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1.
Phytomedicine ; 130: 155687, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38759312

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating interstitial lung disorder characterized by its limited therapeutic interventions. Macrophages, particularly the alternatively activated macrophages (M2 subtype), have been acknowledged for their substantial involvement in the development of pulmonary fibrosis. Hence, targeting macrophages emerges as a plausible therapeutic avenue for IPF. Icariside II (ISE II) is a natural flavonoid glycoside molecule known for its excellent anti-tumor and anti-fibrotic activities. Nevertheless, the impact of ISE II on pulmonary fibrosis and the intricate mechanisms through which it operates have yet to be elucidated. OBJECTIVE: To scrutinize the impact of ISE II on the regulation of M2 macrophage polarization and its inhibitory effect on pulmonary fibrosis, as well as to delve deeper into the underlying mechanisms of its actions. METHODS: The effect of ISE II on proliferation and apoptosis in RAW264.7 cells was assessed through the use of EdU-488 labeling and the Annexin V/PI assay. Flow cytometry, western blot, and qPCR were employed to detect markers associated with the M2 polarization phenotype. The anti-fibrotic effects of ISE II in NIH-3T3 cells were investigated in a co-culture with M2 macrophages. Si-Ctnnb1 and pcDNA3.1(+)-Ctnnb1 plasmid were used to investigate the mechanism of targeted intervention. The murine model of pulmonary fibrosis was induced by intratracheal administration of bleomycin (BLM). Pulmonary function, histopathological manifestations, lung M2 macrophage infiltration, and markers associated with pulmonary fibrosis were evaluated. Furthermore, in vivo transcriptomics analysis was employed to elucidate differentially regulated genes in lung tissues. Immunofluorescence, western blot, and immunohistochemistry were conducted for corresponding validation. RESULTS: Our investigation demonstrated that ISE II effectively inhibited the proliferation of RAW264.7 cells and mitigated the pro-fibrotic characteristics of M2 macrophages, exemplified by the downregulation of CD206, Arg-1, and YM-1, Fizz1, through the inhibition of the PI3K/Akt/ß-catenin signaling pathway. This impact led to the amelioration of myofibroblast activation and the suppression of nuclear translocation of ß-catenin of NIH-3T3 cells in a co-culture. Consequently, it resulted in decreased collagen deposition, reduced infiltration of profibrotic macrophages, and a concurrent restoration of pulmonary function in mice IPF models. Furthermore, our RNA sequencing results showed that ISE II could suppress the expression of genes related to M2 polarization, primarily by inhibiting the PI3K/Akt and ß-catenin signaling pathway. In essence, our findings suggest that ISE II holds potential as an anti-fibrotic agent by orchestrating macrophage polarization. This may have significant implications in clinical practice. CONCLUSION: This study has provided evidence that ISE II exerts a significant anti-fibrotic effect by inhibiting macrophage M2 polarization through the suppression of the PI3K/Akt/ß-catenin signaling pathway. These findings underscore the potential of ISE II as a promising candidate for the development of anti-fibrotic pharmaceuticals in the future.


Assuntos
Flavonoides , Macrófagos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , beta Catenina , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Flavonoides/farmacologia , Células RAW 264.7 , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , beta Catenina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Células NIH 3T3 , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Bleomicina , Camundongos Endogâmicos C57BL , Apoptose/efeitos dos fármacos , Masculino , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico
2.
J Ethnopharmacol ; 317: 116810, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37331450

