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2.
Chem Biol Interact ; 319: 109024, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097614

RESUMO

Silicosis is an occupational pulmonary fibrosis that is caused by inhalation of silica (SiO2), and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a natural product, has been reported to possess antioxidant and anti-fibrotic properties in various diseases. The purpose of the current study was to examine Tan IIA's protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. We found that in vivo treatment with Tan IIA significantly relieved silica-induced lung fibrosis in a silicosis rat model by histological and immunohistochemical analyses. Further, in vitro mechanistic investigations, mainly using western blot and immunofluorescence analyses, revealed that Tan IIA administration markedly inhibited the silica-induced epithelial-mesenchymal transition (EMT) and transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway and also reduced silica-induced oxidative stress and activated the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway in A549 and human bronchial epithelial (HBE) cells. Furthermore, through transfection with siRNA, we demonstrate that Nrf2 activation partially mediates the suppression effects of Tan IIA on EMT and TGF-ß1/Smad signaling pathway activation induced by silica exposure, thus mediating the anti-fibrotic effects of Tan IIA against silica-induced pulmonary fibrosis. In our study, Tan IIA has been identified as a possible anti-oxidative and anti-fibrotic drug for silicosis.


Assuntos
/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Antioxidantes/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/farmacologia
3.
Life Sci ; 246: 117423, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32057902

RESUMO

Bleomycin (BLM) is one of the most common anti-cancer drugs used to treat numerous types of tumors. However, pulmonary toxicity is considered the most dramatic effect of BLM. Therefore, BLM has been frequently used for induction of pulmonary fibrosis. This study aimed to evaluate the effect of nicorandil on BLM-induced pulmonary fibrosis and explore the possible mechanisms. BLM was instilled intratracheally into male Sprague-Dawley rats as a single dose (5 mg/kg) and oral nicorandil was given (30 mg/kg/day) for 6 weeks after BLM challenge. At the end of experimental period, rats were sacrificed, and lung histopathology and biochemical parameters were evaluated. Nicorandil therapy attenuated lung inflammation and fibrosis elicited by BLM. Nicorandil significantly reduced total protein content, lactate dehydrogenase (LDH) activity and total and differential cell counts. Moreover, nicorandil diminished lung levels of malondialdehyde and total nitrite/nitrate, in addition to increasing lung contents of reduced glutathione and superoxide dismutase activity. Nicorandil reduced lung and bronchoalveolar lavage fluid contents of hypoxia inducible factor-1α (HIF-1α) and lung content of thioredoxin-interacting protein (TXNIP). Besides, nicorandil significantly improved histological lesions and reduced collagen deposition as well as hydroxyproline content. Immunohistochemical examination revealed that nicorandil-treated rats exhibited significant diminutions in protein expression levels of transforming growth factor beta-1(TGF-ß1) and inducible nitric oxide synthase (iNOS) and enhanced pulmonary protein expression of endothelial NOS (eNOS). In conclusion, these results illustrate the possible potential effects of nicorandil for managing pulmonary fibrosis caused by BLM.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Proteínas de Ciclo Celular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Nicorandil/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico/metabolismo , Fibrose Pulmonar/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/química , Proteínas de Ciclo Celular/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , L-Lactato Desidrogenase/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Nicorandil/uso terapêutico , Nitratos/análise , Óxido Nítrico/análise , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Nitritos/análise , Fibrose Pulmonar/tratamento farmacológico , Ratos , Ratos Sprague-Dawley
4.
Toxicol Lett ; 319: 168-174, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31698045

RESUMO

Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to asthma, bronchitis, bronchiectasis, airway stenosis, and pulmonary fibrosis. As there are no specific therapeutics available for victims of mustard gas poisoning, current clinical treatments mostly provide only symptomatic relief. In this article, the long-term effects of mustards on the respiratory tract are described in humans and experimental animal models in an effort to define cellular and molecular mechanisms contributing to lung injury and disease pathogenesis. A better understanding of mechanisms underlying pulmonary toxicity induced by mustards may help in identifying potential targets for the development of effective clinical therapeutics aimed at mitigating their adverse effects.


