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1.
Ann Palliat Med ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33548998

RESUMO

BACKGROUND: To quantitatively evaluate lung damage after treatment of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and stereotactic body radiotherapy (SBRT) in patients with nonsmall cell lung cancer (NSCLC), and compare that of SBRT only treatment. METHODS: Eligible patients from an IRB-approved prospective clinical trial had one month of EGFRTKIs treatment followed by SBRT (TKI + SBRT) and with 3-month follow-up high resolution CT. NSCLC patients treated with SBRT alone during the same time period without EGFR-TKIs or other systemic therapies were identified as controls. The lung damage was assessed clinically by pneumonitis and quantitatively using by CT intensity (Hounsfield unit, HU) changes. The mean HU values were extracted for regions of the lungs receiving the same dose range at 10 Gy intervals to generate dose-response curves (DRC). The relationship of HU changes and radiation dose was modeled using a Probit model. RESULTS: Four out of 20 (25%) TKI + SBRT patients and none of 19 (0%) SBRT alone patients had developed grade 2 and above pneumonitis (P=0.053), respectively. Sixty percent of TKI + SBRT patients and 30% SBRT alone patients had HU changes of the normal lung density >200 HU, respectively. There were significant differences in the DRC and in lung HU changes between the two groups (all P<0.05). The physical dose for a 50% complication risk (TD50) of CT lung damage was 52 Gy (CI: 46-59) in TKI + SBRT group versus 72 Gy (CI: 58-107) in SBRT alone group (P<0.01). CONCLUSIONS: Compared to patients treated with SBRT alone, patients treated with EGFR-TKIs followed by SBRT were more incline to develop radiation pneumonitis, and resulted in greater lung CT intensity changes and steeper dose-CT lung damage response relationship at 3 months post treatment. Future study with larger number of patients and longer follow-up period is warranted to validate this finding.

2.
PLoS One ; 16(1): e0244978, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33406133

RESUMO

The location-based services can provide users with the requested location information. But users also need to disclose their current location to the location-based service provider. Therefore, how to protect user's location privacy is a major concern. In this paper, we propose a heterogeneous deniable authenticated encryption scheme called HDAE for location-based services. The proposed scheme permits a sender in a public key infrastructure environment to transmit a message to a receiver in an identity-based environment. Our design utilizes a hybrid encryption method combing the tag-key encapsulation mechanism (tag-KEM) and the data encapsulation mechanism (DEM), which is well adopted for location-based services applications. We give how to design an HDAE scheme utilizing a heterogeneous deniable authenticated tag-KEM (HDATK) and a DEM. We also construct an HDATK scheme and provide security proof in the random oracle model. Comprehensive analysis shows that our scheme is efficient and secure. In addition, we give an application of the HDAE to a location-based services system.

3.
Ther Adv Hematol ; 11: 2040620720927105, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32782768

RESUMO

Atypical chronic myeloid leukemia (aCML) BCR-ABL1 negative is a rare myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) for which no standard treatment currently exists. The advent of next-generation sequencing has allowed our understanding of the molecular pathogenesis of aCML to be expanded and has made it possible for clinicians to more accurately differentiate aCML from similar MDS/MPN overlap syndrome and MPN counterparts, as MPN-associated driver mutations in JAK2, CALR, or MPL are typically absent in aCML. A 55-year old male with main complaints of weight loss and fatigue for more than half a year and night sweats for more than 2 months was admitted to our hospital. Further examination revealed increased white blood cells, splenomegaly, and grade 1 bone marrow fibrosis with JAK2 V617F, which supported a preliminary diagnosis of pre-primary marrow fibrosis. However, in addition to JAK2 V617F (51.00%), next-generation sequencing also detected SETBP1 D868N (46.00%), ASXL1 G645fs (36.09%), and SRSF2 P95_R102del (33.56%) mutations. According to the 2016 World Health Organization diagnostic criteria, the patient was ultimately diagnosed with rare aCML with concomitant JAK2 V617F and SETBP1 mutations. The patient received targeted therapy of ruxolitinib for 5 months and subsequently an additional four courses of combined hypomethylating therapy. The patient exhibited an optimal response, with decreased spleen volume by approximately 35% after therapy and improved symptom scores after therapy. In diagnosing primary bone marrow fibrosis, attention should be paid to the identification of MDS/MPN. In addition to basic cell morphology, mutational analysis using next-generation sequencing plays an increasingly important role in the differential diagnosis. aCML with concomitant JAK2 V617F and SETBP1 mutations has been rarely reported, and targeted therapy for mutated JAK2 may benefit patients, especially those not suitable recipients of hematopoietic stem cell transplants.

