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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803282

RESUMO

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor ß1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.


Assuntos
Bleomicina/efeitos adversos , Butiratos/farmacologia , Disbiose , Fibrose Pulmonar , Dermatopatias , Animais , Bleomicina/farmacologia , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Masculino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Dermatopatias/microbiologia
2.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823870

RESUMO

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Reposicionamento de Medicamentos , Hipóxia/tratamento farmacológico , Adhatoda , Pulmão/efeitos dos fármacos , Extratos Vegetais/farmacologia , Pneumonia/prevenção & controle , Fibrose Pulmonar/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Bleomicina , /virologia , Ceco/microbiologia , Ceco/cirurgia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Mediadores da Inflamação/metabolismo , Adhatoda/química , Ligadura , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Pneumonia/genética , Pneumonia/metabolismo , Pneumonia/microbiologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/microbiologia , Transcriptoma
3.
Front Med ; 15(2): 313-329, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33908025

RESUMO

The medical fungus Hirsutella sinensis has been used as a Chinese folk health supplement because of its immunomodulatory properties. Our previous studies established the antifibrotic action of Hirsutella sinensis mycelium (HSM) in the lung. The epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of idiopathic pulmonary fibrosis. The present study investigates the role of HSM in mediating EMT during the development of pulmonary fibrosis. HSM significantly inhibits bleomycin (BLM)-induced pulmonary fibrosis by blocking the EMT. In addition, the expression levels of midkine are increased in the lungs of the BLM-induced group. Further analysis of the results indicates that the mRNA level of midkine correlated positively with EMT. HSM markedly abrogates the transforming growth factor ß-induced EMT-like phenotype and behavior in vitro. The activation of midkine related signaling pathway is ameliorated following HSM treatment, whereas this extract also caused an effective attenuation of the induction of EMT (caused by midkine overexpression) in vitro. Results further confirm that oral medication of HSM disrupted the midkine pathway in vivo. Overall, findings suggest that the midkine pathway and the regulation of the EMT may be considered novel candidate therapeutic targets for the antifibrotic effects caused by HSM.


Assuntos
Transição Epitelial-Mesenquimal , Fibrose Pulmonar , Bleomicina , Humanos , Midkina , Micélio , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico
4.
J Integr Med ; 19(2): 185-190, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33349611

RESUMO

After one-month of oral treatment with traditional Chinese medicine decoction, without using other drugs, the lung inflammatory exudate, pulmonary fibrosis and quality of life of a 61-year-old female patient with corona virus disease 2019 (COVID-19) were significantly improved. No recurrence or deterioration of the patient's condition was found within seven weeks of treatment and follow-up, and no adverse events occurred, indicating that oral Chinese medicine decoction was able to improve the pulmonary inflammation and fibrosis in a patient recovering from COVID-19, but further research is still needed.


Assuntos
/complicações , Medicamentos de Ervas Chinesas/uso terapêutico , Pulmão/efeitos dos fármacos , Medicina Tradicional Chinesa , Fitoterapia , Fibrose Pulmonar/tratamento farmacológico , Administração Oral , Exsudatos e Transudatos , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Pulmão/patologia , Magnoliopsida , Pessoa de Meia-Idade , Fibrose Pulmonar/etiologia
5.
Life Sci ; 266: 118883, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33316266

RESUMO

Coronavirus disease 2019 (COVID-19) has rapidly spread around the world causing global public health emergency. In the last twenty years, we have witnessed several viral epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV), Influenza A virus subtype H1N1 and most recently Middle East respiratory syndrome coronavirus (MERS-CoV). There were tremendous efforts endeavoured globally by scientists to combat these viral diseases and now for SARS-CoV-2. Several drugs such as chloroquine, arbidol, remdesivir, favipiravir and dexamethasone are adopted for use against COVID-19 and currently clinical studies are underway to test their safety and efficacy for treating COVID-19 patients. As per World Health Organization reports, so far more than 16 million people are affected by COVID-19 with a recovery of close to 10 million and deaths at 600,000 globally. SARS-CoV-2 infection is reported to cause extensive pulmonary damages in affected people. Given the large number of recoveries, it is important to follow-up the recovered patients for apparent lung function abnormalities. In this review, we discuss our understanding about the development of long-term pulmonary abnormalities such as lung fibrosis observed in patients recovered from coronavirus infections (SARS-CoV and MERS-CoV) and probable epigenetic therapeutic strategy to prevent the development of similar pulmonary abnormalities in SARS-CoV-2 recovered patients. In this regard, we address the use of U.S. Food and Drug Administration (FDA) approved histone deacetylase (HDAC) inhibitors therapy to manage pulmonary fibrosis and their underlying molecular mechanisms in managing the pathologic processes in COVID-19 recovered patients.