Assuntos
Alquilantes/toxicidade , Substâncias para a Guerra Química/toxicidade , Compostos de Mostarda/toxicidade , Doenças Respiratórias/induzido quimicamente , Animais , Humanos , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/patologia
5.
Eur J Med Chem ; 185: 111790, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699535

RESUMO

Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-ß-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-ß-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-ß/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T1/2 = 13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.


Assuntos
Cumarínicos/uso terapêutico , Descoberta de Drogas , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Células RAW 264.7 , Relação Estrutura-Atividade
6.
BMC Res Notes ; 12(1): 584, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533801

RESUMO

OBJECTIVE: The aim of this study was to compare in vivo effect of five pharmacological options on inflammation and pulmonary fibrosis induced by paraquat. METHODS: 54 Wistar SPF rats were used. After 2 h post-intoxication with paraquat ion, groups of 9 animals were randomly assigned to (1) cyclophosphamide plus dexamethasone (2) low molecular weight heparin (3) unfractionated heparin (4) vitamin C every 24 h, (5) atorvastatin or (6) placebo with intraperitoneal saline. Lung inflammation, alveolar injury, hepatocyte damage, hepatic regeneration, acute tubular necrosis and kidney congestion were evaluated. RESULTS: In the control group 100% of animals presented moderate and severe lung inflammation, while in the groups with atorvastatin and intratracheal heparin this proportion was lower (55.5%; CI 26.6-81.3%) (p = 0.025). A lower degree of moderate or severe hepatic regeneration was evident in the treatment groups with atorvastatin (p = 0.009). In this study was demonstrated that statins and heparin might have a protective effect in the paraquat-induced destructive phase. More evidence is needed to evaluated of dose-response effects of these drugs before to study in clinical trials.


Assuntos
Tratamento Farmacológico/métodos , Pulmão/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Atorvastatina/farmacologia , Ciclofosfamida/farmacologia , Dexametasona/farmacologia , Quimioterapia Combinada , Heparina/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Pulmão/patologia , Paraquat/toxicidade , Pneumonia/patologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/induzido quimicamente , Ratos Wistar , Resultado do Tratamento
7.
Chem Biodivers ; 16(12): e1900467, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556199

RESUMO

Pulmonary fibrosis (PF) is a chronic obstructive pulmonary disease without effective clinical drug treatment. Qing-Xuan Granule (QX) as a traditional Chinese patent medicine is clinically used to cure children's cough. This study was designed to investigate the effects of QX and possible molecular mechanisms for bleomycin-induced PF. The work used Western blotting and Q-PCR to explore the vitro and vivo mechanisms of QX treatment, while using HPLC-TOF/MS to explore the composition of QX. QX was given daily orally for two weeks after bleomycin intratracheal instillation. The protective effects of QX on lung function, inflammation, growth factors, hydroxyproline content and deposition of extracellular matrix were investigated. QX decreased expression of Col I and α-SMA in lung tissues by down-regulating TGF-ß1-Smad2/3 signaling and suppressed epithelial-mesenchymal transition and effectively reversed abnormal mRNA levels of MMP-1and TIMP-1 as well as LOXL-2 in lung tissues. HPLC-TOF/MS indicate that six substances could be the main active components, which were reported to protect against experimental lung disease.