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Numerous studies have provided evidence supporting the significant roles of icariin, in the prevention of multiple chronic diseases like diabetes, liver fibrosis, cardiac fibrosis, renal fibrosis, and pulmonary fibrosis. In particular, Icariside II (ISE II), a prominent flavonoid glycoside derived from Epimedium brevicornum Maxim, the principal metabolite of icariin, has demonstrated noteworthy anti-inflammatory and anti-oxidant properties, along with its ability to protect against lung remodeling. However, the research exploring ISE Ⅱ's application in treating pulmonary fibrosis remains limited. AIM OF THE STUDY: The aim of this study was to assess the therapeutic efficacy of ISE II in models of pulmonary fibrosis, while also investigating its potential mechanisms of action in cell signaling pathways. MATERIALS AND METHODS: An in vitro model of pulmonary fibrosis was established by treating NIH-3T3 cells with transforming growth factor-ß1 (TGF-ß1). Western blot, RT-qPCR, and scratch test were performed to assess the effect of ISE Ⅱ. In addition, a murine model of pulmonary fibrosis was induced by intratracheal instillation of bleomycin, and the therapeutic effect of ISE Ⅱ was tested by orally administering ISE Ⅱ at a dose of 10 mg/kg. Three weeks later, lung function, micro-CT, hydroxyproline content, pathological staining, and cytokines detection of BALF or serum were used to assess the anti-fibrosis effects of ISE Ⅱ. Next, immunofluorescence staining, flow cytometry, and in vivo transcriptomics were used to investigate the underlying mechanisms of action. RESULTS: Our data revealed a significant inhibitory effect of ISE Ⅱ on the upregulation of α-smooth muscle actin (α-SMA) and collagen production induced by TGF-ß1 in fibroblasts. Meanwhile, ISE Ⅱ exerted a therapeutic effect against bleomycin-induced pulmonary fibrosis in mice by improving lung function, decreasing collagen deposition, and reducing the expression of interleukin (IL)-1ß, tumor necrosis factor α (TNF-α), TGF-ß1 and platelet-derived growth factor (PDGF) in serum and bronchoalveolar lavage fluid (BALF). Additionally, ISE Ⅱ treatment effectively attenuated the infiltration of M2 macrophages, concurrently downregulating the expression level of M2 marker genes, such as CD206, arginase-1(Arg-1), and Chitinase-Like Protein 3 (YM-1). Importantly, we observed a statistically significant reduction in the M2 phenotype of interstitial macrophages (IMs). However, the impact of ISE Ⅱ on the M2 polarization of alveolar macrophages (AMs) did not reach statistical significance. Lastly, transcriptome sequencing results suggested that the anti-pulmonary fibrosis effects of ISE Ⅱ may be mediated by the suppression of the WNT/ß-catenin signaling pathway, which modulated M2 polarization in macrophages and contributed to the amelioration of pulmonary fibrosis. By immunohistochemical analysis, it was verified that ISE Ⅱ treatment dramatically inhibited the activation of ß-catenin in fibrosis murine. CONCLUSION: Our findings indicated that ISE Ⅱ exerted anti-fibrotic effects by inhibiting pro-fibrotic macrophage polarization. The underlying mechanism of action might be mediated by modulating the WNT/ß-catenin signaling pathway to inhibit the M2 program in IMs.


Assuntos
Fibrose Pulmonar , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Bleomicina/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Flavonoides/farmacologia , Macrófagos/metabolismo , Colágeno/metabolismo , Via de Sinalização Wnt , Camundongos Endogâmicos C57BL
3.
BMC Pulm Med ; 23(1): 91, 2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-36944966

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of the lung. How to build a typical human mimicking animal model has been a challenge. Thus, to reveal the mechanism and to make it useful for IPF clinical treatment, a different type of mice model and inspection methods are used to evaluate which one is applicable for the study of IPF. METHOD: 69 Twelve-weeks-old C57BL/6 mice were divided into 3 type groups (n = 7 for each control group, n = 8 for each BLM-induced pulmonary fibrosis groups), as intraperitoneal injection, intratracheal administration, and intravenous administration of bleomycin (BLM) to initiate lung fibrosis. Changes of the lung function measured through mice Pulmonary function test (PFT). Morphological changes in mice were observed by PET/CT, Masson and Picro-Sirius staining, Transmission electron microscopy (TEM). Biochemical changes were tested by Enzyme-linked immunosorbent assay (Elisa). RESULTS: PET/CT of BLM-receiving mice showed an increase in fibrotic consolidations and an increase in non-aerated lung area in BLM-treated mice compared with that in controls. TGF-b1, TNF-a, IL-6, GM-CSF in BALF and serum. PAI-1, HYP in the lung tissue of mice were significantly different in each BLM groups than those in the controls. The results of Masson staining in mice indicate that the lung tissues of all BLM received groups, the intratracheal groups, the intravenous groups, and the intraperitoneal groups have a higher degree of pulmonary septal thickening and collagen fiber consolidation compare to saline control. Picro-Sirius staining results are consistent with the results of Masson staining. Compared with the saline control group, the ratio of Col 1/Col 3 was significantly increased in each BLM group. TEM results found that in BLM group, type I alveolar epithelial cells were degenerated. Exfoliated endothelial cells were swelling, and type II alveolar epithelial cells were proliferated, the shape of the nucleus was irregular, and some tooth-like protrusions were seen. CONCLUSIONS: With three different methods of animal model construction, high dose of each show more compliable, and BLM can successfully induce animal models of pulmonary fibrosis, however, certain differences in the fibrosis formation sites of them three, and tail vein injection of BLM induced PF model is closer to the idiopathic pulmonary interstitial fibrosis.


