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1.
Respir Res ; 23(1): 128, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35596212

RESUMO

BACKGROUND: Pulmonary fibrosis is a progressive and usually lethal pulmonary disease. Despite considerable research efforts, no effective therapeutic strategy for pulmonary fibrosis has been developed. NecroX-5 has been reported to possess anti-inflammatory, anti-oxidative and anti-tumor activities. In the present study, we aimed to determine whether NecroX-5 exhibits antifibrotic property in bleomycin (BLM)-induced pulmonary fibrosis. RESULTS: We found that pre-treatment with NecroX-5 alleviated inflammatory response, reduced oxidative stress, inhibited epithelial-mesenchymal transition (EMT), and ameliorated pulmonary fibrosis in vivo and in vitro. Our data further indicated that NecroX-5 substantially reduced activation of NLRP3 inflammasome and TGF-ß1/Smad2/3 signaling in vivo and in vitro. Additionally, NLRP3 overexpression significantly reversed the protective effects of NecroX-5 in lung epithelial cells exposed to BLM. CONCLUSIONS: Overall, our results demonstrate the potent antifibrotic properties of NecroX-5 and its therapeutic potential for pulmonary fibrosis.


Assuntos
Bleomicina , Fibrose Pulmonar , Bleomicina/efeitos adversos , Transição Epitelial-Mesenquimal/fisiologia , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Sulfonas , Fator de Crescimento Transformador beta1/farmacologia
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(4): 618-624, 2022 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-35527500

RESUMO

OBJECTIVE: To develop a convenient method for rapid purification of fresh Pheretima proteins and assess the inhibitory effect of these proteins against pulmonary fibrosis. METHODS: The crude extract of fresh Pheretima was obtained by freeze-drying method and then purified by size exclusion chromatography. The composition of the purified proteins was analyzed by mass spectrometry. MRC-5 cells were treated with 5 ng/mL TGF-ß1 alone (model group) or in combination with SB431542 (2 µmol/L) or the purified proteins (13.125 µg/mL), and the cytotoxicity of purified proteins and their inhibitory effects on cell proliferation were detected with CCK8 assay. Flow cytometry was used to detect the changes in cell apoptosis, and the cellular expressions of α-SMA, Vimentin, E-cadherin, collagen I, Smad2/3 and P-Smad2/3 were detected using RT-PCR and Western blotting. In the animal experiment, adult male C57BL/6 mice were subjected to intratracheal instillation of bleomycin followed by treatment with the purified proteins (5 mg/mL) for 21 days, after which HE and Masson staining was used to observe the pathological changes in the lung tissue of the mice. RESULTS: We successfully obtained purified proteins from fresh Pheretima protein by size exclusion chromatography. Treatment with the purified proteins significantly inhibited TGF-ß1-induced proliferation of MRC-5 cells (P < 0.01), reduced the cellular expressions of α-SMA, Vimentin and collagen I (P < 0.001 or P < 0.01), increased the expression of E-cadherin (P < 0.01), and inhibited the expressions of Smad2/3 and P-Smad2/3 (P < 0.001 or P < 0.01). In male C57BL/6 mice models of bleomycin-induced pulmonary fibrosis, treatment with the purified proteins obviously reduced the number of inflammatory cells and fibrotic area in the lungs. CONCLUSION: The purified proteins from fresh Pheretima obtained by size exclusion chromatography can inhibit pulmonary fibrosis in mice by regulating the TGF-ß/ Smad pathway.


Assuntos
Produtos Biológicos , Fibrose Pulmonar , Animais , Produtos Biológicos/farmacologia , Bleomicina/efeitos adversos , Caderinas/metabolismo , Colágeno Tipo I , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligoquetos/química , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Vimentina/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-35397413