Assuntos
Substâncias Protetoras/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Bleomicina/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
8.
In Vivo ; 33(5): 1455-1461, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471392

RESUMO

BACKGROUND/AIM: Idiopathic pulmonary fibrosis (PF) is a fatal disorder of unknown aetiology with limited treatment options. Chitosan has antibacterial, antifungal, antioxidant, antitumour, and anti-inflammatory effects. This study aimed to investigate the effects of chitosan administration on bleomycin (BLM)-induced PF in rats. MATERIALS AND METHODS: A PF rat model was established by endotracheal instillation of 5 mg/kg BLM; then, chitosan was administered in drinking water for 3 weeks. Histology, cell counts, and cytokine responses in the bronchoalveolar lavage fluid (BALF) and weight measurements (body and lung) were analyzed to assess its therapeutic effects. RESULTS: Chitosan administration tended to reduce transforming growth factor (TGF)-ß1 and interferon (IFN)-γ levels in BALF, and histopathological examination confirmed that chitosan attenuated the degree of inflammation and fibrosis in the lung. CONCLUSION: This study revealed that oral chitosan exhibits potential antifibrotic effects, as measured by decreased proinflammatory cytokine levels and histological evaluation, in a BLM-induced PF rat model.


Assuntos
Bleomicina/efeitos adversos , Quitosana/administração & dosagem , Substâncias Protetoras/administração & dosagem , Fibrose Pulmonar/etiologia , Administração Oral , Animais , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Imuno-Histoquímica , Masculino , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos , Resultado do Tratamento
9.
Med Sci Monit ; 25: 6523-6531, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31471534

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS) in infants is acute and progressive hypoxic respiratory failure caused by various extrapulmonary pathogenic factors besides cardiogenic factors. Diffuse alveolar injury and progression to pulmonary fibrosis are pathological features of ARDS. The present study sought to determine how puerarin influences the inflammatory response caused by pulmonary fibrosis in ARDS in infants. MATERIAL AND METHODS The human lung fibroblasts cell line HLF1 was treated with different concentrations of puerarin in different groups for various times. TGF-ß1 was overexpressed by TGF-ß1 (2 ng/mL) in routine experiments, and the treated cells and culture supernatant were collected for analysis in each step. Cell apoptosis was measured by flow cytometry, TUNEL assay, and detection of caspase 3 and Bcl-2. Cell proliferation was assessed by CCK-8 assay. Real-time PCR and Western blot assay were used to assess mRNA and protein levels of TGF-ß1 and Smad3, respectively. The related cytokines were assessed by ELISA. RESULTS Results showed that puerarin promoted the apoptosis and inhibited the proliferation of HLF1 cells. Caspase 3 was upregulated, whereas Bcl-2, TGF-ß1, and Smad3 were downregulated by puerarin. IL-1, IL-2, and IL-4, secreted by HLF1 cells, were reduced, but IL-10 showed the opposite trend. When TGF-ß1 was overexpressed, Smad3 was promoted, and IL-1, IL-2, and IL-4 was increased in HLF1 cells. Finally, overexpression of TGF-ß1 reversed the effect of puerarin in HLF1 cells. CONCLUSIONS Puerarin regulated the proliferation and apoptosis of pulmonary fibrosis cells, and affected the secretion of inflammatory cytokines. Thus, puerarin alleviated the inflammatory response resulting from pulmonary fibrosis by regulating the TGF-ß1/Smad3 pathway in infants with ARDS.


Assuntos
Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Inflamação/patologia , Interleucinas/metabolismo , Isoflavonas/farmacologia , Pulmão/embriologia , Pulmão/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/patologia
10.
Biomed Pharmacother ; 119: 109387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487583