Assuntos
Bleomicina , Fibrose Pulmonar Idiopática , Camundongos , Humanos , Animais , Bleomicina/toxicidade , Células Endoteliais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Líquido da Lavagem Broncoalveolar , Camundongos Endogâmicos C57BL , Pulmão , Fibrose Pulmonar Idiopática/induzido quimicamente , Modelos Animais de Doenças
4.
Phytomedicine ; 103: 154187, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35667261

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of unknown aetiology with limited effective treatment options. It is important to explore novel therapeutic targets and develop potential drugs for IPF. PURPOSE: The aim of the present study was to analyse nontargeted plasma metabolites in patients with IPF and investigate whether cannabinoid receptor (CB2) activation mediates the antifibrotic effect of icariin (ICA). METHODS: We used an untargeted metabolomics method to detect the global metabolic profiles in the plasma of stable IPF patients and patients with stable chronic obstructive pulmonary disease (COPD), as well as healthy subjects. The untargeted liquid chromatography-mass spectrometry (LC-MS) analysis revealed that IPF showed differential metabolites and perturbed signalling pathways. ICA is pharmacologically bioactive and possesses extensive therapeutic capacities such as osteoprotective, neuroprotective, cardiovascular protective, anti-cancer, anti-inflammation and reproductive function. Therefore, ICA was administered to a pulmonary fibrosis rat model for 4 weeks and then the effect of ICA on pulmonary fibrosis was examined by dissection and histology. RESULTS: The metabolites in the plasma were determined by untargeted LC-MS. An unsupervised principal component analysis (PCA) was used to observe the distribution of each sample, and a supervised partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) results showed that there was significant separation between any two groups. ROC curve analyses revealed that 8 metabolites with high AUCs above 0.7 between the three groups of plasma samples. Pathway enrichment analysis revealed that 3 metabolites are involved in retrograde endocannabinoid signalling. Meanwhile, Retrograde endocannabinoid signalling was identified significantly different in IPF group from other groups by Kyoto encyclopedia of Genes and Genomes (KEGG) pathway analysis, and then we further confirmed the endocannabinoid signalling by detecting the expression of the main receptors in bleomycin-induced pulmonary fibrosis, COPD rat model and normal rats. Consistent with previous studies, we found that the elevation of CB1 and CB2 in the lung tissues could be a signature of the pulmonary fibrosis rat model. Importantly, ICA may alleviate bleomycin-induced lung injury by decreasing CB1 and CB2 expression in the bleomycin-induced rat model. CONCLUSION: Taken together, we measured the global metabolic profile of IPF patients and identified CB2 as a novel potential target. ICA treatment demonstrated outstanding therapeutic effects on bleomycin-induced pulmonary fibrosis and targeting on CB2 may be the main underlying mechanism. ICA is a promising drug candidate to cure pulmonary fibrosis and mediate antagonists of the CB2 receptor.


