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1.
Oxid Med Cell Longev ; 2021: 4158495, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34426759

RESUMO

Cellular senescence has been considered an important driver of many chronic lung diseases. However, the specific mechanism of cellular senescence in silicosis is still unknown. In the present study, silicotic rats and osteoclast stimulatory transmembrane protein (Ocstamp) overexpression of MLE-12 cells were used to explore the mechanism of OC-STAMP in cellular senescence in alveolar epithelial cell type II (AEC2). We found an increasing level of OC-STAMP in AEC2 of silicotic rats. Overexpression of Ocstamp in MLE-12 cells promoted epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and cellular senescence. Myosin heavy chain 9 (MYH9) was a potential interacting protein of OC-STAMP. Knockdown of Ocstamp or Myh9 inhibited cellular senescence in MLE-12 cells transfected with pcmv6-Ocstamp. Treatment with 4-phenylbutyrate (4-PBA) to inhibit ER stress also attenuated cellular senescence in vitro or in vivo. In conclusion, OC-STAMP promotes cellular senescence in AEC2 in silicosis.

2.
J Cell Sci ; 134(2)2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34432034

RESUMO

Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial-mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1, also known as TP53BP1). The results provide evidence that α-TAT1 and Ac-α-Tub inhibit the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT and why the decrease in α-TAT1 and Ac-α-Tub promotes silicosis fibrosis. This article has an associated First Person interview with the first authors of the paper.


Assuntos
Transição Epitelial-Mesenquimal , Tubulina (Proteína) , Acetilação , Dano ao DNA , Transição Epitelial-Mesenquimal/genética , Humanos , Processamento de Proteína Pós-Traducional , Dióxido de Silício/toxicidade , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
3.
J Cell Sci ; 134(2)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33310909

RESUMO

Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial-mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1, also known as TP53BP1). The results provide evidence that α-TAT1 and Ac-α-Tub inhibit the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT and why the decrease in α-TAT1 and Ac-α-Tub promotes silicosis fibrosis.This article has an associated First Person interview with the first authors of the paper.


Assuntos
Transição Epitelial-Mesenquimal , Tubulina (Proteína) , Acetilação , Dano ao DNA , Transição Epitelial-Mesenquimal/genética , Processamento de Proteína Pós-Traducional , Dióxido de Silício/toxicidade , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
4.
Mol Ther Nucleic Acids ; 20: 851-865, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32464548

RESUMO

To identify potential therapeutic targets for pulmonary fibrosis induced by silica, we studied the effects of this disease on the expression of microRNAs (miRNAs) in the lung. Rattus norvegicus pulmonary silicosis models were used in conjunction with high-throughput screening of lung specimens to compare the expression of miRNAs in control and pulmonary silicosis tissues. A total of 70 miRNAs were found to be differentially expressed between control and pulmonary silicosis tissues. This included 41 miRNAs that were upregulated and 29 that were downregulated relative to controls. Among them, miR-292-5p, miR-155-3p, miR-1193-3p, miR-411-3p, miR-370-3p, and miR-409a-5p were found to be similarly altered in rat lung and transforming growth factor (TGF)-ß1-induced cultured fibroblasts. Using miRNA mimics and inhibitors, we found that miR-1193-3p, miR-411-3p, and miR-370-3p exhibited potent anti-fibrotic effects, while miR-292-5p demonstrated pro-fibrotic effects in TGF-ß1-stimulated lung fibroblasts. Moreover, we also found that miR-411-3p effectively reduced pulmonary silicosis in the mouse lung by regulating Mrtfa expression, as demonstrated using biochemical and histological assays. In conclusion, our findings indicate that miRNA expression is perturbed in pulmonary silicosis and suggest that therapeutic interventions targeting specific miRNAs might be effective in the treatment of this occupational disease.

