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1.
Nat Commun ; 10(1): 1981, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040273

RESUMO

Cardiovascular and metabolic disease (CMD) remains a main cause of premature death worldwide. Berberine (BBR), a lipid-lowering botanic compound with diversified potency against metabolic disorders, is a promising candidate for ameliorating CMD. The liver is the target of BBR so that liver-site accumulation could be important for fulfilling its therapeutic effect. In this study a rational designed micelle (CTA-Mic) consisting of α-tocopheryl hydrophobic core and on-site detachable polyethylene glycol-thiol shell is developed for effective liver deposition of BBR. The bio-distribution analysis proves that the accumulation of BBR in liver is increased by 248.8% assisted by micelles. Up-regulation of a range of energy-related genes is detectable in the HepG2 cells and in vivo. In the high fat diet-fed mice, BBR-CTA-Mic intervention remarkably improves metabolic profiles and reduces the formation of aortic arch plaque. Our results provide proof-of-concept for a liver-targeting strategy to ameliorate CMD using natural medicines facilitated by Nano-technology.


Assuntos
Berberina/farmacologia , Hipoglicemiantes/uso terapêutico , Nanotecnologia/métodos , Animais , Células CACO-2 , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/tratamento farmacológico , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
2.
Biomed Pharmacother ; 114: 108804, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909146

RESUMO

B lymphocytes have been shown to contribute to autoimmune diseases via producing antibodies and proinflammatory cytokines. Depletion of B cells by blocking CD20 can inhibit these diseases. Here we examined whether an antibody against CD20, rituximab (RTX) (Rituxan@), used clinically in oncology could have similar anti-inflammatory effects in cardiac remodeling and heart failure (HF) in mice. Cardiac remodeling was established by pressure overload induced by transverse aortic constriction (TAC). Wild-type (WT) male C57BL/6 J mice were subjected to pressure overload by using transverse aortic constriction and then received RTX for 4 weeks. Administration of RTX markedly improves in vivo heart function, and suppressed heart chamber dilation, myocyte hypertrophy, fibrosis and oxidative stress in mice after TAC operation. RTX treatment also reversed established hypertrophic remodeling induced by TAC. Moreover, TAC-induced activation of multiple signaling pathways including calcineurin A, ERK1/2, STAT3, TGFß/Smad2/3 and IKKα/ß/NF-kB were remarkably attenuated in RTX-treated hearts compared with controls. These inhibitory effects of RTX were associated with inhibition of proinflammatory cytokine expression and Th2 cytokine-mediated IgG production from B cells. In conclusion, this study identifies that administration of RTX can inhibit pressure overload-induced cardiac remodeling and dysfunction in mice, and suggest that RTX may be a promising drug for treating hypertrophic disease.


Assuntos
Linfócitos B/efeitos dos fármacos , Coração/efeitos dos fármacos , Rituximab/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Hipertrofia/tratamento farmacológico , Hipertrofia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
3.
Eur Heart J ; 39(20): 1818-1831, 2018 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-29514257

RESUMO

Aims: Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Methods and results: Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Conclusions: Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.

4.
Drug Deliv ; 24(1): 1537-1548, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28994324

RESUMO

Our previous work proved that sequence specific double strand RNA (dsRNA-p21) effectively activated p21 gene expression of colorectal cancer (CRC) cells and consequently suppressed CRC growth. However, efficient delivery system is a significant challenge to achieve sufficient therapy. In this study, a self-assembled HA/PEI/dsRNA-p21 ternary complex (TC-dsRNA-p21) was developed for the tumor-target delivery of dsRNA-p21 into CRC cells. Hyaluronic acid (HA) was introduced to shield the PEI/dsRNA-p21 binary complexes (BC-dsRNA-p21) for reducing the cytotoxicity of PEI and for increasing the tumor-targeted intracellular uptake by cancer cells through HA-CD44 mediated endocytosis. Comparing to the BC-dsRNA-p21, the TC-dsRNA-p21 showed increase in size, decrease in zeta potential, low cytotoxicity as well as high stability in physiological conditions due to the anionic shielding. Confocal microscopy analysis and flow cytometry confirmed that TC-dsRNA-p21 had high transfection efficiency in the CD44-abundant Lovo cells, as compared with binary complex. In vitro physiological experiment showed that, comparing to the control group, the TC-dsRNA-p21 effectively activated the expression of p21 mRNA and P21 protein, causing blockage of cell cycle at G0/G1 phase and suppression of cancer cell proliferation as well as colony formation. Furthermore, in vivo distribution experiment demonstrated that the TC-dsRNA-p21 could effectively accumulate at rectal wall for up to 10 h, following in situ application. These findings indicated that TC-dsRNA-p21 might hold great potential for delivering dsRNA-p21 to treat CRC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Receptores de Hialuronatos/metabolismo , RNA de Cadeia Dupla/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Expressão Gênica , Humanos , Ácido Hialurônico/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polietilenoimina/química , RNA de Cadeia Dupla/farmacocinética , Propriedades de Superfície , Transfecção
5.
Chin Med J (Engl) ; 129(3): 279-83, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26831228

