Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 53
Filtrar
1.
Biomicrofluidics ; 15(5): 051302, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34733378

RESUMO

Droplet-based microfluidic technology has enabled the production of emulsions with high monodispersity in sizes ranging from a few to hundreds of micrometers. Taking advantage of this technology, attempts to generate monodisperse emulsion drops with high drug loading capacity, ordered interfacial structure, and multi-functionality have been made in the cosmetics industry. In this article, we introduce the practicality of the droplet-based microfluidic approach to the cosmetic industry in terms of innovation in productivity and marketability. Furthermore, we summarize some recent advances in the production of emulsion drops with enhanced mechanical interfacial stability. Finally, we discuss the future prospects of microfluidic technology in accordance with consumers' needs and industrial attributes.

2.
Int J Med Sci ; 18(15): 3395-3402, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522166

RESUMO

Computed tomography (CT) of the chest is one of the main diagnositic tools for coronavirus disease 2019 (COVID-19) infection. To document the chest CT findings in patients with confirmed COVID-19 and their association with the clinical severity, we searched related literatures through PubMed, MEDLINE, Embase, Web of Science (inception to May 4, 2020) and reviewed reference lists of previous systematic reviews. A total of 31 case reports (3768 patients) on CT findings of COVID-19 were included. The most common comorbid conditions were hypertension (18.4%) and diabetes mellitus (8.3%). The most common symptom was fever (78.7%), followed by cough (60.2%). It took an average of 5.6 days from symptom onset to admission. The most common chest CT finding was vascular enlargement (84.8%), followed by ground-glass opacity (GGO) (60.1%), air-bronchogram (47.8%), and consolidation (41.4%). Most lung lesions were located in the lung periphery (72.2%) and involved bilateral lung (76%). Most patients showed normal range of laboratory findings such as white blood cell count (96.4%) and lymphocyte (87.2%). Compared to previous published meta-analyses, our study is the first to summarize the different radiologic characteristics of chest CT in a total of 3768 COVID-19 patients by compiling case series studies. A comprehensive diagnostic approach should be adopted for patients with known COVID-19, suspected cases, and for exposed individuals.


Assuntos
COVID-19/diagnóstico por imagem , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , COVID-19/sangue , Humanos , Pulmão/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Contagem de Linfócitos , Oxigênio/uso terapêutico , Prognóstico
3.
Cancer Gene Ther ; 28(9): 960-970, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34349240

RESUMO

Antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), play a crucial role in bridging innate and adaptive immunity; thereby, innate immune checkpoint blockade-based therapy is an attractive approach for the induction of sustainable tumor-specific immunity. The interaction between the cluster of differentiation 47 (CD47) on tumor and signal-regulatory protein alpha (SIRPα) on phagocytic cells inhibits the phagocytic function of APCs, acting as a "don't eat me" signal. Accordingly, CD47 blockade is known to increase tumor cell phagocytosis, eliciting tumor-specific CD8+ T-cell immunity. Here, we introduced a nature-derived nanocage to deliver SIRPγ for blocking of antiphagocytic signaling through binding to CD47 and combined it with prophagocytic stimuli using a metabolic reprogramming reagent for APCs (CpG-oligodeoxynucleotides). Upon delivering the clustered SIRPγ variant, the nanocage showed enhanced CD47 binding profiles on tumor cells, thereby promoting active engulfment by phagocytes. Moreover, combination with CpG potentiated the prophagocytic ability, leading to the establishment of antitumorigenic surroundings. This combination treatment could competently inhibit tumor growth by invigorating APCs and CD8+ T-cells in TMEs in B16F10 orthotopic tumor models, known to be resistant to CD47-targeting therapeutics. Collectively, enhanced delivery of an innate immune checkpoint antagonist with metabolic modulation stimuli of immune cells could be a promising strategy for arousing immune responses against cancer.

