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1.
Mol Ther ; 28(1): 279-292, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31636038

RESUMO

Inflammation is associated with retinal diseases. Our recent data demonstrate that immunoproteasome catalytic subunit ß2i contributes to angiotensin II (Ang II)-induced retinopathy in mice. Here, we investigated the role of another catalytic subunit ß5i in regulating retinopathy and its underlying mechanisms. We induced a murine model of retinopathy by infusing Ang II (3,000 ng/kg/min) for 3 weeks into wild-type (WT) mice, ß5i-knockout (KO) mice, or WT mice injected with either adenovirus-expressing ß5i (Ad-ß5i) or angiotensin II type 1 receptor (AT1R)-associated protein (Ad-ATRAP), which inhibits AT1R. The ß5i expression and chymotrypsin-like activity were most significantly elevated in Ang II-infused retinas and serum from patients with hypertensive retinopathy. Moreover, Ang II infusion-induced retinopathy was markedly attenuated in ß5i-KO mice but aggravated in Ad-ß5i-injected mice. Accordingly, ß5i KO markedly restored Ang II-induced downregulation of ATRAP and activation of AT1R downstream mediators, which was further enhanced in Ad-ß5i-injected mice. Interestingly, overexpression of ATRAP significantly abrogated Ang II-induced retinopathy in Ad-ß5i-injected mice. This study found that ß5i promoted Ang II-induced retinopathy by promoting ATRAP degradation and activation of AT1R-mediated signals.

2.
Lab Invest ; 100(3): 378-386, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31527830

RESUMO

Monocyte and adhesion infiltration into the arterial subendothelium are initial steps in hypertension development. The endothelial intercellular adhesion molecule-1 (ICAM-1) has been implicated in the recruitment and adhesion of leukocytes in several cardiac diseases. However, the role of ICAM-1 in angiotensin II (Ang II)-induced hypertension development remains unknown. Hypertension was induced by administering an infusion of Ang II (1000 ng/kg/min) to wild-type (WT) mice treated with an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse/day, respectively). Blood pressure was determined using the tail-cuff system. Vascular remodeling was assessed by performing a histological examination. Inflammation and reactive oxygen species (ROS) levels were determined by using immunostaining. Vascular dysfunction was assessed by aortic ring assay. The expression of fibrotic markers, cytokines and NOX was evaluated by quantitative real-time PCR analysis. Our results demonstrate that Ang II infusion markedly increased the ICAM-1 level in the aorta. Blocking ICAM-1 with a neutralizing antibody significantly attenuated Ang II-induced arterial hypertension, vascular hypertrophy, fibrosis, macrophage infiltration, and ROS production and improved vascular relaxation. In conclusion, ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II-induced arterial hypertension and vascular dysfunction. ICAM-1 inhibitors may represent a new therapeutic strategy for the treatment of this disease.

3.
Am J Physiol Heart Circ Physiol ; 317(6): H1301-H1311, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31729904

RESUMO

Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia-reperfusion injury, myocardial infarction, and atherosclerosis. However, the role of ICAM-1 in angiotensin II (ANG II)-induced cardiac remodeling in mice remains unclear. Wild-type mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and ANG II (1,000 ng·kg-1·min-1) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis, and inflammation were assessed by histological examination. The infiltration of lymphocyte function-associated antigen-1 (LFA-1+) monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in ANG II-infused hearts and ICAM-1 levels in serum from human patients with heart failure were significantly increased. Moreover, ANG II infusion markedly enhanced ANG II-induced hypertension, caused cardiac contractile dysfunction, and promoted cardiac hypertrophy, fibrosis, and LFA-1+ macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our in vitro data further demonstrated that blocking ICAM-1 inhibited ANG II-induced LFA-1+ macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in ANG II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1+ macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases.NEW & NOTEWORTHY Leukocyte adhesion to vascular endothelium is a critical step in cardiovascular diseases. ICAM-1 is a member of immunoglobulin-like superfamily of adhesion molecules that binds LFA-1 to mediate leukocytes adhesion and migration. However, the significance of ICAM-1 in ANG II-induced cardiac remodeling remains unclear. This study reveals that blocking of ICAM-1 prevents ANG II-induced cardiac remodeling via modulating adhesion and migration of LFA-1+ monocytes, may serve as a novel therapeutic target for hypertensive cardiac diseases.

