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1.
Fitoterapia ; 169: 105567, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37315715

RESUMO

Eupatorium lindleyanum DC. has been used as a functional food in China for a long time. However, the antifibrotic activity of total sesquiterpenoids from Eupatorium lindleyanum DC. (TS-EL) is still unknown. In this study, we discovered that TS-EL reduced the increase in α-smooth muscle actin (α-SMA), type I collagen and fibronectin content, the formation of cell filaments and collagen gel contraction in transforming growth factor-ß1-stimulated human lung fibroblasts. Intriguingly, TS-EL did not change the phosphorylation of Smad2/3 and Erk1/2. TS-EL decreased the levels of serum response factor (SRF), a critical transcription factor of α-SMA, and SRF knockdown alleviated the transition of lung myofibroblasts. Furthermore, TS-EL significantly attenuated bleomycin (BLM)-induced lung pathology and collagen deposition and reduced the levels of two profibrotic markers, total lung hydroxyproline and α-SMA. TS-EL also decreased the levels of SRF protein expression in BLM-induced mice. These results suggested that TS-EL attenuates pulmonary fibrosis by inhibiting myofibroblast transition via the downregulation of SRF.


Assuntos
Eupatorium , Fibrose Pulmonar , Camundongos , Humanos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Bleomicina/efeitos adversos , Bleomicina/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Estrutura Molecular , Pulmão , Fator de Crescimento Transformador beta1/efeitos adversos , Fator de Crescimento Transformador beta1/metabolismo , Fibroblastos , Colágeno/metabolismo , Diferenciação Celular , Camundongos Endogâmicos C57BL
3.
FASEB J ; 36(2): e22144, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34990050

RESUMO

Renal fibrosis is a progressive, fatal renal disease characterized by the aberrant accumulation of myofibroblasts that produce excess extracellular matrix (ECM) in the renal interstitium and glomeruli. Yes-associated protein (YAP) has been regarded as a crucial modulator in myofibroblast transformation, but its upstream regulator remains a mystery. In the present study investigating the participation of m6A methylation during renal fibrosis through bioinformatics analysis, we identified YTHDF1, a modulator of m6A methylation, as a key contributor for renal fibrosis because it was highly expressed in human fibrotic kidneys and had a significant correction with YAP. Their co-localization in human fibrotic kidneys was additionally shown by immunofluorescence. We then found that YTHDF1 was also up-regulated in fibrotic mouse kidneys induced by unilateral ureteral obstruction (UUO), high-dose folic acid administration, or the unilateral ischemia-reperfusion injury, further supporting a causal role of YTHDF1 during renal fibrosis. Consistent with this notion, YTHDF1 knockdown alleviated the progression of renal fibrosis both in cultured cells induced by transforming growth factor-beta administration and in the UUO mouse model. Meanwhile, YAP was accordingly down-regulated when YTHDF1 was inhibited. Furthermore, the specific binding of YTHDF1 to YAP mRNA was detected using RNA Binding Protein Immunoprecipitation, and the up-regulation of fibrotic related molecules in cultured cells induced by YTHDF1 over-expression plasmid was attenuated by YAP siRNA. Taken together, our data highlight the potential utility of YTHDF1 as an indicator for renal fibrosis and suggest that YTHDF1 inhibition might be a promising therapeutic strategy to alleviate renal fibrosis via downregulating YAP.


Assuntos
Proteínas de Ciclo Celular/genética , Fibrose/genética , Nefropatias/genética , Rim/patologia , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Regulação para Cima/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/genética , Matriz Extracelular/genética , Fibroblastos/patologia , Fibrose/patologia , Humanos , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/patologia , RNA Mensageiro/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Obstrução Ureteral/genética , Obstrução Ureteral/patologia
4.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34675076