4.
Eur J Pharm Biopharm ; 154: 136-143, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32681961

RESUMO

The co-delivery of nanoparticles encapsulating gene therapies and chemotherapeutic drugs can achieve synergistic treatment and reduce side effects in normal tissues relative to the systemic use of single drug delivery. Activated macrophages play a fundamental role in the pathogenesis of rheumatoid arthritis (RA). Hyaluronic acid (HA), a natural polysaccharide, is a specific ligand for CD44 that is overexpressed on the surface of activated macrophages. In this study, HA-coated pH-responsive nanoparticles loaded with MCL-1 small interfering RNA (siRNA) and dexamethasone (HNPs/MD) were developed for RA treatment. The HNPs/MD had a mean particle size of 117.07 ± 2.21 nm and zeta potential of 15.53 ± 1.06 mV. The release rates of both MCL-1 siRNA and dexamethasone from the HNPs/MD at pH 4.5 and 6.0 were higher than those at pH 7.4, indicating that the nanoparticles were acid-sensitive. Cytotoxicity assays showed that compared with single drug loaded nanoparticles, the HNPs/MD showed higher cytotoxicity to activated macrophages. The superior therapeutic effect of HNPs/MD was demonstrated in an adjuvant-induced arthritis rat model. These findings indicate that pH-sensitive and HA-targeting co-delivery nanoparticles provide a new direction for the therapy of RA.

5.
J Thorac Dis ; 11(6): 2438-2447, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31372281

RESUMO

Background: Exacerbations are recognized as the most relevant predictor of future risk in asthmatics. We aimed to evaluate the association between asthma exacerbations, fractional exhaled nitric oxide (FENO), spirometry indices, and other potential risk factors in a non-interventional, real-world study performed in Guangzhou, China. Methods: We performed a prospective 12 months follow-up of Chinese asthmatics. Spirometry and FENO measurements were performed at baseline. Adherence to inhaled corticosteroids (ICS) use was divided into two categories (>80% and <80%). Patients were seen 4 times after the initial baseline visit. Results: A total of 222 patients with asthma (49.1% males) completed the study, of which 51 (23.0%) experienced exacerbations during the study period. Of the patients, 117 (52.7%) had good compliance. We compared lung function indices between the patients with and without exacerbations. There was no difference of forced expiratory volume in 1 s (FEV1) predicted, forced vital capacity (FVC) predicted, and FEVI/FVC (all, P>0.05) between the groups. There was also no significant difference in FENO level between the two groups. Compared to those that had exacerbations, patients without exacerbations had better treatment compliance (P<0.001). Logistic regression analysis identified an association between asthma exacerbations, poor control of symptom [odds ratio (OR) =2.295; 95% confidence interval (CI): 1.130-4.663; P=0.022], and nonadherence to asthma medications (OR =4.718; 95% CI: 2.149-10.359; P<0.001). Conclusions: Poor adherence rather than baseline FENO and FEV1% predicted was associated with the future risk of exacerbations in Chinese asthmatics in real world.

6.
Int J Pharm ; 563: 228-236, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30959236

RESUMO

Bevacizumab, a vascular endothelial growth factor (VEGF)-targeting drug, is widely used as an off-label therapeutic for age-related macular degeneration (AMD). To reduce the monthly administration frequency, this study investigated microspheres comprising a poly(d, l-lactide-co-glycolide)/poly(cyclohexane-1,4-diyl acetone dimethylene ketal) (PLGA/PCADK) blend that could be loaded with bevacizumab-dextran particles using solid-in-oil-in-water (S/O/W) emulsification. Control microspheres were also prepared through water-in-oil-in-water (W/O/W) emulsification. The structural stability of bevacizumab in the polymer monomers was analyzed using dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size exclusion chromatography (SEC-HPLC), circular dichroism (CD) and fluorescence spectroscopy. Subsequently, microspheres were prepared and evaluated in terms of their morphology, encapsulation efficiency and release behavior. PLGA/PCADK microspheres prepared by the S/O/W method with <20% PCADK showed a smooth spherical structure with a uniform distribution of bevacizumab. The microspheres exhibited a release behavior comprising a slight initial burst and an increasing total release over 50 days both in vitro and in vivo. Additionally, the microspheres were well tolerated by ocular tissue. Finally, a chorioallantoic membrane (CAM) assay revealed that the bioactivity of bevacizumab was retained by PCADK. In conclusion, these results suggest the potential for bevacizumab-loaded PLGA/PCADK microspheres prepared by the S/O/W method as a means of intravitreal therapy for ocular diseases.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Polímeros/administração & dosagem , Inibidores da Angiogênese/química , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/química , Bevacizumab/química , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Dextranos/administração & dosagem , Dextranos/química , Liberação Controlada de Fármacos , Oftalmopatias/tratamento farmacológico , Injeções Intravítreas , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Coelhos
7.
Dig Dis Sci ; 64(10): 2911-2922, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31032524