4.
Mol Nutr Food Res ; 63(24): e1900418, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655498

RESUMO

SCOPE: Cardiac fibrosis is a key feature of cardiac remodeling. Recently, a protective role for resveratrol (RES) in pressure-overload-induced cardiac hypertrophy and contractile dysfunction has been demonstrated. However, the effect of RES on cardiac fibrosis and diastolic function in this model remains unclear. METHODS AND RESULTS: Cardiac remodeling is induced in mice by transverse aortic constriction (TAC) for 2-4 weeks. RES is administered at dose of 5 or 50 mg kg-1  d-1 for 2 weeks. It is found that RES administration at 50 mg kg-1  d-1 significantly attenuates TAC-induced adverse cardiac systolic and diastolic function, fibrosis, inflammation, and oxidative stress via inhibiting PTEN degradation and the downstream mediators. However, RES at 5 mg kg-1  d-1 has no significant effects. RES at 50 mg kg-1  d-1 also ameliorates pre-established adverse cardiac function and remodeling induced by TAC. Treatment with PTEN inhibitor VO-OHpic (10 mg kg-1  d-1 ) for 2 weeks abolishes RES-mediated protective effects. Additionally, the effect of RES (100 µm) on inhibition of Ang II-induced fibroblast proliferation and activation in vitro is verified. CONCLUSIONS: The findings provide new evidence that RES plays a critical role in the progression of cardiac fibrosis and diastolic dysfunction, and suggest that RES may be a promising therapeutic agent for cardiac fibrosis.

5.
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
6.
Hypertension ; 73(1): 92-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571551

RESUMO

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and increases the risk of stroke, heart failure, and death. Ang II (angiotensin II) triggers AF, mainly through stimulation of the AT1R (Ang II type I receptor). The immunoproteasome is a highly efficient proteolytic machine derived from the constitutive proteasome, but the role it plays in regulating AT1R activation and triggering AF remains unknown. Here, we show that among the catalytic subunits, ß5i (PSMB8) expression, and chymotrypsin-like activity were the most significantly upregulated in atrial tissue of Ang II-infused mice or serum from patients with AF. ß5i KO (ß5i knockout) in mice markedly attenuated Ang II-induced AF incidence, atrial fibrosis, inflammatory response, and oxidative stress compared with WT (wild type) animals, but injection with recombinant adeno-associated virus serotype 9-ß5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of ß5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9-ß5i-injected mice. Mechanistically, Ang II upregulated ß5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-ß1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF. In summary, this study identifies ß5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting ß5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.


Assuntos
Angiotensina II , Fibrilação Atrial , Átrios do Coração , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Imunoproteínas/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos
7.
Redox Biol ; 20: 390-401, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30412827

RESUMO

Sustained cardiac hypertrophy is a major cause of heart failure (HF) and death. Recent studies have demonstrated that resveratrol (RES) exerts a protective role in hypertrophic diseases. However, the molecular mechanisms involved are not fully elucidated. In this study, cardiac hypertrophic remodeling in mice were established by pressure overload induced by transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiography and invasive pressure-volume analysis. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein and gene expressions of signaling mediators and hypertrophic markers were examined. Our results showed that administration of RES significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and apoptosis and improved in vivo heart function in mice. RES also reversed pre-established hypertrophy and restoring contractile dysfunction induced by chronic pressure overload. Moreover, RES treatment blocked TAC-induced increase of immunoproteasome activity and catalytic subunit expression (ß1i, ß2i and ß5i), which inhibited PTEN degradation thereby leading to inactivation of AKT/mTOR and activation of AMPK signals. Further, blocking PTEN by the specific inhibitor VO-Ohpic significantly attenuated RES inhibitory effect on cardiomyocyte hypertrophy in vivo and in vitro. Taken together, our data suggest that RES is a novel inhibitor of immunoproteasome activity, and may represent a promising therapeutic agent for the treatment of hypertrophic diseases.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , PTEN Fosfo-Hidrolase/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Resveratrol/farmacologia , Animais , Biomarcadores , Pressão Sanguínea , Cardiomegalia/diagnóstico , Cardiomegalia/tratamento farmacológico , Cardiotônicos/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Ecocardiografia , Testes de Função Cardíaca , Masculino , Camundongos , Modelos Moleculares , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Complexo de Endopeptidases do Proteassoma/imunologia , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR
8.
Cell Physiol Biochem ; 48(3): 983-992, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30036880

