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1.
Nat Immunol ; 22(9): 1140-1151, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426691

RESUMO

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360888

RESUMO

Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-ß (TGF-ß) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-ß signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1ß and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-ß signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1ß was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Osteoartrite/metabolismo , Transdução de Sinais/genética , Proteína Smad2/química , Proteína Smad2/metabolismo , Proteína Smad3/química , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Animais , Bovinos , Linhagem Celular Tumoral , Humanos , Hipertrofia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/farmacologia , Osteoartrite/genética , Osteoartrite/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Domínios Proteicos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad3/genética , Membrana Sinovial/metabolismo , Transfecção , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/farmacologia
3.
Artigo em Russo | MEDLINE | ID: mdl-34460152

RESUMO

OBJECTIVE: To study clinical/laboratory signs of primary vasculitis (PV) of the internal carotid artery (ICA) and vertebral artery (VA). MATERIAL AND METHODS: We examined 31 patients (23 men, 74%, mean age - 36.2±5.7 years) with ICA/VA PV verified by vessel wall contrast enhancement on black blood MRI (T1-weighted fat and blood suppressed sequences with- and without contrast injection) at the Research Center of Neurology (Moscow) from January 2012 to September 2019. Systemic vasculitis was excluded in all cases. Interleukins (IL-1ß, IL-2, IL-6, IL-17), TNF-a, transforming growth factor beta 1 (TGF-ß1) and basic fibroblast growth factor (bFGF) were analyzed by ELISA in 25 patients. Control group consisted of 21 healthy volunteers (12 men, 57%; mean age - 35.3±10.2 years). RESULTS: Clinical manifestations of ICA/VA PV included: ischemic stroke (IS) (94%), which combined with transient ischemic attacks (TIA) in 35%; isolated TIA (3%); Tolosa-Hunt syndrome (3%). Recurrent strokes were observed in 41% of patients on average in 5.3±2.1 months. Carotid artery was involved in 77%, VA - in 16%, both arteries - in 7%. Concomitant involvement of ICA/VA branches was in 19% patients. The level of arterial damage was follows: Intracranial part of arteries involved in 55%, intra-extracranial - in 35%, extracranial - in 10%. Bilateral involvement was found in 26%. Headache/neck pain in the acute IS period was observed in 21%. IS severity (NIHSS) was as follows: moderate (59%), mild (34%), moderately severe (7%). Disability after 3 months according to mRankin scale was as follows: mild (72%) moderate (21%), none (7%). The laboratory study revealed an increased levels of IL-6 (8.19±3.89 pg/ml vs 4.7±1.48 in control, p=0.000), IL-2 (5.64±1.82 pg/ml vs 4.30±1.65, p=0.013), TNF-a (36.9±33.66 pg/ml vs 12.68±5.93, p=0.000), TGF ß1 (2.77±1.60 pg/ml vs 1.63±0.64, p=0.006) and bFGF (417.67±132.68 pg/ml vs 335.71±105.08, p=0.018). The levels of IL-1ß and IL-17 did not differ significantly from the control. CONCLUSION: ICA/VA PV has a number of clinical peculiarities. Proinflammatory cytokines produced by Th17 and Th1 CD4+ lymphocytes as well as bFGF and TGR-ß1 play a role in its pathogenesis. Normal levels of IL-1ß and IL-17 suggest that they are not significant in the development of isolated inflammation in ICA/PA, in contrast to systemic inflammation in giant cell arteritis, in which, according to literature data, their level increases. Isolated ICA/PA inflammation seems to be caused by transaxonal (trigeminal nerve, upper-cervical roots, autonomic nerves) spread of pathogens that initiate immune inflammation in the ICA/PA wall.


Assuntos
Fator 2 de Crescimento de Fibroblastos , Ataque Isquêmico Transitório , Fator de Crescimento Transformador beta1/metabolismo , Vasculite , Adulto , Artéria Carótida Interna/diagnóstico por imagem , Citocinas , Humanos , Masculino , Artéria Vertebral/diagnóstico por imagem
4.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328199