4.
Environ Res ; 198: 111265, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33939981

RESUMO

BACKGROUND: The effect of exposure to particulate matter (PM) on human health is a global public health concern. To develop an effective strategy to reduce PM exposure, we performed detailed questionnaire surveys regarding the type of lifestyle required to avoid PM exposure in patients with chronic obstructive pulmonary disease (COPD). We correlated the data with real-time PM concentration during the winter season. METHODS: We enrolled 104 patients with COPD aged 40 years or older. Detailed questionnaire surveys were conducted among participants, and internet of things-based sensors were installed at their homes to measure the indoor PM2.5 concentration, which was continuously monitored between December 2019 and February 2020. The associations among PM2.5 concentration, patients' lifestyles, and the impact of both concentration and lifestyle on COPD exacerbation were analyzed. RESULTS: Mean outdoor PM2.5 concentration was higher than mean indoor PM2.5 concentration during the study period (21.28 ± 5.09 µg/m3 vs. 12.75 ± 7.64 µg/m3), with a mean difference of 8.53 ± 7.99 µg/m3. Among the various social factors and practices that aim to avoid exposure to PM, six practices and economic statuses were confirmed to reduce indoor PM2.5 concentration compared to outdoor concentration; Contrarily, these practices created a significant difference between the outdoor and indoor PM2.5 concentrations. The six practice items that showed a significant difference were 1) checking air quality forecast (the difference: -13.31 ± 1.35 µg/m3, p = 0.013), 2) indoor air filter operated (-15.43 ± 1.32 µg/m3, p < 0.001), 3) ventilating home by opening the windows (-13.14 ± 1.28 µg/m3, p = 0.013), 4) checking filters of the air filter (-13.95 ± 1.50 µg/m3, p = 0.002), 5) refraining from going out when outside PM is high (-12.52 ± 1.37 µg/m3, p = 0.039), 6) wearing a mask when going out (-13.38 ± 1.32 µg/m3, p = 0.017). The higher the household income and economic level, the more significant the difference in the PM2.5 concentration. Severe exacerbation was more prevalent among patients with acute exacerbation as the exposure time of PM2.5≥35 µg/m3 or PM2.5≥75 µg/m3. CONCLUSION: Lifestyle and economic levels can affect the indoor PM2.5 concentration, which may impact COPD exacerbation.


Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Doença Pulmonar Obstrutiva Crônica , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental , Humanos , Material Particulado/análise , Doença Pulmonar Obstrutiva Crônica/epidemiologia
5.
Sci Rep ; 11(1): 9644, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958649

RESUMO

Several studies have suggested that extracellular matrix (ECM) remodeling and the microenvironment are tightly associated with adipogenesis and adipose angiogenesis. In the present study, we demonstrated that transforming growth factor-beta induced (TGFBI) suppresses angiogenesis stimulated by adipocyte-conditioned medium (Ad-CM), both in vitro and in vivo. TGFBI knockout (KO) mice exhibited increased numbers of blood vessels in adipose tissue, and blood vessels from these mice showed enhanced infiltration into Matrigel containing Ad-CM. The treatment of Ad-CM-stimulated SVEC-10 endothelial cells with TGFBI protein reduced migration and tube-forming activity. TGFBI protein suppressed the activation of the Src and extracellular signaling-related kinase signaling pathways of these SVEC-10 endothelial cells. Our findings indicated that TGFBI inhibited adipose angiogenesis by suppressing the activation of Src and ERK signaling pathways, possibly because of the stimulation of the angiogenic activity of endothelial cells.