RESUMO

BACKGROUND: The elderly assess higher incidence of gastric diseases and may meet challenges and contraindications when flexible esophagogastroduodenoscopy intubating. Magnetic-controlled capsule endoscopy (MCE) is declared as a promising alternative, but its applications in elderly population do not attach enough importance. AIMS: To explore MCE's efficiency and safety in the elderly. METHODS: A single-center retrospective study has been conducted. Data from the elderly group (>65 year-old) who underwent MCE examination, including indications, MCE outcomes, gastric conditions, evaluations from MCE manipulators and endoscopists, subjective discomforts, adverse events, etc., had been collected, then analyzed, and compared with the ones from the middle-aged group (>40, ≤ 65 year-old). RESULTS: During April 2015 and September 2018, 98 elderly patients and 72 middle-aged patients underwent MCE examination. In the elderly, the indications included poor physical condition (28.6%), severe angiocardiopathy (39.8%), EGD rejection (13.3%), severe respiratory disorder (8.2%), craniocerebral injury (8.2%), and allergy to anesthetics (2.0%). Rate of complete gastric observation and positive finding were 98.0% and 72.4% (vs. middle-aged group, 94.4%, 56.9%, P = 0.220, 0.035), and gastric conditions showed relatively inferior. Gastric preparation and MCE procedure were generally tolerated, but three elderly patients (3.1%) experienced capsule blockage in stomach. CONCLUSIONS: Our preliminary data support that MCE offers considerable benefit and is general safe for the elderly. We hope such data promote greater awareness of innovative attempts for the specific elderly, and expect multi-center, large-scale trials with randomized controlled design bring optimized strategies for better gastric visibility, efficacy and lower potential risk.


Assuntos
Endoscopia por Cápsula , Imãs , Gastropatias/diagnóstico , Estômago/diagnóstico por imagem , Fatores Etários , Idoso , Endoscopia por Cápsula/efeitos adversos , Endoscopia por Cápsula/instrumentação , Endoscopia por Cápsula/métodos , China/epidemiologia , Feminino , Avaliação Geriátrica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Estudos Retrospectivos , Gastropatias/epidemiologia , Resultado do Tratamento
8.
Molecules ; 24(1)2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30609724

RESUMO

Activated macrophages play a vital role in rheumatoid arthritis (RA) pathophysiology. CD44 is an overexpressed receptor on activated macrophages that is a potential target site for RA treatment. In this study, we prepared hyaluronic acid (HA) coated acid-sensitive polymeric nanoparticles (HAPNPs) composed of egg phosphatidylcholine, polyethylenimine, and poly (cyclohexane-1,4-diyl acetone dimethylene ketal) (PCADK) loaded with dexamethasone (Dex) for the treatment of RA. PCADK was used to form polymeric cores because of its acid-sensitivity. The HAPNPs were about 150 nm in size and had a zeta potential of -2.84 mV. The release rate of Dex from HAPNPs/Dex in vitro increased markedly when the pH decreased from 7.4 to 4.5, indicating that the HAPNPs were pH-sensitive. In a cellular uptake study, stronger fluorescence signals were observed in activated macrophages treated with HAPNPs, suggesting that HAPNPs could be effective nanodevices target to activated macrophages. In rats with adjuvant-induced arthritis, HAPNPs could inhibited the progression of RA. Taken together, these results suggest that the HAPNPs could be useful in RA therapy.


