfection with dsDNA. The activation of the inflammasome, and the production of IL-18 and IL-1ß were also restrained by HPV E7. Mass spectrometry and immunoprecipitation showed that HPV E7 interacted with IFI16 and TRIM21. We also discovered that HPV E7 recruited the E3 ligase TRIM21 to ubiquitinate and degrade the IFI16 inflammasome, leading to the inhibition of cell pyroptosis and self-escape from immune surveillance. Thus, our study reveals an important immune escape mechanism in HPV infection and may provide targets for the development of a novel immunotherapeutic strategy to effectively restore antiviral immunity.

18.
Nanotechnology ; 31(47): 475707, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-32885793

RESUMO

In high-voltage direct current transmission systems, charges accumulate at the gas-solid interface, distorting the local field strength, causing a reduction in the flashover voltage, and threatening the safe and reliable operation of the power system. The latest research has found that doping metal nanoparticles into an epoxy resin effectively suppresses the surface charge accumulation on insulators and improves their flashover voltage. This paper further analyzes the microscopic mechanism of this phenomenon, establishes a single-electron tunneling mode, and draws two conclusions: when there is no agglomeration of the doped nanoparticles, a higher doping concentration can be achieved, which provides a better insulative performance. The optimal metal nanoparticle radius is several to tens of nanometers. This work provides theoretical guidance for the future improvement of insulating materials through metal nanoparticle doping and has good prospects in engineering applications.

19.
Front Genet ; 11: 819, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849815

RESUMO

High-risk human papillomavirus (HPV) infections are the predominant cause of cervical cancer and its early gene E7 plays an important role in cellular proliferation and cell-cycle progression. While tremendous progress has been made in exploring the molecular mechanisms in late tumorigenesis, many pathways showing how HPV deregulates host gene expression in early inapparent infections and early tumorigenesis still remain undefined. Digital RNA sequencing was performed and a total of 195 differentially expressed genes were identified between the HPV16 E7-transfected NHEKs and control cells (p < 0.05, fold-change > 2). GO enrichment showed that HPV16 E7 primarily affected processes involved in anti-viral and immune responses, while KEGG pathway analysis showed enrichment of gene clusters of associated with HPV infection and MAPK signaling. Of the differentially expressed genes, IFI6, SLC39A9 and ZNF185 showed a strong correlation with tumor progression and patient survival in the OncoLnc database while roles for AKAP12 and DUSP5 in carcinogenesis and poor prognosis have previously been established for other cancer types. Our study identified several novel HPV16 E7-regulated candidate genes with putative functions in tumorigenesis, thus providing new insights into HPV persistence in keratinocytes and early onset of tumorigenesis.

20.
Environ Int ; 143: 105931, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32634670

RESUMO

Methylsiloxanes (MSs) are ubiquitous in indoor air and pose an important health risk. Thus, assessments of indoor inhalation exposure by measuring MSs levels in plasma are needed. In this study, we measured plasma MSs concentrations and evaluated daily indoor inhalation exposure in potentially exposed populations, including residents of industrial areas, university campus, and residential areas, all located in southwestern China. The concentrations of MSs in indoor air (gas-phase and PM2.5) collected from factory housing and from girls' dormitories on university campus were approximately one to three orders of magnitude higher than in parallel samples from other areas. The consequences of MSs exposure were investigated by measuring MSs levels in the plasma samples of the exposed populations. Relatively high levels of cyclic MSs (CMSs: D4-D6) were found in the plasma of the co-resident family members of factory workers and in female college students living in campus dormitories. The highest levels of CMSs (D4-D6) and linear MSs (L5-L16), 2.3 × 102 and 2.0 × 102 ng/mL, respectively, were detected in the very young (0-3 years old) co-resident children of factory workers. The average daily dose via inhalation (ADDinh) in different groups showed that the ADDinh values of all MSs (D4-D6, L5-L16) were one to two orders of magnitude higher in the co-resident family members of factory workers and in female college students than in other groups, indicating that both populations should be considered as potentially highly exposed to MSs. A further assessment showed that inhalation exposure is the main source of CMSs (D4-D6) in plasma for people exposed to high indoor air levels of these compounds. Although the health risk assessment showed that the health risk from inhalation exposure to D4 and D5 was acceptable for all of the studied groups based on the current chronic reference dose (cRfD), the maximum ADDinh,CMSs value in 0- to 3-year-old children was only 7.9-fold below the cRfD. Because the toxicity of other MSs is unknown, the potential health risk of MSs to very young children via inhalation exposure should be further analysed.


Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Pré-Escolar , China , Monitoramento Ambiental , Feminino , Habitação , Humanos , Lactente , Recém-Nascido , Exposição por Inalação , Plasma/química , Medição de Risco , Siloxanas/análise
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