RESUMO

BACKGROUND: This study aimed to observe the differences in brain gray matter volume in drug-naive female patients after the first episode of major depression with and without stressful life events (SLEs) before the onset of depression. METHODS: Forty-three drug-naive female patients voluntarily participated in the present study after the first major depressive episode. The life event scale was used to evaluate the severity of the impact of SLEs during 6 months before the onset of the major depressive episode. High-field magnetic resonance imaging (MRI) scans were obtained, and the VBM and SPM8 software process were used to process and analyze the MRI. RESULTS: Compared to that in patients without SLEs, the volume of brain gray matter was lower in the bilateral temporal lobe, right occipital lobe, and right limbic lobe in the SLE group. However, the gray matter volume did not differ significantly between the two groups after the application of false discovery rate (FDR) correction. CONCLUSIONS: Although the results of the present study suggest the absence of significant differences in brain gray matter volume between female drug-naive patients after the first episode of major depression with and without SLEs after FDR correction, the study provides useful information for exploring the definitive role of stress in the onset of depression.


Assuntos
Depressão/fisiopatologia , Substância Cinzenta/anatomia & histologia , Estresse Fisiológico/fisiologia , Adolescente , Adulto , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Software , Adulto Jovem
6.
Chin J Nat Med ; 13(12): 906-14, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26721709

RESUMO

The present study was designed to evaluate the immune-modulating effects of the polysaccharide from Grifola frondosa (GFP) by using mouse peritoneal macrophage and cytoxan (CTX) induced immunosuppression models. Our results from the phagocytotic and mononuclear phagocytic system function assays showed that GFP-A (one component from GFP) stimulated the phagocytosis of the phagocytes. The splenocyte proliferation assay showed that GFP-A acted the effect combing ConA or LPS in splenocyte proliferation. The results showed that GFP-A increased indices of thymus and spleen, the levels of LDH and ACP in the spleen, the mRNA levels of IL-1ß, IL-2, IL-6 and IFN-γ in splenocyte. And GFP-A also significantly increased the expression of CD4(+) and CD8(+) splenic T lymphocytes, which were suppressed by the CTX in peripheral blood. In conclusion, our results indicate that the GFP-A is involved in immunomodulatory effects leading to its modulatory effects on immunosuppression.


Assuntos
Grifola/química , Fatores Imunológicos/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Células Cultivadas , Feminino , Fatores Imunológicos/isolamento & purificação , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
7.
Beijing Da Xue Xue Bao Yi Xue Ban ; 44(5): 765-9, 2012 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-23073589

RESUMO

OBJECTIVE: To investigate the role of aeroallergen and food allergen IgE in the pathogenesis of allergen diseases and the relationship between environments, diet, exposed factors and prevalence rate in allergic skin diseases. METHODS: Food allergen specific IgE (sIgE) antibody quantitative detection kit was used to detect 142 allergen cases, including artemisia, mixture of epithelia, mixed molds, mixed botany, mixed pollens, willow, poplar, egg, milk, shrimp, mutton, beef, fish, crab, staple foods, etc. RESULTS: Mixed molds and mixed botany were the most common allergens in the allergy dermatitis group (positive rate 60%), eczema group (43%), urticaria group (46%), and allergic purpuria group (71%). The milk revealed that it was the most common allergen in the allerge dermatitis group and eczema group (42% and 56%, respectively). While seafood was the most common allergen in the urticaria group (34%). There was no significant relationship between the exposure and prevalence rate. CONCLUSION: The detection of allergen IgE provides valuable basis for analysis of the cause in allergic disease.


Assuntos
Alérgenos/imunologia , Dermatite Alérgica de Contato/imunologia , Eczema/imunologia , Imunoglobulina E/sangue , Urticária/imunologia , Adulto , Ar/análise , Alérgenos/análise , Feminino , Hipersensibilidade Alimentar/imunologia , Humanos , Hipersensibilidade/imunologia , Masculino
8.
Int J Mol Med ; 28(2): 153-60, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21567075