Assuntos
Artrite Experimental/tratamento farmacológico , Dexametasona/administração & dosagem , Portadores de Fármacos/química , Ácido Hialurônico/química , Terapia de Alvo Molecular , Nanopartículas/química , Animais , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Receptores de Hialuronatos/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Tamanho da Partícula , Fosfatidilcolinas/química , Polietilenoimina/química , Polímeros/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície
9.
Mol Med Rep ; 19(3): 1595-1602, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30592277

RESUMO

The present study aimed to investigate the effects of butyl stearate on t­butoxyl paliperidone derivative (isoperidone)­loaded poly(lactide­co­glycolide) (PLGA) microspheres. The mechanism of drug release rate delay by butyl stearate was examined by accelerated testing, morphological observation, thermal and fluorescence analyses. In vivo pharmacokinetic study was conducted on female beagle dogs. Spherical microspheres with smooth surfaces, small internal pores and shell structures were initially prepared. It was found that 3% (w/w) butyl stearate prolonged the in vitro drug release period from 46 to 82 days, and in vivo release period from 20 to 27 days. Furthermore, the results demonstrated that the green fluorescence imaging of isoperidone approaching the cores of microspheres with 3% butyl stearate was brighter than in microspheres without additives. In conclusion, it was shown that butyl stearate affected the microsphere structure, isoperidone microsphere distribution and isoperidone crystallinity. The results of the present study thus provide a potential method to develop sustained­release preparations.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Microesferas , Palmitato de Paliperidona/análogos & derivados , Esquizofrenia/tratamento farmacológico , Animais , Preparações de Ação Retardada/química , Cães , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Ácido Láctico/administração & dosagem , Ácido Láctico/química , Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Esquizofrenia/patologia , Estearatos/administração & dosagem , Estearatos/química
10.
PLoS One ; 13(12): e0208311, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30562351

RESUMO

A smart grid, considered the next-generation type of power grid, combines a traditional power grid with information and communication technologies to effectively facilitate power generation and ensure transmission security and reliability in real-time. Only authorized consumers should be able to access the smart grid because the information gathered by smart meters includes users' private information. However, smart grid security is still a challenge. Motivated by this challenge, in this paper, we propose a heterogeneous signcryption (HSC) scheme for secure communication between smart meters and the utility. We demonstrate that this scheme is indistinguishable against adaptive chosen-ciphertext attacks (IND-CCA2), existentially unforgeable against adaptive chosen-message attacks (EUF-CMA) and ciphertext-anonymous against adaptive chosen ciphertext attacks (ANON-CCA2) under the computational Diffie-Hellman (CDH) problem in the random oracle model. Our scheme simultaneously achieves confidentiality, integrity, authentication, non-repudiation and ciphertext anonymity in a single logical step. It supports heterogeneous systems, allowing a meter in an identity-based cryptography (IBC) environment to transmit electrical usage data to a utility in a public key infrastructure (PKI) environment. Compared with other existing related schemes, our scheme has the lowest communication overhead and energy consumption for the smart grid. Based on these features, our scheme is highly suitable for secure power transmissions in a smart grid.


Assuntos
Algoritmos , Redes de Comunicação de Computadores , Segurança Computacional
11.
Int J Pharm ; 552(1-2): 148-153, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30268854

RESUMO

Ketoprofen, a non-steroid anti-inflammatory drug, is widely used for relieving the pain and swelling caused by rheumatoid arthritis. However, ketoprofen can't suppress disease progression effectively. In this study, in an effort to improve the therapeutic effect for rheumatoid arthritis (RA), microRNA-124 (miR-124), a promising new therapeutic agent for RA, was co-loaded with ketoprofen into poly (lactic-co-glycolic acid) (PLGA) microspheres and administrated to adjuvant-induced arthritis rats. PLGA microspheres loaded with ketoprofen and miR-124 were prepared by a modified multiple emulsion-solvent evaporation method. In vivo pharmacodynamics experimental results indicated ketoprofen in co-loaded microspheres could significantly reduce inflammation of the joints and miR-124 in the microspheres could reduce bone damage. In addition, ketoprofen and miR-124 co-loaded PLGA microspheres had a remarkable advanced activity over delivery of either miR-124 or ketoprofen in suppressing adjuvant-induced arthritis (AA) in rats. Results of western blot and immunohistochemistry revealed that miR-124 could reduce the level of receptor activator of nuclear factor kappa-B ligand (RANKL). These results suggested co-delivery of ketoprofen and miR-124 could achieve synergistic effects on preventing inflammation and bone damage caused by AA. Ketoprofen and miR-124 co-loaded PLGA microspheres could be a promising combined therapeutic strategy against RA.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Cetoprofeno/administração & dosagem , MicroRNAs/administração & dosagem , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/metabolismo , Articulação do Tornozelo/patologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Masculino , Ligante RANK/metabolismo , Ratos Sprague-Dawley
12.
Sensors (Basel) ; 18(9)2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30200308