RESUMO

Myocardial fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix in myocardial interstitial spaces. Myocardial fibrosis is a fundamental process in ventricular remodeling and a primary contributor to the progression of heart failure. Liquiritigenin (LQ) is a flavanone compound with anti­oxidative, anti­carcinogenic, anti­inflammatory and estrogenic properties. The present study aimed to investigate the regulatory potential of LQ treatment in a mouse model of isoprenaline (ISO)­induced cardiac fibrosis and in cultured H9C2 cardiomyocytes stimulated with angiotensin II (Ang II). The treatment of ISO­induced mice with LQ significantly decreased the levels of cardiac injury­related proteins in the serum and ECM accumulation in mouse heart tissues. LQ treatment also effectively alleviated cardiac dysfunction in ISO­treated mice. Further analyses revealed that LQ inhibited ISO­induced collagen formation and activation of the transforming growth factor­ß1 (TGF­ß1)/Smad2 and protein kinase B (AKT)/extracellular signal­regulated kinase (ERK) signaling pathways. As a major pathological event in myocardial fibrosis, the apoptosis of cardiomyocytes has been considered a key mechanism contributing to impaired left ventricle performance. The pretreatment of rat cardiomyocytes with LQ significantly reduced the apoptosis of H9C2 cells, and inhibited Ang II­induced activation of the TGF­ß1/Smad2 and AKT/ERK pathways. In conclusion, the present study revealed that LQ ameliorated ISO­induced myocardial fibrosis in mice and inhibited the apoptosis of cardiomyocytes in vitro by inhibiting the TGF­ß1/Smad2 and AKT/ERK signaling pathways. These results suggested the anti­fibrotic and cardioprotective potential of LQ in fibrosis, thus supporting the use of LQ for the management of cardiomyocyte injury and myocardial fibrosis in patients with cardiac diseases.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose/tratamento farmacológico , Flavanonas/farmacologia , Cardiopatias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Angiotensina II/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Fibrose/induzido quimicamente , Flavanonas/uso terapêutico , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Testes de Função Cardíaca/efeitos dos fármacos , Isoproterenol/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores
5.
Anticancer Res ; 41(8): 3801-3808, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281839

RESUMO

BACKGROUND/AIM: Colorectal adenocarcinoma has a poor prognosis due to its propensity for metastasis. It has been experimentally demonstrated that the microRNA (miRNA) let-7a can effectively inhibit tumor proliferation and metastasis by regulating the transforming growth factor (TGF)-ß signaling pathway; however, limited research has been conducted in the area of on colorectal cancer. Herein, we aimed to clarify the role and regulation of let-7a in a colorectal adenocarcinoma cell line (LS-174T). MATERIALS AND METHODS: LS-174T cells were transfected to express let-7a. Let-7a miRNA expression was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Cell growth was assessed by methyl thiazolyl tetrazolium (MTT) assay; invasion and migration were examined by Matrigel invasion and wound healing assays. The expression levels of matrix metalloproteinase (MMP)-2, phosphorylated Drosophila mothers against decapentaplegic 2 (p-SMAD2), and TGF-ß1 were analyzed by western blotting. The mRNA expression levels of TGFB1 were also analyzed by RT-qPCR. RESULTS: Overexpression of let-7a resulted in significant inhibition of LS-174T cell proliferation in vitro. The invasion and migration abilities of the cells overexpressing let-7a were decreased, compared to the control group and miR-negative control group. Transfection of LS-174T cells with let-7a resulted in down-regulation of MMP-2, as well as of TGF-ß1 and p-SMAD2 protein expression. Moreover, TGF-ß1 mRNA levels were reduced following let-7a overexpression. CONCLUSION: Let-7a inhibited the growth and metastasis of colonic mucinous adenocarcinoma cells, at least partially, by regulating the TGF-ß/Smad signaling pathway.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , MicroRNAs/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Transdução de Sinais/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
6.
Acta Cir Bras ; 36(6): e360604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34287607

RESUMO

PURPOSE: Herein we evaluated the effects of platelet concentrate (PC) and platelet-poor plasma (PPP) on bone repair using noncritical defects in the calvaria of rabbits and compared them to the presence of TGF-ß1 and osteocalcin on reparative sites. METHODS: Five noncritical defects of 8.7 mm in diameter were created on the calvaria of 15 animals. Each defect was treated differently, using autograft (ABG), ABG associated with PC (ABG + PC), ABG with PPP (ABG + PPP), isolated PPP, and blood clot (control). The animals were submitted to euthanasia on the second, fourth and sixth week post-surgery. RESULTS: The defects that received ABG+PC or PPP demonstrated lower bone formation when compared to specimens that received ABG in the same period. These results coincided to significant higher immunopositivity for TGF-ß1 for specimens that received PC, and lower presence of cytokine in the group PPP. However, either higher or lower presence of TGF-ß1 were also correlated to lower presence of osteocalcin. Likewise, these results were similar to findings in specimens treated only with PPP when compared to control. CONCLUSIONS: PC and PPP were not effective when applied in association with ABG. Similarly, isolated use of PPP was not beneficial in optimizing the bone repair.


