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1.
J Pharmacol Sci ; 141(1): 64-69, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31640919

RESUMO

Activation of both adenosine A2A and A2B receptors (A2BR) contributes to coronary vasodilation. We previously demonstrated that uridine adenosine tetraphosphate (Up4A) is a novel vasodilator in the porcine coronary microcirculation, acting mainly on A2AR in smooth muscle cells (SMC). We further investigated whether activation of A2BR is involved in Up4A-mediated coronary SMC relaxation. Both A2AR and A2BR may stimulate H2O2 production leading to activation of KATP channels in SMCs, we also studied the involvement of H2O2 and KATP channels in Up4A-mediated effect. Coronary small arteries dissected from the apex of porcine hearts were mounted on wire myograph for Up4A concentration responses. Up4A-induced coronary SMC relaxation was attenuated by A2AR but not A2BR antagonism or non-selective P2R antagonism, despite greater endogenous A2BR expression vs. A2AR in both coronary small arteries and primary cultured coronary SMCs. Moreover, Up4A-induced coronary SMC relaxation was blunted by H2O2 catabolism. This effect was not altered by KATP channel blockade. Combination of H2O2 catabolism and A2AR antagonism attenuated Up4A-induced coronary SMC relaxation to the similar extent as A2AR antagonism alone. Collectively, Up4A-induced porcine coronary SMC relaxation is mediated by activation of A2AR-H2O2 pathway. This process does not involve A2BR, P2R or KATP channels.

2.
Circulation ; 139(21): 2466-2482, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-30894016

RESUMO

BACKGROUND: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown. METHODS: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics. RESULTS: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation. CONCLUSIONS: We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.

3.
JACC Basic Transl Sci ; 4(1): 72-82, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30847421

RESUMO

As a consequence of the success of present-day cancer treatment, radiotherapy-induced vascular disease is emerging. This disease is caused by chronic inflammatory activation and is likely orchestrated in part by microRNAs. In irradiated versus nonirradiated conduit arteries from patients receiving microvascular free tissue transfer reconstructions, irradiation resulted in down-regulation of miR-29b and up-regulation of miR-146b. miR-29b affected inflammation and adverse wound healing through its targets pentraxin-3 and dipeptidyl-peptidase 4. In vitro and in vivo, we showed that miR-29b overexpression therapy, through inhibition of pentraxin-3 and dipeptidyl-peptidase 4, could dampen the vascular inflammatory response.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30743073

RESUMO

A new Schiff base derivative fluorescence-colorimetric chemosensor 2-hydroxy-5-[(2-hydroxy-1-naphthyl)methylideneamino]benzoic acid (H3L), has been designed and synthesized. H3L displayed high selectivity and sensitivity for detecting Cr3+, Cu2+, Fe3+ and Al3+ ions in DMF/H2O (v/v = 1/1) solution. When Cr3+, Cu2+ or Fe3+ ions were added, the solution of H3L in DMF/H2O exhibited different color changes. While with the addition of Fe3+ or Al3+ ions, the solution of H3L in DMF/H2O displayed different fluorescence responses. The bonding modes and bonding ratios of H3L and metal ions were explored by the Job's plot, 1H NMR titration, and electrospray ionization mass spectrometry (ESI-MS). The detection limits of H3L with Cr3+, Cu2+, Fe3+and Al3+ ions were 3.37 × 10-7 M, 4.65 × 10-7 M, 3.58 × 10-7 M and 4.89 × 10-7 M, respectively.

5.
Sensors (Basel) ; 18(4)2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29670023

RESUMO

Aircraft service process is in a state of the composite load of pressure and temperature for a long period of time, which inevitably affects the inherent characteristics of some components in aircraft accordingly. The flow field of aircraft wing materials under different Mach numbers is simulated by Fluent in order to extract pressure and temperature on the wing in this paper. To determine the effect of coupling stress on the wing’s material and structural properties, the fluid-structure interaction (FSI) method is used in ANSYS-Workbench to calculate the stress that is caused by pressure and temperature. Simulation analysis results show that with the increase of Mach number, the pressure and temperature on the wing’s surface both increase exponentially and thermal stress that is caused by temperature will be the main factor in the coupled stress. When compared with three kinds of materials, titanium alloy, aluminum alloy, and Haynes alloy, carbon fiber composite material has better performance in service at high speed, and natural frequency under coupling pre-stressing will get smaller.