RESUMO

The vegetation supply water index (VSWI = NDVI/LST) is an effective metric estimating soil moisture in areas with moderate to dense vegetation cover. However, the normalized difference vegetation index (NDVI) exhibits a long water stress lag and the land surface temperature (LST), sensitive to water stress, does not contribute considerably to surface soil moisture monitoring due to the constraints of the mathematical characteristics of VSWI: LST influences VSWI less when LST value is sufficiently high. This paper mathematically analyzes the characteristics of VSWI and proposes a new operational dryness index (surface water content temperature index, SWCTI) for the assessment of surface soil moisture status. SWCTI uses the surface water content index (SWCI), which provides a more accurate estimation of surface soil moisture than that of NDVI, as the numerator and the modified surface temperature, which has a greater influence on SWCTI than that of LST, as the denominator. The validation work includes comparison of SWCTI with in situ soil moisture and other remote sensing indices. The results show SWCTI demonstrates the highest correlation with in situ soil moisture; the highest correlation R = 0.801 is found between SWCTI and the 0⁻5 cm soil moisture in a sandy loam. SWCTI is a functional and effective method that has a great potential in surface soil moisture monitoring.

13.
Toxicol Lett ; 299: 149-158, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30261222

RESUMO

We previously demonstrated receptor for advanced glycation end products (RAGE) was required for ß-catenin stabilization in a toluene diisocyanate (TDI)-induced asthma model, suggesting it plays an important role in TDI-induced airway inflammation. The aim of this study was to examine whether RAGE mediates ß-catenin stabilization via activation of the Src/p-Cav-1 axis in TDI-induced asthma model. To generate a chemical-induced asthma model, male BALB/c mice were sensitized and challenged with TDI. Before each challenge, FPS-ZM1 (RAGE inhibitor) and PP2 (Src inhibitor) was given via intraperitoneal injection. In the TDI-exposed mice, airway reactivity, airway inflammation, goblet cell metaplasia, and the release of Th2 cytokines and IgE increased significantly. The level of membrane ß-catenin decreased but was increased in the cytoplasm. Increased expression of RAGE, p-Src, and p-Cav-1 was also detected in TDI-exposed lungs. However, all these changes were inhibited by FPS-ZM1 and PP2. In TDI-HSA stimulated human airway epithelial (16HBE) cells, the expression of p-Src and p-Cav-1, and the abnormal distribution of ß-catenin were significantly increased, and then inhibited in RAGE knockdown cells. Similarly, PP2 or non-phosphorylatable Cav-1 mutant (Y14F-Cav-1) treated 16HBE cells had the same effect on the distribution of ß-catenin. In addition, blockage of RAGE signaling and phosphorylation of Cav-1 eliminated the translocation of ß-catenin from cytomembrane to cytoplasm. Our results showed that RAGE modulates ß-catenin aberrant distribution via activation of Src/p-Cav-1 in a chemical-induced asthma model.


Assuntos
Asma/metabolismo , Caveolina 1/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , beta Catenina/metabolismo , Quinases da Família src/metabolismo , Animais , Asma/induzido quimicamente , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos BALB C , Estabilidade Proteica , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Transdução de Sinais , Tolueno 2,4-Di-Isocianato
14.
Biomed Res Int ; 2018: 3424956, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30112378