RESUMO

PURPOSE: To observe the effect of astragaloside ASV (ASV) on silicosis fibroblasts, and further investigate its regulatory mechanism on TGF-ß1/Smad3 signaling pathway. METHODS: Silica-induced rats model was established in this study. RT-qPCR was performed to detect α-SMA, Collagen I, Collagen III, Smad2, Smad3 and Smad7 expression. Immunofluorescence was conducted to detect α-SMA, Collagen I, Collagen III and p-Smad3 protein and the nucleoplasmic distribution of p-Smad3.Western-blotting was performed to detect the protein of Smad2, p-Smad2, Smad3, p-Smad3 and Smad7. RESULTS: 20 µg/mL ASV could effectively reduce the expression of α-SMA, Collagen I, Collagen III. TGF-ß1 stimulated the proliferation of fibroblasts, promoted phosphorylation of Smad2 and Smad3, and down-regulated Smad7 expression. Among them, continuous phosphorylation of Smad3 is a major factor in causing fibrosis. Besides, ASV can inhibit silica-induced lung fibroblast fibrosis through TGF-ß1/Smad3 signaling pathway, thereby inhibiting the formation of silicosis. CONCLUSION: ASV could inhibit the expression of collagen in fibroblasts and the transformation to myofibroblasts, and has an anti-silicosis fibrosis effect, which may be related to the continuous phosphorylation of Smad3 in the TGF-ß1/Smad signaling pathway.


Assuntos
Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Saponinas/uso terapêutico , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/uso terapêutico , Actinas/genética , Actinas/metabolismo , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Pulmão/patologia , Fosforilação/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício , Silicose/tratamento farmacológico , Silicose/metabolismo , Silicose/patologia , Proteína Smad2/metabolismo , Triterpenos/farmacologia
11.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509965

RESUMO

Collagen Tissue Disease-associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1ß, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-ß mRNA. However, upon analyzing TGF-ß release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients.


Assuntos
Bronquiolite Obliterante/tratamento farmacológico , Ácido Hialurônico/farmacologia , Lipossomos/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Células A549 , Adulto , Bronquiolite Obliterante/patologia , Sistemas de Liberação de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Ácido Hialurônico/química , Lipossomos/química , Microscopia Confocal , Monócitos/efeitos dos fármacos , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular/genética
12.
Int Immunopharmacol ; 75: 105755, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377591

RESUMO

Pulmonary fibrosis is an irreversible lung disorder with predictable decline in lung function leading to respiratory insufficiency. Incidence of pulmonary fibrosis has been apparently increasing worldwide. Though aetiology of this disease remains unclear, potential roles of infection, disordered cell biology, genetic influence etc. have been proposed. Pirfenidone and nintedanib are the only two US FDA approved drugs to treat pulmonary fibrosis. Autophagy is a catabolic intracellular pathway that plays a crucial role in maintaining cellular homeostasis, which is involved in many disorders including fibrotic diseases. The present study investigated the role of Nimbolide, an important active constituent of Neem in TGF-ß1 induced in vitro and bleomycin induced in vivo model of pulmonary fibrosis, with a slight emphasis on regulation of fibrosis related autophagy. Protein expression studies showed significant reduction in mesenchymal, fibrotic markers and a substantial up regulation of epithelial markers upon treatment with Nimbolide. Nimbolide regulated autophagy signaling by dampening LC-3 and p-62 expression and increasing Beclin 1 expression as evidenced by immunohistochemistry and confocal microscopy. Our study demonstrates Nimbolide as a potent anti-fibrotic agent and its ability to regulate fibrosis associated autophagy.


Assuntos
Limoninas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Bleomicina , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Hidroxiprolina/metabolismo , L-Lactato Desidrogenase/metabolismo , Limoninas/farmacologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta1
13.
J Agric Food Chem ; 67(35): 9789-9795, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31373816