6.
Mol Ther ; 26(4): 1040-1055, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29503197

RESUMO

miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR-21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.


Assuntos
Aterosclerose/genética , Aterosclerose/patologia , MicroRNAs/genética , Animais , Apoptose/genética , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Modelos Animais de Doenças , Fibrose , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Genótipo , Humanos , Imuno-Histoquímica , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/administração & dosagem , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-28688335

RESUMO

This manuscript studies the fluorescent property of 3-[(2-hydroxy-1-naphthyl)methylideneamino]benzoic acid (H2L). Fluorescent spectra show that in different solvents, H2L displays different fluorescent properties, which can be attributed to the interaction between the solvents and H2L. Further study indicates that H2L exhibits a highly selective and sensitive recognition for Hg2+ ions in dimethylsulfoxide (DMSO), Al3+ ions in methanol and N,N'-dimethylformamide/water (DMF/H2O, 1/1, v/v). The bonding modes and bonding ratio of H2L and metal ions in different solvents are explored by Job's plot, 1H NMR titration, and electrospray ionization mass spectrometry (ESI-MS). The probable mechanisms were discussed.

8.
Purinergic Signal ; 13(4): 591-600, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28929376

RESUMO

Uridine adenosine tetraphosphate (Up4A) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for Up4A in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of Up4A on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X1 receptor (P2X1R) expression in isolated mouse coronary arteries. In vivo effects of Up4A on coronary blood flow (CBF) were assessed using ultrasound. Infusion of Up4A (10-9-10-5 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2X1R antagonist MRS2159 restored Up4A-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2X1R expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2X1R in ApoE KO + HFD mice. In contrast, Up4A (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, Up4A decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2X1R. In contrast, Up4A increases CBF in vivo regardless of the atherosclerotic model.


Assuntos
Aterosclerose/metabolismo , Circulação Coronária/efeitos dos fármacos , Fosfatos de Dinucleosídeos/farmacologia , Receptores Purinérgicos P2X1/metabolismo , Animais , Preparação de Coração Isolado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Antagonistas do Receptor Purinérgico P2X/farmacologia
9.
Am J Hypertens ; 30(3): 304-312, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28034895

RESUMO

OBJECTIVE: We previously showed that uridine adenosine tetraphosphate (Up4A)-mediated aortic contraction is partly mediated through purinergic P2X1 receptors (P2X1R). It has been reported that the plasma level of Up4A is elevated in hypertensive patients, implying a potential role for Up4A-P2X1R signaling in hypertension. This study investigated the vasoactive effect of Up4A in aortas isolated from angiotensin (Ang) II-infused (21 days) hypertensive mice. METHODS: Blood pressure was measured by tail cuff plethysmography. Aortas were isolated for isometric tension measurements, and protein expression was analyzed by western blot. RESULTS: Mean and systolic arterial pressures were elevated by ~50% in Ang II-infused mice. Protein levels of both AT1R and P2X1R were upregulated in Ang II-infused aortas. Surprisingly, Up4A (10-9-10-5 M)-induced concentration-dependent contraction was significantly impaired in Ang II-infused mice. Studies in control mice revealed that both P2X1R (MRS2159) and AT1R (losartan) antagonists significantly attenuated Up4A-induced aortic contraction. In addition, desensitization of AT1R by prior Ang II (100 nM) exposure had no effect on Up4A-induced aortic contraction. However, subsequent serial exposure responses to Up4A-induced aortic contraction were markedly reduced, suggesting a desensitization of purinergic receptors. This desensitization was further confirmed in control mice by prior exposure of aortas to the P2X1R desensitizer α, ß-methylene ATP (10 µM). CONCLUSION: Despite upregulation of AT1R and P2X1R in hypertension, Up4A-mediated aortic contraction was impaired in Ang II-infused mice, likely through the desensitization of P2X1R but not AT1R. This implies that vascular P2X1R activity, rather than plasma Up4A level, may determine the role of Up4A in hypertension.


