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1.
Transl Neurodegener ; 8: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428316

RESUMO

Background: Parkinson's disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies (LB). During the course of disease, misfolded α-synuclein, the major constituent of LB, spreads to different regions of the brain in a prion-like fashion, giving rise to successive non-motor and motor symptoms. Etiology is likely multifactorial, and involves interplay among aging, genetic susceptibility and environmental factors. Main body: The prevalence of PD rises exponentially with age, and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death. However, the majority of those over the age of 80 do not have PD, thus other factors in addition to aging are needed to cause disease. Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk. Nevertheless, the causality of most environmental factors is not conclusively established, and alternative explanations such as reverse causality and recall bias cannot be excluded. The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD. Rare mutations as well as common variants in genes such as SNCA, LRRK2 and GBA are associated with risk of PD, but Mendelian causes collectively only account for 5% of PD and common polymorphisms are associated with small increase in PD risk. Heritability of PD has been estimated to be around 30%. Thus, aging, genetics and environmental factors each alone is rarely sufficient to cause PD for most patients. Conclusion: PD is a multifactorial disorder involving interplay of aging, genetics and environmental factors. This has implications on the development of appropriate animal models of PD which take all these factors into account. Common converging pathways likely include mitochondrial dysfunction, impaired autophagy, oxidative stress and neuroinflammation, which are associated with the accumulation and spread of misfolded α-synuclein and neurodegeneration. Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

2.
Gastroenterol Rep (Oxf) ; 7(3): 193-198, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31217983

RESUMO

Background: In addition to the stepwise manner of lymph-node metastasis from the primary tumour, the skip lymph-node metastasis (SLNM) was identified as a low-incidence metastasis of gastric cancer (GC). So far, both the mechanism and outcome of SLNM have not been elucidated completely. The purpose of this study was to analyse the clinical significance and the potential mechanism of SLNM in GC patients who had lymph-node metastasis. Methods: Clinicopathological data and follow-up information of 505 GC patients who had lymph-node metastasis were analysed to demonstrate the significance of SLNM in evaluating the prognostic outcome. According to the pathological results, all GC patients who had lymph-node metastasis were categorized into three groups: patients with the perigastric lymph-node metastasis, patients with the perigastric and extragastric lymph-node metastasis and patients with SLNM.Results: Among the 505 GC patients who had lymph-node metastasis, 24 (4.8%) had pathologically identified SLNM. The location of lymph-node metastasis was not significantly associated with 5-year survival rate and overall survival (OS) (P = 0.194). The stratified survival analysis results showed that the status of SLNM was significantly associated with the OS in patients with pN1 GC (P = 0.001). The median OS was significantly shorter in 19 pN1 GC patients with SLNM than in 100 patients with perigastric lymph-node metastasis (P < 0.001). The case-control matched logistic regression analysis results showed that tumour size (P = 0.002) was the only clinicopathological factor that may predict SLNM in pN1 GC patients undergoing curative surgery. Among the 19 pN1 GC patients with SLNM, 17 (89.5%) had metastatic lymph nodes along the common hepatic artery, around the celiac artery or in the hepatoduodenal ligament. Conclusions: SLNM may be considered a potentially practicable indicator for prognosis among various subgroups of pN1 GC patients.

4.
Brief Bioinform ; 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30649184

RESUMO

Post-translational modification (PTM)-based regulation can be mediated not only by the modification of a single residue but also by the interplay of different modifications. Accurate prediction of PTM cross-talk is a highly challenging issue and is in its infant stage. Especially, less attention has been paid to the structural preferences (except intrinsic disorder and spatial proximity) of cross-talk pairs and the characteristics of individual residues involved in cross-talk, which may restrict the improvement of the prediction accuracy. Here we report a structure-based algorithm called PCTpred to improve the PTM cross-talk prediction. The comprehensive residue- and residue pair-based features were designed for paired PTM sites at the sequence and structural levels. Through feature selection, we reserved 23 newly introduced descriptors and 3 traditional descriptors to develop a sequence-based predictor PCTseq and a structure-based predictor PCTstr, both of which were integrated to construct our final prediction model. According to pair- and protein-based evaluations, PCTpred yielded area under the curve values of approximately 0.9 and 0.8, respectively. Even when removing the distance preference of samples or using the input of modeled structures, our prediction performance was maintained or moderately reduced. PCTpred displayed stable and reliable improvements over the state-of-the-art methods based on various evaluations. The source code and data set are freely available at https://github.com/Liulab-HZAU/PCTpred or http://liulab.hzau.edu.cn/PCTpred/.