RESUMO

Myopia is a leading cause of visual impairment and blindness worldwide. However, a safe and accessible approach for myopia control and prevention is currently unavailable. Here, we investigated the therapeutic effect of dietary supplements of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on myopia progression in animal models and on decreases in choroidal blood perfusion (ChBP) caused by near work, a risk factor for myopia in young adults. We demonstrated that daily gavage of ω-3 PUFAs (300 mg docosahexaenoic acid [DHA] plus 60 mg eicosapentaenoic acid [EPA]) significantly attenuated the development of form deprivation myopia in guinea pigs and mice, as well as of lens-induced myopia in guinea pigs. Peribulbar injections of DHA also inhibited myopia progression in form-deprived guinea pigs. The suppression of myopia in guinea pigs was accompanied by inhibition of the "ChBP reduction-scleral hypoxia cascade." Additionally, treatment with DHA or EPA antagonized hypoxia-induced myofibroblast transdifferentiation in cultured human scleral fibroblasts. In human subjects, oral administration of ω-3 PUFAs partially alleviated the near-work-induced decreases in ChBP. Therefore, evidence from these animal and human studies suggests ω-3 PUFAs are potential and readily available candidates for myopia control.


Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Miopia/prevenção & controle , Administração Oral , Animais , Transdiferenciação Celular , Células Cultivadas , Corioide/irrigação sanguínea , Suplementos Nutricionais , Modelos Animais de Doenças , Progressão da Doença , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Cobaias , Humanos , Hipóxia/dietoterapia , Hipóxia/fisiopatologia , Hipóxia/prevenção & controle , Camundongos , Miofibroblastos/patologia , Miopia/dietoterapia , Miopia/fisiopatologia , Adulto Jovem
5.
Phytomedicine ; 81: 153428, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341025

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive fibrotic lung disease lacking a validated and effective therapy. Aberrant activation of the Wnt/ß-catenin signaling cascade plays the key role in the pathogenesis of IPF. Betulinic acid is a natural pentacyclic triterpenoid molecule that has excellent antitumor and antiviral activities. HYPOTHESIS: We hypothesized that BA has an anti-pulmonary fibrosis effect mediated by the suppression of the Wnt/ß-catenin pathway. Study design Pulmonary fibrosis markers were detected in vitro and in vivo to confirm the antifibrotic effect of BA. The Wnt/ß-catenin pathway-related proteins were overexpressed to determine the effect of BA on Wnt signaling. METHODS AND RESULTS: BA dose-dependently inhibited Wnt3a-induced fibroblast activation in vitro. Moreover, BA decreased Wnt3a- and LiCl-induced transcriptional activity, as assessed by the TOPFlash assay in fibroblasts, and repressed the expression of the Wnt target genes cyclin D1, axin 2, and S100A4. Further investigation indicated that BA restrained the nuclear accumulation of ß-catenin, mainly by increasing the phospho-ß-catenin ratio (S33/S37/T41 and S45), inhibited the phosphorylation of DVL2 and LRP, and decreased the levels of Wnt3a and LRP6. In agreement with the results of the in vitro assays, the in vivo experiments indicated that BA significantly decreased bleomycin-induced pulmonary fibrosis in mice and suppressed myofibroblast activation by inhibiting Wnt/ß-catenin signaling. CONCLUSION: BA may directly interfere with the Wnt/ß-catenin pathway to subsequently repress myofibroblast activation and pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Triterpenos Pentacíclicos/farmacologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Bleomicina/toxicidade , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Ácido Betulínico
6.
Biochem Pharmacol ; 183: 114344, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33221275

RESUMO

Renal fibrosis is a frequent axis contributing to the occurrence of end-stage nephropathy. Previously, it has been reported that atractylenolide Ⅰ (ATL-1), a natural compound extracted from Atractylodes macrocephala, has anti-cancer and antioxidant effects. However, the renal anti-fibrotic effects of action remain unclear. In this study, the anti-fibrotic effects of ATL-1 were examined in fibroblasts, tubular epithelial cells (TECs) triggered by TGF-ß1 in vitro, and using a unilateral ureteral obstruction (UUO) mouse model in vivo. We found that ATL-1 represses the myofibroblastic phenotype and fibrosis development in UUO kidneys by targeting the fibroblast-myofibroblast differentiation (FMD), as well as epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of ATL-1 were associated with reduced cell growth in the interstitium and tubules, leading to suppression of the proliferation-linked cascades activity consisting of JAK2/STAT3, PI3K/Akt, p38 MAPK, and Wnt/ß-catenin pathways. Besides, ATL-1 treatment repressed TGF-ß1-triggered FMD and the myofibroblastic phenotype in fibroblasts by antagonizing the activation of proliferation-linked cascades. Likewise, TGF-ß1-triggered excessive activation of the proliferation-linked signaling in TECs triggered EMT. The myofibroblastic phenotype was repressed by ATL-1. The anti-fibrotic and anti-proliferative effects of ATL-1 were linked to the inactivation of Smad2/3 signaling, partially reversing FMD, as well as EMT and the repression of the myofibroblastic phenotype. Thus, the inhibition of myofibroblastic phenotype and fibrosis development in vivo and in vitro through proliferation-linked cascades of ATL-1 makes it a prospective therapeutic bio-agent to prevent renal fibrosis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Lactonas/uso terapêutico , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Sesquiterpenos/uso terapêutico , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/patologia , Lactonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/patologia , Fenótipo , Ratos , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
7.
Am J Chin Med ; 48(7): 1715-1729, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33148003