Assuntos
Osteogênese , Fator de Crescimento Transformador beta1 , Animais , Autoenxertos , Osteocalcina , Coelhos , Crânio/cirurgia , Fator de Crescimento Transformador beta1/metabolismo
7.
Biomed Pharmacother ; 138: 111486, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311523

RESUMO

Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (H2S) as a dynamic mediator of the erection process. H2S is a potent endogenous relaxant gas. It has been shown to relax human and animal penile tissue in vitro and induce erection in animals in vivo. The reported penile expression of H2S-synthesizing enzymes also supports the potential role of the endogenous L-cysteine/H2S pathway in penile homeostasis. Several pathological changes take place in the diabetic penile tissue, including inflammation, oxidative stress, neuropathy and fibrosis of the corpus cavernosum (CC), the major erectile structure of the penis. The present study is experimental and has been performed in the diabetic rat model. The study will investigate the role of H2S as a potential protective mediator against diabetes-induced structural and functional alterations in the CC by examining if it: (1) reduces corporal contraction and/or enhances corporal relaxation following pharmacological stimulation, (2) attenuates fibromuscular changes in diabetic CC, and (3) whether there is a link with H2S plasma/urine level and CC tissue generation, as well as studying the expression of some proteins in the transforming growth factor (TGF)-ß1-associated pathway. The major findings of the study reveal that- compared to the nondiabetic controls - the diabetic animals CC showed: (1) augmented contraction and attenuated relaxation in response to phenylephrine and carbachol, respectively, (2) marked fibromuscular degeneration with a significantly lower smooth muscle/collagen ratio and upregulation of TGF-ß-1/Smad/CTGF fibrosis signaling pathway, (3) reduced H2S plasma and urinary levels and cavernosal tissue generation. Chronic GYY4137 treatment prevented most of these pathological changes in diabetic CC, thus may be considered a potential new strategy for the prevention and/or treatment of diabetes-induced ED.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Disfunção Erétil/prevenção & controle , Morfolinas/farmacologia , Compostos Organotiofosforados/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Disfunção Erétil/etiologia , Disfunção Erétil/metabolismo , Disfunção Erétil/fisiopatologia , Fibrose , Sulfeto de Hidrogênio/metabolismo , Masculino , Pênis/metabolismo , Pênis/patologia , Pênis/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais , Estreptozocina
8.
Biomed Pharmacother ; 138: 111522, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311526

RESUMO

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder with complex pathogenesis and lacks effective treatment. Chronic inflammation is the main pathogenesis of Hunner-type IC/BPS. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related transforming growth factor-ß (TGF-ß)/Smad signaling pathway plays a crucial role in inflammation-related tissue fibrosis. Lipopolysaccharide (LPS) and protamine sulfate (LPS/PS) were instilled into the mouse bladder twice a week for 5 consecutive weeks to establish a chronic inflammation-induced IC/BPS model (LPS/PS model). Following LPS/PS treatment, curcumin (oral, 100 mg/kg; a potent NLRP3 modulator) was administered for 2 weeks in the curcumin treatment group, and normal saline was used for the sham group. Bladder function was evaluated by performing the voiding spot assay and examining the status of urothelial denudation and fibrosis in bladder tissues. The expression of NLRP3 inflammasome, interleukin-1ß, TGF-ß, Smad, vimentin, and E-cadherin in bladder tissues was evaluated through immunohistochemistry staining. Results revealed that the repeated instillation of LPS/PS leads to voiding dysfunction, bladder urothelium denudation, and detrusor muscle fibrosis through the upregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway and the increased epithelial-mesenchymal transition process in bladder tissues. The downregulation of the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway in bladder tissues through curcumin effectively mitigated bladder injury in the LPS/PS model. In conclusion, the NLRP3 inflammasome/IL-1ß-related TGF-ß/Smad pathway plays a crucial role in bladder injury in the LPS/PS model, and modulation of this pathway, such as by using curcumin, can effectively mitigate the sequelae of chronic inflammation-induced IC/BPS.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Cistite Intersticial/tratamento farmacológico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Bexiga Urinária/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Animais , Cistite Intersticial/metabolismo , Cistite Intersticial/patologia , Cistite Intersticial/fisiopatologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fibrose , Camundongos Endogâmicos BALB C , Transdução de Sinais , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacos
9.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202024