RESUMO

Our previous studies showed that Shuangshen Pingfei Formula (SSPF) exhibited anti-fibrosis effect, but its biochemical changes at the metabolic level remain unclear. In this study, an integrative approach of gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-Q Exactive-mass spectrometry (UPLC-QE-MS)-based non-targeted metabolomics and multivariate statistical analysis was employed to explore the metabolic changes of serum samples from different stages of bleomycin-induced pulmonary fibrosis (PF) rats (PFRs: M7, M14, M21 and M28) treated with SSPF extracts. Potential biomarkers for PF were screened. Benzenebutanoic acid, pyroglutamic acid, cholic acid, 1-monopalmitin, succinic acid and palmitoleic acid may be potential biomarkers of the early inflammation stage of PF (M7-M14). 3,4-dimethylbenzoic acid, glutamic acid, glycine, proline, serine, taurine, etc. may be potential biomarkers for the advanced pulmonary fibrosis stage (M21-M28) of PF. The disturbance was mainly related to the disorder of lipid, amino acid metabolism. After SSPF treatment, the disorder was regulated and 67 metabolites were restored to a certain extent. Serine, proline, glutamine, 4-guanidinobutyric acid, phosphatidylethanolamine, lecithin and 9,10-epoxyoctadecene acids may be useful as biomarkers of the anti-fibrosis effect of SSPF.


Assuntos
Fibrose Pulmonar , Animais , Biomarcadores , Bleomicina/efeitos adversos , Cromatografia Líquida de Alta Pressão/métodos , Metabolômica/métodos , Prolina , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Ratos , Serina/efeitos adversos
4.
J Dtsch Dermatol Ges ; 20(4): 470-481, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35384261

RESUMO

BACKGROUND: Electrochemotherapy (ECT) is an effective local treatment for cutaneous tumors. The aim of this study was to compare the effectiveness of ECT in ulcerated vs. non-ulcerated tumors and investigate the effect on tumor-associated symptoms. METHODS: Twenty cancer centers in the International Network for Sharing Practices on Electrochemotherapy (InspECT) prospectively collected data. ECT was performed following ESOPE protocol. Response was evaluated by lesion size development. Pain, symptoms, performance status (ECOG-Index) and health status (EQ-5D questionnaire) were evaluated. RESULTS: 716 patients with ulcerated (n = 302) and non-ulcerated (n = 414) cutaneous tumors and metastases were included (minimum follow-up of 45 days). Non-ulcerated lesions responded to ECT better than ulcerated lesions (complete response 65 % vs. 51 %, p = 0.0061). Only 38 % (115/302) with ulcerated lesions before ECT presented with ulcerated lesions at final follow-up. Patients with ulcerated lesions reported higher pain and more severe symptoms compared to non-ulcerated lesions, which significantly and continuously improved following ECT. In non-ulcerated lesions however, pain spiked during the treatment. No serious adverse events were reported. CONCLUSIONS: ECT is a safe and effective local treatment for cutaneous tumors. While ECT improves symptoms especially in patients with ulcerated lesions, data suggest the implementation of a perioperative pain management in non-ulcerated lesions during ECT.


Assuntos
Eletroquimioterapia , Neoplasias Cutâneas , Bleomicina/efeitos adversos , Eletroquimioterapia/efeitos adversos , Eletroquimioterapia/métodos , Humanos , Dor/etiologia , Estudos Prospectivos , Neoplasias Cutâneas/patologia , Resultado do Tratamento
5.
Biomed Res Int ; 2022: 7367328, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35402615

RESUMO

Bleomycin is a common antitumor agent used to treat many different types of malignancies; however, its main side effect is pulmonary fibrosis. The mechanism of bleomycin-induced pulmonary fibrosis (BIPF) has not been fully elucidated. Therefore, to further explore the molecular mechanisms of BIPF, we screened for microRNA (miRNA) and mRNA expression obtained from BIPF samples from the Gene Expression Omnibus database. Subsequently, we identified the differentially expressed miRNAs and genes that overlapped with the differentially expressed miRNAs target genes, predicted by using the miRWalk database selected as a candidate. The candidate genes were visualized based on Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses. A protein-protein interaction network was constructed. Hub differentially expressed genes were selected and corresponding miRNAs to construct a miRNA-mRNA regulation network. Then, we chose three key miRNAs to study their regulatory relationship in bleomycin-induced pulmonary fibrosis. Finally, mouse lung epithelial cells TC-1 and MLE-12 were treated with bleomycin with qPCR to validate the results of three important hub genes and all key miRNAs. And dual-luciferase report experiment was carried out to verify the interaction of mmu-miR-1946a and serpina3n. The results revealed that the imbalance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a pivotal role in the occurrence and development of BIPF. In addition, Serpina3n and mmu-miR-1946a were proved interaction and may be involved in the regulation of the balance between MMP-9 and TIMP-1. The experimental results also verify the analysis. Our findings provide new insights into the key mediators and pathways related to the molecular mechanisms of BIPF.