RESUMO

Pterostilbene (PTB) is a derivative of resveratrol present in grapes and blueberries. PTB is structurally similar to resveratrol, possessing properties such as being analgesic, anti-aging, antidiabetic, anti-inflammatory, anti-obesity, anti-oxidation, cholesterol-reductive, and neuroprotective. However, there have not been reports on the effect of PTB on macrophage-myofibroblast transition (MMT) induced fibrosis in kidney. In this study, we investigated the antifibrotic effects of PTB on the in vivo mouse unilateral ureteral obstruction (UUO) model and in vitro MMT cells. Kidneys subjected to UUO with PTB treatment were collected for the investigation of PTB mediating MMT derived renal interstitial fibrosis. We conducted kidney RNA-seq transcriptomes and TGF-[Formula: see text]1-induced bone marrow-derived macrophages assays to determine the mechanisms of PTB. We found that PTB treatment suppressed the interstitial fibrosis in UUO mice. PTB also attenuated the number of MMT cells in vivo and in vitro. The transcriptomic analysis showed that CXCL10 may play a central role in the process of PTB-treated renal fibrosis. The siRNA-mediated CXCL10 knockdown decreased the number of MMT cells in TGF-[Formula: see text]1-induced bone marrow-derived macrophages. Our results suggested that PTB attenuated renal interstitial fibrosis by mediating MMT by regulating transcriptional activity of CXCL10.


Assuntos
Mirtilos Azuis (Planta)/química , Fibrose/tratamento farmacológico , Fibrose/patologia , Rim/patologia , Macrófagos/patologia , Miofibroblastos/patologia , Fitoterapia , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia , Animais , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Estilbenos/isolamento & purificação , Obstrução Ureteral/etiologia
8.
Phytomedicine ; 78: 153298, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32781391

RESUMO

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a progressive inflammatory disorder driven by a fibrotic cascade of events such as epithelial to mesenchymal transition, extracellular matrix production and collagen formation in the lungs in a sequential manner. IPF incidences were raising rapidly across the world. FDA approved pirfenidone and nintedanib (tyrosine kinase inhibitors) are being used as a first-line treatment drugs for IPF, however, neither the quality of life nor survival rates have been improved because of patient noncompliance due to multiple side effects. Thus, the development of novel therapeutic approaches targeting TGF-ß mediated cascade of fibrotic events is urgently needed to improve the survival of the patients suffering from devastating disease. PURPOSE: The aim of this study was to investigate and validate the anti-fibrotic properties of Biochanin-A (isoflavone) against TGF-ß mediated fibrosis in in vitro, ex vivo, in vivo models and to determine the molecular mechanisms that mediate these anti-fibrotic effects. METHODS: The therapeutic activity of BCA was determined in in vitro/ex vivo models. Cells were pre-treated with BCA and incubated in presence or absence of recombinant-TGF-ß to stimulate the fibrotic cascade of events. Pulmonary fibrosis was developed by intratracheal administration of bleomycin in rats. BCA treatment was given for 14 days from post bleomycin instillation and then various investigations (collagen content, fibrosis gene/protein expression and histopathological changes) were performed to assess the anti-fibrotic activity of BCA. RESULTS: In vitro/ex vivo (Primary normal, IPF cell line and primary IPF cells/ Precision cut mouse lung slices) experiments revealed that, BCA treatment significantly (p < 0.001) reduced the expression of TGF-ß modulated fibrotic genes/protein expressions (including their functions) which are involved in the cascade of fibrotic events. BCA treatment significantly (p < 0.01) reduced the bleomycin-induced inflammatory cell-infiltration, inflammatory markers expression, collagen deposition and expression of fibrotic markers in lung tissues equivalent or better than pirfenidone treatment. In addition, BCA treatment significantly (p < 0.001) attenuated the TGF-ß1/BLM-mediated increase of TGF-ß/Smad2/3 phosphorylation and resulted in the reduction of pathological abnormalities in lung tissues determined by histopathology observations. CONCLUSION: Collectively, BCA treatment demonstrated the remarkable therapeutic effects on TGF-ß/BLM mediated pulmonary fibrosis using IPF cells and rodent models. This current study may offer a novel treatment approach to halt and may be even rescue the devastating lung scarring of IPF.