RESUMO

Orbital fibrosis, a hallmark of tissue remodeling in Graves' ophthalmopathy (GO), is a chronic, progressive orbitopathy with few effective treatments. Orbital fibroblasts are effector cells, and transforming growth factor ß1 (TGF-ß1) acts as a critical inducer to promote myofibroblast differentiation and subsequent tissue fibrosis. Curcumin is a natural compound with anti-fibrotic activity. This study aims to investigate the effects of curcumin on TGF-ß1-induced myofibroblast differentiation and on the pro-angiogenic activities of orbital fibroblasts. Orbital fibroblasts from one healthy donor and three patients with GO were collected for primary cell culture and subjected to myofibroblast differentiation under the administration of 1 or 5 ng/mL TGF-ß1 for 24 h. The effects of curcumin on TGF-ß1-induced orbital fibroblasts were assessed by measuring the cellular viability and detecting the expression of myofibroblast differentiation markers, including connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). The pro-angiogenic potential of curcumin-treated orbital fibroblasts was evaluated by examining the transwell migration and tube-forming capacities of fibroblast-conditioned EA.hy926 and HMEC-1 endothelial cells. Treatment of orbital fibroblasts with curcumin inhibited the TGF-ß1 signaling pathway and attenuated the expression of CTGF and α-SMA induced by TGF-ß1. Curcumin, at the concentration of 5 µg/mL, suppressed 5 ng/mL TGF-ß1-induced pro-angiogenic activities of orbital fibroblast-conditioned EA hy926 and HMEC-1 endothelial cells. Our findings suggest that curcumin reduces the TGF-ß1-induced myofibroblast differentiation and pro-angiogenic activity in orbital fibroblasts. The results support the potential application of curcumin for the treatment of GO.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Curcumina/farmacologia , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Células Cultivadas , Células Endoteliais/metabolismo , Oftalmopatia de Graves/etiologia , Oftalmopatia de Graves/metabolismo , Oftalmopatia de Graves/patologia , Humanos , Miofibroblastos/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia
10.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202139

RESUMO

Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy in pre-clinical murine models of SSc. However, their precise action mechanism is still not fully understood. Because of the lack of availability of fibroblasts isolated from SSc patients (SSc-Fb), our aim was to determine whether a TGFß1-induced model of human myofibroblasts (Tß-Fb) could reproduce the characteristics of SSc-Fb and be used to evaluate the anti-fibrotic function of ASCs and their EVs. We found out that Tß-Fb displayed the main morphological and molecular features of SSc-Fb, including the enlarged hypertrophic morphology and expression of several markers associated with the myofibroblastic phenotype. Using this model, we showed that ASCs were able to regulate the expression of most myofibroblastic markers on Tß-Fb and SSc-Fb, but only when pre-stimulated with TGFß1. Of interest, ASC-derived EVs were more effective than parental cells for improving the myofibroblastic phenotype. In conclusion, we provided evidence that Tß-Fb are a relevant model to mimic the main characteristics of SSc fibroblasts and investigate the mechanism of action of ASCs. We further reported that ASC-EVs are more effective than parental cells suggesting that the TGFß1-induced pro-fibrotic environment may alter the function of ASCs.


Assuntos
Tecido Adiposo/citologia , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Escleroderma Sistêmico/etiologia , Escleroderma Sistêmico/metabolismo , Animais , Biomarcadores , Comunicação Celular , Suscetibilidade a Doenças , Fibroblastos/metabolismo , Fibrose , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/citologia , Camundongos , Miofibroblastos/metabolismo , Escleroderma Sistêmico/patologia , Fator de Crescimento Transformador beta1/metabolismo
11.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204432

RESUMO

Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-ß1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-ß1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-ß1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-ß1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.


Assuntos
Antígeno Ca-125/genética , Expressão Gênica , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Proteínas de Membrana/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Idoso , Biomarcadores , Antígeno Ca-125/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células , Suscetibilidade a Doenças , Feminino , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Imuno-Histoquímica , Pulmão/metabolismo , Pulmão/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Miofibroblastos/metabolismo , Fosforilação , Testes de Função Respiratória
12.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198681