Assuntos
MicroRNAs , Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Metaloproteinase 9 da Matriz/genética , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética
6.
Eur Rev Med Pharmacol Sci ; 26(4): 1350-1363, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35253191

RESUMO

OBJECTIVE: The aim of this study was to identify features mainly involved in determining the partial response (PR) to the Electrochemotherapy (ECT) in patients with recurrent and/or metastatic head and neck (H&N) tumor; the identified features were also used in a decision chart in order to provide the clinician with a support tool in deciding further therapies. PATIENTS AND METHODS: 131 patients (186 treatment sessions) with recurrent and/or metastatic H&N neoplasm were subjected to ECT. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 two months after the ECT. The grade of bleeding and pain before, at the end and one week after ECT treatment were evaluated. Univariate and multivariate analysis were performed to identify features involved in determining the patient PR. RESULTS: In the context of the univariate analysis, tumor size significantly influenced the response to ECT, with higher PR rate of 58.3%: 28 among 48 patients with lesion size ≤ 3 centimeters (p-value < 0.001 at Chi-square test). Pain and bleeding pre-treatment were positively correlated to PR (p-value < 0.001 at Chi-square test). A difference in the current flowing in the tissue during treatment was also observed in partially responsive patients, where the median current value (6.6 A) was higher than that achieved in patients that did not show PR (3.3 A). In the context of the multivariate analysis, the best performances are achieved with the BART method (accuracy of 84%). The main clinical factors to predict the partial response, among investigated features, that have shown to be considered were the pain value felt before performing the treatment and the median current delivered during the ECT treatment. A decision-making support tool to predict the patient prognosis in terms of response rate could be represented by the decision tree obtained with CART algorithm, where a pain pre-treatment more than 5 and a median delivered current not less than 2.8 A led to the prediction a partial responsive patient with an accuracy of 75%. CONCLUSIONS: The study confirmed that ECT is an interesting antitumoral therapy in advanced chemo- and radio-refractory H&N neoplasms, able to reduce frequent symptoms and to improve the quality of life. Pain pre-treatment and delivered current are the most important variables when predicting the partial response of patients.


Assuntos
Eletroquimioterapia , Neoplasias de Cabeça e Pescoço , Neoplasias Cutâneas , Bleomicina/efeitos adversos , Eletroquimioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Dor/tratamento farmacológico , Cuidados Paliativos/métodos , Qualidade de Vida , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
7.
Biochem Biophys Res Commun ; 603: 88-93, 2022 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-35278885

RESUMO

Pulmonary fibrosis is a progressive fibrotic disease with a poor prognosis and has suboptimal therapeutic options. The complement protein, C1q, which has various functions, such as promoting phagocytosis and signal transduction, has been shown to exacerbate several fibrosis-related diseases such as myofibrosis. In this study, we examined the role and cellular targets of C1q in pulmonary fibrosis. Silica-induced pulmonary fibrotic C1q-deficient mice showed improvement in fibrosis, and intratracheal administration of C1q to normal mice led to the induction of fibrotic changes. Single-cell RNA sequencing analysis revealed the early activation of fibroblasts and type 2 alveolar epithelial cells after intratracheal administration of C1q, and treatment of primary lung fibroblasts with C1q induced the expression of profibrotic genes. Thus, the inhibition of C1q may be regarded as a therapeutic target for pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Complemento C1q , Fibroblastos/metabolismo , Fibrose , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/metabolismo , Dióxido de Silício/efeitos adversos
8.
Curr Oncol ; 29(3): 1672-1682, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35323339