5.
Protein Sci ; 27(9): 1723-1735, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29931702

RESUMO

It remains challenging to accurately discriminate between biological and crystal interfaces. Most existing analyses and algorithms focused on the features derived from a single side of the interface. However, less attention has been paid to the properties of residue pairs across protein interfaces. To address this problem, we defined a novel co-evolutionary feature for homodimers through integrating direct coupling analysis and image processing techniques. The residue pairs across biological homodimeric interfaces were significantly enriched in co-evolving residues compared to those across crystal contacts, resulting in a promising classification accuracy with area under the curves (AUCs) of >0.85. Considering the availability of co-evolutionary feature, we also designed other residue pair based features that were useful for both homodimers and heterodimers. The most informative residue pairs were identified to reflect the interaction preferences across protein interfaces. Regarding the other extant properties, we designed the new descriptors at the interface residue level as well as at the pairwise contact level. Extensive validation showed that these single properties can be used to identify biological interfaces with AUCs ranging from 0.60 to 0.88. By integrating co-evolutionary feature with other residue pair based properties, our final prediction model output excellent performance with AUCs of >0.91 on different datasets. Compared to existing methods, our algorithm not only yielded better or comparable results but also provided complementary information. An easy-to-use web server is freely accessible at http://liulab.hzau.edu.cn/RPAIAnalyst.


Assuntos
Algoritmos , Proteínas/química , Bases de Dados de Proteínas , Ligação Proteica , Conformação Proteica , Proteínas/metabolismo
6.
Molecules ; 22(7)2017 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-28672840

RESUMO

Six new conjugates were designed and synthesized by introducing glucose, methyl glucuronate or glucuronic acid moieties on tralopyril. Phytotoxicity and phloem mobility results demonstrated that the introduction of glucose, methyl glucuronate or glucuronic acid moieties can simultaneously solve the tough phytotoxicity problem and phloem mobility transformation of tralopyril. Conjugates 12 and 18 containing the glucuronic acid moiety exhibited higher phloem mobility than conjugates 9, 11, 15 and 17. Conjugates 15, 17 and 18 with methoxymethyl groups on the tralopyril pyrrole nitrogen atom showed activity against Plutella xylostella, while conjugates 9, 11 and 12 with a methene group on the pyrrole N showed no activity. Cabbage roots were incubated in a buffered solution containing conjugates 15, 17 and 18 at 4 mM for 72 h. Only 18 showed systemic insecticidal activity with 100% mortalityagainst P. xylostella, while 15 and 17 showed lower activity andchlorfenapyr showed no activity. The glucuronic acid promoiety imparted more phloem mobility to tralopyril than glucose and methyl glucuronate. The methoxymethyl group bond on the tralopyril skeleton was the key factor in determining the insecticidal activity of the conjugates. A promising systemic proinsecticide containing glucuronic acid and tralopyril moieties was proposed.


Assuntos
Inseticidas/síntese química , Floema/metabolismo , Pirróis/química , Brassica/metabolismo , Ácido Glucurônico/química , Inseticidas/química , Inseticidas/farmacologia , Estrutura Molecular , Floema/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia
7.
Bioprocess Biosyst Eng ; 40(5): 703-714, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28220238

RESUMO

The calcium phosphate [Ca3(PO4)2] precipitation was used for improving the clarification efficiency in harvest process of the monoclonal antibody (mAb) containing cell culture fluid (CCF) with high turbidity and product titer. The flocculation conditions (concentration, addition order of flocculants, pH, and operation time), and the effect of flocculants on the mAb physical chemical properties (such as distribution of charge variants and aggregates) and process-related impurities removal (such as DNA and CHOP) were evaluated in this study. The results showed that the turbidity of CCF supernatant was significantly reduced at pH 7, 120 min with addition of phosphate ions first, while a high mAb recovery yield was kept in the CCF supernatant after flocculation. Addition of calcium ions at 15-60 mM was sufficient for flocculation in this study. A relationship between turbidity/mAb recovery yield and the concentration of calcium ions was established. More than 85% DNA in the CCF were effectively removed by the addition of optimal concentration of flocculants. Flocculation process of Ca3(PO4)2 is an effective pretreatment method in purification processes of mAbs from the CCF with high turbidity and product titer.