Assuntos
Tecido Adiposo/irrigação sanguínea , Endotélio Vascular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Neovascularização Fisiológica , Fator de Crescimento Transformador beta/metabolismo , Tecido Adiposo/metabolismo , Animais , Capilares/crescimento & desenvolvimento , Capilares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
Int Immunopharmacol ; 96: 107635, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33857806

RESUMO

OBJECTIVES: The Cat Eye Syndrome Critical Region, Candidate 1 (CECR1) gene encoding adenosine deaminase 2 (ADA2) is mainly expressed by macrophages. Given the immunomodulatory functions of butyrate, we examined the effect of butyrate on CECR1 expression of macrophages and the relationship between ADA2 and M1/M2 macrophages-associated chemokines in pleural fluid of patients with tuberculous pleural effusion (TPE). METHODS: Expression of CECR1 was evaluated in lipopolysaccharide (LPS)-stimulated and/or butyrate treated THP-1 cells. The role of CECR1 on butyrate-induced immune response was evaluated using siRNA transfected THP-1 cells. M1/M2 chemokines and ADA2 were measured in pleural fluid of patients with TPE. RESULTS: Butyrate promoted the expression of CECR1 and M2-macrophage markers in THP-1 cells. CECR1 was found to be involved in regulating M2 polarization in THP-1 cells treated with LPS and butyrate. Among chemokines measured in pleural fluid of patients with TPE, there was a significant negative correlation between CCL21 and ADA2 levels and between CCL25 and ADA2 levels, and a significant positive correlation between TGF-ß and ADA2 levels and between IL-22 and ADA2 levels. CONCLUSIONS: CECR1 played an important role in the butyrate-modulated inflammatory responses in LPS-stimulated THP-1 cells. ADA2 may exert anti-inflammatory effects during the process of pleural inflammation in patients with TPE.

7.
Cell Signal ; 78: 109848, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33246003

RESUMO

We have recently reported that capping protein regulator and myosin 1 linker 3 (CARMIL3), first identified as an oncofetal-like gene, is required for metastasis of breast and prostate cancer cells via regulating the actin cytoskeletal dynamics near the plasma membrane. Here, we demonstrate a novel function of CARMIL3 as an essential regulator of the transcription of several key proinflammatory cytokines in macrophages engulfing apoptotic cells and/or exposed to lipopolysaccharides (LPS). CARMIL3-deficient macrophages expressed strongly abrogated levels of interleukin (IL)-6, TNF-α, IL-1ß and IL-23 in response to LPS, whereas IL-10 expression was enhanced. An RNA-seq analysis of CARMIL3-deficient and wild-type (WT) RAW264.7 cells stimulated with LPS revealed many differentially expressed genes, impacting several important inflammatory pathways. At the molecular level, CARMIL3 deficiency caused a strong impairment in LPS-activated nuclear factor-κB (NF-κB) signaling with decreased IKKα/ß and IκBα phosphorylation and severely reduced p65 protein levels. This study uncovers a crucial role of CARMIL3 in impacting the balance between inflammation and tissue homeostasis via regulating major cytokines production in phagocytic cells.

8.
Genomics Inform ; 18(3): e33, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33017877

RESUMO

This paper describes a community effort to improve earlier versions of the full-text corpus of Genomics & Informatics by semi-automatically detecting and correcting PDF-to-text conversion errors and optical character recognition errors during the first hackathon of Genomics & Informatics Annotation Hackathon (GIAH) event. Extracting text from multi-column biomedical documents such as Genomics & Informatics is known to be notoriously difficult. The hackathon was piloted as part of a coding competition of the ELTEC College of Engineering at Ewha Womans University in order to enable researchers and students to create or annotate their own versions of the Genomics & Informatics corpus, to gain and create knowledge about corpus linguistics, and simultaneously to acquire tangible and transferable skills. The proposed projects during the hackathon harness an internal database containing different versions of the corpus and annotations.