Assuntos
Angiotensina II , Fosfatos de Dinucleosídeos/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Contração Miocárdica/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptores Purinérgicos P2X1/efeitos dos fármacos , Vasoconstritores , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/efeitos dos fármacos , Pressão Arterial , Pressão Sanguínea , Contração Isométrica/efeitos dos fármacos , Losartan/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Circ Res ; 120(4): 633-644, 2017 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-27895035

RESUMO

RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.


Assuntos
MicroRNAs/administração & dosagem , MicroRNAs/biossíntese , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/terapia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/terapia , Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Estenose das Carótidas/terapia , Células Cultivadas , Estudos de Coortes , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Microdissecção e Captura a Laser/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/análise , Placa Aterosclerótica/patologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle
11.
J Nanosci Nanotechnol ; 16(3): 2719-24, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27455697

RESUMO

Zn(1-x)Co(x)O (x = 0-0.07) single-crystalline nanorods were prepared by a modified microemulsion route. The crystalline structure, morphology, optical, and hysteresis loop at low and room temperature of as-prepared materials were characterized by XRD, TEM, PL spectra, and magnetic measurement respectively. The nanorods are 80-250 nm in diameter and about 3 µm in length. X-ray diffraction data, TEM images confirm that the materials synthesized in optimal conditions are ZnO:Co single crystalline solid solution without any impurities related to Co. The PL spectra show that the ferromagnetic samples exhibit strong Zn interstitials and oxygen vacancy emission indicating defects may stabilize ferromagnetic order in the obtained diluted magnetic semiconductors. Magnetic measurements show that the Zn(1-x)Co(x)O nanorods exist obvious ferromagnetic characteristics with T(c) above 300 K. M(s) and coercivities first increase and then decrease with dopant concentration increasing, reaching the highest for 3% doping level. The structural and magnetic properties of these samples support the hypothesis that the FM of DMS nanorods is due to a defect mediated mechanism instead of cobalt nanoclusters and carrier mediated.


Assuntos
Cobalto/química , Magnetismo , Nanotubos , Oxigênio/química , Óxido de Zinco/química , Microscopia Eletrônica de Transmissão , Difração de Raios X
12.
Vascul Pharmacol ; 73: 78-85, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25921923

RESUMO

Uridine adenosine tetraphosphate (Up4A), a novel endothelium-derived vasoactive agent, is proposed to play a role in cardiovascular disorders and induces aortic contraction through activation of cyclooxygenases (COXs). We and others demonstrated that activation of A1 or A3 adenosine receptors (ARs) results in vascular contraction via thromboxane (TX) A2 production. However, the mechanisms of Up4A-induced vascular contraction in mouse aorta are not understood. We hypothesize that Up4A-induced aortic contraction is through COX-derived TXA2 production, which requires activation of A1 and/or A3AR. Concentration responses to Up4A were conducted in isolated aorta. The TXB2 production, a metabolite of TXA2, was also measured. Up4A (10(-9)-10(-5)M) produced a concentration-dependent contraction >70%, which was markedly attenuated by COX and COX1 but not by COX2 inhibition. Notably, Up4A-induced aortic contraction was blunted by both TX synthase inhibitor ozagrel and TXA2 receptor (TP) antagonist SQ29548. Surprisingly, A3AR deletion had no effect on Up4A-induced contraction. Moreover, A1AR deletion or antagonism as well as A1/A3AR deletion potentiated Up4A-induced aortic contraction, suggesting a vasodilator influence of A1AR. In contrast, non-selective purinergic P2 receptor antagonist PPADS significantly blunted Up4A-induced aortic contraction to a similar extent as selective P2X1R antagonist MRS2159, the latter of which was further reduced by addition of ozagrel. Endothelial denudation almost fully attenuated Up4A-induced contraction. Furthermore, Up4A (3µM) increased TXB2 formation, which was inhibited by either MRS2159 or ozagrel. In conclusion, Up4A-induced aortic contraction depends on activation of TX synthase and TP, which partially requires the activation of P2X1R but not A1 or A3AR through an endothelium-dependent mechanism.