Assuntos
Anticorpos Monoclonais Humanizados/biossíntese , Fosfatos de Cálcio/farmacologia , Técnicas de Cultura de Células/métodos , Animais , Células CHO , Cricetinae , Cricetulus , Floculação/efeitos dos fármacos , Humanos
8.
Sci Rep ; 7: 40887, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28098219

RESUMO

Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2R1441G (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild-type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial Complex-I (NDUFS4) in rotenone-treated mutant but not in similarly treated wild-type mice. Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of PD.


Assuntos
Apoptose/efeitos dos fármacos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/patologia , Rotenona/farmacologia , Administração Oral , Envelhecimento , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Técnicas de Introdução de Genes , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutagênese Sítio-Dirigida , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Rotenona/uso terapêutico , Sinaptossomos/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo
9.
Oncotarget ; 8(65): 108498-108508, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29312546

RESUMO

Hepatocellular carcinoma (HCC) remains the third cause of cancer-related mortality. Resection and transplantation are the only curative treatments available but are greatly hampered by high recurrence rates and development of metastasis, the initiation of cancer metastasis requires migration and invasion of cells, which is enabled by epithelial-mesenchymal transitions (EMT). TGF-ß1 is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis. TGF-ß1 is known as a major inducer of EMT, and it was reported that TGF-ß1 induced EMT via Smad-dependent and Smad-independent pathways. However, the extrinsic signals of TGF-ß1 regulated the EMT in hepatoma cells remains to be elucidated, and searching drugs to inhibit TGF-ß1 induced EMT may be considered to be a potentially effective therapeutic strategy in HCC. Fortunately, in this study, we found that curcumin inhibited TGF-ß1-induced EMT in hepatoma cells. Furthermore, we demonstrated that curcumin inhibited TGF-ß1-induced EMT via inhibiting Smad2 phosphorylation and nuclear translocation, then suppressing Smad2 combined with the promoter of Snail which inhibited the transcriptional expression of Snail. These findings suggesting curcumin could be a useful agent for antitumor therapy and also a promising drug combined with other strategies to preventing and treating HCC.

10.
Cancer Immunol Res ; 5(1): 42-51, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27923823

RESUMO

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC). Patients with intermediate and advanced stage NPC receiving only radiotherapy have limited survival, so newer immunotherapeutic approaches are sought. The major impediment to better clinical outcomes is tumor immune tolerance. Indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme, is a major inducer of immune tolerance during tumor development; therefore, inhibition of the IDO pathway is an important modality for cancer treatment. We show that bortezomib, a proteasomal inhibitor, inhibited the pathways leading to STAT1 and IRF-1 activation, both of which are necessary for IDO expression. Bortezomib downregulated IFNγ-induced IDO expression via inhibition of STAT1 phosphorylation and nuclear translocation, thereby suppressing STAT1-driven IDO transcription in NPC cells. Bortezomib also promoted IκB-α phosphorylation-ubiquitination, which released NF-κB from IκB-α. However, the released NF-κB could not enter the nucleus to conduct its biological effects and accumulated in the cytoplasm. Negative feedback inhibited the transcription of NF-κB, which is important for activating IRF-1 expression. IDO expression is regulated by two important transcription factor binding sites, ISREs, which bind STAT1 and IRF-1, and GASs, which binds STAT1. Bortezomib upregulated IRF-1 protein by inhibiting its proteasome-dependent degradation, but it also inhibited STAT1 phosphorylation, which directly inhibited the activation of GAS and indirectly inhibited the activation of ISRE, which needs both STAT1 and IRF-1. These discoveries provide a mechanism for the antitumor action of bortezomib and have implications for the development of clinical cancer immunotherapy for preventing and treating NPC. Cancer Immunol Res; 5(1); 42-51. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Bortezomib/farmacologia , Carcinoma/imunologia , Carcinoma/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/metabolismo , Fator de Transcrição STAT1/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Interferon gama/farmacologia , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Fosforilação , Ligação Proteica
11.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(1): 20-6, 2016 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-27228733