RESUMO

Bone metastases induce pain, risk of fracture, and neural compression, and reduced mobility and quality of life. Electrochemotherapy (ECT) is a minimally invasive local treatment based on a high-voltage electric pulse combined with an anticancer drug. Preclinical and clinical studies have supported the use of ECT in patients with metastatic bone disease, demonstrating that it does not damage the mineral structure of the bone and its regenerative capacity, and that is feasible and efficient for the treatment of bone metastases. Since 2009, 88 patients with bone metastasis have received ECT at the Rizzoli Institute. 2014 saw the start of a registry of patients with bone metastases treated with ECT, whose data are recorded in a shared database. We share the Rizzoli Institute experience of 38 patients treated with ECT for a bone metastasis, excluding patients not included in the registry (before 2014) and those treated with bone fixation. Mean follow-up was 2 months (1-52). Response to treatment using RECIST criteria was 29% objective responses, 59% stable disease, and 16% progressive disease. Using PERCIST, the response was 36% OR, 14% SD, and 50% PD with no significant differences between the two criteria. A significant decrease in pain and better quality of life was observed at FU.


Assuntos
Neoplasias Ósseas , Eletroquimioterapia , Bleomicina/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Eletroquimioterapia/efeitos adversos , Humanos , Dor/etiologia , Qualidade de Vida
10.
Am J Respir Cell Mol Biol ; 66(5): 484-496, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35148253

RESUMO

Pulmonary fibrosis (PF) is an abnormal remodeling of cellular composition and extracellular matrix that results in histological and functional alterations in the lungs. Apoptosis signal-regulating kinase-1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase family that is activated by oxidative stress and promotes inflammation and apoptosis. Here we show that bleomycin-induced PF is reduced in Ask1 knockout mice (Ask1-/-) compared with wild-type (WT) mice, with improved survival and histological and functional parameters restored to basal levels. In WT mice, bleomycin caused activation of ASK1, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) in lung tissue, as well as changes in redox indicators (thioredoxin and heme-oxygenase-1), collagen content, and epithelial-mesenchymal transition markers (EMTs). These changes were largely restored toward untreated WT control levels in bleomycin-treated Ask1-/- mice. We further investigated whether treatment of WT mice with an ASK1 inhibitor, selonsertib (GS-4997), during the fibrotic phase would attenuate the development of PF. We found that pharmacological inhibition of ASK1 reduced activation of ASK1, p38, and ERK1/2 and promoted the restoration of redox and EMT indicators, as well as improvements in histological parameters. Our results suggest that ASK1 plays a central role in the development of bleomycin-induced PF in mice via p38 and ERK1/2 signaling. Together, these data indicate a possible therapeutic target for PF that involves an ASK1/p38/ERK1/2 axis.


Assuntos
Bleomicina , Fibrose Pulmonar , Animais , Apoptose/fisiologia , Bleomicina/efeitos adversos , MAP Quinase Quinase Quinase 5 , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno , Fibrose Pulmonar/induzido quimicamente , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Biomed Pharmacother ; 148: 112731, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35220029