RESUMO

BACKGROUND/AIMS: Angiotensin II (Ang II)-mediated hypertension is a major risk factor for cardiovascular diseases. Ang II induces changes in vessel structure and function through the activation of genes related to signaling pathways. However, the changes in the gene expression profiles of blood vessels in response to Ang II remain unclear. METHODS: Wild-type C57BL/6 mice were infused with Ang II (1500 ng/kg/min) using an osmotic pump for 1, 3, and 7 days. Vascular wall inflammation and remodeling were evaluated by pathological examination. Time-series microarray and quantitative PCR analyses were performed. Bioinformatics analyses were conducted to identify key genes, pathways, and biological processes. RESULTS: After Ang II infusion, blood pressure and aortic remodeling were increased over time. Microarray analysis identified a totally of 3631 differentially expressed genes in aortas at days 1, 3, and 7 of Ang II infusion. These genes were involved in multiple biological processes, including cell adhesion, angiogenesis, cell migration, protein phosphorylation, immune system, and cell cycle, which may play important roles in regulating Ang II-induced arterial injury during hypertension. The genes were classified into 50 profiles by hierarchical cluster analysis, and finally, 14 significant profiles were identified. Among these genes, protein kinase cAMP-activated catalytic subunit alpha (Prkaca), a gene that directly regulated 137 neighboring genes, was located at the center of the gene network in Ang II-infused aortas. Further, Prkaca protein expression and cAMP level were downregulated in a time-dependent manner in Ang II-infused aortas. CONCLUSIONS: The combined use of DNA microarrays and cluster and gene network analyses identified Prkaca as a key Ang II-responsive gene that may mediate early vascular injury and hypertension.


Assuntos
Angiotensina II/farmacologia , Transcriptoma/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Pressão Sanguínea/efeitos dos fármacos , Análise por Conglomerados , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Hipertensão/etiologia , Hipertensão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Tempo
9.
Eur Heart J ; 39(20): 1818-1831, 2018 05 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.


Assuntos
Cardiomegalia/metabolismo , Quimiocina CXCL1/fisiologia , Monócitos/fisiologia , Receptores de Interleucina-8B/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensina II , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Cardiomegalia/prevenção & controle , Movimento Celular/fisiologia , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/sangue , Feminino , Fibrose , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miocárdio/patologia , Receptores de Interleucina-8B/sangue , Receptores de Interleucina-8B/deficiência , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
10.
Redox Biol ; 16: 129-138, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29499566

RESUMO

Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKß specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBα phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II-induced retinopathy. Strategies for inhibiting LMP10 or IKKß activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy.


Assuntos
Inflamação/genética , Complexo de Endopeptidases do Proteassoma/genética , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/farmacologia , Animais , Feminino , Humanos , Retinopatia Hipertensiva/induzido quimicamente , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Inflamação/sangue , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Fosforilação , Complexo de Endopeptidases do Proteassoma/sangue , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Theranostics ; 8(21): 5995-6007, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30613277