9.
Anticancer Res ; 40(10): 5463-5469, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988868

RESUMO

BACKGROUND/AIM: Periostin exists as an extracellular matrix protein in several carcinomas and is related to metastasis and poor prognosis. It is mainly secreted from cancer associated fibroblasts, and not from carcinoma cells. As a tumor microenvironment component, periostin usually mediates tumor cell stemness, metastasis, angiogenesis and lymphangiogenesis. This study aimed to examine the role of periostin in chondrosarcoma. MATERIALS AND METHODS: To evaluate the effect of periostin on the proliferation of chondrosarcoma cells, MTT assay was performed on SW1353 cells and periostin knockdown SW1353 cells. Migration activity was examined using Boyden chamber. RESULTS: Periostin, secreted from chondrosarcoma cells, was found to support proliferation, and maintain stemness and migration of chondrosarcoma cells. Periostin also induced proliferation and migration of lymphatic endothelial cells. CONCLUSION: Periostin plays an important role in chondrosarcoma development and disease progression.


Assuntos
Moléculas de Adesão Celular/genética , Proliferação de Células/genética , Condrossarcoma/genética , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Condrossarcoma/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Linfangiogênese/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Microambiente Tumoral/genética
10.
In Vivo ; 34(5): 3005-3012, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32871844

RESUMO

BACKGROUND/AIM: This study was conducted to investigate transforming growth factor beta-induced protein (TGFBI) expression and analyze the clinical and prognostic significance of TGFBI in oropharyngeal squamous cell carcinoma (OPSCC). PATIENTS AND METHODS: We evaluated TGFBI expression by immunohistochemistry in 94 patients with OPSCC. For comprehensive analysis, TGFBI expression was subdivided into tumor cell score (T), stroma score (S), and the sum of two scores (TS) calculated using H-score. Clinicopathological features and survival outcomes were compared between groups of high expression and low expression of TGFBI in each area. RESULTS: Overall, 12 patients (12.8%) showed high T score, and 41 patients (43.6%) revealed high S score. Although T score showed no significant difference both in overall survival (OS) (p=0.080) and recurrence free survival (RFS) (p=0.272), high S score patients had significantly worse OS (p=0.003) and worse RFS (p=0.043). High TS score also showed significant association with worse OS (p=0.011) and worse RFS (p=0.021). High S score was an independent prognostic factor predicting shorter OS (HR=6.352, 95%CI=1.206-40.050, p=0.029) and RFS (HR=18.843, 95%CI=1.030-344.799, p=0.048) in the multivariate analysis. CONCLUSION: High S score of TGFBI was a significant predictor of poor prognosis in OPSCC. TGFBI could be a useful new predictive and prognostic biomarker in OPSCC.


Assuntos
Carcinoma de Células Escamosas , Proteínas da Matriz Extracelular/genética , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Fator de Crescimento Transformador beta/genética , Carcinoma de Células Escamosas/genética , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço
11.
Tuberculosis (Edinb) ; 123: 101940, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32452425

RESUMO

Pleural fluid (PF) immune response in anergic tuberculous pleural effusion (TPE) patients is poorly understood. This study aimed to compare PF biochemical parameters and chemokine levels between anergic and non-anergic TPE patients. Chemokine arrays, cytokine measurements, and flow cytometry were performed in 58 patients (TPE [non-anergic (n = 32) and anergic (n = 10)] and malignant pleural effusion (MPE) [n = 16]). PF adenosine deaminase 2 (ADA2) levels were significantly lower in anergic TPE patients than in non-anergic TPE patients (p = 0.048). Among the 40 chemokines tested, PF CCL27 levels were significantly higher in anergic TPE patients than in non-anergic TPE and MPE patients (p < 0.001). The percentage of CD4+CCR10+T cells in PF was higher in anergic TPE patients than in non-anergic TPE and MPE patients (p = 0.001). We reported here that CCL27/CCR10 interactions might contribute to pathophysiology in anergic TPE. PF CCL27 and CD4+CCR10+T cells may help in diagnosing TPE in patients with moderate elevation of PF ADA levels.