RESUMO

Pulmonary fibrosis (PF) is a chronic progressive disease that portends a very poor prognosis. It has been suggested that STAT3 is a potential target in PF. This study highlights the importance of cubosomes as a drug delivery system in enhancing the bioavailability of nifuroxazide (NXZD), a poorly soluble STAT3 inhibitor. NXZD-loaded cubosomes (NXZD-LC) were in vitro and in vivo evaluated. In vitro, cubosomes presented a poly-angular nanosized particles with a mean size and zeta potential of 223.73 ± 4.73 nm and - 20.93 ± 2.38 mV, respectively. The entrapment efficiency of nifuroxazide was 90.56 ± 4.25%. The in vivo pharmacokinetic study and the lung tissue accumulation of NXZD were performed by liquid chromatography-tandem mass spectrometry after oral administration to rats. The nanoparticles exhibited a two-fold increase and 1.33 times of bioavailability and lung tissue concentration of NXZD compared to NXZD dispersion, respectively. In view of this, NXZD-LC effectively attenuated PF by targeting STAT3 and NF-κB signals. As a result, NXZD-LC showed a potential anti-inflammatory effect as revealed by the significant decrease in MCP-1, ICAM-1, IL-6, and TNF-α and suppressed fibrogenic mediators as indicated by the significant reduction in TGF-ß, TIMP-1, and PDGF-BB in lung tissues. Besides, NXZD-LC improved antioxidant defense mechanisms and decreased LDH and BALF total protein. These effects contributed to decreased collagen deposition. To conclude, cubosomes represent an advantageous pharmaceutical delivery system for enhancing pulmonary delivery of poorly soluble drugs. Additionally, repurposing NXZD as an antifibrotic agent is a promising challenge and new therapeutic approach for unmet therapeutic needs.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Hidroxibenzoatos/farmacologia , NF-kappa B/metabolismo , Nanopartículas/química , Nitrofuranos/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , /farmacologia , Disponibilidade Biológica , Bleomicina/efeitos adversos , Hidroxibenzoatos/farmacocinética , Pulmão/patologia , Masculino , Nitrofuranos/farmacocinética , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
12.
PLoS One ; 17(2): e0264413, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35213624

RESUMO

The caveolin-1 scaffolding domain (CSD, amino acids 82-101 of caveolin-1) has been shown to suppress bleomycin-induced lung and skin fibrosis and angiotensin II (AngII)-induced myocardial fibrosis. To identify active subregions within CSD, we split its sequence into three slightly overlapping 8-amino acid subregions (82-89, 88-95, and 94-101). Interestingly, all three peptides showed activity. In bleomycin-treated mice, all three subregions suppressed the pathological effects on lung and skin tissue morphology. In addition, while bone marrow monocytes isolated from bleomycin-treated mice showed greatly enhanced migration in vitro toward CXCL12, treatment in vivo with CSD and its subregions almost completely suppressed this enhanced migration. In AngII-induced heart failure, both 82-89 and 88-95 significantly suppressed fibrosis (both Col I and HSP47 levels), microvascular leakage, and heart weight/ body weight ratio (HW/BW) while improving ventricular function. In contrast, while 94-101 suppressed the increase in Col I, it did not improve the other parameters. The idea that all three subregions can be active depending on the assay was further supported by experiments studying the in vitro migration of human monocytes in which all three subregions were extremely active. These studies are very novel in that it has been suggested that there is only one active region within CSD that is centered on amino acids 90-92. In contrast, we demonstrate here the presence of other active regions within CSD.


Assuntos
Caveolina 1/metabolismo , Movimento Celular , Monócitos/metabolismo , Fibrose Pulmonar/metabolismo , Dermatopatias/metabolismo , Animais , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Dermatopatias/induzido quimicamente
13.
Redox Biol ; 50: 102226, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35150970

RESUMO

Tissue fibrosis occurs in response to dysregulated metabolism, pro-inflammatory signaling and tissue repair reactions. For example, lungs exposed to environmental toxins, cancer therapies, chronic inflammation and other stimuli manifest a phenotypic shift to activated myofibroblasts and progressive and often irreversible lung tissue scarring. There are no therapies that stop or reverse fibrosis. The 2 FDA-approved anti-fibrotic drugs at best only slow the progression of fibrosis in humans. The present study was designed to test whether a small molecule electrophilic nitroalkene, nitro-oleic acid (NO2-OA), could reverse established pulmonary fibrosis induced by the intratracheal administration of bleomycin in C57BL/6 mice. After 14 d of bleomycin-induced fibrosis development in vivo, lungs were removed, sectioned and precision-cut lung slices (PCLS) from control and bleomycin-treated mice were cultured ex vivo for 4 d with either vehicle or NO2-OA (5 µM). Biochemical and morphological analyses showed that over a 4 d time frame, NO2-OA significantly inhibited pro-inflammatory mediator and growth factor expression and reversed key indices of fibrosis (hydroxyproline, collagen 1A1 and 3A1, fibronectin-1). Quantitative image analysis of PCLS immunohistology reinforced these observations, revealing that NO2-OA suppressed additional hallmarks of the fibrotic response, including alveolar epithelial cell loss, myofibroblast differentiation and proliferation, collagen and α-smooth muscle actin expression. NO2-OA also accelerated collagen degradation by resident macrophages. These effects occurred in the absence of the recognized NO2-OA modulation of circulating and migrating immune cell activation. Thus, small molecule nitroalkenes may be useful agents for reversing pathogenic fibrosis of lung and other organs.