5.
Biomed Pharmacother ; 125: 109980, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32028236

RESUMO

OBJECTIVE: The role and molecular mechanism of long non-coding RNA (lncRNA)-related pathways in silicosis have not been elucidated clearly. The aims of this study were to evaluate the expression of lncRNAs during silica-induced pulmonary fibrosis and verify the function and molecular mechanism of LOC103691771 in myofibroblast differentiation induced by transforming growth factor-ß1 (TGF-ß1). METHODS: RNA-sequencing was performed to assess differential expression of lncRNAs in control and silicotic rat lungs. Differential expression of lncRNAs was analyzed by Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes to identify their biological roles. LOC103691771, LOC102549714, LOC102550137, LOC103693125, and LOC103692016 were selected to verify their expression by real-time PCR of silicotic rat lung tissue and lung fibroblasts stimulated by TGF-ß1. Specific small interfering RNA and an LOC103691771 overexpression plasmid were used to analyze the molecular mechanism in myofibroblast differentiation induced by TGF-ß1. RESULT: A total of 306 lncRNAs were expressed differentially in silicotic rat lungs, including 224 upregulated and 82 downregulated lncRNAs. The expression of LOC103691771, LOC102549714 and LOC102550137 was upregulated, while the expression of LOC103693125 and LOC103692016 was downregulated in silicotic rat lungs and TGF-ß1-induced fibroblast, which was consistent with the results of RNA-sequencing. Furthermore, LOC103691771 gene silencing attenuated myofibroblast differentiation, whereas LOC103691771 overexpression promoted myofibroblast differentiation via regulation of the TGF-ß1-Smad2/3 signaling pathway. CONCLUSION: Our findings revealed that differential expression of lncRNAs was related to the development of silicosis, and LOC103691771 played a major role in myofibroblast differentiation induced by TGF-ß1, which may serve as a potential therapeutic target for silicosis.


Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica , Miofibroblastos/citologia , Miofibroblastos/metabolismo , RNA Longo não Codificante/genética , Silicose/genética , Silicose/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Biologia Computacional/métodos , Modelos Animais de Doenças , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Silicose/patologia , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
Exp Cell Res ; 388(2): 111878, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004504

RESUMO

Occupational exposure to silica dust particles was the major cause of pulmonary fibrosis, and many miRNAs have been demonstrated to regulate target mRNAs in silicosis. In the present study, we found that a decreasing level of miR-411-3p in silicosis rats and lung fibroblasts induced by TGF-ß1. Enlargement of miR-411-3p could inhibit the cell proliferation and migration in lung fibroblasts with TGF-ß1 treatment and attenuate lung fibrosis in silicotic mice. In addition, a mechanistic study showed that miR-411-3p exert its inhibitory effect on Smad ubiquitination regulatory factor 2 (Smurf2) expression and decrease ubiquitination degradation of Smad7 regulated by smurf2, result in blocking of TGF-ß/Smad signaling. We proposed that increased expression of miR-411-3p abrogates silicosis by blocking activation of TGF-ß/Smad signaling through decreasing ubiquitination degradation effect of smurf2 on Smad7.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , Fibrose Pulmonar/prevenção & controle , Dióxido de Silício/toxicidade , Silicose/prevenção & controle , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Ratos , Ratos Wistar , Silicose/genética , Silicose/patologia , Fator de Crescimento Transformador beta/genética , Ubiquitina-Proteína Ligases/genética
7.
Theranostics ; 10(4): 1719-1732, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32042332

RESUMO

The purpose of this study was to determine the effects of Kinesin family member 3A (KIF3A) on primary cilia and myofibroblast differentiation during silicosis by regulating Sonic hedgehog (SHH) signalling. Methods: Changes in primary cilia during silicosis and myofibroblast differentiation were detected in silicotic patients, experimental silicotic rats, and a myofibroblast differentiation model induced by SiO2. We also explored the mechanisms underlying KIF3A regulation of Glioma-associated oncogene homologs (GLIs) involved in myofibroblast differentiation. Results: Primary cilia (marked by ARL13B and Ac-α-Tub) and ciliary-related proteins (IFT 88 and KIF3A) were increased initially and then decreased as silicosis progressed. Loss and shedding of primary cilia were also found during silicosis. Treatment of MRC-5 fibroblasts with silica and then transfection of KIF3A-siRNA blocked activation of SHH signalling, but increased GLI2FL as a transcriptional activator of SRF, and reduced the inhibitory effect of GLI3R on ACTA2. Conclusion: Our findings indicate that primary cilia are markedly altered during silicosis and the loss of KIF3A may promote myofibroblast differentiation induced by SiO2.


