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1.
Signal Transduct Target Ther ; 9(1): 127, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38782919

RESUMO

DEAD-box helicase 17 (DDX17) is a typical member of the DEAD-box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice (Ddx17-cKO), cardiomyocyte-specific Ddx17 transgenic mice (Ddx17-Tg), and various models of cardiomyocyte injury and heart failure (HF). DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury. Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis, leading to progressive cardiac dysfunction, maladaptive remodeling and progression to heart failure. Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6 (BCL6) and inhibit the expression of dynamin-related protein 1 (DRP1). When DDX17 expression is reduced, transcriptional repression of BCL6 is attenuated, leading to increased DRP1 expression and mitochondrial fission, which in turn leads to impaired mitochondrial homeostasis and heart failure. We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.


Assuntos
RNA Helicases DEAD-box , Insuficiência Cardíaca , Miócitos Cardíacos , Animais , Humanos , Camundongos , Apoptose/genética , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Dinaminas/genética , Dinaminas/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/metabolismo , Homeostase/genética , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
2.
Water Res ; 238: 120016, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37146397

RESUMO

Anammox bacteria rely heavily on iron and have many iron storage sites. However, the biological significance of these iron storage sites has not been clearly defined. In this study, we explored the properties and location of iron storage sites to better understand their cellular function. To do this, the Candidatus Kuenenia stuttgartiensis iron storage protein, bacterioferritin (K.S Bfr), was successfully expressed and purified. In vitro, correctly assembled globulins were observed by transmission electron microscopy. The self-assembled K.S Bfr has active redox and can bind Fe2+ and mineralize it in the protein cavity. In vivo, engineered bacteria with K.S Bfr showed good adaptability to Fe2+, with a survival rate of 78.9% when exposed to 5 mM Fe2+, compared with only 66.0% for wild-type bacteria lacking K.S Bfr. A potential iron regulatory strategy similar to that of Anammox was identified in transcriptomic analysis of engineered bacteria. This system may be controlled by the iron uptake regulator Furto transport Fe2+ via FeoB and store excess Fe2+ in K.S Bfr to maintain cellular homeostasis. K.S Bfr has superior iron storage capacity both intracellularly and in vitro. The discovery of K.S Bfr reveals the storage location of iron-rich nanoparticles, increases our understanding of the adaptability of iron-dependent bacteria to Fe2+, and suggests possible iron regulation strategies in Anammox bacteria.


Assuntos
Ferritinas , Ferro , Ferro/metabolismo , Ferritinas/química , Ferritinas/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bactérias/metabolismo , Oxirredução , Homeostase
3.
Oxid Med Cell Longev ; 2022: 5184135, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186188

RESUMO

OBJECTIVE: To investigate the protective effects and regulatory mechanism of miR-488-3p on doxorubicin-induced cardiotoxicity. METHODS: The C57BL/6 mice and primary cardiomyocytes were used to construct doxorubicin-induced cardiomyocyte injury models in vivo and in vitro. The levels of miR-488-3p and its downstream target genes were analyzed by quantitative real-time PCR. Mouse cardiac function, cell survival, cellular injury-related proteins, and the apoptosis level of cardiomyocytes were analyzed by echocardiography, MTT analysis, Western blotting, and DNA laddering separately. RESULTS: Cardiomyocyte injury caused by a variety of stimuli can lead to the reduction of miR-488-3p level, especially when stimulated with doxorubicin. Doxorubicin led to significant decrease in cardiac function, cell autophagic flux blockage, and apoptosis in vivo and in vitro. The expression of miR-488-3p's target gene, CyclinG1, increased remarkably in the doxorubicin-treated neonatal mouse cardiomyocytes. Overexpression of miR-488-3p inhibited CyclinG1 expression, increased cardiomyocyte viability, and attenuated doxorubicin-induced cardiomyocyte autophagic flux blockage and apoptosis. CONCLUSIONS: miR-488-3p is one of the important protective miRNAs in doxorubicin-induced cardiotoxicity by inhibiting the expression of CyclinG1, which provides insight into the possible clinical application of miR-488-3p/CyclinG1 as therapeutic targets in doxorubicin-induced cardiovascular diseases.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Ciclina G1/antagonistas & inibidores , Doxorrubicina/efeitos adversos , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Animais , Humanos , Masculino , Camundongos , Ratos
4.
J Immunol Res ; 2021: 1815098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307691

RESUMO

Adiponectin is a small peptide secreted and a key component of the endocrine system and immune system. Although globular adiponectin protects myocardial ischemia/reperfusion-induced cardiomyocyte injury, the protective mechanisms remain largely unresolved. Using a neonatal rat ventricular myocyte hypoxia/reoxygenation model, we investigated the role of its potential mechanisms of necroptosis in globular adiponectin-mediated protection in hypoxia/reoxygenation-induced cardiomyocyte injury as compared to apoptosis. We found that globular adiponectin treatment attenuated cardiomyocyte injury as indicated by increased cell viability and reduced lactate dehydrogenase release following hypoxia/reoxygenation. Immunofluorescence staining and Western blotting demonstrated that both necroptosis and apoptosis were triggered by hypoxia/reoxygenation and diminished by globular adiponectin. Necrostatin-1 (RIP1-specific inhibitor) and Z-VAD-FMK (pan-caspase inhibitor) only mimicked the inhibition of necroptosis and apoptosis, respectively, by globular adiponectin in hypoxia/reoxygenation-treated cardiomyocytes. Globular adiponectin attenuated reactive oxygen species production, oxidative damage, and p38MAPK and NF-κB signaling, all important for necroptosis and apoptosis. Collectively, our study suggests that globular adiponectin inhibits hypoxia/reoxygenation-induced necroptosis and apoptosis in cardiomyocytes probably by reducing oxidative stress and interrupting p38MAPK signaling.