Assuntos
Ácidos Graxos , Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Ácidos Graxos/uso terapêutico , Fibrose , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia
14.
Adv Sci (Weinh) ; 9(8): e2103676, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34994102

RESUMO

Local pulmonary administration of therapeutic siRNA represents a promising approach to the treatment of lung fibrosis, which is currently hampered by inefficient delivery. Development of perfluorooctylbromide (PFOB) nanoemulsions as a way of improving the efficiency of pulmonary polycation-based delivery of siRNA is reported. The results show that the polycation/siRNA/PFOB nanoemulsions are capable of efficiently silencing the expression of STAT3 and inhibiting chemokine receptor CXCR4-two validated targets in pulmonary fibrosis. Both in vitro and in vivo results demonstrate that the nanoemulsions improve mucus penetration and facilitate effective cellular delivery of siRNA. Pulmonary treatment of mice with bleomycin-induced pulmonary fibrosis shows strong inhibition of the progression of the disease and significant prolongation of animal survival. Overall, the study points to a promising local treatment strategy of pulmonary fibrosis.


Assuntos
Fluorcarbonetos , Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Bleomicina/metabolismo , Fluorcarbonetos/efeitos adversos , Fluorcarbonetos/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/terapia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacologia
15.
Mol Cell Biochem ; 477(4): 995-1007, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34988855

RESUMO

Systemic sclerosis (SSc) is a connective tissue disease that often causes pulmonary fibrosis. Dipeptidyl peptidase 4 (DPP4) inhibitor has shown anti-fibrotic properties in various fibrotic diseases. However, only two studies have reported its anti-fibrosis effects in pulmonary fibrosis, and the mechanism is not completely clear. In the present study, we further investigated the protective effects of linagliptin, a highly specific DPP4 inhibitor, on pulmonary fibrosis in SSc mouse model and the potential mechanisms. The results showed that linagliptin ameliorated pulmonary fibrosis in SSc mouse model, as evidenced by improved pathological changes of lung and body weight loss induced by BLM. Linagliptin also reduced BLM-induced oxidative stress, inflammation in lung in vivo. We revealed that linagliptin attenuated BLM-induced endothelial-to-mesenchymal transition (EndMT) in vitro and in vivo. BLM-induced enhanced migration ability of endothelial cells was also alleviated by linagliptin. Moreover, we confirmed that the Akt/mammalian target of rapamycin pathway was involved in BLM-induced EndMT in vivo, which was suppressed by linagliptin. In summary, we further confirmed the therapeutic effects of linagliptin on pulmonary fibrosis in SSc mouse model, which is based on its inhibitory effects on EndMT, oxidative stress, and inflammation.


Assuntos
Bleomicina/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Endoteliais/metabolismo , Linagliptina/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Escleroderma Sistêmico/tratamento farmacológico , Animais , Bleomicina/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/metabolismo
18.
Clin Exp Dermatol ; 47(4): 730-734, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34610164

RESUMO

The treatment of warts has always been a challenging prospect for dermatologists. In some cases, these warts can become resistant or recalcitrant to treatment. Although a plethora of therapeutic and destructive options is available for wart management, to date no treatment has been found to be completely effective because none of the agents induce specific antiviral immunity. We conducted a study to evaluate the efficacy and safety of skin needling with topical 100% trichloroacetic acid (TCA) against the same type of skin needling with bleomycin in patients with recalcitrant cutaneous warts. In total, 33 (63.5%) patients in the TCA group and 35 (81.4%) in the bleomycin group had complete clearance of all the warts, which was not statistically significant (P = 0.13). There was also no statistically significant difference between the treated and untreated warts in the bleomycin group, whereas in the TCA group there was a significantly higher response rate in the treated warts. The most common adverse event (AE) in both groups was transient procedure site pain. We found that the use of needling plus TCA leads to a faster resolution of warts compared with needling plus bleomycin, with a comparable safety profile. Additionally, we found that TCA is superior to bleomycin for management of multiple warts. However, needling with either TCA or bleomycin has excellent and fairly comparable efficacy, and these methods should be used for the management of multiple or recalcitrant warts, as they have minimal AEs and recurrence rates.