RESUMO

A methane (CH4) detection system based on tunable diode laser absorption spectroscopy (TDLAS) technique was experimentally demonstrated. A distributed feedback (DFB) laser around 1 654 nm, an open reflective sensing probe and two InGaAs photodiodes were adopted in the system. The electrical part of the system mainly includes the laser temperature control & modulation module and the orthogonal lock-in amplifier module. Temperature and spectrum tests on the DFB laser indicate that, the laser temperature fluctuation can be limited to the range of -0.02-0.02 degrees C, the laser's emitting wavelength varies linearly with the temperature and injection current, and also good operation stability of the laser was observed through experiments. Under a constant working temperature, the center wavelength of the laser is varied linearly by adjusting the driving current. Meanwhile, a 5 kHz sine wave signal and a 10 Hz saw wave signal were provided by the driving circuit for the harmonic extraction purpose. The developed orthogonal lock-in amplifier can extract the If and 2f harmonic signals with the extraction error of 3.55% and 5% respectively. By using the open optical probe, the effective optical pass length was doubled to 40 cm. Gas detection experiment was performed to derive the relation between the harmonic amplitude and the gas concentration. As the concentration increases from 1% to 5%, the amplitudes of the 1f harmonic and the 2f harmonic signal were obtained, and good linear ration between the concentration and the amplitude ratio was observed, which proves the normal function of the developed detection system. This system is capable to detect other trace gases by using relevant DFB lasers.

12.
Huan Jing Ke Xue ; 37(1): 193-7, 2016 Jan 15.
Artigo em Chinês | MEDLINE | ID: mdl-27078958

RESUMO

The p-arsanilic acid (ASA) is an important organoarsenical compound and its removal is more difficult compared to inorganic arsenic, however, little attention has been paid to the removal of ASA in aqueous environment. The influence of P25 on the adsorption of ASA, effect of P25 dosage, pH and illumination intensity on the photo-catalysis, the production analysis and main mechanism of photo-degradation were investigated in this study. The results showed that in the P25 catalysis process, simulated natural light could degrade ASA into As (V) by oxidation. The total As was reduced to about 0.34 mg x L(-1) within 0.5 h under the following condition: the initial concentration of ASA was 2 mg x L(-1) and the dosage of TiO2 was 1 g x L(-1). The result showed that the removal rate of ASA in acidic conditions was much higher than that in alkaline conditions. The optimal strength of light was 68.5 mW x Cm(-2). Hydroxide radical played a major role in photocatalytic oxidation of ASA by P25.


Assuntos
Ácido Arsanílico/química , Luz , Titânio/química , Adsorção , Catálise , Oxirredução
13.
Oncotarget ; 7(22): 33472-82, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-26985769

RESUMO

Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Fibroblastos Associados a Câncer/efeitos dos fármacos , Gelatinases/antagonistas & inibidores , Imunoterapia/métodos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/terapia , Animais , Fibroblastos Associados a Câncer/enzimologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Morte Celular/efeitos dos fármacos , Gelatinases/imunologia , Gelatinases/metabolismo , Humanos , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/imunologia , Neoplasias/patologia , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Evasão Tumoral , Microambiente Tumoral
14.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(11): 3501-5, 2016 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30198654

RESUMO

Based on tunable diode laser absorption spectroscopy (TDLAS) technique, an acetylene (C2H2) online detection system was developed by using the absorption band at the wavelength of 1.534 µm of C2H2 molecule. The sensing system consists of four modules including a distributed feedback (DFB) laser, a DFB laser driver, a gas cell with single optical path and a data processing module. With the prepared standard C2H2 gas sample, detailed measurements were carried out to study the detection performance of the system. Experimental results reveal that, the limit of the system (LOD) is about 0.02%; a good linear relationship is observed between C2H2 gas concentration and the amplitude of the 2f signal is within the range of 0.02%~1%. A long-term measurement lasting for 20 h on a 0.5% C2H2 gas sample was carried out to test the stability of the system. Compared with the C2H2 detection systems utilizing quantum cascaded lasers (QCLs) and wideband incandescence, this system has great advantage due to the capability of using long-distance and low-loss optical fiber for remote monitoring. With self-developed DFB laser driver and lock-in amplifier, the system has good prospects in industrial field because of its simple structure, low price and capability of easy to be integrated.