Assuntos
Colágeno/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Genisteína/farmacologia , Miofibroblastos/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina/toxicidade , Diferenciação Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Humanos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Ratos Wistar , Reprodutibilidade dos Testes , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia
9.
J Ethnopharmacol ; 261: 113203, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-32721552

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic foot ulcer is one of the most serious complications of diabetes. Effective medical treatment regarding improvement of ulcer healing in patients is essential. Pien Tze Huang (PZH), a valuable Chinese traditional medicine, has been found significant efficacy on the curing of diabetic wound in clinic recently. AIM OF THE STUDY: This work was conducted to confirm the efficacy, and compare the therapeutic effect through the oral administration and local delivery route, providing a rationale for the new PZH form development; besides, the mechanisms through which PZH promoted the wound healing was also discussed. MATERIALS AND METHODS: First, the chemical composition of PZH was characterized by 1H-NMR and HPLC. The anti-apoptosis effects of PZH on high concentration glucose injured epidermal fibroblast (HFF-1) was investigated in a dose dependent way. Then, the effects of the systematical administration of PZH, and the topical used route on excisional wounds of Streptozotocin (STZ) induced diabetic mice were compared. RESULTS: The results illustrated that PZH decreased the reactive oxygen species (ROS) levels in cells, preventing cell damage/apoptosis through an ROS/Bcl-2/Bax/Caspase-3 pathway. The in vivo study proved that topical use of PZH exceeded the systematical route both in accelerating the wound closure and improving the healing quality. Meanwhile, PZH promoted wound closure through stimulating the secretion of Col-I, decreasing fibroblast apoptosis, and enhancing myo-fibroblast differentiation, in consistent with the mechanism study in vitro. CONCLUSIONS: Local used PZH improves wound healing by inhibiting the abnormal HFF-1 apoptosis and senescence. The study held a great promise for development of a topical dosage form of PZH for diabetic wound healing.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fibroblastos/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Administração Cutânea , Administração Oral , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Glicemia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Medicamentos de Ervas Chinesas/administração & dosagem , Fibroblastos/metabolismo , Fibroblastos/patologia , Masculino , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Espécies Reativas de Oxigênio/metabolismo , Pele/lesões , Pele/metabolismo , Pele/patologia , Estreptozocina , Fatores de Tempo , Ferimentos e Lesões/complicações , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
10.
Lasers Med Sci ; 35(1): 51-61, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30919284

RESUMO

The aim of this study was to evaluate the photobiomodulation of red and green lights in the repair process of third-degree skin burns in rats through clinicopathological and immunohistochemical parameters. Sixty male Wistar rats were divided into three groups: control (CTRL) (n = 20), red LED (RED) (n = 20), and green LED (GREEN) (n = 20), with subgroups (n = 5) for each time of euthanasia (7, 14, 21, and 28 days). Daily applications in RED (λ630 ± 10 nm, 300 mW) and GREEN groups (λ520 ± 30 nm, 180 mW) were performed at four points of the wound (total 36 J/cm2 in RED and 240 J/cm2 in GREEN). After euthanasia, the wound retraction index (WRI) was evaluated. In histological sections, the re-epithelialization degree, the angiogenic index (AI), and the amount of myofibroblasts in wounds were analyzed. At 14 and 21 days, the RED group induced higher re-epithelialization and WRI compared to CTRL (p > 0.05) and GREEN groups (p < 0.05). At 7 and 14 days, greater AI were observed in the GREEN group, with significant difference in relation to CTRL group at 7 days (p < 0.05). At 21 and 28 days, a trend was observed for greater amount of myofibroblasts in the GREEN group, with significant difference in relation to CTRL group at 21 days (p < 0.05). The results suggest greater potential of the green light to stimulate angiogenesis in the initial periods and myofibroblastic differentiation in the final periods of the repair of third-degree skin burns. Red light may stimulate further re-epithelialization and wound retraction, especially in advanced repair phases.