RESUMO

Type 1 diabetes mellitus (T1DM) is receiving increased attention. To obtain a better understanding of the mechanism underlying T1DM, we performed a proteomic study on a rat model induced by streptozotocin. Pancreatic proteins were separated by two-dimensional gel electrophoresis. Eighteen protein spots were differentially expressed (P<0.05) with 2-fold or more increased or decreased intensity in the diabetic rats as compared with controls, of which 11 protein spots were up-regulated and 7 protein spots were down-regulated. These protein spots were successfully identified by liquid chromatography-electrospray ionization tandem mass spectrometry. The 60 kDa heat shock protein, the carbonyl reductase 1 (Cbr1), the hydroxyacyl-CoA dehydrogenase, Δ(3,5),Δ(2,4)-dienoyl-CoA isomerase, the elongation factor 1-δ, the 26S protease regulatory subunit 7 and the transitional endoplasmic reticulum ATPase were up-regulated, while the 78 kDa glucose-regulated protein, peroxiredoxin 4 and plakoglobin were down-regulated. The expression change of Cbr1 which is closely related to diabetic complications was further validated by western blotting. Our results and those of the bioinformatics analysis suggest that oxidative stress, the Wnt pathway, fatty acid degradation and glucose transport may be closely related to T1DM.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Pâncreas/metabolismo , Proteoma , Oxirredutases do Álcool/metabolismo , Animais , Glicemia/metabolismo , Biologia Computacional , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Modelos Animais de Doenças , Eletroforese em Gel Bidimensional , Masculino , Pâncreas/fisiopatologia , Mapeamento de Interação de Proteínas , Ratos , Ratos Sprague-Dawley
9.
Zhonghua Jie He He Hu Xi Za Zhi ; 32(1): 33-6, 2009 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-19484959

RESUMO

OBJECTIVE: To investigate the effects of umbilical cord mesenchymal stem cell (UC-MSCs) transplantation on interstitial pneumonitis in MRL/lpr mice. METHODS: Twenty four 18-week-old MRL/lpr female mice were randomly divided into 3 groups: the single dose group received a single dose of UC-MSCs (1 x 10(6)) transfusion intravenously, the 3 dose group received 3 injections of UC-MSCs (1 x 10(6)) weekly for 3 weeks, and the control mice were treated with saline. Both the control and the treated mice were sacrificed at 29 weeks. The histopathology of the lungs were assessed by HE staining. RESULTS: In comparison to the control mice, UC-MSCs transplantation significantly attenuated interstitial pneumonitis in the MRL/lpr mice. The peribronchiolar lesion indices of the single dose treatment group (1.40 +/- 0.24) and the 3 dose treatment group (1.02 +/- 0.29) were significantly decreased as compared to the control group (1.95 +/- 0.35), q = 0.551, 0.937, all P < 0.01. The perivascular lesion index of the single dose treatment group (1.20 +/- 0.18) and the 3 dose treatment group (1.08 +/- 0.16) were also significantly reduced as compared to the control group (1.56 +/- 0.32), q = 0.360, 0.479, P < 0.05, P < 0.01. The inflammatory cell infiltration index of the control group (1.72 +/- 0.34) was significantly increased compared to the single dose treatment group (1.30 +/- 0.21) and the 3 dose treatment group (1.05 +/- 0.15), q = 0.417, 0.673, P < 0.05, P < 0.01. CONCLUSIONS: These findings indicate that UC-MSCs have a pleiotropic therapeutic effect on pneumonitis in MRL/lpr mice.


Assuntos
Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/terapia , Transplante de Células-Tronco Mesenquimais , Animais , Modelos Animais de Doenças , Feminino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos MRL lpr , Cordão Umbilical/citologia
10.
Acta Pharmacol Sin ; 26(4): 500-12, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15780201

RESUMO

AIM: To build up a theoretical model of organic compounds for the prediction of the activity of small molecules through the blood-brain barrier (BBB) in drug design. METHODS: A training set of 37 structurally diverse compounds was used to construct quantitative structure-activity relationship (QSAR) models. Intermolecular and intramolecular solute descriptors were calculated using molecular mechanics, molecular dynamics simulations, quantum chemistry and so on. The QSAR models were optimized using multidimensional linear regression fitting and stepwise method. A test set of 8 compounds was evaluated using the models as part of a validation process. RESULTS: Significant QSAR models (R=0.955, s=0.232) of the BBB penetration of organic compounds were constructed. BBB penetration was found to depend upon the polar surface area, the octanol/water partition coefficient, Balaban Index, the strength of a small molecule to combine with the membrane-water complex, and the changeability of the structure of a solute-membrane-water complex. CONCLUSION: The QSAR models indicate that the distribution of organic molecules through BBB is not only influenced by organic solutes themselves, but also relates to the properties of the solute-membrane-water complex, that is, interactions of the molecule with the phospholipid-rich regions of cellular membranes.


Assuntos
Barreira Hematoencefálica/fisiologia , Membranas Artificiais , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Relação Quantitativa Estrutura-Atividade , Barreira Hematoencefálica/efeitos dos fármacos , Dimiristoilfosfatidilcolina , Desenho de Drogas , Estrutura Molecular , Preparações Farmacêuticas/química
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