RESUMO

Radiotherapy is an important strategy for rectal cancer patient treatment. However, the efficiency of radiation is usually poor, especially in patients with advanced stage rectal cancer due to the radio-resistance developed. At the present study, OCT4 was found to play a critical role in radio-resistance development in human rectal cancer cells by improving the epithelial-mesenchymal transition process (EMT). Endogenous OCT4 expression could confer resistant phonotype on human rectal cancer cells, which was supported by the data from clonogenic forming assay and cell cycle arrest recovering experiment. EMT related transcription factor ZEB1 might take part in the radio-resistance induced by OCT4, as its expression could be upregulated by OCT4 and its silence could reverse the OCT4 induced resistance to radiation in SW480 cells. More interestingly, CHK1 was also upregulated in OCT4/ZEB1 dependent manner conferring stronger DNA damage repair activity on cancer cells, which might explain the underlying mechanisms why OCT4/ZEB1 axis could promote the resistance of human rectal cancer cell to radiation. Taken together, our results provided a novel mechanism for radio-resistance development in human rectal cancer cells and a new target to overcome this resistance.


Assuntos
Transição Epitelial-Mesenquimal , Fator 3 de Transcrição de Octâmero/fisiologia , Tolerância a Radiação/genética , Neoplasias Retais/patologia , Linhagem Celular Tumoral , Movimento Celular , Dano ao DNA , Proteínas de Homeodomínio , Humanos , Neoplasias Retais/genética , Neoplasias Retais/radioterapia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
15.
Eur J Pharm Biopharm ; 130: 39-47, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29928978

RESUMO

Methotrexate (MTX), as a disease modifying antirheumatic drug (DMARD), was first line drug to treat rheumatoid arthritis. However, the severe side effect during long term and high dosage usage limit its application. The aim of this study was to develop dual-functional lipid polymeric hybrid pH-responsive nanoparticles to deliver MTX to inflamed joints selectively. The designed MTX loaded stearic acid-octa-arginine and folic acid decorated poly lactic-co-glycolic acid (PLGA) -PK3-based lipid polymeric hybrid nanoparticles (Sta-R8-FA-PPLPNs/MTX) were composed of PK3, Folate-PEG-PLGA, egg PC, and Sta-R8. The nanoparticles exhibited smooth spherical morphology and particle size of 100-150 nm. The in vitro release study indicated that MTX was released faster in phosphate buffered solution (PBS) of pH 5.0 than that in PBS of pH 7.4 from Sta-R8-FA-PPLPNs/MTX. The cellular uptake study revealed that Sta-R8-FA-PPLPNs/MTX were internalized through folate receptor mediated endocytosis into activated macrophages. Therapeutic effects on adjuvant-induced arthritis (AIA) rats further confirm that Sta-R8-FA-PPLPNs/MTX could be promising against rheumatoid arthritis.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Nanopartículas , Animais , Antirreumáticos/farmacocinética , Arginina/química , Artrite Experimental/tratamento farmacológico , Peptídeos Penetradores de Células/química , Portadores de Fármacos/química , Ácido Fólico/química , Concentração de Íons de Hidrogênio , Ácido Láctico/química , Lipídeos/química , Masculino , Metotrexato/farmacologia , Camundongos , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polímeros/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Ácidos Esteáricos/química
16.
Int Immunopharmacol ; 59: 187-196, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29656209

RESUMO

BACKGROUND: We have previously demonstrated that the receptor for advanced glycation end products (RAGE)/ß-catenin axis plays a vital role in regulating airway inflammation and airway remodeling in a toluene diisocyanate (TDI)-induced murine asthma model. However, the exact mechanism of ß-catenin activation remains unclear. Given that phosphorylation of the low-density lipoprotein receptor-related protein 6 (Lrp6) is a key step in mediating ß-catenin stabilization in canonical wnt/ß-catenin signaling, we explored the possible relationship between RAGE and Lrp6 in regulating ß-catenin stabilization in TDI-induced asthma. METHODS: In this study, a TDI-induced murine asthma model was generated, and mice were treated with a specific inhibitor of RAGE. In vitro, the human bronchial epithelial cell line 16HBE was treated with TDI-human serum albumin (TDI-HSA). RAGE overexpression or knockdown cells were also constructed and assessed. RESULTS: The results showed that RAGE inhibition or RAGE knockdown decreased ß-catenin nuclear accumulation and the expression of relevant ß-catenin targeted genes (VEGF, MMP9, TGF-ß1) in the TDI-induced murine asthma model and TDI-HSA-treated 16HBE cells, respectively. Silencing of RAGE reversed the TDI-induced increase in phospho-ERK1/2 (p-ERK) and phospho-Lrp6 (p-Lrp6) in 16HBE cells. Pretreatment with the extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 suppressed TDI-induced Lrp6 phosphorylation. Furthermore, knockdown of Lrp6 in 16HBE cells decreased ß-catenin nuclear translocation and the expression of VEGF, MMP9, and TGF-ß1. CONCLUSION: These data suggested that the RAGE/ERK axis modulates Lrp6 phosphorylation, contributing to ß-catenin stabilization in a TDI-induced murine model.