RESUMO

Rationale: Sustained cardiac hypertrophy often leads to heart failure (HF). Understanding the regulation of cardiomyocyte growth is crucial for the treatment of adverse ventricular remodeling and HF. Cell division cycle 20 (CDC20) is an anaphase-promoting complex activator that is essential for cell division and tumorigenesis, but the role of CDC20 in cardiac hypertrophy is unknown. We aimed to test whether CDC20 participates in the regulation of pathological cardiac hypertrophy and investigate the underlying mechanism in vitro and in vivo. Methods: Male C57BL/6 mice were administered a recombinant adeno-associated virus serotype 9 (rAAV9) vector expressing CDC20 or a siRNA targeting CDC20 and their respective controls by tail intravenous injection. Results: Microarray analysis showed that CDC20 was significantly upregulated in the heart after angiotensin II infusion. Knockdown of CDC20 in cardiomyocytes and in the heart reduced cardiac hypertrophy upon agonist stimulation or transverse aortic constriction (TAC). Conversely, enforced expression of CDC20 in cardiomyocytes and in the heart aggravated the hypertrophic response. Furthermore, we found that CDC20 directly targeted LC3, a key regulator of autophagy, and promoted LC3 ubiquitination and degradation by the proteasome, which inhibited autophagy leading to hypertrophy. Moreover, knockdown of LC3 or inhibition of autophagy attenuated Ang II-induced cardiomyocyte hypertrophy after deletion of CDC20 in vitro. Conclusions: Our study reveals a novel cardiac hypertrophy regulatory mechanism that involves CDC20, LC3 and autophagy, and suggests that CDC20 could be a new therapeutic target for patients with hypertrophic heart diseases.


Assuntos
Autofagia , Cardiomegalia/fisiopatologia , Proteínas Cdc20/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Proteínas Cdc20/genética , Dependovirus/genética , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Vetores Genéticos , Masculino , Camundongos Endogâmicos C57BL , Análise em Microsséries , Infecções por Parvoviridae , Transdução Genética
12.
Artigo em Inglês | MEDLINE | ID: mdl-25218220

RESUMO

Two novel complexes [Cu(L)2(Ac)2]·3H2O (1) (L=N-2-methyl benzimidazole demethylcantharate imide, C16H15N3O3, Ac=acetate, C2H3O2) and [Cu(bimz)2(DCA)] (2) (bimz=benzimidazole, C7H6N2; DCA=demethylcantharate, C8H8O5) were synthesized and characterized by elemental analysis, infrared spectra and X-ray diffraction techniques. Cu(II) ion was four-coordinated in complex 1, Cu(II) ion was five-coordinated in complex 2. A large amount of intermolecular hydrogen-bonding and π-π stacking interactions were observed in these complex structures. The DNA-binding properties of these complexes were investigated using electronic absorption spectra, fluorescence spectra, viscosity measurements and agarose gel electrophoresis. The interactions between the complexes and bovine serum albumin (BSA) were investigated by fluorescence spectra. The antiproliferative activities of the complexes against human hepatoma cells (SMMC7721) were tested in vitro. And the results showed that these complexes could bind to DNA in moderate intensity via partial intercalation, and complexes 1 and 2 could cleave plasmid DNA through hydroxyl radical mechanism. Title complexes could effectively quench the fluorescence of BSA through static quenching. Meanwhile, title complexes had stronger antiproliferative effect compared to L and Na2(DCA) within the tested concentration range. And complex 1 possessed more antiproliferative active than complex 2.


Assuntos
Antineoplásicos/química , Benzimidazóis/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Complexos de Coordenação/química , Cobre/química , Substâncias Intercalantes/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Cristalografia por Raios X , DNA/metabolismo , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Modelos Moleculares , Soroalbumina Bovina/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-24220672