Assuntos
Queimaduras/radioterapia , Luz , Terapia com Luz de Baixa Intensidade , Pele/patologia , Pele/efeitos da radiação , Cicatrização/efeitos da radiação , Animais , Masculino , Miofibroblastos/patologia , Miofibroblastos/efeitos da radiação , Neovascularização Fisiológica/efeitos da radiação , Ratos Wistar , Reepitelização/efeitos da radiação
11.
Toxicol Lett ; 321: 103-113, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31706003

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no effective medication. Andrographolide (Andro), extracted from Chinese herbal Andrographis paniculata, could attenuate bleomycin (BLM)-induced pulmonary fibrosis via inhibition of inflammation and oxidative stress, however, the anti-fibrotic mechanisms have not been clarified. Myofibroblasts are the primary cell types responsible for the accumulation of extracellular matrix (ECM) in fibrotic diseases, and targeting fibroblast proliferation and differentiation is an important therapeutic strategy for the treatment of IPF. Hence, this study aimed to investigate the effects of Andro on the fibroblast proliferation and differentiation in the in vivo and in vitro models. The results showed that Andro improved pulmonary function and inhibited BLM-induced fibroblast proliferation and differentiation and ECM deposition in the lungs. In vitro, Andro inhibited proliferation and induced apoptosis of TGF-ß1-stimulated NIH 3T3 fibroblasts and primary lung fibroblasts (PLFs). Andro also inhibited TGF-ß1-induced myofibroblast differentiation and ECM deposition in both cells. We also found that Andro suppressed TGF-ß1-induced Smad2/3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediates Andro-induced effects on TGF-ß1-induced fibroblast proliferation and differentiation. These results indicated that Andro has novel and potent anti-fibrotic effects in lung fibroblasts via inhibition of the proliferation and myofibroblast differentiation of fibroblasts and subsequent ECM deposition, which are modulated by TGF-ß1-mediated Smad-dependent and -independent pathways.


Assuntos
Bleomicina , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose Pulmonar Idiopática/prevenção & controle , Pulmão/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Células NIH 3T3 , Ratos Sprague-Dawley , Transdução de Sinais
12.
Biochem Biophys Res Commun ; 514(3): 913-918, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-31084931

RESUMO

Liver fibrosis is a common consequence of various chronic hepatitis and liver injuries. The myofibroblasts, through the accumulation of extracellular matrix (ECM) proteins, are closely associated with the progression of liver fibrosis. However, the molecular mechanisms underlying transcriptional regulation of fibrogenic genes and ECM proteins in myofibroblasts remain largely unknown. Using tamoxifen inducible myofibroblast-specific Cre-expressing mouse lines with selective deletion of the transcription factor Yin Yang 1 (YY1), here we show that YY1 deletion in myofibroblasts mitigates carbon tetrachloride-induced liver fibrosis. This protective effect of YY1 ablation on liver fibrosis was accompanied with reduced expression of profibrogenic genes and ECM proteins, including TNF-α, TGF-ß, PDGF, IL-6, α-SMA and Col1α1 in liver tissues from YY1 mutant mice. Moreover, using the human hepatic stellate cell (HSC) line LX-2, we found that knockdown of YY1 in myofibroblasts by siRNA treatment diminished myofibroblast proliferation, α-SMA expression, and collagen deposition. Collectively, our findings reveal a specific role of YY1 in hepatic myofibroblasts and suggest a new therapeutic strategy for hepatic fibrosis-associated liver diseases.