Assuntos
Adiponectina/metabolismo , Traumatismo por Reperfusão Miocárdica/imunologia , Miócitos Cardíacos/patologia , Animais , Animais Recém-Nascidos , Apoptose/imunologia , Hipóxia Celular/imunologia , Sobrevivência Celular , Células Cultivadas , Meios de Cultura/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/imunologia , Necroptose/imunologia , Estresse Oxidativo/imunologia , Gravidez , Cultura Primária de Células , Ratos , Espécies Reativas de Oxigênio/metabolismo
5.
Acta Pharmacol Sin ; 42(10): 1653-1664, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33441995

RESUMO

Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg-1·d-1, ig), or ibrutinib (25 mg·kg-1·d-1, ig) or acalabrutinib (25 mg·kg-1·d-1, ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Células B de Memória/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Autoanticorpos/metabolismo , Inflamação/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pirimidinas/uso terapêutico , Alcaloides de Pirrolizidina/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Biomed Res Int ; 2020: 5107193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190669

RESUMO

The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade.


Assuntos
Apoptose/efeitos dos fármacos , Dexrazoxano/farmacologia , Doxorrubicina/efeitos adversos , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/patologia , Sobrevivência Celular/efeitos dos fármacos , Dexrazoxano/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , PTEN Fosfo-Hidrolase/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
Mol Med Rep ; 21(2): 631-640, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974607

RESUMO

Cardiac shock wave therapy (SWT) has been described as a novel therapeutic strategy that is able to alleviate myocardial ischemic injury. microRNA (miRNA/miR)­210 plays a cytoprotective role in cardiomyocytes in response to hypoxia by regulating cell apoptosis. The aim of the present study was to investigate whether cardiac SWT could protect cardiomyocytes from hypoxia­induced injury by regulating miR­210 expression. The murine adult cardiomyocyte cell line HL­1 was incubated for 5 h in hypoxic conditions, followed by reoxygenation for 12 h and treatment with SWT immediately following hypoxia in the present study. The cell viability was determined using an MTS assay. Western blot analyses were performed in order to detect cell signaling changes. Reactive oxygen species production was detected using dihydroethidium staining, and malondialdehyde levels were measured using the thiobarbituric acid method. miRNA and mRNA expression levels were confirmed via reverse transcription­quantitative PCR. Apoptosis was evaluated by means of flow cytometry. HL­1 cells were then transfected with miR­210 mimics or inhibitors in order to alter miR­210 expression levels, and the effects on HL­1 cells were determined. Hypoxia led to elevated oxidative stress, enhanced cell apoptosis and upregulated miR­210 expression levels in HL­1 cells, while SWT could alleviate hypoxia­induced cell injury and further promote miR­210 expression. miR­210 overexpression decreased apoptosis and oxidative stress during hypoxic stress in HL­1 cells, whereas inhibition of miR­210 increased cell apoptosis and promoted oxidative stress. Furthermore, miR­210 inhibition could reverse the effects of SWT on HL­1 cells. Finally, the mRNA analysis revealed that SWT significantly attenuated apoptosis­inducing factor mitochondrion­associated 3 and caspase 8 associated protein 2 mRNA expression levels in cardiomyocytes exposed to hypoxia, which were two targets of miR­210. SWT could exert cardioprotective effects against hypoxia­induced cardiac injury by modulating miR­210.


Assuntos
Citoproteção , Tratamento por Ondas de Choque Extracorpóreas , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Animais , Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Hipóxia Celular/genética , Linhagem Celular , Citoproteção/genética , Camundongos , MicroRNAs/genética , Estresse Oxidativo/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Oncotarget ; 8(3): 4837-4848, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-27902477

RESUMO

Doxorubicin (adriamycin), an anthracycline antibiotic, is commonly used to treat many types of solid and hematological malignancies. Unfortunately, clinical usage of doxorubicin is limited due to the associated acute and chronic cardiotoxicity. Previous studies demonstrated that Astragalus polysaccharide (APS), the extracts of Astragalus membranaceus, had strong anti-tumor activities and anti-inflammatory effects. However, whether APS could mitigate chemotherapy-induced cardiotoxicity is unclear thus far. We used a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model to explore the function of APS. GFP-LC3 adenovirus-mediated autophagic vesicle assays, GFP and RFP tandemly tagged LC3 (tfLC3) assays and Western blot analyses were performed to analyze the cell function and cell signaling changes following APS treatment in cardiomyocytes. First, doxorubicin treatment led to C57BL/6J mouse heart failure and increased cardiomyocyte apoptosis, with a disturbed cell autophagic flux. Second, APS restored autophagy in doxorubicin-treated primary neonatal rat ventricular myocytes and in the doxorubicin-induced heart failure mouse model. Third, APS attenuated doxorubicin-induced heart injury by regulating the AMPK/mTOR pathway. The mTOR inhibitor rapamycin significantly abrogated the protective effect of APS. These results suggest that doxorubicin could induce heart failure by disturbing cardiomyocyte autophagic flux, which may cause excessive cell apoptosis. APS could restore normal autophagic flux, ameliorating doxorubicin-induced cardiotoxicity by regulating the AMPK/mTOR pathway.


Assuntos
Astragalus propinquus/química , Cardiotoxicidade/tratamento farmacológico , Doxorrubicina/toxicidade , Insuficiência Cardíaca/tratamento farmacológico , Testes de Função Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Autofagia , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
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