Assuntos
/complicações , Reposicionamento de Medicamentos , Inibidores de Histona Desacetilases/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , /terapia , Infecções por Coronavirus/patologia , Matriz Extracelular/patologia , Matriz Extracelular/virologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Pessoa de Meia-Idade , Fibrose Pulmonar/virologia , Fatores de Risco , Transdução de Sinais , Sobreviventes
6.
Drug Discov Ther ; 14(5): 259-261, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33116043

RESUMO

Regardless of the severity of coronavirus disease 2019 (COVID-19), a high proportion of patients struggle with persistent respiratory or systemic symptoms after recovery. This is called "postCOVID syndrome", for which pulmonary fibrosis is one of the pathogenesis. Besides T-lymphocytes and macrophages, mast cells also contribute to the development of cytokine storm and thus stimulate the activity of fibroblasts. Additionally, by the exocytotic release of fibroblast-activating factors, mast cells directly facilitate the progression of pulmonary fibrosis. In our previous basic studies, anti-allergic drugs (olopatadine, ketotifen), antibiotics (clarithromycin) and corticosteroids (hydrocortisone, dexamethasone) inhibited the process of exocytosis and showed their potency as highly effective mast cell stabilizers. Given such pharmacological properties of these commonly used drugs, they may be useful in the treatment of post-COVID-19 pulmonary fibrosis and in relieving the symptoms of post-COVID syndrome.


Assuntos
Corticosteroides/uso terapêutico , Antialérgicos/uso terapêutico , Antibacterianos/uso terapêutico , Betacoronavirus/patogenicidade , Degranulação Celular/efeitos dos fármacos , Infecções por Coronavirus/virologia , Mastócitos/efeitos dos fármacos , Pneumonia Viral/virologia , Fibrose Pulmonar/tratamento farmacológico , Animais , Infecções por Coronavirus/imunologia , Interações Hospedeiro-Patógeno , Humanos , Mastócitos/imunologia , Mastócitos/virologia , Pandemias , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/virologia
7.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 231-233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093788

RESUMO

Background: A subgroup of patients with fibrotic ILD experience progression and several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. Objective: To describe a possible new phenotype of rapidly non IPF progressive fibrosing with an IPF-like outcome. Methods: Three previously fit and well patients who developed a rapidly progressive ILD and died within 6 to 7 months from the initial development of respiratory symptoms. Results: Unlike what is currently known, our patients developed a severe fibrosing ILD with an IPF-like outcome despite a) being younger than the average patient with IPF, b) having received a non-IPF MDT diagnosis, c) having a non-UIP pattern on HRCT. Moreover and similarly to IPF, they failed to respond to immunosuppressive treatment which is the preferred treatment option in these cases. Conclusion: We believe that patients who present with similar characteristics should be considered as likely to develop a phenotype of rapidly progressive ILD and be treated with antifibrotic medications instead of immunosuppressive ones according to the favourable treatment response to antifibrotic therapy observed in clinical trials of patients with progressive fibrosing ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 231-233).


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pulmão/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico , Tomografia Computadorizada por Raios X , Adulto , Antibacterianos/uso terapêutico , Progressão da Doença , Evolução Fatal , Volume Expiratório Forçado , Humanos , Imunossupressores/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Capacidade Vital
8.
J Proteome Res ; 19(11): 4327-4338, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32883081

RESUMO

The COVID-19 pandemic rapidly became a worldwide healthcare emergency affecting millions of people, with poor outcomes for patients with chronic conditions and enormous pressure on healthcare systems. Pulmonary fibrosis (PF) has been cited as a risk factor for a more severe evolution of COVID-19, primarily because its acute exacerbations are already associated with high mortality. We reviewed the available literature on biochemical, pathophysiological, and pharmacological mechanisms of PF and COVID-19 in an attempt to foresee the particular risk of infection and possible evolution of PF patients if infected with SARS-COV-2. We also analyzed the possible role of medication and risk factors (such as smoking) in the disease's evolution and clinical course. We found out that there is a complexity of interactions between coexisting idiopathic pulmonary fibrosis/interstitial lung disease (ILD) and COVID-19 disease. Also, patients recovering from severe COVID-19 disease are at serious risk of developing PF. Smokers seem to have, in theory, a chance for a better outcome if they develop a severe form of COVID-19 but statistically are at much higher risk of dying if they become critically ill.