Assuntos
Cirrose Hepática/patologia , Miofibroblastos/patologia , Fator de Transcrição YY1/genética , Animais , Linhagem Celular , Deleção de Genes , Humanos , Cirrose Hepática/genética , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Interferência de RNA
13.
PLoS One ; 13(11): e0207872, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30485339

RESUMO

Pathological features of pulmonary fibrosis include accumulation of myofibroblasts and increased extracellular matrix (ECM) deposition in lung tissue. Contractile α-smooth muscle actin (α-SMA)-expressing myofibroblasts that produce and secrete ECM are key effector cells of the disease and therefore represent a viable target for potential novel anti-fibrotic treatments. We used primary normal human lung fibroblasts (NHLF) in two novel high-throughput screening assays to discover molecules that inhibit or revert fibroblast-to-myofibroblast differentiation. A phenotypic high-content assay (HCA) quantified the degree of myofibroblast differentiation, whereas an impedance-based assay, multiplexed with MS / MS quantification of α-SMA and collagen 1 alpha 1 (COL1) protein, provided a measure of contractility and ECM formation. The synthetic prostaglandin E1 (PGE1) alprostadil, which very effectively and potently attenuated and even reversed TGF-ß1-induced myofibroblast differentiation, was identified by screening a library of approved drugs. In TGF-ß1-induced myofibroblasts the effect of alprostadil was attributed to activation of prostanoid receptor 2 and 4 (EP2 and EP4, respectively). However, selective activation of the EP2 or the EP4 receptor was already sufficient to prevent or reverse TGF-ß1-induced NHLF myofibroblast transition. Our high-throughput assays identified chemical structures with potent anti-fibrotic properties acting through potentially novel mechanisms.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP4/agonistas , Desdiferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Miofibroblastos/patologia , Fenótipo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Aprendizado de Máquina Supervisionado
14.
Ear Nose Throat J ; 97(8): E31-E33, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30138523

RESUMO

Inflammatory myofibroblastic tumor (IMT) is a benign neoplasm of intermediate biologic potential. It rarely occurs in the larynx, and it has not been previously reported in the epiglottis. We treated a 66-year-old woman who presented with progressive dysphonia and a mass on her suprahyoid epiglottis. The tumor was completely excised with a CO2 laser; no adjuvant therapy was administered. Histopathology revealed that the mass was an IMT. No evidence of recurrence was noted after 6 months of follow-up. We present what we believe is the first case of an epiglottic IMT to be reported in the literature, and we propose CO2 laser excision without adjuvant therapy as an acceptable treatment.


Assuntos
Epiglote , Granuloma de Células Plasmáticas , Lasers de Gás/uso terapêutico , Idoso , Disfonia/etiologia , Epiglote/patologia , Epiglote/cirurgia , Feminino , Granuloma de Células Plasmáticas/diagnóstico , Granuloma de Células Plasmáticas/fisiopatologia , Granuloma de Células Plasmáticas/cirurgia , Humanos , Doenças da Laringe/diagnóstico , Doenças da Laringe/cirurgia , Miofibroblastos/patologia , Resultado do Tratamento
15.
J Med Food ; 21(3): 215-224, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29336663

RESUMO

Disruption of the balance among the microbiota, epithelial cells, and resident immune cells in the intestine is involved in the pathogenesis of inflammatory bowel disease (IBD). Probiotics exert protective effects against IBD, and probiotic commensal Lactobacillus species are common inhabitants of the natural microbiota, especially in the gut. To investigate the effects of Lactobacillus acidophilus on the development of IBD, L. acidophilus was administered orally in mice with dextran sodium sulfate (DSS)-induced colitis. DSS-induced damage and the therapeutic effect of L. acidophilus were investigated. Treatment with L. acidophilus attenuated the severity of DSS-induced colitis. Specifically, it suppressed proinflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor-α, IL-1ß, and IL-17 in the colon tissues, which are produced by T helper (Th) 17 cells. Moreover, in vitro L. acidophilus treatment directly induced T regulatory (Treg) cells and the production of IL-10, whereas the production of IL-17 was suppressed in splenocytes. In addition, we found that L. acidophilus treatment decreased the levels of α-smooth muscle actin, a marker of activated myofibroblasts, and type I collagen compared with control mice. These results suggest that L. acidophilus may be a novel treatment for IBD by modulating the balance between Th17 and Treg cells, as well as fibrosis development.