Assuntos
Aorta/efeitos dos fármacos , Fosfatos de Dinucleosídeos/farmacologia , Agonistas Purinérgicos/farmacologia , Receptores Purinérgicos P2X1/efeitos dos fármacos , Receptores de Tromboxano A2 e Prostaglandina H2/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Aorta/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor A1 de Adenosina/genética , Receptor A1 de Adenosina/metabolismo , Receptor A3 de Adenosina/genética , Receptor A3 de Adenosina/metabolismo , Receptores Purinérgicos P2X1/metabolismo , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tromboxano A2/metabolismo , Tromboxano B2/metabolismo , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/metabolismo
13.
J Immunol ; 192(4): 1815-23, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24453242

RESUMO

IL-37 is a potent inhibitor of innate immunity by shifting the cytokine equilibrium away from excessive inflammation. Psoriasis is thought to be initiated by abnormal interactions between the cutaneous keratinocytes and systemic immune cells, triggering keratinocyte hyperproliferation. In the current study, we assessed IL-37 in two well-known psoriasis models: a human keratinocyte cell line (HaCaT) and the keratin 14 VEGF-A-transgenic mouse model. First, we used the HaCaT cell line, which was transiently transfected with an overexpressing IL-37 vector, and tested the effect of IL-37 on these cells using a mixture of five proinflammatory cytokines. IL-37 was effective in suppressing the production of CXCL8, IL-6, and S100A7, which were highly upregulated by the mixture of five proinflammatory cytokines. Keratin 14 VEGF-A-transgenic mice were treated with plasmid coding human IL-37 sequence-formulated cationic liposomes, and we observed potent immunosuppressive effects over the 18-d period. In this model, we observed reduced systemic IL-10 levels, local IFN-γ gene transcripts, as well as mild mast cell infiltration into the psoriatic lesions of the mice. Immunohistochemical analysis indicated that IL-37 was expressed by effector memory T cells, as well as macrophages, in human psoriatic plaques. In conclusion, our studies strongly indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of both experimental psoriasis models in vitro and in vivo by downregulating proinflammatory cytokines. Importantly, our findings highlight new therapeutic strategies that can be designed to use this immunosuppressive anti-inflammatory cytokine in psoriasis and other inflammatory cutaneous diseases.


Assuntos
Inflamação/imunologia , Interleucina-1/metabolismo , Psoríase/imunologia , Animais , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Memória Imunológica/imunologia , Imunossupressão , Interferon gama/genética , Interleucina-1/genética , Interleucina-10/metabolismo , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Queratina-14/genética , Queratinócitos/imunologia , Queratinócitos/metabolismo , Macrófagos/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Transgênicos , Psoríase/metabolismo , Psoríase/patologia , Proteína A7 Ligante de Cálcio S100 , Proteínas S100/biossíntese , Pele/imunologia , Pele/patologia , Linfócitos T/imunologia , Transfecção , Fator A de Crescimento do Endotélio Vascular/genética
14.
PLoS One ; 7(6): e39770, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22761896

RESUMO

BACKGROUND: Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1-7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1-7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression. CONCLUSIONS/SIGNIFICANCE: Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases.