Assuntos
Adenosina Desaminase/análise , Quimiocina CCL27/análise , Peptídeos e Proteínas de Sinalização Intercelular/análise , Derrame Pleural/imunologia , Tuberculose Pleural/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico , Derrame Pleural/microbiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Análise Serial de Proteínas , Receptores CCR10/análise , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/microbiologia
12.
Biomaterials ; 247: 119984, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278214

RESUMO

Blockade of programmed cell death ligand-1 (PD-L1) restores T-cell activity and enhances anti-tumor immunity. Screening a phage-displayed peptide library for peptides that selectively bind to PD-L1-overexpressing cells identified two peptides, CLQKTPKQC and CVRARTR (PD-L1Pep-1 and PD-L1Pep-2, respectively) that appeared to block PD-L1. PD-L1Pep-1 and PD-L1Pep-2 preferentially bound to high PD-L1-expressing cells over low PD-L1-expressing cells; binding was further enhanced by interferon-γ, an inducer of PD-L1 expression. Binding affinities of PD-L1Pep-1 and PD-L1Pep-2 were approximately 373 and 281 nM, respectively. Cellular binding of the PD-L1-binding peptides was reduced by silencing PD-L1 gene expression or competition with anti-PD-L1 antibody. PD-L1Pep-1 and PD-L1Pep-2 induced the internalization and downregulated cell surface levels of PD-L1. The PD-L1-binding peptides restored cytokine secretion and T-cell proliferation to cells inhibited by co-culture with tumor cells or culture on PD-L1-coated plates. Intravenously injected PD-L1Pep-1 and PD-L1Pep-2 efficiently homed to tumor tissues, inhibited tumor growth, and increased CD8+/FoxP3+ ratio in mice. The PD-L1-binding peptides in combination with doxorubicin or PD-L1-targeted liposomal doxorubicin inhibited tumor growth and increased CD8+/FoxP3+ ratio more efficiently than doxorubicin alone and untargeted liposomal doxorubicin, respectively. These results suggest that PD-L1Pep-1 and PD-L1Pep-2 block PD-L1 and reinvigorate T-cell activity, inhibiting tumor growth by enhancing anti-tumor immunity.


Assuntos
Antígeno B7-H1 , Bacteriófagos , Animais , Linhagem Celular Tumoral , Camundongos , Peptídeos , Linfócitos T
13.
Biomed Pharmacother ; 103: 135-139, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29649628

RESUMO

Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is a flavonoid compound from Artemisia species that possesses beneficial biological activities such as anti-cancer, anti-oxidation, and anti-inflammatory activities. However, an anti-adipogenic effect has not yet been reported. In this study, we found that eupatilin significantly inhibited the adipogenesis of 3T3-L1 adipocytes. Eupatilin decreased intracellular lipid accumulation and suppressed the expression level of key adipogenic regulators in 3T3-L1 adipocytes, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα), in a concentration-dependent manner. These results show that eupatilin significantly inhibits 3T3-L1 cell differentiation and suggest that it has potential as a novel anti-obesity therapy.


Assuntos
Adipogenia/efeitos dos fármacos , Flavonoides/farmacologia , PPAR gama/metabolismo , Células 3T3-L1 , Adipogenia/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Flavonoides/química , Regulação da Expressão Gênica/efeitos dos fármacos , Espaço Intracelular/metabolismo , Lipídeos/química , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
14.
J Clin Pathol ; 71(7): 579-583, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29593061

RESUMO

Clinical outcome prediction is major concern to patients with cancer. Various molecular markers in various carcinomas have been identified in the past few decades. However, accurate predictors in chondrosarcoma have not been developed, even though chondrosarcoma is the second most common primary bone tumour. Chondrosarcoma is the cartilage-forming malignancy and shows a wide spectrum of clinicopathological behaviours. The majority of chondrosarcoma grows slowly and rarely metastasises, and adequate surgery leads to a good prognosis. However, wide surgical excision is acquired in high-grade chondrosarcoma, because this tumour is highly resistant to chemotherapy and radiotherapy. To decide best therapy, accurate diagnostic markers are also necessary in chondrosarcoma. It is reported that angiogenesis and lymphangiogenesis increase by chondrosarcoma staging, and they are promoted by leptin and adiponectin. Several microRNAs to regulate vascular endothelial growth factor (VEGF)-A and VEGF-C are also reported. Alpha-methylacyl-CoA racemase and periostin are proposed as new biomarkers for differential diagnosis of enchondroma and chondrosarcoma. This review summarises that chondrosarcoma diagnostic markers are currently reported.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Ósseas/química , Condrossarcoma/química , Biomarcadores Tumorais/genética , Biópsia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Condrossarcoma/genética , Condrossarcoma/patologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes
15.
Biomaterials ; 159: 161-173, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29329051