Assuntos
Colite/dietoterapia , Colo/imunologia , Mucosa Intestinal/imunologia , Lactobacillus acidophilus/imunologia , Probióticos/uso terapêutico , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Actinas/metabolismo , Animais , Biomarcadores/metabolismo , Células Cultivadas , Colite/imunologia , Colite/patologia , Colágeno Tipo I/metabolismo , Colo/metabolismo , Colo/patologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/metabolismo , Fibrose , Regulação da Expressão Gênica , Interleucina-10/agonistas , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos C57BL , Miofibroblastos/imunologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Distribuição Aleatória , Organismos Livres de Patógenos Específicos , Baço/imunologia , Baço/metabolismo , Baço/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Células Th17/metabolismo , Células Th17/patologia
16.
Am J Chin Med ; 45(5): 1061-1074, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28659031

RESUMO

Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl[Formula: see text] three times a week for two weeks. Then, CCl4 was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-[Formula: see text]1) with or without GPs for 48[Formula: see text]h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ([Formula: see text]-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). In the 5M CCl4 group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ([Formula: see text], [Formula: see text]). Immunostaining showed that the number of Sox9 and [Formula: see text]-SMA double-positive cells was higher in the 5M CCl4 group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of [Formula: see text]-SMA and Col I was significantly increased after treatment with TGF-[Formula: see text], whereas in the GPs treatment group, expression was markedly decreased ([Formula: see text]). The levels of TGF-[Formula: see text] and TGF-[Formula: see text]R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl4-induced liver fibrosis via the inhibition of TGF-[Formula: see text] signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Gynostemma/química , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Fígado/citologia , Miofibroblastos/patologia , Fitoterapia , Células-Tronco/citologia , Actinas/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Células Cultivadas , Colágeno Tipo I/metabolismo , Depressão Química , Queratina-19/metabolismo , Cirrose Hepática/induzido quimicamente , Masculino , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fatores de Transcrição SOX9/metabolismo , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
17.
Chin J Integr Med ; 23(5): 362-369, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-26956464

RESUMO

OBJECTIVE: To study the effect of curcumin on fibroblasts in rats with cardiac fibrosis. METHODS: The rats were randomly divided into 4 groups (n=12 in each group): the normal control, isoproterenol (ISO), ISO combined with low-dose curcumin (ISO+Cur-L), and ISO combined with high-dose curcumin (ISO+Cur-H) groups. ISO+Cur-L and ISO+Cur-H groups were treated with curcumin (150 or 300 mg•kg-1•day-1) for 28 days. The primary culture of rat cardiac fibroblast was processed by trypsin digestion method in vitro. The 3rd to 5th generation were used for experiment. Western blot method was used to test the expression of collagen type I/III, α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-ß1, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was applied to test the proliferation of fibroblast. RESULT: Curcumin significantly decreased interstitial and perivascular myocardial collagen deposition and cardiac weight index with reducing protein expression of collagen type I/III in hearts (P<0.05). In addition, curcumin directly inhibited angiotensin (Ang) II-induced fibroblast proliferation and collagen type I/III expression in cardiac fibroblasts (P<0.05). Curcumin also inhibited fibrosis by inhibiting myofibroblast differentiation, decreased TGF-ß1, MMP-9 and TIMP-1 expression (P<0.05) but had no effects on Smad3 in Ang II incubated cardiac fibroblasts. CONCLUSIONS: Curcumin reduces cardiac fibrosis in rats and Ang II-induced fibroblast proliferation by inhibiting myofibroblast differentiation, decreasing collagen synthesis and accelerating collagen degradation through reduction of TGF-ß1, MMPs/TIMPs. The present findings also provided novel insights into the role of curcumin as an antifibrotic agent for the treatment of cardiac fibrosis.


Assuntos
Curcumina/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Miocárdio/patologia , Miofibroblastos/patologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Angiotensina II , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Eletrocardiografia , Fibrose , Isoproterenol , Masculino , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Ratos Sprague-Dawley , Proteína Smad3/metabolismo
18.
Biomed Res Int ; 2016: 4874809, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27298823