Assuntos
Infecções por Coronavirus , Pandemias , Pneumonia Viral , Fibrose Pulmonar , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Comorbidade , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Humanos , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Prognóstico , Fibrose Pulmonar/complicações , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/fisiopatologia , Fatores de Risco , Fumar
9.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 216-222, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981275

RESUMO

Objective: To observe whether the mechanism of small dose capsaicin (Cap) against pulmonary fibrosis in mouse is mediated by agitating transient receptor potential vanilloid 1 (TRPV1). Methods: A total of 60 BALB/c mice were randomly divided into control (CON) group, bleomycin (BLM)group, Cap (0.5, 1,2 mg/kg) groups and Cap (2 mg/kg) plus SB-452533 (2.5 mg/kg) group. C57BL/6 mice were intratracheally injected with 3.5 mg/kg BLM to induce pulmonary fibrosis model. Animals for drugs treatment received daily drug via subcutaneous injection for 21 days. The morphological changes and collagen deposition in lung tissues were analysed by HE staining, Masson staining and immunohistochemistry. The concentration of calcitonin gene-related peptide (CGRP) in plasma was determined by ELISA. The mRNA and (or) proteins levels of α-CGRP, ß-CGRP, collagen I, collagen III, E-Cadherin, zonula occludens-1 (ZO-1), vimentin, alpha smooth muscle actin (α-SMA), TRPV1, p-ERK1/2 and eukaryotic initiation factor 3a (eIF3a) were detected by qPCR and (or) Western blot. Results: Compared with the BLM group, small dose Cap significantly reduced bleomycin-induced pulmonary fibrosis in mice and obviously reversed alveolar epithelial cells epithelial-mesenchymal transition (EMT) (the expression of E-cadherin and ZO-1 were increased(P<0.05 or P<0.01)and the expression of α-SMA and Vimentin were decreased (P<0.05 or P<0.01) after drugs treatment for 21 day, concomitantly with the increase the expressions of TRPV1 and CGRP (P<0.05 or P<0.01), and inhibiting ERK1/2 phosphorylation and eIF3a expression (P<0.05 or P<0.01). These effects of small dose Cap were abolished in the presence of TRPV1 receptor antagonist SB-452533. Conclusion: The results suggest that small dose Cap can reverse alveolar epithelial cells EMT and alleviate bleomycin-induced pulmonary fibrosis in mice by inhibiting ERK1/2/eIF3asignaling pathway, which is related to agitating TRPV1 receptor and releasing of CGRP.


Assuntos
Células Epiteliais Alveolares , Capsaicina , Transição Epitelial-Mesenquimal , Fibrose Pulmonar , Células Epiteliais Alveolares/efeitos dos fármacos , Animais , Antipruriginosos/farmacologia , Antipruriginosos/uso terapêutico , Bleomicina/toxicidade , Capsaicina/administração & dosagem , Capsaicina/farmacologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Distribuição Aleatória , Fator de Crescimento Transformador beta1
10.
Front Immunol ; 11: 2069, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973815

RESUMO

COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Galectina 3/antagonistas & inibidores , Galectina 3/sangue , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Índice de Gravidade de Doença , Animais , Betacoronavirus/química , Biomarcadores/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Progressão da Doença , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Prognóstico , Fibrose Pulmonar/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo
11.
Lancet Respir Med ; 8(9): 925-934, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32890499

RESUMO

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pesquisa Biomédica , Progressão da Doença , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Fibrose Pulmonar/tratamento farmacológico , Pesquisa
12.
Life Sci ; 260: 118399, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32918977