RESUMO

Lack of adult cells' ability to produce sufficient amounts of elastin and assemble functional elastic fibers is an issue for creating skin substitutes that closely match native skin properties. The effects of female sex hormones, primarily estrogen, have been studied due to the known effects on elastin post-menopause, thus have primarily included older mostly female populations. In this study, we examined the effects of female sex hormones on the synthesis of elastin by female and male human dermal fibroblasts in engineered dermal substitutes. Differences between the sexes were observed with 17ß-estradiol treatment alone stimulating elastin synthesis in female substitutes but not male. TGF-ß levels were significantly higher in male dermal substitutes than female dermal substitutes and the levels did not change with 17ß-estradiol treatment. The male dermal substitutes had a 1.5-fold increase in cAMP concentration in the presence of 17ß-estradiol compared to no hormone controls, while cAMP concentrations remained constant in the female substitutes. When cAMP was added in addition to 17ß-estradiol and progesterone in the culture medium, the sex differences were eliminated, and elastin synthesis was upregulated by 2-fold in both male and female dermal substitutes. These conditions alone did not result in functionally significant amounts of elastin or complete elastic fibers. The findings presented provide insights into differences between male and female cells in response to female sex steroid hormones and the involvement of the cAMP pathway in elastin synthesis. Further explorations into the signaling pathways may identify better targets to promote elastic fiber synthesis in skin substitutes.


Assuntos
Monofosfato de Adenosina/farmacologia , Derme/fisiologia , Elastina/biossíntese , Estradiol/farmacologia , Caracteres Sexuais , Pele Artificial , Engenharia Tecidual , Adulto , Meios de Cultura , AMP Cíclico/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Receptores de Superfície Celular/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto Jovem
13.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34240225

RESUMO

Tracheal stenosis following injury cannot be effectively treated. The current study compared the protective effects of different anti­inflammatory drugs on tracheal stenosis and investigated their possible mechanisms. Rabbit tracheal stenosis models following injury were constructed and confirmed using hematoxylin and eosin (H&E) staining. A total of 30 rabbits were divided into the control (CON), penicillin (PEN), erythromycin (ERY), budesonide (BUD) and PEN + ERY + BUD groups (n=6). Stenotic tracheal tissue, serum and bronchoalveolar lavage fluid (BALF) were collected 10 days after continuous treatment. Pathological changes in the tracheas were observed by H&E staining. Histone deacetylase 2 (HDAC2) expression in tracheal tissues was detected by immunofluorescence. Immunohistochemistry was performed to detect collagen I (Col­I) and collagen III (Col­III) levels in tracheal tissues. Transforming growth factor ß1 (TGF­ß1), vascular endothelial growth factor (VEGF) and interleukin 8 (IL­8) levels in serum and BALF samples were determined using ELISA kits. Western blotting detected HDAC2, IL­8, TGF­ß1 and VEGF levels in tracheal tissues. H&E staining demonstrated that tracheal epithelial hyperplasia and fibroblast proliferation in the ERY and PEN + ERY + BUD groups markedly improved compared with the CON group. Furthermore, in tracheal tissues, HDAC2 expression was significantly increased and IL­8, TGF­ß1, VEGF, Col­I and Col­III levels were significantly decreased in the ERY and PEN + ERY + BUD groups compared with the CON group. Additionally, the results for the PEN + ERY + BUD were more significant compared with the ERY group. In serum and BALF samples, IL­8, TGF­ß1 and VEGF levels in the ERY and PEN + ERY + BUD groups were significantly lower compared with the CON group, with the results of the PEN + ERY + BUD group being more significant compared with the ERY group. There were no significant differences between the PEN, BUD and CON groups. ERY inhibited tracheal granulation tissue proliferation and improved tracheal stenosis following injury and synergistic effects with PEN and BUD further enhanced these protective effects. The mechanism may involve HDAC2 upregulation and inhibition of local airway and systemic inflammatory responses.


Assuntos
Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Eritromicina/uso terapêutico , Penicilinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Estenose Traqueal/metabolismo , Estenose Traqueal/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/química , Budesonida/farmacologia , Colágeno/metabolismo , Modelos Animais de Doenças , Eritromicina/farmacologia , Tecido de Granulação/efeitos dos fármacos , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Penicilinas/farmacologia , Substâncias Protetoras/farmacologia , Coelhos , Traqueia/lesões , Traqueia/patologia , Estenose Traqueal/etiologia , Estenose Traqueal/patologia , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Am J Pathol ; 191(8): 1412-1430, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34111429