RESUMO

Pulmonary fibrosis is a chronic lung disease characterized by abnormal accumulation of the extracellular matrix (ECM). Chronic damage of the alveolar epithelium leads to a process called "epithelial-mesenchymal transition" (EMT) and increases synthesis and deposition of ECM proteins. Therefore, inhibition of EMT might be a promising therapeutic approach for the treatment of pulmonary fibrosis. ß-Sitosterol is one of the most abundant phytosterols in the plant kingdom and the major constituent in corn silk, which is derived from the stigma and style of maize (Zea mays). In this study, we elucidated that ß-sitosterol inhibited transforming growth factor-ß1 (TGF-ß1)-induced EMT and consequently had an antifibrotic effect. ß-Sitosterol (1-10 µg/mL) significantly downregulated the TGF-ß1-induced fibrotic proteins, such as collagen, fibronectin, and α-smooth muscle actin in human alveolar epithelial cells (p < 0.01). After 24 h, relative wound density (RWD) was increased in TGF-ß1 treated group (82.16 ± 5.70) compare to the control group (64.63 ± 2.21), but RWD was decreased in ß-sitosterol cotreated group (10 µg/mL: 71.54 ± 7.39; 20 µg/mL: 65.69 ± 6.42). In addition, the changes of the TGF-ß1-induced morphological shape and protein expression of EMT markers, N-cadherin, vimentin, and E-cadherin, were significantly blocked by ß-sitosterol treatment (p < 0.01). The effects of ß-sitosterol on EMT were found to be associated with the TGF-ß1/Snail pathway, which is regulated by Smad and non-Smad signaling pathways. Taken together, these findings suggest that ß-sitosterol can be used to attenuate pulmonary fibrosis through suppression of EMT by inhibiting the TGF-ß1/Snail pathway.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/fisiopatologia , Sitosteroides/farmacologia , Zea mays/química , Actinas/genética , Actinas/metabolismo , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Extratos Vegetais/química , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiopatologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
14.
J Ethnopharmacol ; 245: 112126, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31421181

RESUMO

ETHNOPHARMACOLOGICAL EVIDENCE: Pulmonary fibrosis (PF) is a progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity. Few effective drugs have been developed to reverse PF or even halt the disease progression. Yangfei Huoxue Decoction (YHD), a Traditional Chinese Medicine, which consisted of Astragalus membranacus(AM), Glehnia littoralis(GL), Schisandra chinensis(SC), Salvia miltiorrhiza Bunge(SB), Reynoutria japonica(RJ), Ligusticum chuanxiong(LX), and Euonymus alatus(EA) , has been used in China for the treatment of PF for many years with remarkable efficacy. According to the clinic observation of the results, we conducted experiments on animals, the process of BLM-induced pulmonary fibrosis in rats was interfered by YHD, through the detection of pulmonary fibrosis rats' blood cells and plasma, we selected the related molecules that may exert proinflammatory(IL-1ß), promote angiogenesis(vascular endothelial growth factor ,VEGF). For further explicitly research, we should know what the chemical composition the prescription (YHD) contains and what the related bioactive components have. In accordance with in-house library and evaluating the characteristic MS fragmentation patterns, the schisandra chinensis methanol, lignin, flavonol, polyphenol, tanshinone, salvianolic acid, anthraquinone, ligustrazine, etc. had a retardant and inhibitory effect on the development and formation of pulmonary fibrosis. These results will aid in the quality control of YHD, as well as provide fundamental data for further pharmaco-mechanisms studies. AIM OF THE STUDY: To discover the pulmonary immune related bioactive components of YHD. MATERIALS AND METHODS: Animal Experiment:144 SD rats, based on the principles of randomization divided into eight groups, Control group, bleomycin(BLM) group, BLM + dexamethasone(BLM + DXM) group, BLM + Yangfei(YF) group, BLM + Huoxue(HX) group, BLM + high-doseYHD(YHD-H) group, BLM + medium-doseYHD(YHD-M) group, and BLM + low-doseYHD(YHD-L) group, each group of 18 rats. After endotracheal administration of Bleomycin by tracheotomy, rats were sacrificed on day 7, day 14 and day 28, blood and plasma were taken at the same time. Respectively, the VEGF, an immune molecule associated with angiogenesis, and IL-1ß in plasma were detected by ELISA at three time periods. Component testing: 100 g YHD were constituted of SB 15 g, LX 12 g, EA 10 g, RJ 15 g, AM 20 g, GL 20 g and SC 8 g. All herbs were obtained from Beijing Tong Ren Tang (Group) Co ltd. The voucher specimens were identified by Prof. Jiening Gong (Nanjing University of Chinese Medicine). YHD were extracted by sonication with 1 L ethanol/water (70:30, v/v) for two cycle (1 h per cycle) at room temperature. The combined extracts were filtered, condensed, and reconstituted with 50 mL methanol before analysis. Standard Cianidanol, Ferulic Acid, Polydatin, Calycosin 7-O-glucoside, Tanshinone IIA, Salvianolic acid B, Schizandrol A, and Isoimperatorin were prepared in methanol. After centrifuging at 20,000 rpm for 10 min, 4 µL supernatant was injected into the Ultra-Performance Liquid Chromatography coupled with Quadrupole Time-of-Flight tandem mass spectrometry (UPLC/QTOF-MSE) combined with UNIFI informatics platform for analysis. CONCLUSION: The experiment results revealed that the vascularized VEGF, inflammatory factor expression of IL-1ß was restrained by YHD. The UPLC/QTOF-MSE method, an automatic database screening platform and the characteristic MS fragmentation patterns have efficiently facilitated the post data process, so we test for the identification of major components in YHD by this technology, more than seven or more active ingredients, the results showed that YHD contained a total of 55 components, including 11 lignans, 12 flavonoids, 7 tanshinones, 9 organic acid, 5 polyphenols, 4 anthraquinones, 5 senkyunolides and 2 others. Based on this, we can ensure the discovery and analysis of biologically active compounds in YHD, as well as provide a reference for the quality evaluation. We expect the method presented here could be applied to other multi-component TCM formula. In addition, we can conduct more in-depth research, such as mechanism research, molecular detection, gene target and so on.