RESUMO

Two novel copper(II) complexes with Schiff base of benzimidazole [Cu(L)Cl]2·CH3OH have been synthesized. HL(1) (N-(benzimidazol-2-ymethyl)-5-chlorosalicylideneimine, C15H11ClN3O) and HL(2) (N-(benzimidazol-2-ymethyl)-salicylideneimine, C15H12N3O) are ligands of complex (1) and complex (2), respectively. The complexes were characterized by elemental analysis, IR, UV-Vis, TGA and X-ray diffraction. Within the complexes, Cu(II) ions were four coordinated by two nitrogen atom of azomethine and imine, one phenolic oxygen atom from HL and one chloride atom. A distorted quadrilateral structure was formed. Complex (1) crystallized in the triclinic crystal system. Results showed that π-π stacking effect occurred due to the existence of aromatic ring from Schiff base and hydrogen bonding between methanol and adjacent atoms. The DNA binding properties of the complexes were investigated by electronic absorption spectra, fluorescence spectra and viscosity measurements. Results indicated that complexes bound to DNA via partial intercalation mode. The DNA binding constants Kb/(L mol(-1)) were 1.81×10(4) (1), 1.37×10(4) (2), 6.27×10(3) (HL(1)) and 3.14×10(3) (HL(2)) at 298 K. The title complexes could quench the emission intensities of EB-DNA system significantly. The results of agarose gel electrophoresis indicated complex (1) could cleave supercoiled DNA through the oxidative mechanism. The inhibition ratios revealed that complex (1) and HL(1) had strong antiproliferative activities against human breast cancer cells (MCF-7) lines and human colorectal cancer cells (COLO205) lines in vitro. The antiproliferative activities of complex (1) against MCF-7 lines (IC50=16.9±1.5 µmol L(-1)) and against COLO205 lines (IC50=16.5±3.4 µmol L(-1)) is much stronger than that of HL(1), which had the potential to develop anti-cancer drug.


Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Cobre/farmacologia , DNA/metabolismo , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Absorção , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cobre/química , Cristalografia por Raios X , Humanos , Conformação Molecular , Plasmídeos/metabolismo , Bases de Schiff/química , Espectrometria de Fluorescência , Termogravimetria , Viscosidade/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-23557779

RESUMO

Three new transition metal complexes [Mn2(DCA)2(bipy)2]·5H2O (1), [M2(DCA)2(bipy)2(H2O)]·10H2O(M=Ni(II)(2);Zn(II)(3)), (DCA=demethylcantharate, 7-oxabicyclo[2,2,1]heptane-2,3-dicarboxylate, C8H8O5) were synthesized and characterized by elemental analysis, molar conductance, infrared spectra and X-ray diffraction techniques. Each metal ion was six-coordinated in complexes. Complex 1 has a Mn2O2 center. Complexes 2 and 3 have asymmetric binuclear structure. Great amount of intermolecular hydrogen-bonding and π-π(*) stacking interactions were formed in these complex structures. The DNA-binding properties of complexes were investigated by electronic absorption spectra and viscosity measurements. The DNA binding constants Kb/(Lmol(-1)) were 1.71×10(4) (1), 2.62×10(4) (2) and 1.59×10(4) (3) at 298 K. The complexes could quench the intrinsic fluorescence of bovine serum albumin (BSA) strongly through static quenching. The protein binding constants Ka/(L mol(-1)) were 7.27×10(4) (1), 4.55×10(4) (2) and 7.87×10(4) L mol(-1) (3) and binding site was one. The complexes bind more tightly with DNA and BSA than with ligands. Complexes 1 and 3 had stronger inhibition ratios than Na2(DCA) against human hepatoma cells (SMMC-7721) lines and human gastric cancer cells (MGC80-3) lines in vitro. Complex 3 showed the strongest antiproliferative activity against SMMC-7721 (IC50=29.46±2.12 µmol L(-1)) and MGC80-3 (IC50=27.02±2.38 µmol L(-1)), which shows potential in anti-cancer drug development.