RESUMO

Idiopathic subglottic stenosis (iSGS) is a progressive fibrotic disease characterized by life-threatening airway narrowing. Although the molecular underpinnings are unknown, previous reports showing that subglottic serial intralesional steroid injections (SILSIs) improve clinical outcomes suggest a steroid-sensitive pathway in iSGS. Herein, a prospective study was conducted to determine the changes in profibrotic markers during SILSI to identify steroid-sensitive profibrotic drivers. Seven newly diagnosed patients with iSGS were recruited for SILSI. Subglottic biopsies before and after SILSI treatments were evaluated for histologic and molecular markers by confocal microscopy and RT-qPCR. At baseline, iSGS subglottises contained abundant vimentin-positive/α-smooth muscle actin-negative fibroblasts, intermingled with a matrix of fibronectin and types I and VI collagen. Transforming growth factor (TGF)-ß1 was up-regulated primarily in glandular epithelium. Cellular communication network factor 2 (CCN2) was mainly up-regulated in stromal fibroblasts surrounding TGF-ß1-positive glandular structures. SILSI improved iSGS by reducing fibroblast infiltration and increasing matrix remodeling. Mechanistically, SILSI counteracted the effects of TGF-ß1 by inducing matrix metalloprotease 9 (MMP9) expression while repressing CCN2 expression, without affecting TGFß1 levels. Treatment of primary iSGS-derived fibroblasts with TGF-ß1 recapitulated aspects of the disease in vivo, demonstrating that the induction in CCN2 and repression of MMP9 are caused by changes in histone acetylation induced by TGF-ß1. Triamcinolone counteracted the coregulation of these genes by impairing SMAD2/3 binding to promoter regions, and not through histone acetylation. In conclusion, this study shows that SILSI counteracts a dysregulated TGF-ß1/CCN2/MMP9 axis involved in iSGS development.


Assuntos
Anti-Inflamatórios/uso terapêutico , Laringoestenose/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Triancinolona/uso terapêutico , Fator de Crescimento do Tecido Conjuntivo/efeitos dos fármacos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Regulação para Baixo , Humanos , Injeções Intralesionais , Laringoestenose/metabolismo , Laringoestenose/patologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
15.
Aging (Albany NY) ; 13(12): 16009-16023, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34096887

RESUMO

In this study, we investigated the effects of calycosin on breast cancer cell progression and their underlying mechanisms. Calycosin dose- and time-dependently inhibited proliferation, migration, and invasion by T47D and MCF-7 breast cancer cells by downregulating basic leucine zipper ATF-like transcription factor (BATF) expression. Moreover, BATF promoted breast cancer cell migration and invasiveness by increasing TGFß1 mRNA and protein levels. Bioinformatics analysis, dual luciferase reporter assays, and chromatin immunoprecipitation assays confirmed the presence of BATF-binding sites in the promoter sequence of TGFß1 gene. Calycosin treatment inhibited epithelial-mesenchymal transition (EMT) of breast cancer cells by significantly increasing E-cadherin levels and decreasing N-cadherin, Vimentin, CD147, MMP-2, and MMP-9 levels through downregulation of BATF and TGFß1. TGFß1 knockdown reduced the migration and invasiveness of BATF-overexpressing breast cancer cells, whereas incubation with TGFß1 enhanced the migration and invasiveness of calycosin-treated breast cancer cells. Our findings demonstrated that calycosin inhibited EMT and progression of breast cancer cells by suppressing BATF/TGFß1 signaling. This suggests calycosin would be a promising therapeutic option for breast cancer patients.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Isoflavonas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Sequência de Bases , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Invasividade Neoplásica , Metástase Neoplásica
16.
Biomed Pharmacother ; 140: 111781, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34090052

RESUMO

AIM: To investigate the prophylactic efficacy of gut microbiota-based treatments on nonalcoholic steatohepatitis (NASH) management via modulation of Hippo signaling pathway-related genes (YAP1, LATS1 and NF2), and their epigenetic regulators (miR-1205 and lncRNA SRD5A3-AS1) retrieved from in-silico data analysis. MATERIALS & METHODS: Histopathological, biochemical, molecular and immunohistochemistry analyses were used to assess the effects of multistrain probiotic mixture and prebiotic inulin fiber on high sucrose high fat (HSHF) diet-induced NASH in rats. These treatments were administered orally either alone or in combination, along with HSHF diet. RESULTS: Both probiotic mixture and prebiotic inulin fiber attenuated steatosis, inflammation and fibrosis grades in HSHF diet-induced NASH rats. Moreover, the applied treatments significantly prevented the elevation of serum liver enzymes and improved lipid panel. At the molecular level, both treatments down-regulated hepatic YAP1 mRNA and miR-1205 expressions, and concomitantly up-regulated the expression of hepatic LATS1& NF2 mRNAs and the lncRNA SRD5A3-AS1. At the protein level, both treatments decreased the hepatic content of the inflammatory marker IL6 and the fibrotic marker TGFß1. Moreover, an observable reduction in α-SMA together with noticeable elevation in LATS1/2 protein expression levels were detected in liver sections compared to the untreated rats. CONCLUSION: Probiotic mixture and prebiotic inulin fiber, either alone or in combination, attenuated NASH progression and ameliorated both fibrosis and hepatic inflammation in the applied animal model. The produced effect was correlated with modulation of the retrieved (YAP1, LATS1 and NF2) - (miR-1205) - (lncRNA SRD5A3-AS1) RNA panel.