Assuntos
Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina , Feminino , Interleucina-1beta/sangue , Masculino , Medicina Tradicional Chinesa , Fibrose Pulmonar/sangue , Fibrose Pulmonar/induzido quimicamente , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/sangue
15.
Biomed Pharmacother ; 118: 109293, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401393

RESUMO

Pulmonary fibrosis (PF) is a crippling disease characterized by progressive dyspnea and associated with a high mortality rate, but its origin is unknown and there is no effective treatment. Yifei Sanjie formula (YFSJF) is a Chinese medicine that is widely used for treatment of respiratory systems disease. However, the molecular basis for the function of YFSJF has not been determined. Here we investigate the contribution of YFSJF in BLM-induced PF mice. Administration with YFSJF significantly alleviated the degree of BLM-induced collagen I and III deposition and the inflammatory injuring in the lungs and suppressed hydroxyproline release in PF animals. The active components of YFSJF are comprised with flavonoid, amino acids, saponins, oligosaccharide, organic acid, vitamin, esters, purine nucleosides. Additionally, there was a significant increase in autophagosomes, after treatment with YFSJF in PF animals. Interestingly, autophagy dysfunction by the blocker chloroquine (CQ) resulted in collagen deposition and inducing the expression of fibrosis-related genes. In addition, YFSJF-induced autophagy is mediated by the PI3K-AKT-mTOR pathway, and knockdown of PI3K by siRNA up-regulated the expression of autophagy-related genes and down-regulated the expression of collagen in human lung fibroblasts (HLF). Our findings provide a detailed understanding that YFSJF-antifibrotic effects are mainly mediated by triggering autophagy, and suppressing phosphorylation of the PI3K-AKT-mTOR pathway is required for YFSJF-curative effect.