Assuntos
Ácido Tricloroacético , Verrugas , Administração Cutânea , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Humanos , Injeções Intralesionais , Resultado do Tratamento , Ácido Tricloroacético/efeitos adversos , Verrugas/tratamento farmacológico , Verrugas/etiologia
19.
Int J Radiat Oncol Biol Phys ; 112(4): 890-900, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34767937

RESUMO

PURPOSE: The Children's Oncology Group protocol AHOD0831, for pediatric patients with high-risk classical Hodgkin lymphoma (cHL), used response-adapted radiation fields, rather than larger involved-field radiation therapy (IFRT) that were historically used. This retrospective analysis of patterns of relapse among patients enrolled in the study was conducted to study the potential effect of a reduction in RT exposure. METHODS AND MATERIALS: From December 2009 to January 2012, 164 eligible patients under 22 years old with stage IIIB (43%) and stage IVB (57%) enrolled on AHOD0831. All patients received 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Those patients with a slow early response (SER) after the first 2 ABVE-PC courses were nonrandomly assigned to 2 intensification cycles with ifosfamide/vinorelbine before the final 2 ABVE-PC cycles. Response-adapted RT (21 Gy) was prescribed to initial areas of bulky disease and SER sites. Rapid early response (RER) sites without bulk were not targeted. Imaging studies at the time of progression or relapse were reviewed centrally for this retrospective analysis. Relapses were characterized with respect to site (initial, new, or both; and initial bulk or initial nonbulk), initial chemotherapy response, and radiation field (in-field, out-of-field, or both). RESULTS: Of the entire cohort, 140 patients were evaluable for the patterns of failure analyses. To investigate the pattern of failure, this analysis focuses on 23 patients who followed protocol treatment and suffered relapses at a median 1.05 years with 7.97-year median follow-up time. These 23 patients (11 RER and 12 SER) experienced a relapse in 105 total sites (median, 4; range, 1-11). Of the 105 relapsed sites, 67 sites (64%) occurred within an initial site of involvement, with 12 of these 67 sites (18%) at an initial site of bulky disease and 63 of these 67 relapses (94%) occurring in sites that were not fluorodeoxyglucose (FDG)-avid after 2 cycles of ABVE-PC (PET2-negative). Of the 105 relapsed sites, 34 sites (32%) occurred in a new site of disease (that would not have been covered by RT); and, overall, only 4 of 140 patients (2.8%) (occurring in 3 RER and 1 SER) experienced isolated out-of-field relapses that would have been covered by historical IFRT. CONCLUSIONS: For a cohort of high-risk patients with cHL patients, most failures occurred in nonbulky, initially involved sites, largely due to response-based consolidation RT delivered to patients with bulky disease. In this analysis, we discovered low rates of failures outside of these modern risk-adapted radiation treatment volumes. Also, FDG uptake on PET2 did not identify most relapse sites.


Assuntos
Doença de Hodgkin , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/efeitos adversos , Criança , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prednisona/efeitos adversos , Estudos Retrospectivos , Vincristina/efeitos adversos , Adulto Jovem
20.
Dis Model Mech ; 15(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34845494

RESUMO

Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the bleomycin mouse model of IPF, we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids and lipids and extracellular matrix turnover. Energy production was upregulated, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, lactate production and fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Because the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the bleomycin-induced pulmonary fibrosis model. Surprisingly, except for cytidine, we did not detect any significantly differential metabolites or lipids between old and young bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation, which might serve to improve diagnostic and therapeutic options for fibrotic lung diseases in the future.


Assuntos
Bleomicina , Fibrose Pulmonar Idiopática , Animais , Bleomicina/efeitos adversos , Bleomicina/metabolismo , Fibrose , Lipidômica , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL
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