Assuntos
Inulina/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Prebióticos , Probióticos/uso terapêutico , Simbióticos , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Interleucina-6/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Proteínas de Membrana/genética , MicroRNAs , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Longo não Codificante , Ratos Wistar , Fator de Crescimento Transformador beta1/metabolismo
17.
Phytomedicine ; 88: 153609, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126414

RESUMO

BACKGROUD: Schisandra chinensis, a traditional Chinese medicine for liver protection, can significantly improve liver fibrosis. However, it is still unclear which active components in Schisandra chinensis play an anti-fibrosis role. PURPOSE: The purpose of present study was to observe the anti-fibrosis effect of schisantherin A (SCA) on liver fibrosis and explore its underlying mechanism. METHODS: The liver fibrosis model of mice was constructed by the progressive intraperitoneal injection of thioacetamide (TAA), and SCA (1, 2, and 4 mg/kg) was administered by gavage for 5 weeks. The biochemical indicators and inflammatory cytokines were measured, changes in the pathology of the mice liver were observed by hematoxylin & eosin (H&E) and Masson stainings for studying the anti-fibrosis effect of SCA. A hepatic stellate cell (HSCs) activation model induced by transforming growth factor-ß1 (TGF-ß1) was established, and the effect of SCA on the HSCs proliferation was observed by MTT assay. The expressions of target proteins related to transforming growth factor-ß-activated kinase 1 (TAK1)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were evaluated by western blotting, immunohistochemistry or immunofluorescence analysis, to explore the potential mechanism of SCA. RESULTS: SCA could significantly ameliorate the pathological changes of liver tissue induced by TAA, and reduce the serum transaminase level, the hydroxyproline level and the expression of α-smooth muscle actin (α-SMA) and collagen 1A1 (COL1A1) proteins in the liver tissue. SCA could significantly lower the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the serum and liver tissue, and down-regulate the expression of target proteins related to TAK1/MAPK and NF-κB pathways in the liver tissue. The in vitro studies demonstrated that SCA significantly inhibited the proliferation and activation of HCS-T6 cells induced by TGF-ß1, decreased TNF-α and IL-6 levels, and inhibited the TAK1 activation induced by TGF-ß1 and then the expression of MAPK and NF-κB signaling pathway-related proteins. CONCLUSION: Together, SCA can ameliorate the liver fibrosis induced by TAA and the HSC-T6 cell activation induced by TGF-ß1 in mice, and its mechanism may be to inhibit the HSCs activation and inflammatory response by inhibiting TGF-ß1 mediated TAK1/MAPK and signal pathways.


Assuntos
Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Lignanas/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/patologia , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Tioacetamida/toxicidade
18.
J Agric Food Chem ; 69(26): 7399-7408, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34170130

RESUMO

Propiconazole (PCZ) is a hepatotoxic triazole fungicide. There are insufficient data on how PCZ induces liver fibrosis in humans. This study aimed to investigate the effect of PCZ on liver fibrosis and its underlying mechanisms. HepG2 cells and Sprague-Dawley rats were exposed to PCZ at doses of 0-160 µM (3-72 h) and 0.5-50 mg/kg body weight/day (28 days), respectively. PCZ-treated cells activated intracellular oxidative stress via cytochrome P450 and had higher mRNA levels of interleukin-1ß, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-9, and transforming growth factor-ß (TGF-ß) than the control. PCZ treatment in cells induced a morphological transition with E-cadherin decrease and vimentin and Snail increase via the oxidative stress and TGF-ß/Smad pathways. PCZ administration in rats induced liver fibrosis through pathological changes, epithelial-mesenchymal transition, and collagen deposition. Thus, our data suggest that exposure of PCZ to humans may be a risk factor for the functional integrity of the liver.