Assuntos
Cílios/metabolismo , Cinesina/farmacologia , Dióxido de Silício/farmacologia , Silicose/patologia , Proteína Gli3 com Dedos de Zinco/farmacologia , Actinas , Animais , Diferenciação Celular/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/metabolismo , Proteínas Hedgehog/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Cinesina/metabolismo , Masculino , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Dióxido de Silício/efeitos adversos , Silicose/metabolismo , Fatores de Transcrição/metabolismo , Proteína Gli3 com Dedos de Zinco/metabolismo
8.
Mol Ther Nucleic Acids ; 19: 350-360, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31877411

RESUMO

Silicosis is a fatal profession-related disease linked to long-term inhalation of silica. The present study aimed to determine whether meprin α, a master regulator of anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), is diminished by miR-155-5p in silicotic and control lung macrophages and fibroblasts upon activation. NR8383 macrophages, primary lung fibroblasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin α and miR-155-5p. In vitro meprin α manipulation was performed by recombinant mouse meprin α protein, actinonin (its inhibitor), and small interfering RNA knockdown. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, and immunohistochemical staining. The roles of meprin α and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin α level was stably repressed in silicotic rats. In vitro, silica decreased meprin α, and exogenous meprin α reduced activation of macrophages and fibroblasts induced by profibrotic factors. miR-155-5p negatively regulated Mep1a by binding to the 3' untranslated region. Treatment with anti-miR-155-5p elevated meprin α, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin α and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/meprin α are two of the major regulators of silicosis.

9.
J Cell Sci ; 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34005428

RESUMO

Silicosis is characterized by silica exposure-induced lung interstitial fibrosis and formation of silicotic nodules, resulting in lung stiffening. The acetylation of microtubules mediated by α-tubulin N-acetyltransferase 1 (α-TAT1) is a posttranslational modification that promotes microtubule stability in response to mechanical stimulation. α-TAT1 and downstream-acetylated α-tubulin (Ac-α-Tub) are decreased in silicosis, promoting the epithelial-mesenchymal transition (EMT); however, the underlying mechanisms are unknown. We found that silica, matrix stiffening, or their combination triggered Ac-α-Tub downregulation in alveolar epithelial cells, followed by DNA damage and replication stress. α-TAT1 elevated Ac-α-Tub to limit replication stress and the EMT via trafficking of p53-binding protein 1 (53BP1). The results provide evidence that α-TAT1/Ac-α-Tub inhibits the EMT and silicosis fibrosis by preventing 53BP1 mislocalization and relieving DNA damage. This study provides insight into how the cell cycle is regulated during the EMT, and why the decrease in α-TAT1/Ac-α-Tub promotes silicosis fibrosis.

10.
Exp Physiol ; 104(10): 1562-1574, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31290182

RESUMO

NEW FINDINGS: What is the central question of this study? What are the effects of the antifibrotic peptide acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas axis during the occurrence and progression of silicosis? What is the main finding and its importance? Ac-SDKP inhibited lung fibrosis in rats exposed to silica by activation of the ACE2-angiotensin-(1-7)-Mas axis. Angiotensin-(1-7) potentially promotes Ac-SDKP by increasing the level of meprin α, the major synthetase of Ac-SDKP. Thus, the interaction Ac-SDKP and angiotesin-(1-7) in silicosis could provide a new therapeutic strategy. ABSTRACT: The central role of angiotensin-converting enzyme (ACE) in the occurrence and progression of silicosis has been established. The antifibrotic peptide acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) can be degraded by ACE. The ACE2-angiotensin-(1-7)-Mas axis is protective and acts to counterbalance the detrimental effects of ACE-angiotensin II (Ang II)-Ang II type 1 receptor and exerts antifibrotic effects. Here, we demonstrate an interaction between Ac-SDKP and Ang-(1-7) in the inhibition of collagen deposition and myofibroblast differentiation in rats exposed to silica. Treatment with Ac-SDKP increased the level of ACE2-Ang-(1-7)-Mas in rats or in cultured fibroblasts and decreased the levels of collagen type I and α-smooth muscle actin. Furthermore, exogenous Ang-(1-7) had similar antifibrotic effects and increased the level of meprin α, a major Ac-SDKP synthetase, both in vivo and in vitro. Compared with non-silicotic patients exposed to silica, the level of serum ACE was increased in patients with silicosis phase III; the levels of Ang II and Ang-(1-7) were high in patients with silicosis phase II; and the level of Ac-SDKP was high in the silicosis phase III group. These data imply that Ac-SDKP and Ang-(1-7) have an interactive effect as regulatory peptides of the renin-angiotensin system and exert antifibrotic effects.