Assuntos
Fibrose Pulmonar Idiopática , Doença Pulmonar Obstrutiva Crônica , Animais , Bleomicina/efeitos adversos , Endocanabinoides/uso terapêutico , Flavonoides , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Ratos , Receptores de Canabinoides/uso terapêutico
5.
Int J Biol Sci ; 18(5): 2060-2074, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35342361

RESUMO

Although cisplatin is the most effective first-line drug in the management of advanced non-small cell lung cancer (NSCLC), drug resistance remains a major clinical challenge. There is increasing evidence that icariside II (IS) exhibits antitumour activity in a variety of cancers. In the current study, we investigated the anticancer effects of icariside II combined with cisplatin and elucidated the underlying mechanism in NSCLC. Here, we showed that cotreatment with IS and cisplatin inhibited cell proliferation and induced cellular apoptosis. Using mRNA sequencing (mRNA-seq), we identified differentially expressed genes (DEGs) in which there was an enrichment in PERK-mediated unfolded protein response (UPR) signalling. The western blot results revealed that IS activated endoplasmic reticulum (ER) stress, including three branches of UPR signalling, PERK, IRE1 and ATF6, and the downstream PERK-eIF2α-ATF4-CHOP pathway, thus potentiating the apoptosis induced by cisplatin. In addition, the combination of IS with cisplatin significantly reduced xenograft tumour growth in C57BL/6 and BALB/c nude mice in vivo. Notably, the combination therapy displayed no evident toxicity. Taken together, IS enhances cisplatin-induced apoptosis partially by promoting ER stress signalling in NSCLC, suggesting that combination treatment with IS and cisplatin is a novel potential therapeutic strategy for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Estresse do Retículo Endoplasmático , Flavonoides , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , RNA Mensageiro , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-32774431

RESUMO

The red peony root derived from Paeonia lactiflora has been applied to treat human inflammatory diseases. To investigate its therapeutic potential in treating moderately severe acute pancreatitis (MSAP), which has been rarely studied, this study was designed as a double-blinded, placebo-controlled, randomized clinical trial. A total of 60 MSAP patients were enrolled and randomly divided into an experimental (n = 30) group and a control group (n = 30), who received a coloclyster of 15 g of red peony root or placebo granules dissolved in 150 mL of water, respectively. The patients' demographic and clinical characteristics were recorded. The results showed that the experimental group had a shorter remission time of fever (p < 0.05) and abdominal pain (p < 0.01) and faster resumption of self-defecation (p < 0.01) than did the control group. In addition, the coloclyster of red peony root decreased the modified Balthazar CT score as well as the serum interleukin-6 and tumor necrosis factor-alpha levels to a greater extent than did the placebo coloclyster (p < 0.05). The remission times for the normalization of white blood cells and percentage of neutrophils and lymphocytes in the experimental group were also significantly shorter than those in the control group (p < 0.05). In conclusion, a coloclyster of red peony root could help alleviate the clinical symptoms and shorten the course of MSAP by possibly attenuating systematic inflammation. This trial is registered with 14004664.

7.
Medicine (Baltimore) ; 96(36): e7867, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28885340

RESUMO

RATIONALE: Coexistence of lung adenocarcinoma and polyserous effusions is quite rare. This complexity of etiology adds difficulty to the diagnosis and is likely to cause misdiagnosis and maldiagnosis. PATIENT CONCERNS: A 43-year-old woman was admitted with symptoms of dry cough, chest suffocation, polyserous effusions, and generalized edema. Only a small number of heterocysts were detected in the ascites, and malignant cells were detected in the pleural and pericardial effusions. After cytology tests of pericardial, pleural effusions, and ascites, puncture biopsy of the left lung lesion was performed with CT guidance, and immunohistochemical tests were performed. DIAGNOSES: The diagnosis of lung adenocarcinoma was histopathologically confirmed by puncture biopsy with CT guidance of the left lower lung lesion. INTERVENTIONS: Combined treatments(pemetrexed/cisplatin) was administered after the left lung lesion immunohistochemistry. OUTCOMES: The patient has survived more than 1 year after pemetrexed/cisplatin combination chemotherapy. LESSONS: Coexistence of lung adenocarcinoma and polyserous effusions is quite rare. Close attention should be paid whenever a patient with coexistence of ascites, pleural effusion, and pericardial effusion. More diverse methods could be helpful to identify the diagnosis and avoid misdiagnosis. Patients with advanced lung adenocarcinoma need individualized therapy, including pemetrexed/cisplatin combination chemotherapy.


Assuntos
Adenocarcinoma/complicações , Neoplasias Pulmonares/complicações , Derrame Pleural/complicações , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico
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