RESUMO

Pulmonary fibrosis is the end stage of many interstitial lung diseases, characterized by the deposition of excess extracellular matrix (ECM), destruction of normal alveolar structure, and resulting in the obstruction of gas exchange and respiratory failure. The idiopathic pulmonary fibrosis (IPF) is the most common form of pulmonary fibrosis with little effective therapies. 5-Methoxytryptophan (5-MTP) is a newly found tryptophan metabolite. Previous studies suggested that 5-MTP has the effects of anti-inflammatory, anti-tumorigenesis, vascular protection and anti-fibrosis in renal disease. Whether 5-MTP has therapeutic effect on pulmonary fibrosis is not clear. In our study, we used TGF-ß1 to stimulate human lung fibroblasts (HLFs) and bleomycin (BLM) induced pulmonary fibrosis model to investigate the effect of 5-MTP on pulmonary fibrosis. Our study demonstrated that 5-MTP could improve the lung function and attenuate the destruction of alveolar structure in BLM-induced pulmonary fibrosis mice. Furthermore, 5-MTP significantly decreased accumulation of myofibroblasts and the deposition of ECM by inhibiting the differentiation of fibroblasts to myofibroblasts and suppressing the protein expression of the ECM both in vivo and in vitro. Our results also revealed 5-MTP could inhibit the proliferation and migration of the fibroblasts in vitro, which played an important role in the progressive pulmonary fibrosis. To further investigate the mechanism of the anti-fibrosis of 5-MTP, several canonical and noncanonical signaling pathways were examined. Our results revealed that 5-MTP could inhibit the pulmonary fibrosis through downregulating the phosphorylation of TGF-ß/SMAD3, PI3K/AKT signaling pathways. Together, our study indicated that 5-MTP promises to be therapeutic agent of pulmonary fibrosis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triptofano/análogos & derivados , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Diferenciação Celular , Matriz Extracelular , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Triptofano/farmacologia
13.
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
15.
Medicine (Baltimore) ; 99(31): e21310, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756114

RESUMO

BACKGROUND: Since December 2019, there have been many cases of viral pneumonia of unknown causes in Wuhan City, Hubei Province. During the period of novel coronavirus, according to the observation of limited autopsy and biopsy pathological results, pulmonary interstitial fibrosis appeared in some pathological changes of lung. Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia with unknown etiology and pathological changes limited to the lung. At present, there is still a lack of reevaluation of systematic evaluation of traditional Chinese medicine treatment IPF. Therefore, a systematic re-evaluation of the systematic evaluation of traditional Chinese medicine in the treatment of pulmonary fibrosis may help to understand the effective treatment scheme of traditional Chinese medicine in the treatment of pulmonary fibrosis and provide more reliable evidence for the first-line clinicians to treat novel coronavirus. METHODS: We will search 3 foreign electronic databases (Cochrane Library, Embase, PubMed) and 4 Chinese electronic databases (China National Knowledge Infrastructure [CNKI], WangFang Database, Chinese Biomedical Literature Database [CBM], and Chinese Scientific Journal Database [VIP]) to collect potential systematic reviews from their inceptions to February 2020. The language of publication is limited to Chinese or English. We will consider SRs and meta-analysis of Traditional Chinese Medicine for the Treatment of pulmonary fibrosis. Two reviewers will identify relevant studies, and then assess the methodological quality by assessment of multiple systematic reviews-2 tool. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) report checklist to assess the quality of reports included in the study. In order to better evaluate the systematic evaluation included in this research, risk of bias in systematic review tool is included in this research to evaluate the methodological quality. The quality of evidence of the included systematic reviews was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The Primary outcomes include: Clinical total effective rate, curative effect of TCM symptoms, pulmonary function and blood gas analysis. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSIONS: We expect to obtain reliable evidence from systematic analysis of traditional Chinese medicine treatment of pulmonary fibrosis in an available and useful document. REGISTRATION NUMBER: INPLASY202060029.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Pneumonia Viral/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Infecções por Coronavirus/complicações , Feminino , Humanos , Masculino , Metanálise como Assunto , Pandemias , Pneumonia Viral/complicações , Fibrose Pulmonar/virologia , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento
16.
Carbohydr Polym ; 247: 116740, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32829859

RESUMO

Pulmonary fibrosis (PF) is a lung disease with highly heterogeneous and mortality rate, but its therapeutic options are now still limited. Corona virus disease 2019 (COVID-19) has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients.


Assuntos
Betacoronavirus , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Polissacarídeos/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Bleomicina/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Proteína Forkhead Box O3/fisiologia , Fungos/química , Ribonucleoproteína Nuclear Heterogênea D0/fisiologia , Humanos , Macrófagos/efeitos dos fármacos , Medicina Tradicional Chinesa , Camundongos , Neutrófilos/efeitos dos fármacos , Fitoterapia , Plantas Medicinais/química , Polissacarídeos/farmacologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/prevenção & controle , RNA Longo não Codificante/antagonistas & inibidores , Ratos , Alga Marinha/química , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/fisiologia , Proteína Smad3/fisiologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores
17.
Adv Exp Med Biol ; 1207: 569-579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671775

RESUMO

Pulmonary fibrosis is a progressive chronic inflammatory disease with a poor clinical outcome. Although pirfenidone and nintedanib have been approved by FDA to treat idiopathic pulmonary fibrosis (IPF), these drugs can only slow the progression of IPF. Autophagy plays an important role in the pathogenesis of pulmonary fibrosis. Whether the autophagic flux is blocked or not is directly related to the development direction of pulmonary fibrosis. Defining how autophagy activity regulates the pathogenesis of pulmonary fibrosis will greatly advance the progression of pulmonary fibrosis therapy.