Assuntos
Angiotensina I/sangue , Oligopeptídeos/uso terapêutico , Fragmentos de Peptídeos/sangue , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Silicose/tratamento farmacológico , Actinas/metabolismo , Angiotensina II/sangue , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Colágeno Tipo I/análise , Colágeno Tipo I/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Peptidil Dipeptidase A/sangue , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/patologia
11.
Exp Cell Res ; 380(2): 131-140, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029634

RESUMO

Transforming growth factor-ß1 (TGF-ß1) alters the fibroblast phenotype by promoting transdifferentiation into myofibroblasts, which exhibit the ability to promote collagen synthesis and extracellular matrix (ECM) deposition, thereby playing a significant role in the pathology of silicosis. In this study, we investigated the regulatory mechanisms involved in myofibroblast transdifferentiation. Two-dimensional gel electrophoresis showed that Rho GDP-dissociation inhibitor α (RhoGDIα) was upregulated following myofibroblast transdifferentiation stimulated by TGF-ß1. We hypothesised that RhoGDIα may induce myofibroblast transdifferentiation and thus result in silicosis. Accordingly, the biological significance of RhoGDIα in cell proliferation and apoptosis was investigated by deletion of RhoGDIα in MRC-5 cells. In addition, a mechanistic study showed that fasudil, an inhibitor of the RhoA/Rho kinase (ROCK) signalling pathway, reduced the levels of RhoGDIα, RhoA, and phospho-myosin phosphatase (phospho-MYPT) in MRC-5 cells and silicosis model rats. Knockdown of RhoGDIα inhibited myofibroblast transdifferentiation and collagen deposition through RhoGDIα/RhoA/ROCK signalling in silicosis model mice. Overall, downregulation of RhoGDIα may significantly promote cell apoptosis and inhibit cell growth, resulting in reversal of myofibroblast transdifferentiation by RhoA/ROCK in vitro and in vivo. These data will facilitate further exploration of the potential use of RhoGDIα as a target for silicosis therapy.


Assuntos
Silicose/tratamento farmacológico , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
12.
Ying Yong Sheng Tai Xue Bao ; 25(4): 1145-50, 2014 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-25011311

RESUMO

The heavy metals pollution is one of the ecological problems which have been paid close attention to Spodoptera exigua Hübner, one of the key pests on vegetables and cotton in the Yangtze River and its southern area in China, has broken out more frequently in recent years. In this study, accumulation of Pb2+ in S. exigua and its excretion were detected when fed with artificial diets with different Pb2+ concentrations (0.3, 1.2, 4.8, 19.2 and 76.8 mg x kg(-1), respectively). Life table was constructed according to the survival and growth of different stages of S. exigua. The effect of lead on three successive generations of beet armyworm was studied using the life table in the laboratory. It was found that the Pb2+ contents were significantly different when S. exigua was reared at different Pb2+ concentrations in the same generation in a significant dose-dependent manner. The concentration of Pb2+ increased with prolonging the stress time at the same time. The Pb2+ concentrations at the three developmental stages of beet armyworm followed the order of larvae > adult > pupa. The beet armyworm could excrete heavy metals by means of faeces, prepupa exuviate and puparium, and the concentrations of Pb2+ in faeces and prepupa exuviate were far higher than in puparium. According to the survival rates of different developmental stages, the female ratios and the egg numbers, the laboratory population life table was constructed. It showed that low doses of Pb2+ promoted the growth of the population, and high doses inhibited the growth, and the index of population trend (I) declined more rapidly with the increase of stress time. The study could provide references for long-term and objective assessment of heavy metal hazard and its effect on the populations of important agricultural pests.


Assuntos
Chumbo/metabolismo , Spodoptera/metabolismo , Animais , China , Dieta/veterinária , Poluentes Ambientais/metabolismo , Feminino , Larva , Pupa
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