Assuntos
Asma/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , beta Catenina/metabolismo , Animais , Asma/induzido quimicamente , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Fosforilação , Tolueno 2,4-Di-Isocianato
17.
Sci Rep ; 7(1): 14369, 2017 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-29084974

RESUMO

MicroRNA-21 (mir-21) induced by angiotensin II (AngII) plays a vital role in the development of pulmonary fibrosis, and the NLRP3 inflammasome is known to be involved in fibrogenesis. However, whether there is a link between mir-21 and the NLRP3 inflammasome in pulmonary fibrosis is unknown. Angiotensin-converting enzyme 2/angiotensin(1-7) [ACE2/Ang(1-7)] has been shown to attenuate AngII-induced pulmonary fibrosis, but it is not clear whether ACE2/Ang(1-7) protects against pulmonary fibrosis by inhibiting AngII-induced mir-21 expression. This study's aim was to investigate whether mir-21 activates the NLRP3 inflammasome and mediates the different effects of AngII and ACE2/Ang(1-7) on lung fibroblast apoptosis and collagen synthesis. In vivo, AngII exacerbated bleomycin (BLM)-induced lung fibrosis in rats, and elevated mir-21 and the NLRP3 inflammasome. In contrast, ACE2/Ang(1-7) attenuated BLM-induced lung fibrosis, and decreased mir-21 and the NLRP3 inflammasome. In vitro, AngII activated the NLRP3 inflammasome by up-regulating mir-21, and ACE2/Ang(1-7) inhibited NLRP3 inflammasome activation by down-regulating AngII-induced mir-21. Over-expression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry1, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts. These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang(1-7) on AngII-induced activation of the NLRP3 inflammasome by targeting Spry1 in lung fibroblasts.


Assuntos
Angiotensina I/farmacologia , Fibroblastos/metabolismo , MicroRNAs/fisiologia , Fragmentos de Peptídeos/farmacologia , Angiotensina I/genética , Angiotensina II/metabolismo , Animais , Apoptose/efeitos dos fármacos , Bleomicina/efeitos adversos , Células Cultivadas , Colágeno Tipo I/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Inflamassomos/genética , Inflamassomos/metabolismo , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Fragmentos de Peptídeos/genética , Hormônios Peptídicos/metabolismo , Fibrose Pulmonar/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
18.
Oncotarget ; 8(48): 83831-83844, 2017 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-29137386

RESUMO

Background: A shift from oxygen phosphorylation to aerobic glycolysis was known as the Warburg effect and a characteristic of cancer cell metabolism facilitating metastasis. Mitochondrial calcium uniporter (MCU), a key ion channel that mediates Ca2+ uptake into mitochondria, was found to promote cancer progression and metastasis. However, its explicit role in shifting metabolism of breast cancer cells has not been defined. Methods: We evaluated MCU overexpression or knock-down on migration, invasion and glucose metabolismin breast cancer cells. Mitochondrial Ca2+ dynamics were monitored with Rhod-2 fluorescence imaging. Luciferase reporter assay was used to confirm the interaction between miR-340 and 3'-untranslated region (3'-UTR) of MCU gene. Mouse models of lung metastasis were used to determine whether gain-/loss-of-MCU impacts metastasis. MCU expression was assessed in 60 tumor samples from breast cancer patients by immunohistochemistry (IHC). Results: Knockdown of MCU in MDA-MB-231 cells significantly reduced cell migration and invasion in vitro and lung metastasis in vivo; whereas overexpression of MCU in MCF-7 cells significantly increased migration and invasion in vitro and lung metastasis in vivo. Overexpression of MCU promoted lung metastasis by enhancing glycolysis, whereas suppression of MCU abolished this effect. Moreover, a novel mechanism was identified that MCU was a direct target of microRNA-340, which suppressed breast cancer cell motility by inhibiting glycolysis. Consistently, significantly increased MCU protein was found in metastatic breast cancer patients. Conclusions: We identified a novel mechanism that upregulated MCU promotes breast cancer metastasis via enhancing glycolysis, and that this process is posttranscriptionally and negatively regulated by microRNA-340.