Assuntos
Regulação da Expressão Gênica/fisiologia , Hormônio Liberador de Gonadotropina/genética , Histona Desacetilases/metabolismo , Fatores de Transcrição Otx/fisiologia , Animais , Western Blotting , Linhagem Celular , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Histona Desacetilases/fisiologia , Ácidos Hidroxâmicos/farmacologia , Camundongos , Regiões Promotoras Genéticas , Transcrição Genética/fisiologia , Ácido Valproico/farmacologia
15.
Bioorg Med Chem Lett ; 22(9): 3122-5, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22483608

RESUMO

A novel class of acetylhydrazone derivatives (5a-x) containing 2-(phenylthiomethyl)-1H-benzo-[d]-imidazole moieties are synthesizer, and their antitumor activities against A549, HCT116, HepG2, PC-9, and A375 were determined by the MTT assay. Among them are N-(2,4-dihydroxybenzylidene)-2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide (5a) and N-(5-bromo-2-hydroxy-benzylidene)-2-(2-(phenylthiomethyl)-1H-benzo[d]-imidazol-1-yl)acetohydrazide (5d) which displayed excellent cancer inhibitory activity against the tested cancer cells (IC(50) 4-17 µM), compared with 5-FU and SU11248. The others have moderate to weak inhibitory activity against the tested cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Hidrazonas/síntese química , Imidazóis/síntese química , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/farmacologia , Imidazóis/farmacologia , Concentração Inibidora 50 , Relação Estrutura-Atividade
16.
Artigo em Inglês | MEDLINE | ID: mdl-22259493

RESUMO

In the title mol-ecule, C(28)H(18)O(10), the two central benzene rings form a dihedral angle of 31.0 (1)°. In the phthalic acid fragments, the carb-oxy groups in the meta positions are approximately coplanar with the attached benzene rings, being inclined to their planes at 2.7 (1) and 10.3 (1)°, while the carb-oxy groups in the ortho positions are twisted from the benzene ring planes by 83.5 (1) and 75.4 (1)°. In the crystal, O-H⋯O hydrogen bonds link the mol-ecules into layers parallel to the bc plane. Weak C-H⋯O hydrogen bonds and π-π inter-actions between the aromatic rings [centroid-centroid distance = 3.7674 (3) Å] further consolidate the crystal packing.

17.
Molecules ; 17(1): 873-83, 2012 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-22252503

RESUMO

In a previous hit-to-lead research program targeting anticancer agents, two promising lead compounds, 1a and 1b, were found. However, the poor solubility of 1a and 1b made difficult further in vivo studies. To solve this problem, a lead optimization was conducted through introducing N-methyl-piperazine groups at the 2-position and 6-position. To our delight, the optimized analogue 1d showed comparable antiproliferative activity in vitro with better solubility, compared with 1a. Based on this result, the replacement of the benzothiazole scaffold with benzimidazole and benzoxazole moieties afforded 1f and 1g, whose activities were fundamentally retained. In the preliminary in vitro biological evaluation, the immunofluorescence staining of HCT116 cells indicated that 1d, 1f and 1g led to cytosolic vacuolization which was not induced by 1a at low micromolecular concentrations. These results suggest that these optimized compounds might potentially constitute a novel class of anticancer agents, which merit further studies.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Benzotiazóis/farmacologia , Benzoxazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzotiazóis/síntese química , Benzotiazóis/química , Benzoxazóis/síntese química , Benzoxazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade
18.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 11): m1433, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23284393

RESUMO

In the title complex, [Co(C(10)H(7)O(4))(2)(C(12)H(12)N(2))(H(2)O)(2)](n), the Co(II) ion is located on a crystallographic centre of symmetry and is six-coordinated by two N atoms from two 1,2-bis-(4-pyrid-yl)ethane ligands, two carboxylate O atoms from two 1,3-dihydro-3-oxo-1-isobenzofuran-acetate ligands and two terminal water ligands. The 1,2-bis(4-pyrid-yl)ethane ligands act as bidentate ligands, and bridge the Co(II) ions into infinite chains extending parallel to [010]. In these chains, there are intra-mol-ecular O-H⋯O hydrogen bonding between the coordination water mol-ecules and carboxyl-ate groups. Inter-mol-ecular O-H⋯O hydrogen bonding between the adjacent chains and π⋯π stacking inter-actions result in the formation of a three-dimensional supra-molecular network.