RESUMO

Adoptive transfer of cytotoxic T lymphocytes (CTLs) has been used as an immunotherapy in melanoma. However, the tumor homing and therapeutic efficacy of transferred CTLs against melanoma remain unsatisfactory. Interleukin-4 receptor (IL-4R) is commonly up-regulated in tumors including melanoma. Here, we studied whether IL-4R-targeted CTLs exhibit enhanced tumor homing and therapeutic efficacy against melanoma. CTLs isolated from mice bearing melanomas were non-genetically engineered with IL4RPep-1, an IL-4R-binding peptide, using a membrane anchor composed of dioleylphosphatidylethanolamine. Compared to control CTLs, IL-4R-targeted CTLs showed higher binding to melanoma cells and in vivo tumor homing. They also exerted a more rapid and robust effector response, including increased cytokine secretion and cytotoxicity against melanoma cells and enhanced reprogramming of M2-type macrophages to M1-type macrophages. Moreover, IL-4R-targeted CTLs efficiently inhibited melanoma growth and reversed the immunosuppressive tumor microenvironment. These results suggest that non-genetically engineered CTLs targeting IL-4R have potential as an adoptive T cell therapy against melanoma.


Assuntos
Citocinas/metabolismo , Melanoma/metabolismo , Receptores de Interleucina-4/metabolismo , Linfócitos T Citotóxicos/metabolismo , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Imunoterapia/métodos , Interferon gama/metabolismo
16.
Nanomedicine ; 14(3): 633-642, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29309907

RESUMO

The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (µPn); CLT recognizes fibrin-fibronectin complexes in clots, µPn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-µPn) into nanocage structure protects the activated-µPn from its circulating inhibitors. Importantly, activated CLT-sFt-µPn thrombolytic nanocage showed a prolonged circulatory life over activated-µPn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-µPn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies.


Assuntos
Trombose Coronária/prevenção & controle , Ferritinas/química , Fibrinolisina/química , Fibrinolíticos/administração & dosagem , Nanopartículas/administração & dosagem , Fragmentos de Peptídeos/química , Terapia Trombolítica/métodos , Trombose Venosa/prevenção & controle , Animais , Trombose Coronária/patologia , Modelos Animais de Doenças , Fibrinolíticos/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , Ratos , Ratos Sprague-Dawley , Trombose Venosa/patologia
17.
J Immunol ; 200(4): 1480-1488, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29298830

RESUMO

Golgi phosphoprotein 2 (GOLPH2), a widely expressed Golgi type II transmembrane protein, has been implicated in several important physiological and pathological processes, including virus infections, cancer cell proliferation, and metastasis. However, its biological functions and mechanisms, particularly in the immune system, remain highly obscure. In this study, we report the biochemical identification of GOLPH2 from B cell lymphoma culture supernatant and show that the secreted protein could inhibit IL-12 production by dendritic cells (DCs) and IL-12-induced IFN-γ production by activated T cells. Further molecular analysis revealed that GOLPH2's IL-12-inhibiting activity was mediated through a proximal IL12p35 promoter element involving a previously identified transcriptional repressor named GC-binding protein that is induced during phagocytosis of apoptotic cells by macrophages. We subsequently generated global golph2 knockout mice, which exhibited little developmental abnormality but were more susceptible to LPS-induced endotoxic shock than were wild-type mice with elevated serum IL-12 levels. Furthermore, we found that GOLPH2 played a regulatory role in macrophage polarization toward the M2 type. A comprehensive analysis of gene expression profiles of activated wild-type and GOLPH2-deficient DCs by RNA sequencing uncovered mechanistic insights into the way GOLPH2 potentially modulates DC function during inflammatory insults. Our functional study of GOLPH2 helps advance the scientific understanding of the biological and pathogenic roles of this novel and intriguing molecule with great potential as a diagnostic and prognostic marker as well as a therapeutic target in many acute and chronic inflammatory disorders.