19.
Nan Fang Yi Ke Da Xue Xue Bao ; 37(10): 1301-1307, 2017 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-29070458

RESUMO

OBJECTIVE: To explore the role of the receptor for advanced glycation end products (RAGE) in regulating the expression of MUC5AC and mucus production in a mouse model of toluene diisocyanate (TDI)?induced asthma. METHODS: BALB/c mice were randomly divided into control group, vehicle (AOO) group, TDI?induced asthma group and RAGE inhibitor (FPS?ZM1) group. PAS staining, Western blotting, and immunohistochemistry were used to analyze the changes in mucus production and MUC5AC expression in the airway of the mice, and the expression of p?ERK was detected with Western blotting. In vitro cultured human bronchial epithelial cell line 16HBE was transfected with lentiviral vector carrying short hairpin RNA targeting RAGE (shRNA?RAGE) and subsequently challenged with a TDI?human serum albumin (TDI-HSA) conjugate, and the changes in cellular MUC5AC mRNA expression as detected using RT-PCR; the protein expressions of ERK and p?ERK in the cells were examined with Western blotting. The effect of ERK inhibitor U0126 pretreatment on MUC5AC mRNA expression was also analyzed in the cells. RESULTS: Compared with the control mice, TDI-induced asthmatic mice showed significantly higher rates of PAS positivity and increased MUC5AC and p?ERK expressions in the airway (P<0.05). Treatment with FPS?ZM1 significantly decreased PAS positivity and lowered MUC5AC and p?ERK expressions in the airway of the asthmatic mice (P<0.05). Exposure of 16HBE cells to TDI?HSA caused a significant increase in MUC5AC mRNA expression and p?ERK protein expression (P<0.05), while RAGE knockdown obviously suppressed TDI?HSA-induced upregulation of p-ERK and MUC5AC mRNA (P<0.05). Treatment with the ERK inhibitor U0126 also lowered TDI?HSA?induced up?regulation of MUC5AC mRNA in the cells (P<0.05). CONCLUSION: RAGE signaling induces MUC5AC expression via extracellular signal-regulated kinase pathway to promote mucus overproduction in mice with TDI-induced asthma.


Assuntos
Asma/metabolismo , Mucina-5AC/metabolismo , Muco/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Asma/induzido quimicamente , Benzamidas/farmacologia , Butadienos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Nitrilos/farmacologia , Distribuição Aleatória , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Tolueno 2,4-Di-Isocianato
20.
Int J Nanomedicine ; 12: 6735-6746, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28932117

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive cartilage and bone destruction. Activated macrophages that overexpress folic acid (FA) receptors play an important role in RA, due to their abundance in inflamed synovial membrane and joints. In an effort to deliver drugs to the inflamed tissues, multifunctional FA receptor-targeting and pH-responsive nanocarriers were developed. They were composed of lipids, polyethylene glycol (PEG)-poly(lactic-co-glycolic acid) (PLGA) forming a hydrophilic shell, FA around the hydrophilic shell as a targeting ligand, and poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) and PLGA as a hydrophobic core. PCADK also acts as a pH-responsive material. Methotrexate (Mtx) was encapsulated in the nanoparticles, which exhibited pH-responsive release in vitro. Cellular uptake and cytotoxicity experiments revealed that FA-PEG-PLGA/PCADK-lipid nanoparticles loaded with Mtx (FA-PPLNPs) exhibited superior cellular uptake and higher cytotoxicity to activated macrophages than PPLNPs/Mtx. The therapeutic effect of FA-PPLNPs/Mtx in RA was confirmed in an adjuvant-induced arthritis rat model. These results suggest that the multifunctional folate receptor-targeting and pH-responsive nanocarriers are promising for the treatment of RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Metotrexato/administração & dosagem , Nanopartículas/administração & dosagem , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/química , Artrite Experimental/tratamento farmacológico , Modelos Animais de Doenças , Portadores de Fármacos/química , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Masculino , Metotrexato/química , Terapia de Alvo Molecular/métodos , Nanopartículas/química , Poliésteres , Polietilenoglicóis , Polímeros/química , Ratos Sprague-Dawley
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