Assuntos
2,2'-Dipiridil/farmacologia , Antineoplásicos/farmacologia , Cantaridina/análogos & derivados , Complexos de Coordenação/farmacologia , Manganês/farmacologia , Níquel/farmacologia , Zinco/farmacologia , 2,2'-Dipiridil/química , 2,2'-Dipiridil/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Cantaridina/química , Cantaridina/metabolismo , Cantaridina/farmacologia , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , DNA/metabolismo , Humanos , Manganês/química , Manganês/metabolismo , Modelos Moleculares , Neoplasias/tratamento farmacológico , Níquel/química , Níquel/metabolismo , Soroalbumina Bovina/metabolismo , Zinco/química , Zinco/metabolismo
15.
Artigo em Chinês | MEDLINE | ID: mdl-23510838

RESUMO

OBJECTIVE: In order to study the feature of T cell TCR-CD3 complex-mediated gene in lead poisoning patients. METHODS: Real-time PCR with SYBR Green I technique was used for determination of the expression levels of CD3 genes in peripheral blood mononuclear cells of 46 cases lead poisoning patients (11 cases in observation group and 35 cases in mild lead poisoning group) and 31 cases in control group. RESULTS: The median expression levels of CD3γ gene in observation group and mild lead poisoning group (6.89%, 5.87 %) were higher than the control group (P < 0.05). The median expression levels of CD3δ gene in observation group and mild lead poisoning group (0.54%, 0.70%) were lower than the control group (P < 0.05). The median expression levels of CD3ε gene in observation group and mild lead poisoning group (10.22%, 6.08%) were higher than the control group (P < 0.05). A significant Positive correlation was found between CD3γ, CD3ε and seniority in lead poisoning patients. A significant negative correlation was found between CD3ε and blood ZPP, urea δ-ALA (r = -0.358, P < 0.05; r = -0.385, P < 0.05), but there was no significant correlation between them after controlling for blood lead, urea lead. The expression levels of CD3 genes prove to be a descending order of CD3γ, CD3ε, CD3δ in control group, while it was changed for CD3ε, CD3γ, CD3δ in the observation group as well as in mild lead poisoning group. CONCLUSION: Expression of T cell TCR-CD3 complex-mediated gene was changed in lead poisoning patients, it might be related to the body immunodeficiency. The expression level of CD3ε gene can be used as sensitive immune function screening indicator in Lead poisoning patients.


Assuntos
Intoxicação por Chumbo/imunologia , Doenças Profissionais/imunologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-22995471

RESUMO

Four new transition metal complexes (Habtz)(2)[M(DCA)(2)]·6H(2)O (M=Co(II) (1), Ni(II) (2), Cu(II) (3), Zn(II) (4); DCA=demethylcantharate, 7-oxabicyclo [2.2.1]heptane-2,3-dicarboxylate, C(8)H(8)O(5); Habtz=2-aminobenzothiazole acid, C(7)H(7)N(2)S) were synthesized and characterized by elemental analysis, molar conductance, infrared spectra and thermogravimetric analysis. The coordination number of complex was six. The X-ray diffraction analysis indicated that complex 3 crystallized in the triclinic crystal system with P1¯ space group. The DNA-binding properties of the complexes were investigated by electronic absorption spectra, fluorescence spectra, viscosity measurements. Title complexes could bind to DNA via partial intercalative mode. The K(b) of the complexes were 5.33×10(4) (1), 7.04×10(4) (2), 9.91×10(4) (3) and 5.03×10(4) L mol(-1) (4). The results of agarose gel electrophoresis showed that Cu(II) complex could cleave pBR322 plasmid DNA via radical-based mechanism. The complexes could quench the intrinsic fluorescence of bovine serum albumin (BSA) through a static quenching with the binding constants K(a) of 1.11×10(4) (1), 1.24×10(6) (2), 8.42×10(5) (3) and 1.75×10(4) L mol(-1) (4). The complexes had intense antiproliferative activities against human hepatoma cell lines (SMMC7721) and human gastric cancer cells (MGC80-3) lines in vitro. Cu(II) complex had the strongest activity against human gastric cancer cells.


Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Cantaridina/análogos & derivados , Complexos de Coordenação/farmacologia , Elementos de Transição/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzotiazóis/química , Benzotiazóis/metabolismo , Cantaridina/química , Cantaridina/metabolismo , Cantaridina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , DNA/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Modelos Moleculares , Soroalbumina Bovina/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Elementos de Transição/química , Elementos de Transição/metabolismo
17.
J Fluoresc ; 22(5): 1395-406, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22733190

RESUMO

Three novel transition metal complexes (Hapy)(2)[M(DCA)(2)]·6H(2)O (M = Mn(II) (1), Ni(II) (2), Cu(II) (3); DCA = demethylcantharate, 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylate, C(8)H(8)O(5); Hapy = 2-aminopyridine acid, C(5)H(7)N(2)) were synthesized and characterized by elemental analysis, infrared spectra, thermogravimetric analysis and X-ray diffraction. DNA binding properties of the complexes were investigated by electronic absorption spectra, fluorescence spectra and viscosity measurements. Results indicated the complexes could bind to DNA through partial intercalation mode with binding constants K ( b )/(L·mol(-1)) of 1.91 × 10(4) (1), 5.13 × 10(4) (2) and 1.12 × 10(5) (3) at 298 K. Meanwhile, the interactions of the complexes with BSA were also studied by fluorescence spectra. The results suggested that the complexes could quench the fluorescence of BSA through static quenching with the binding constants K ( A )/(L·mol(-1)) of 1.44 × 10(6) (1), 1.14 × 10(7) (2) and 2.98 × 10(4) (3). And the main contribution was tryptophan residues of BSA. The antiproliferative activity test revealed that complexes showed more intense inhibition ratios against human hepatoma cells lines and human gastric cancer cells lines in vitro. Copper(II) complex (3) possesses the strongest inhibition ratio against human hepatoma cells.


Assuntos
Aminopiridinas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Cantaridina/análogos & derivados , Cantaridina/química , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Soroalbumina Bovina/metabolismo , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cobre/química , Cristalografia por Raios X , Humanos , Manganês/química , Níquel/química , Compostos Organometálicos/química , Ligação Proteica , Análise Espectral , Viscosidade
18.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 6): m818, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22719361

RESUMO

In the structure of the title complex, (C(7)H(7)N(2)S)(2)[Cd(C(8)H(8)O(5))(2)]·6H(2)O, the Cd(II) atom is located on an inversion center and is O,O',O''-chelated by two symmetry-related 7-oxabicyclo-[2.2.1]heptane-2,3-dicarboxyl-ate ligands in a distorted octa-hedral geometry. The 2-amino-benzothia-zolium cation links with the Cd complex anion via N-H⋯O hydrogen bonding. Extensive O-H⋯O and N-H⋯O hydrogen bonds involving lattice water mol-ecules occur in the crystal structure.

19.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 5): m684, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22590166

RESUMO

In the title hydrated mol-ecular salt, (C(7)H(7)N(2)S)(2)[Zn(C(8)H(8)O(5))(2)]·6H(2)O, which is isotypic with its Mn(II), Co(II) and Ni(II) analogues, the Zn(2+) ion lies on a crystallographic inversion centre and a distorted ZnO(6) octa-hedral coordination geometry arises from the two doubly deprotonated O,O',O''-tridentate ligands. In the crystal, the components are linked by N-H⋯O(a), N-H⋯O(w), O(w)-H⋯O(a) and O(w)-H⋯O(w) hydrogen bonds (w = water and a = anion).

20.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 2): m146, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22346827

RESUMO

The polymeric title complex, [Co(C(8)H(8)O(5))(H(2)O)(2)](n) was synthesized by reaction of cobalt acetate with 7-oxabicyclo-[2,2,1]heptane-2,3-dicarb-oxy-lic anhydride. The Co(II) ion is six-coordinated in a distorted octa-hedral environment, binding to two water O atoms, to the ether O atom of the bicyclo-heptane unit, to two carboxyl-ate O atoms from two different carboxyl-ate groups of the same anion and to one carboxyl-ate O atom from a symmetry-related anion. The bridging character of the dianion leads to the formation of ribbons along [001]. The ribbons are linked into a layered network parallel to (010) by several O-H⋯O hydrogen-bonding inter-actions involving the coordinating water mol-ecules as donors and the carboxyl-ate O atoms of neighbouring ribbons as acceptors. The crystal under investigation was an inversion twin.

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