Assuntos
Células Dendríticas/imunologia , Proteínas da Matriz do Complexo de Golgi/imunologia , Interleucina-12/biossíntese , Ativação de Macrófagos/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Knockout
18.
Tuberc Respir Dis (Seoul) ; 80(1): 77-82, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28119750

RESUMO

BACKGROUND: Delayed hypersensitivity plays a large role in the pathogenesis of tuberculous pleural effusion (TPE). Macrophages infected with live Mycobacterium tuberculosis (MTB) increase the levels of adenosine deaminase2 (ADA2) in the pleural fluid of TPE patients. However, it is as yet unclear whether ADA2 can be produced by macrophages when challenged with MTB antigens alone. This study therefore evaluated the levels of ADA2 mRNA expression, using monocyte-derived macrophages (MDMs) stimulated with MTB antigens. METHODS: Purified monocytes from the peripheral blood mononuclear cells of healthy volunteers were differentiated into macrophages using granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). The MDMs were stimulated with early secretory antigenic target protein 6 (ESAT6) and culture filtrate protein 10 (CFP10). The mRNA expression levels for the cat eye syndrome chromosome region, candidate 1 (CECR1) gene encoding ADA2 were then measured. RESULTS: CECR1 mRNA expression levels were significantly higher in MDMs stimulated with ESAT6 and CFP10, than in the unstimulated MDMs. When stimulated with ESAT6, M-CSF-treated MDMs showed more pronounced CECR1 mRNA expression than GM-CSF-treated MDMs. Interferon-γ decreased the ESAT6- and CFP10-induced CECR1 mRNA expression in MDMs. CECR1 mRNA expression levels were positively correlated with mRNA expression of tumor necrosis factor α and interleukin 10, respectively. CONCLUSION: ADA2 mRNA expression increased when MDMs were stimulated with MTB antigens alone. This partly indicates that pleural fluid ADA levels could increase in patients with culture-negative TPE. Our results may be helpful in improving the understanding of TPE pathogenesis.

19.
Sci Rep ; 6: 38502, 2016 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-27917934

RESUMO

In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Crizotinibe , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Immunol ; 197(8): 3393-3405, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27619993

RESUMO

Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes, including cellular proliferation, neuron development, and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. In this study, we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production. Conversely, administration of rPGRN decreases the susceptibility of PGRN-deficient mice to LPS-induced endotoxemic shock and augments IL-10 production by LPS-activated macrophages in a TNFR-dependent manner. Molecular analysis reveals a direct role of the transcription factor C/EBPα in PGRN-regulated IL-10 expression. C/EBPα-deficient macrophages produce less IL-10 in response to LPS. Furthermore, mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. Lastly, the defective IL-10 production by PGRN-deficient cells is primarily due to reduced C/EBPα protein stability via the E3 ubiquitin-conjugating enzyme E6AP and proteasome-mediated degradation. To our knowledge, this study provides the first evidence that PGRN is a nonredundant regulator of systemic inflammation via modulating the levels and activity of C/EBPα, IL-10, and the ubiquitin-proteasome proteolysis pathway. The results bear strong and profound implications for PGRN insufficiency and its mutation-associated systemic and organ-specific inflammatory human diseases.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-10/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Sepse/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Granulinas , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Progranulinas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...