Assuntos
Fungicidas Industriais , Animais , Transição Epitelial-Mesenquimal , Fungicidas Industriais/toxicidade , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Ratos , Ratos Sprague-Dawley , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Triazóis/toxicidade
19.
FASEB J ; 35(7): e21725, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34110636

RESUMO

Renal fibrosis leads to chronic kidney disease, which affects over 15% of the U.S. population. PAI-1 is highly upregulated in the tubulointerstitial compartment in several common nephropathies and PAI-1 global ablation affords protection from fibrogenesis in mice. The precise contribution of renal tubular PAI-1 induction to disease progression, however, is unknown and surprisingly, appears to be independent of uPA inhibition. Human renal epithelial (HK-2) cells engineered to stably overexpress PAI-1 underwent dedifferentiation (E-cadherin loss, gain of vimentin), G2/M growth arrest (increased p-Histone3, p21), and robust induction of fibronectin, collagen-1, and CCN2. These cells are also susceptible to apoptosis (elevated cleaved caspase-3, annexin-V positivity) compared to vector controls, demonstrating a previously unknown role for PAI-1 in tubular dysfunction. Persistent PAI-1 expression results in a loss of klotho expression, p53 upregulation, and increases in TGF-ßRI/II levels and SMAD3 phosphorylation. Ectopic restoration of klotho in PAI-1-transductants attenuated fibrogenesis and reversed the proliferative defects, implicating PAI-1 in klotho loss in renal disease. Genetic suppression of p53 reversed the PA1-1-driven maladaptive repair, moreover, confirming a pathogenic role for p53 upregulation in this context and uncovering a novel role for PAI-1 in promoting renal p53 signaling. TGF-ßRI inhibition also attenuated PAI-1-initiated epithelial dysfunction, independent of TGF-ß1 ligand synthesis. Thus, PAI-1 promotes tubular dysfunction via klotho reduction, p53 upregulation, and activation of the TGF-ßRI-SMAD3 axis. Since klotho is an upstream regulator of both PAI-1-mediated p53 induction and SMAD3 signaling, targeting tubular PAI-1 expression may provide a novel, multi-level approach to the therapy of CKD.


Assuntos
Células Epiteliais/metabolismo , Glucuronidase/metabolismo , Rim/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Insuficiência Renal Crônica/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular , Fibroblastos/metabolismo , Fibrose/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Fosforilação/fisiologia , Transdução de Sinais , Proteína Smad3/metabolismo , Regulação para Cima/fisiologia
20.
Ecotoxicol Environ Saf ; 220: 112372, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082245

RESUMO

Silicosis is a devastating interstitial lung disease arising from long-term exposure to inhalable silica. Regrettably, no therapy currently can effectively reverse the silica-induced fibrotic lesion. Emerging evidence has indicated that the dysregulation of microRNAs is involved in silica-induced pulmonary fibrosis. The aim of this study is to explore the expression pattern and underlying mechanisms of miR-770-5p in silica-induced pulmonary fibrosis. Consistent with our previous miRNA microarray analysis, the results of qRT-PCR showed that miR-770-5p expression was downregulated in silica-induced pulmonary fibrosis in humans and animal models. Administration of miR-770-5p agomir significantly reduced the fibrotic lesions in the lungs of mice exposed to silica dust. MiR-770-5p also exhibited a dramatic reduction in TGF-ß1-activated human pulmonary fibroblasts (MRC-5). Transfection of miR-770-5p mimics significantly decreased the viability, migration ability, and S/G0 phase distribution, as well as the expression of fibronectin, collagen I, and α-SMA in TGF-ß1-treated MRC-5 cells. Transforming growth factor-ß receptor 1 (TGFBR1) was confirmed as a direct target of regulation by miR-770-5p. The expression of TGFBR1 was significantly increased in pulmonary fibrosis. Knockdown of TGFBR1 blocked the transduction of the TGF-ß1 signaling pathway and attenuated the activation of MRC-5 cells, while overexpression of TGFBR1 effectively restored the activation of MRC-5 cells inhibited by miR-770-5p. Together, our results demonstrated that miR-770-5p exerted an anti-fibrotic effect in silica-induced pulmonary fibrosis by targeting TGFBR1. Targeting miR-770-5p might provide a new therapeutic strategy to prevent the abnormal activation of pulmonary fibroblasts in silicosis.


Assuntos
Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Dióxido de Silício/efeitos adversos , Silicose/metabolismo , Adulto , Idoso , Animais , Regulação para Baixo , Fibroblastos/metabolismo , Fibrose , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais , Silicose/patologia , Fator de Crescimento Transformador beta1/metabolismo
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