15.
Surg Neurol Int ; 6: 159, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26539310

RESUMO

BACKGROUND: This study is a retrospective case analysis of 143 patients who suffered from severe intracranial hemorrhage and underwent a fast and simple procedure of cranial drilling followed with external ventricle drain treatment (referred as Fast-D here after) during 2003-2013 to evaluate the clinical effectiveness of the treatment. METHODS: Fast-D procedure was conducted on 143 patients with severe acute craniocerebral diseases. Those patients were evaluated using activities of daily living (ADL) scales at hospital discharge and after 6-month of physical therapy, and were compared to 36 patients with similar craniocerebral diseases but received the traditional Dandy's surgical treatment. RESULTS: At discharge, 11% (16 cases) was classified as ADL I (fully functional for physical and social activities); 26% (37 cases) had ADL II (fully functional for physical activities but partially impaired for social activities); 34% (49 cases) was ADL III (require assistance performing physical activities); 9% (13 cases) was ADL IV (being conscious, but completely lost ability of physical activities); 27% (10 cases) was ADL V (vegetative stage); and 13% (18 cased) was ADL VI (died) among the 143 patients. Six-month physical therapy improved ADL in 88% of the patients. Those outcomes are equal or better than the more complicated Dandy's procedure probably due to the time-saving factor. CONCLUSION: Fast-D procedure is much faster (6.7 min vs. 53.6 min of the Dandy's procedure) and can be performed outside operating rooms (computed tomography room or bedside). This technique could serve as a tool to rapidly release intracranial pressure and reduce subsequent morbidity and mortality of severe craniocerebral diseases when resource and condition are limited and more elaborate operating room procedures are not possible.

16.
Oncotarget ; 6(28): 25932-42, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26305550

RESUMO

Fibroblast activation protein α (FAPα) is a potential target for cancer therapy. However, elimination of FAPα+ fibroblasts activates secretion of IFN-γ and TNF-α. IFN-γ can in turn induce expression indolamine-2,3-dioxygenase (IDO), thereby contributing to immunosuppression, while TNF-α can induce EMT. These two reactive effects would limit the efficacy of a tumor vaccine. We found that curcumin can inhibit IDO expression and TNF-α-induced EMT. Moreover, FAPαc vaccine and CpG combined with curcumin lavage inhibited tumor growth and prolonged the survival of mice implanted with melanoma cells. The combination of FAPαc vaccine, CpG and curcumin stimulated FAPα antibody production and CD8+ T cell-mediated killing of FAPα-expressing stromal cells without adverse reactive effects. We suggest a combination of curcumin and FAPαc vaccine for melanoma therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Gelatinases/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Animais , Western Blotting , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Gelatinases/imunologia , Gelatinases/metabolismo , Imuno-Histoquímica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/administração & dosagem , Serina Endopeptidases/imunologia , Serina Endopeptidases/metabolismo , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
17.
Exp Ther Med ; 10(1): 187-192, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26170933

RESUMO

The pathogenesis of atherosclerosis is multifactorial. The proliferation and migration of vascular smooth muscle cells (VSMCs) are significant in the genesis and development of atherosclerosis plaques, and the degradation of VSMCs plays a crucial role in the process. Mimecan is a member of the Keratan sulfate family of proteoglycans, which are leucine-rich proteoglycans. It has been demonstrated that mimecan is associated with arteriogenesis and atherosclerosis. In the present study, the effect of mimecan on the characteristics of cultured human aortic smooth muscle cells (HASMCs) was investigated. In vitro, human mimecan was stably overexpressed in HASMCs using a lentiviral system. It was observed that the proliferation rate of HASMCs transduced with mimecan was lower compared with that of control cells; overexpression of mimecan induced HASMC apoptosis. To determine the effect of mimecan on HASMC migration, a Transwell cell culture chamber and sterile cloning cylinder assays were used, and it was noted that mimecan enhanced the migration of HASMCs horizontally and vertically. These data indicated that mimecan may be involved in the pathogenesis of atherosclerosis by regulating the proliferation, apoptosis and migration of VSMCs.

