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1.
Cells ; 11(4)2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35203308

RESUMO

Kidney fibrosis has been accepted to be a common pathological outcome of chronic kidney disease (CKD). We aimed to examine serum levels and tissue expression of chemokine (C-C motif) ligand 8 (CCL8) in patients with CKD and to investigate their association with kidney fibrosis in CKD model. Serum levels and tissue expression of CCL8 significantly increased with advancing CKD stage, proteinuria level, and pathologic deterioration. In Western blot analysis of primary cultured human tubular epithelial cells after induction of fibrosis with rTGF-ß, CCL8 was upregulated by rTGF-ß treatment and the simultaneous treatment with anti-CCL8 mAb mitigated the rTGF-ß-induced an increase in fibronectin and a decrease E-cadherin and BCL-2 protein levels. The antiapoptotic effect of the anti-CCL8 mAb was also demonstrated by Annexin V/propidium iodide staining assay. In qRT-PCR analysis, mRNA expression levels of the markers for fibrosis and apoptosis showed similar expression patterns to those observed by western blotting. The immunohistochemical analysis revealed CCL8 and fibrosis- and apoptosis-related markers significantly increased in the unilateral ureteral obstruction model, which agrees with our in vitro findings. In conclusion, CCL8 pathway is associated with increased risk of kidney fibrosis and that CCL8 blockade can ameliorate kidney fibrosis and apoptosis.


Assuntos
Anticorpos Monoclonais , Quimiocina CCL8 , Insuficiência Renal Crônica , Obstrução Ureteral , Anticorpos Monoclonais/farmacologia , Células Cultivadas , Quimiocina CCL8/antagonistas & inibidores , Células Epiteliais , Fibrose , Humanos , Túbulos Renais/citologia , Insuficiência Renal Crônica/patologia , Obstrução Ureteral/complicações
2.
Biosci Biotechnol Biochem ; 84(8): 1585-1593, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32432500

RESUMO

C-C motif Chemokine ligand 8 (CCL8) has been found in diseases' pathogenesis. But its molecular mechanism in atherosclerosis (AS) remains to be elucidated. Human aortic smooth muscle cells (HASMCs) were stimulated by PDGF-BB to establish cell model. α-SMA in PDGF-BB-stimulated HASMCs was measured by immunofluorescence staining. Relative gene expressions in PDGF-BB-stimulated HASMCs were detected by quantitative real-time polymerase chain reaction and western blot. HASMCs proliferation, migration, and cell cycle were assessed by cell counting kit-8, wound-healing assay, and flow cytometry. HASMCs viability was increased after PDGF-BB stimulation, with α-SMA downregulation yet CCL8 upregulation. Silencing CCL8 inhibited PDGF-BB-stimulated HASMCs proliferation and migration, and increased cells percentage in G1 phases but decreased those in S phase. Also, silencing CCL8 decreased OPN and cyclinD1 expressions and AKT and ERK1/2 phosphorylation while increased those of α-SMA and Sm22α. However, upregulating CCL8 led to opposite effects, suggesting CCL8 could be an atherosclerosis therapeutic target.


Assuntos
Becaplermina/farmacologia , Ciclo Celular/efeitos dos fármacos , Quimiocina CCL8/genética , Miócitos de Músculo Liso/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Aorta/citologia , Aorta/metabolismo , Ciclo Celular/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL8/antagonistas & inibidores , Quimiocina CCL8/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
3.
FASEB J ; 24(7): 2292-300, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20181935

RESUMO

MicroRNA-mediated regulation of gene expression appears to be involved in a variety of cellular processes, including development, differentiation, proliferation, and apoptosis. Mir-146a is thought to be involved in the regulation of the innate immune response, and its expression is increased in tissues associated with chronic inflammation. Among the predicted gene targets for mir-146a, the chemokine CCL8/MCP-2 is a ligand for the CCR5 chemokine receptor and a potent inhibitor of CD4/CCR5-mediated HIV-1 entry and replication. In the present study, we have analyzed changes in the expression of mir-146a in primary human fetal microglial cells upon infection with HIV-1 and found increased expression of mir-146a. We further show that CCL8/MCP-2 is a target for mir-146a in HIV-1 infected microglia, as overexpression of mir-146a prevented HIV-induced secretion of MCP-2 chemokine. The clinical relevance of our findings was evaluated in HIV-encephalitis (HIVE) brain samples in which decreased levels of MCP-2 and increased levels of mir-146a were observed, suggesting a role for mir-146a in the maintenance of HIV-mediated chronic inflammation of the brain.


Assuntos
Quimiocina CCL8/antagonistas & inibidores , Infecções por HIV/etiologia , HIV-1/patogenicidade , MicroRNAs/genética , Microglia/virologia , Células Cultivadas , Encefalite Viral/patologia , Regulação da Expressão Gênica/imunologia , Infecções por HIV/genética , Infecções por HIV/imunologia , Humanos , Inflamação/virologia
4.
Blood ; 112(8): 3455-64, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18660381

RESUMO

Through the activity of macrophage-specific matrix metalloproteinase-12 (MMP-12), we found that macrophages dampen the lipopolysaccharide (LPS)-induced influx of polymorphonuclear leukocytes (PMNs)-thus providing a new mechanism for the termination of PMN recruitment in acute inflammation. MMP-12 specifically cleaves human ELR(+) CXC chemokines (CXCL1, -2, -3, -5, and -8) at E-LR, the critical receptor-binding motif or, for CXCL6, carboxyl-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1, -2, and -3 at E-LR. MMP-12-cleaved mCXCL2 (macrophage-inflammatory protein-2 [MIP-2]) and mCXCL3 (dendritic cell inflammatory protein-1 [DCIP-1]) lost chemotactic activity. Furthermore, MMP-12 processed and inactivated monocyte chemotactic proteins CCL2, -7, -8, and -13 at position 4-5 generating CCR antagonists. Indeed, PMNs and macrophages in bronchoalveolar lavage fluid were significantly increased 72 hours after intranasal instillation of LPS in Mmp12(-/-) mice compared with wild type. Specificity occurred at 2 levels. Macrophage MMP-1 and MMP-9 did not cleave in the ELR motif. Second, unlike human ELR(+)CXC chemokines, mCXCL5 (LPS-induced CXC chemokine [LIX]) was not inactivated. Rather, mMMP-12 cleavage at Ser4-Val5 activated the chemokine, promoting enhanced PMN early infiltration in wild-type mice compared with Mmp12(-/-) mice 8 hours after LPS challenge in air pouches. We propose that the macrophage, specifically through MMP-12, assists in orchestrating the regulation of acute inflammatory responses by precise proteolysis of ELR(+)CXC and CC chemokines.


Assuntos
Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Quimiocina CCL8/metabolismo , Quimiocinas CXC/metabolismo , Regulação da Expressão Gênica , Macrófagos/metabolismo , Metaloproteinase 12 da Matriz/fisiologia , Proteínas Quimioatraentes de Monócitos/metabolismo , Neutrófilos/metabolismo , Motivos de Aminoácidos , Animais , Movimento Celular , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL7/antagonistas & inibidores , Quimiocina CCL8/antagonistas & inibidores , Feminino , Humanos , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Quimioatraentes de Monócitos/antagonistas & inibidores , Neutrófilos/citologia
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