19.
Biochem Biophys Res Commun ; 399(2): 167-72, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20638362

RESUMO

CD38 is a multifunctional enzyme that has both ADP-ribosyl cyclase and cADPR hydrolase activities, being capable of cleaving NAD(+) to cyclic ADP ribose (cADPR) and hydrolyzing cADPR to ADPR. It has been reported that there is markedly a reduction of cADPR and elevation of NAD in many tissues from CD38 knockout (CD38(-/-)) mice. Cyclic ADPR is a potent second messenger for intracellular Ca(2+) mobilization, and NAD is a key cellular metabolite for cellular energetic and a crucial regulator for multiple signaling pathways in cells. We hypothesize that CD38 knockout may have a protective effect in oxidative stresses through elevating NAD and decreasing cADPR. In the present study, we observed that the mouse embryonic fibroblasts (MEFs) from CD38(-/-) mice were significantly resistant to oxidative stress such as H(2)O(2) injury and hypoxia/reoxygenation compared with wild type MEFs (WT MEFs). We further found that production of reactive oxygen species (ROS) and concentrations of intracellular Ca(2+) ([Ca(2+)](i)) in CD38(-/-) MEFs were markedly reduced compared with WT MEFs during hypoxia/reoxygenation. Coincidence with these results, a remarkably lower mRNA level of Nox1, one of the enzymes responsible for ROS generation, was observed in CD38(-/-) MEFs. Furthermore, we found that transcription of Nox1 mRNA in WT MEFs could be elevated by calcium ionophore ionomycin in a dose-dependent manner, indicating that the expression of Nox1 mRNA can be regulated by elevation of intracellular [Ca(2+)]. Therefore we concluded that CD38(-/-) MEFs are resistant to oxidative stresses through inhibiting intracellular Ca(2+) overload and ROS production which may be regulated by Ca(2+)-mediated inhibition of Nox1 expression. Our data should provide an insight for elucidating the roles of CD38 in oxidative stresses and a novel perspective of dealing with the ischemia/reperfusion-related diseases.


Assuntos
ADP-Ribosil Ciclase 1/genética , Cálcio/metabolismo , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Embrião de Mamíferos/citologia , Fibroblastos/enzimologia , Camundongos , Camundongos Knockout , NADH NADPH Oxirredutases/biossíntese , NADPH Oxidase 1
20.
Peptides ; 30(10): 1816-21, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19619601

RESUMO

Peptide aptamers are molecules which can specifically bind to a given target protein and have the potential to selectively block the function of the target protein. It has been reported that a peptide aptamer (C1-1) identified from a randomized expression library specifically bound to the core protein of hepatitis B virus and inhibited viral capsid formation and DNA replication in vitro. Adenoviral systems are popular platforms for reliable gene delivery and high-level transient expression in any mammalian cell type in vitro, and have a natural tropism for the liver after systemic administration. In the present study, we explored the feasibility of gene therapy against HBV infection with adenoviral system, and found that systematic administration of recombinant adenovirus encoding the peptide aptamer (C1-1) significantly inhibited viral capsid formation, HBV DNA replication and virion production in vivo. These results suggest an efficient antiviral treatment against HBV infection by delivery of anti-HBV peptide aptamer with recombinant adenovirus.


Assuntos
Adenoviridae/genética , Aptâmeros de Peptídeos , Replicação do DNA , DNA Viral/metabolismo , Vírus da Hepatite B/fisiologia , Proteínas do Core Viral/metabolismo , Adenoviridae/metabolismo , Animais , Aptâmeros de Peptídeos/genética , Aptâmeros de Peptídeos/metabolismo , Linhagem Celular , DNA Viral/genética , Terapia Genética/métodos , Vetores Genéticos , Vírus da Hepatite B/genética , Humanos , Camundongos , Camundongos Transgênicos , Proteínas do Core Viral/genética
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