Assuntos
Autofagia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Humanos , Inflamação/complicações , Inflamação/patologia , Pulmão/patologia , Masculino , Fosforilação/efeitos dos fármacos , Fibrose Pulmonar/complicações , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
16.
Niger J Physiol Sci ; 34(1): 63-68, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449273

RESUMO

Amiodarone, a drug that treats arrhythmias induces pulmonary toxicity through interplay between oxidative stress and inflammation. Quercetin, a flavonoid widely occurring in natural products possesses antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the effects of quercetin on pulmonary responses in rats after amiodarone intra-tracheal instillation. Eighteen female Wistar rats (150-250 g) were randomly assigned into three groups of six animals each namely; control, amiodarone (AMI) and amiodarone + Quercetin (AMI + Quercetin) groups. AMI group received 2 intra-tracheal instillations of amiodarone (6.25mg/kg in 0.3ml of water) on days 0 and 2 and 0.4ml of 2% DMSO (Dimethyl sulfoxide) orally from day 0 for 3 weeks. AMI + Quercetin group was administered 2 intratracheal instillations of amiodarone on days 0 and 2 and 20mg/kg body weight of quercetin in 2% DMSO from day 0 for 3 weeks. Thereafter, the animals were sacrificed and bronchoalveolar lavage fluid (BALF) was collected to determine total cell polymorphonuclear (PMN) cell and macrophage counts. Inflammation of the lung tissues was also assessed. Macrophage count of AMI + Quercetin group was significantly lowered (p<0.01) compared to AMI group. Inflammation rate of the AMI + Quercetin group was significantly reduced compared to AMI group (p<0.01). Quercetin treatment markedly suppressed amiodarone induced toxicity in the pulmonary tissues.


Assuntos
Amiodarona/administração & dosagem , Amiodarona/toxicidade , Antioxidantes/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/toxicidade , Líquido da Lavagem Broncoalveolar , Feminino , Injeções Espinhais , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Fibrose Pulmonar/fisiopatologia , Ratos , Ratos Wistar
17.
Am J Chin Med ; 47(5): 1113-1131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352786

RESUMO

Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF-ß1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF-ß1/Smad3 signaling by downregulating protein kinase C delta (PKC-δ) and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF-ß1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo, which might be associated with activation of Nrf2 pathway and inhibition of TGF-ß1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Salvia miltiorrhiza/química , Animais , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , NADPH Oxidase 4/genética , Fator 2 Relacionado a NF-E2/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
18.
Biomed Pharmacother ; 118: 109239, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351431

RESUMO

Diazepam could regulate immune system and inflammation, which might be a potential therapeutic agent for pulmonary fibrosis in clinic. This study showed that diazepam reversed LPS-induced inhibition of cell proliferation and promotion of cell apoptosis. Of note, LPS specifically induced Caspase-11 dependent cell pyroptosis, which were significantly attenuated by diazepam or pyroptosis inhibitor necrosulfonamide (NSA) treatment. In addition, α4- and α5-subunits of GABAARs were highly expressed in human bronchial 16HBE cells, human pulmonary epithelial cells (BEAS-2B) and pulmonary epithelial cells isolated from mice (mPECs). Further results showed that only knock-down of α4-GABAARs abrogated the effects of diazepam on LPS induced cell pyroptosis, apoptosis and proliferation. Similiarly, either diazepam or NSA treatment could alleviate development of LPS induced inflammatory reactions and pulmonary fibrosis in mice, which were abrogated by synergistically knocking down α4-GABAARs. Taken together, diazepam alleviated LPS-induced cell pyroptosis and development of pulmonary fibrosis in mice by activating α4-GABAARs.


Assuntos
Diazepam/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Piroptose , Receptores de GABA-A/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diazepam/farmacologia , Modelos Animais de Doenças , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/patologia , Piroptose/efeitos dos fármacos
19.
Respir Res ; 20(1): 168, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358001