RESUMO

Vitamin A is essential to mucosal immunity and cell differentiation. The fact that lack of it might involve chronic inflammation and increased risk of cancer has been reported. Little is known about the mechanism of vitamin A deficiency in the development of colitis and its influence on development of colorectal cancer. To determine the influence of vitamin A deficiency on colitis and colorectal cancer development, an experimental study using a colitis mouse model was performed. Dextran sulfate sodium (DSS) colitis was induced in vitamin A-deficient and vitamin A-supplemented mice. Further, colorectal carcinoma was induced by a combination of azoxymethane preinjection and DSS colitis. Results were compared between the two groups mainly by immunohistochemical analysis. Colitis was more severe and recovery from colitis was slower in vitamin A-deficient mice than in vitamin A-supplemented mice. Compared with vitamin A-supplemented mice, vitamin A-deficient mice had decreases in colonic subepithelial myofibroblasts and the ratio of mucosal IgA(+)/IgG(+) cells, increases in CD11c(+) dendritic cells, and a higher rate of development of colorectal carcinoma with colitis following azoxymethane. Vitamin A lipid droplets in subepithelial myofibroblasts were decreased in vitamin A-deficient mice, suggesting alterations in colonic crypt niche function. Thus, vitamin A inhibited colitis and the development of colorectal cancer.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/tratamento farmacológico , Vitamina A/uso terapêutico , Doença Aguda , Animais , Carcinogênese/patologia , Células Dendríticas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Homeostase/efeitos dos fármacos , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Camundongos Endogâmicos BALB C , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Vitamina A/farmacologia
19.
Biochim Biophys Acta ; 1860(7): 1551-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27040591

RESUMO

BACKGROUND: Dermal fibroblasts activated by conductive polymer-mediated electrical stimulation (ES) have shown myofibroblast characteristics that favor wound healing. However, the signaling pathway related to this phenotype switch remains unclear, and the in vivo survival of the electrically activated cells has never been studied. METHODS: Primary human skin fibroblasts were exposed to pulsed-ES mediated through polypyrrole (PPy) coated fabrics. The expression of α-smooth muscle actin (α-SMA) and the signaling pathways were investigated by ELISA, Western blot and specific inhibition test, and immunocytochemistry staining as well as qRT-PCR analysis. In vivo implantation was performed in a mouse model to clarify the cell fate or contractile phenotype maintenance following ES stimulation. RESULTS: We demonstrated the upregulation of TGFß1 and phosph-ERK, and the NF-κB nuclear enrichment in the ES-activated cells. The ES-activated fibroblasts retained high level of α-smooth muscle actin expression even after prolonged subculture. Subcutaneous implantation for 15 days revealed more human myofibroblasts in the experimental groups. CONCLUSIONS: These findings demonstrate for the first time the involvement of the TGFß1/ERK/NF-κB signaling pathway in ES-activated fibroblasts. The ES induced phenotype switch proves stable in subculture and in animal, pointing potential application in wound healing. GENERAL SIGNIFICANCE: Reveal of how ES activates cells and the implication of ES activated cells in wound healing.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , NF-kappa B/metabolismo , Pele/enzimologia , Estimulação Elétrica Nervosa Transcutânea/métodos , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização , Actinas/metabolismo , Movimento Celular , Células Cultivadas , Humanos , Miofibroblastos/enzimologia , Miofibroblastos/patologia , Fenótipo , Fosforilação , Cultura Primária de Células , Transdução de Sinais , Pele/patologia , Fatores de Tempo
20.
Development ; 142(17): 2981-95, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26329601

RESUMO

Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation whereas Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching and caused airway dilation similar to that seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be partly explained by the reduced expression of Shh, a transcriptional target of YY1, in lung endoderm, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the crucial requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB.


Assuntos
Epitélio/embriologia , Epitélio/metabolismo , Pulmão/embriologia , Pulmão/metabolismo , Morfogênese , Fator de Transcrição YY1/metabolismo , Animais , Apoptose , Padronização Corporal , Cartilagem/anormalidades , Cartilagem/embriologia , Cartilagem/patologia , Diferenciação Celular , Proliferação de Células , RNA Helicases DEAD-box/metabolismo , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Endoderma/embriologia , Endoderma/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fator 10 de Crescimento de Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Pneumopatias/congênito , Pneumopatias/patologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Miócitos de Músculo Liso/metabolismo , Miofibroblastos/patologia , Fenótipo , Blastoma Pulmonar/metabolismo , Blastoma Pulmonar/patologia , Ribonuclease III/metabolismo , Traqueia/anormalidades , Traqueia/embriologia , Traqueia/patologia
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