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1.
Exp Physiol ; 109(7): 1188-1198, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38774964

RESUMO

Previous studies have shown that podocyte injury is involved in the development of proteinuria in rats under hypobaric hypoxia conditions. Prolyl hydroxylase inhibitors (PHIs) may reduce proteinuria. This study aimed to further investigate whether the protective effects of hypoxia-inducible factor 1α (HIF1α) on podocyte injury induced by hypobaric hypoxia are related to Krüppel-like factor 4 (KLF4). Rats were housed in a low-pressure oxygen chamber to simulate a high-altitude environment (5000 m), and a PHI was intraperitoneally injected. Urinary protein electrophoresis was performed and the morphology of the podocytes was observed by electron microscopy. Rat podocytes were cultured under 1% O2, and siRNA was used to interfere with KLF4 expression. The protein expression levels of HIF1α, KLF4, CD2-associated protein (CD2AP) and nephrin were determined by western blotting. Compared with those in the experimental group, the rats in the intervention group on day 14 had lower urinary protein levels, increased protein expression levels of CD2AP and nephrin, and reduced podocyte injury. The results of in vitro experiments showed that the protein expression levels of KLF4, CD2AP and nephrin were greater in the PHI intervention group and lower in the HIF1α inhibitors group than in the low-oxygen group. The protein expression of CD2AP and nephrin in the siKLF4-transfected podocytes treated with PHI and HIF1α inhibitors did not differ significantly from that in the low-oxygen group. HIF1α may be involved in reducing progressive high-altitude proteinuria by regulating KLF4 expression and contributing to the repair of podocyte injury induced by hypobaric hypoxia.


Assuntos
Altitude , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Podócitos , Ratos Sprague-Dawley , Regulação para Cima , Animais , Podócitos/metabolismo , Podócitos/patologia , Fator 4 Semelhante a Kruppel/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteinúria/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/genética , Hipóxia/metabolismo , Proteínas Adaptadoras de Transdução de Sinal
2.
Acta Pharmaceutica Sinica B ; (6): 3782-3801, 2023.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-1011153

RESUMO

Toll-like receptor 2 (TLR2) mediated macrophages regulate the protective immune response to infectious microorganisms, but the aberrant activation of macrophages often leads to pathological inflammation, including tissue damage. In this study, we identified antagonists of TLR2 by screening 2100 natural products and subsequently identified Taspine, an aporphine alkaloid, as an excellent candidate. Furthermore, analysis of the 10 steps chemical synthesis route and structural optimization yielded the Taspine derivative SMU-Y6, which has higher activity, better solubility, and improved drug-feasible property. Mechanistic studies and seq-RNA analysis revealed that SMU-Y6 inhibited TLR2 over other TLRs, hindered the formation of TLR2/MyD88 complex, and blocked the downstream NF-κB and MAPK signaling pathway, thus suppressing the release of inflammatory cytokines. SMU-Y6 could stabilize TLR2 and bind to TLR2 protein with a Kd of 0.18 μmol/L. Additionally, SMU-Y6 could efficiently reverse the M1 phenotype macrophage polarization, reduce the production of cytokines as well as infiltration of neutrophiles and alleviate the local inflammation in mice with acute paw edema and colitis. Collectively, we reported the first aporphine alkaloid derivative that selectively inhibits TLR2 with high binding affinity and superior drug-feasible property, thus providing an urgently-needed molecular probe and potential drug candidate for inflammatory and autoimmune disease therapy.

3.
J BUON ; 19(3): 656-61, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25261648

RESUMO

PURPOSE: Breast cancer is a multifactorial disease and identification of the genes and proteins regulating breast carcinogenesis is critical in exploring novel targeted therapies. The aim of this study was to investigate the role CETN1 in breast cancer growth and metastasis. METHODS: CETN1 expression levels were measured in breast tissue samples by immunohistochemistry (IHC). We selected high CETN1-expressing cell lines from human breast carcinoma cells with metastatic potential. The proliferation of cells was evaluated by MTS assay. Changes in progression of cell division were assessed by cell cycle analysis. Changes in CETN1 levels in breast tumor cells were analysed by Western blot. RESULTS: Our results demonstrated that overexpression of CETN1 occurred mainly in breast cancer cells in which CETN1 expression was low. Knockdown of CETN1 by lentivirus- shRNA significantly inhibited breast cancer cells' proliferation, growth and metastasis. CONCLUSION: CETN1 is overexpressed in breast cancer tissue and promotes cells'proliferation, tumor growth and metastasis.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Proteínas de Ciclo Celular/fisiologia , Proliferação de Células , Animais , Neoplasias da Mama/patologia , Ciclo Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Interferência de RNA , Ratos , Ratos Endogâmicos Lew
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