RESUMO

BACKGROUND: Pulmonary fibrosis is a progressive disease characterized by structural distortion of the lungs. Transforming growth factor-beta (TGF-beta) is a key cytokine implicated in the pathogenesis of pulmonary fibrosis. TGF-beta-induced myofibroblast differentiation characterized by expression of smooth muscle alpha-actin and extracellular matrix proteins is a key process in pathogenesis of fibrotic disease. Tannic acid is a natural polyphenol with diverse applications. In this study, we investigated the effect of tannic acid on myofibroblast differentiation and pulmonary fibrosis in cultured cells and in bleomycin model of the disease. METHODS: Primary cultured human lung fibroblasts (HLF) were used. The relative levels of proteins were determined by Western blotting. HLF contraction was measured by traction microscopy. Bleomycin-induced pulmonary fibrosis in mice was used as the disease model. RESULTS: Tannic acid inhibited TGF-beta-induced expression of collagen-1 and smooth muscle alpha-actin (SMA) as well as force generation by HLF. Tannic acid did not affect initial phosphorylation of Smad2 in response to TGF-beta, but significantly inhibited sustained Smad2 phosphorylation, which we recently described to be critical for TGF-beta-induced myofibroblast differentiation. Accordingly, tannic acid inhibited Smad-dependent gene transcription in response to TGF-beta, as assessed using luciferase reporter for the activity of Smad-binding elements. Finally, in mouse model of bleomycin-induced pulmonary fibrosis, therapeutic application of tannic acid resulted in a significant reduction of lung fibrosis, decrease in collagen-1 content and of Smad2 phosphorylation in the lungs. CONCLUSIONS: This study demonstrates the anti-fibrotic effect of tannic acid in vitro and in vivo through a regulation of sustained Smad2 phosphorylation.


Assuntos
Antifibrinolíticos/farmacologia , Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Taninos/farmacologia , Animais , Antifibrinolíticos/uso terapêutico , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Pulmão/citologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Taninos/uso terapêutico
20.
J Ethnopharmacol ; 243: 112096, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31323300

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Arenaria kansuensis is used in traditional medicine to treat lung inflammation for a long time. However, the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of this plant have not been studied extensively. AIM OF THE STUDY: The purpose of this study was to investigate the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of A. kansuensis and its possible mechanism. MATERIALS AND METHODS: In vivo experiment, the anti-pulmonary fibrosis effects of the fraction (Part1) enriched from ethyl acetate extracts of the whole plant A. kansuensis were evaluated through bleomycin (BLM)-induced pulmonary fibrosis mice (five groups, n = 10) daily at doses of 50, 100 and 150 mg/kg for 15 days. In vitro experiment, the anti-inflammation and reversed epithelial-mesenchymal transition (EMT) effect of 12 ß-carboline alkaloids isolated from Part1 were evaluated through lipopolysaccharide (LPS)-induced RAW264.7 inflammatory cell model and TGF-ß1 induced A549 cell model. RESULTS: In this study, a fraction named Part1 extracted from Arenaria kansuensis presented strong anti-pulmonary fibrosis effect at the dose of 150 mg/kg. Vivo experiments showed that the survival rate and body weight of mice significantly increased after Part1 treatment. Part1 could significantly inhibit the initial of inflammation, deposition of collagen and expression of TGF-ß1 and α-SMA, moreover, the expression of E-cadherin was significantly elevated after administration of Part1. All the cure effects of Part1 were in dose dependent manner. A total of 12 ß-carboline alkaloids were identified in Part1 and they all showed suppressive effect on inflammatory cytokines including MCP-1, TNF-α, IL-6 and IL-1ß through inhibition of NF-kb/p65 phosphorylation, and that epithelial-mesenchymal transition (EMT) process was reversed by different compounds in different levels. The expression of indicators of EMT including α-SMA, vimentin and E-cadherin was significantly improved after given different ß-carboline alkaloids. CONCLUSIONS: This study showed that antifibrogenic effect of ß-carboline alkaloids was due to inhibiting the initial of inflammation through NF-kb/p65 pathway and reversing the process of EMT.


Assuntos
Alcaloides , Anti-Inflamatórios , Arenaria (Planta) , Carbolinas , Extratos Vegetais , Fibrose Pulmonar/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Bleomicina , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/metabolismo
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