Assuntos
Autofagia , Fibrose Pulmonar , Progressão da Doença , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Piridonas/farmacologia , Piridonas/uso terapêutico
18.
Int J Mol Sci ; 21(14)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708322

RESUMO

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Catequina/análogos & derivados , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antioxidantes/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Catequina/uso terapêutico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Humanos , NF-kappa B/antagonistas & inibidores , Pandemias , Extratos Vegetais/uso terapêutico , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
19.
Rev Med Suisse ; 16(698): 1256-1260, 2020 Jun 17.
Artigo em Francês | MEDLINE | ID: mdl-32558455

RESUMO

A significant proportion - up to 40 % - of patients suffering from fibrosing interstitial pneumonia will acquire a progressive phenotype which shares genetic and pathogenic mechanisms, as well a clinical behavior similar to those of idiopathic pulmonary fibrosis (IPF). It therefore makes sense to suggest that molecules with antifibrotic properties such as pirfenidone and nintedanib could be effective in patients with progressive fibrosing interstitial lung disease as they are in patients with IPF. The first studies published on this topic show encouraging results which however have to be confirmed on a larger scale.


Assuntos
Fibrose Pulmonar/tratamento farmacológico , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Indóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Fibrose Pulmonar/patologia , Piridonas/uso terapêutico
20.
Zhongguo Zhong Yao Za Zhi ; 45(7): 1481-1487, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32489024

RESUMO

Since February 2020, a large number of patients infected with new coronavirus has been cured and discharged with the controlling of epidemic. Pulmonary fibrosis, which may be one of the sequela caused by COVID-19, not only brings dyspnea and deterioration of lung function, but also affects patients' life because of its high mortality and poor prognosis. Vascular endothelial growth factor receptor(VEGFR) and fibroblast growth factor receptor(FGFR) can inhibit the proliferation, activation and migration of fibroblasts by regulating the signal transduction pathway involved in the process of pulmonary fibrosis. Chinese herbal formulas pose a good therapeutic effect on pulmonary fibrosis. Present study explores the intervention effect on pulmonary fibrosis of traditional Chinese medicine(TCM) by screening the potential inhibitors of VEGFR and FGFR. The docking models of VEGFR and FGFR were established to obtain the potential active ingredients which were filtered by the docking score. According to 2 prescriptions in the Protocol for the diagnosis and treatment of coronavirus disease 2019(7th edition)and 9 prescriptions in Traditional Chinese medicine prescriptions for treating blight, 959 and 1 047 potential ingredients were obtained as the inhibitors of VEGFR and FGFR respectively with the screening thres-hold set as eighty percent of the docking score of the initial ligands. The potential herbs were then filtered by the components with a hit rate higher than 30%, such as Scutellariae Radix, Adenophorae Radix, Pinelliae Rhizoma, Coicis Semen, etc. To discuss the rule of TCM in the treatment of pulmonary fibrosis, the networks of TCM-channel tropism and TCM-efficacy of the potential herbs was constructed. The potential herbs for treating pulmonary fibrosis mostly belong to lung(degree=14) and spleen(degree value=8), and the efficacy is focused on reinforcing deficiency(degree=9). Qiyin Prescription and Buzhong Yiqi Decoction contain the largest number of the potential herbs. The main symptom of COVID-19 is damp-heat stagnating in the lung, which always causes impairment of body fluid and Qi. Clinical observation shows that patients in the recovery period are mostly at the status that the remaining virus toxicity is not exhausted while the vital Qi have not recovered. The results of this study are expected to provide references for clinical medication in preventing and treating pulmonary fibrosis caused by COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Medicamentos de Ervas Chinesas , Pandemias , Pneumonia Viral , Fibrose Pulmonar , Humanos , Medicina Tradicional Chinesa , Fibrose Pulmonar/tratamento farmacológico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento do Endotélio Vascular
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