18.
Trials ; 16: 265, 2015 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26058489

RESUMO

BACKGROUND: Osteoporosis (OP) and osteoarthritis (OA) are prevalent skeletal disorders among postmenopausal women. Coexistence is common especially that of postmenopausal osteoporosis (PMO) and lumbar OA. An hypothesis has been raised that OP and OA might share the same pathogenic mechanism, and pulsed electromagnetic fields (PEMFs) were reported to have anti-osteoporosis and anti-osteoarthritis properties, but this suggestion was based primarily on biomarker data. Therefore, whether these two effects could take place simultaneously has not yet been investigated. This randomized controlled trial (RCT) is designed to explore the effect of PEMFs for PMO and concomitant lumbar OA. METHODS/DESIGN: The study will include PMO patients (postmenopausal women; aged between 50 and 70 years; have been postmenopausal for at least 5 years and diagnosed with OP using proximal femur T-score) with concomitant lumbar OA (patients with confounding disorders like diabetes, hypertension, hyperlipidemia, and previous fracture history, etcetera, will be excluded) will be randomly assigned to two arms: PEMFs group and sham PEMFs group. There will be 25 participants in each arm (50 in total) and the outcome assessment, including the primary endpoint (proximal femur bone mineral density), will be performed at 5 weeks, 3 months and 6 months after enrollment. DISCUSSION: PMO and lumbar OA are prominent public health problem, especially for postmenopausal women. We hope this RCT will provide scientific evidence to primary care of the postmenopausal women regarding the use of these nonpharmaceutical, noninvasive modalities, PEMFs, in managing PMO and lumbar OA. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-14005156 (28 August 2014).


Assuntos
Densidade Óssea , Campos Eletromagnéticos , Fêmur/fisiopatologia , Vértebras Lombares/fisiopatologia , Terapia de Campo Magnético/métodos , Osteoartrite/terapia , Osteoporose Pós-Menopausa/terapia , Absorciometria de Fóton , Fatores Etários , Idoso , China , Protocolos Clínicos , Campos Eletromagnéticos/efeitos adversos , Determinação de Ponto Final , Feminino , Fêmur/diagnóstico por imagem , Humanos , Vértebras Lombares/diagnóstico por imagem , Terapia de Campo Magnético/efeitos adversos , Pessoa de Meia-Idade , Osteoartrite/complicações , Osteoartrite/diagnóstico , Osteoartrite/fisiopatologia , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/fisiopatologia , Estudos Prospectivos , Projetos de Pesquisa , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento
19.
J Atheroscler Thromb ; 22(11): 1124-40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26040753

RESUMO

AIM: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. METHODS: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE-/- mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. RESULTS: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor α (LXRα) activation, which was confirmed by the observation that LXRα siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. CONCLUSIONS: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXRα-dependent pathway.


Assuntos
Apolipoproteínas E/fisiologia , Aterosclerose/prevenção & controle , Células Espumosas/citologia , Lipoproteínas LDL/farmacologia , Macrófagos Peritoneais/citologia , Receptores Nucleares Órfãos/metabolismo , Proteínas/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Western Blotting , Células Cultivadas , Colesterol/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células HEK293 , Humanos , Receptores X do Fígado , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Nucleares Órfãos/genética , Proteínas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais
20.
Curr Microbiol ; 70(6): 769-78, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25682073

RESUMO

PPE68 is a Mycobacterium tuberculosis-specific protein which is absent from the vaccine strains of BCG. A panel of 14 PPE68-derived peptides predicted to bind to HLA-A*0201 was synthesized. The HLA-A*0201 restriction of these peptides was determined in T2 cell line and HLA-A*0201 transgenic mice. The specificity of peptides was assessed in pulmonary tuberculosis (TB) patients using IFN-γ enzyme-linked immunospot (ELISPOT) assay, and immunodominant peptides were further used to evaluate their diagnostic potential in HLA-A*0201-positive pulmonary TB patients. 13 out of 14 peptides were identified as high-affinity binders. Of these peptides, 12 peptides induced significant IFN-γ-secreting T cell response in transgenic mice and 9 peptides were efficiently recognized by peripheral blood mononuclear cells of 10 HLA-A*0201-positive TB patients. Four immunodominant HLA-A*0201-restricted epitopes (PPE68126-134, PPE68133-141, PPE68140-148, and PPE68148-156) were recognized by the most of 80 HLA-A*0201-positive TB patients (81, 86, 74, and 84 %, respectively). These epitopes may be used for a potential diagnosis of M. tuberculosis infection.


Assuntos
Proteínas de Bactérias/imunologia , Epitopos de Linfócito T , Antígeno HLA-A2/metabolismo , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/diagnóstico , Animais , Proteínas de Bactérias/metabolismo , ELISPOT , Humanos , Interferon gama/metabolismo , Camundongos Transgênicos , Sensibilidade e Especificidade , Linfócitos T/imunologia , Linfócitos T/microbiologia , Tuberculose/microbiologia
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