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1.
Eur J Med Chem ; 178: 589-605, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220676

RESUMO

In an effort to develop novel Bax activators for breast cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC50 values of 3.22 µM and 0.07 µM against triple-negative breast cancer MDA-MB-231 and 3.81 µM and 0.06 µM against ER-positive breast cancer MCF-7 cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to cancer cell apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteína X Associada a bcl-2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína X Associada a bcl-2/metabolismo
2.
Nat Chem Biol ; 15(7): 657-665, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209350

RESUMO

BCL-2 family protein interactions regulate apoptosis, a critical process that maintains tissue homeostasis but can cause a host of human diseases when deregulated. Venetoclax is the first FDA-approved drug to reactivate apoptosis in cancer by selectively targeting an anti-apoptotic BCL-2 family member. The drug's activity relies on an 'inhibit the inhibitor' mechanism, whereby blockade of a key surface groove on BCL-2 disables its capacity to neutralize pro-apoptotic effectors, such as BAX, a chief executioner protein of the apoptotic pathway. A series of physiologic and pharmacologic regulatory sites that mediate the activation or inhibition of BAX have recently been identified, providing blueprints for the development of alternative apoptosis modulators to block pathologic cell survival or avert unwanted cell death by drugging BAX directly.


Assuntos
Bibliotecas de Moléculas Pequenas/farmacologia , Proteína X Associada a bcl-2/antagonistas & inibidores , Morte Celular/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Proteína X Associada a bcl-2/metabolismo
3.
Nat Chem Biol ; 15(4): 322-330, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718816

RESUMO

BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Upon binding by BH3-only proteins, cytosolic BAX undergoes conformational activation and translocation, resulting in mitochondrial outer-membrane permeabilization. Efforts to rationally target BAX and develop inhibitors have been elusive, despite the clear therapeutic potential of inhibiting BAX-mediated cell death in a host of diseases. Here, we describe a class of small-molecule BAX inhibitors, termed BAIs, that bind directly to a previously unrecognized pocket and allosterically inhibit BAX activation. BAI binding around the hydrophobic helix α5 using hydrophobic and hydrogen bonding interactions stabilizes key areas of the hydrophobic core. BAIs inhibit conformational events in BAX activation that prevent BAX mitochondrial translocation and oligomerization. Our data highlight a novel paradigm for effective and selective pharmacological targeting of BAX to enable rational development of inhibitors of BAX-mediated cell death.


Assuntos
Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Sequência de Aminoácidos , Apoptose/fisiologia , Sítios de Ligação/fisiologia , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Mitocôndrias/fisiologia , Modelos Moleculares , Fragmentos de Peptídeos/fisiologia , Permeabilidade , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
4.
Cell Death Dis ; 9(10): 991, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250224

RESUMO

Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.


Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/metabolismo , Proteínas Mitocondriais/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteína bcl-X/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Citocromos c/antagonistas & inibidores , Feminino , Fluoruracila/farmacologia , Inativação Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Fosfoproteínas Fosfatases/genética , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/antagonistas & inibidores
5.
PLoS One ; 13(8): e0201136, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30071053

RESUMO

Cyclophosphamide (CTX) has immunosuppressive effects and has been wildly used as one anti-cancer drug in clinical. Significant toxicity has been noticed particularly in the reproductive system. CTX promotes the maturation of ovarian follicles, decreases follicular reserve, and ultimately lead to ovarian failure or even premature ovarian failure (POF). The placental extract (HPE) has been shown to have some beneficial impact on reproductive system; however, little is known regarding to the effect of HPE on protecting CTX-induced ovarian injury and the mechanism involved. Whether human placental extracts (HPE) has a protective effect on CTX-induced toxicity on ovarian was studied by using a CTX-induced ovarian injury animal model. The effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels, and apoptosis in granulosa cells were studied in mice with CTX or control vehicle. Our results have demonstrated that HPE inhibited p-Rictor, reduced the expression of Bad, Bax and PPAR, and activated Akt and Foxo3a (increased their phosphorylation). Mice treated with HPE showed higher ovarian weight, lower number of atretic follicles, higher serum levels of the hormones E2 and progesterone, and lower apoptosis and serum levels of LH and FSH in granulosa cells, than that in the control animal group. Our data show that ovarian injury can be attenuated by HPE. HPE likely protects follicular granulosa cells from undergoing significant apoptosis and reduce atresia follicle formation, therefore, alleviates CTX-induced ovarian injury.


Assuntos
Ciclofosfamida/toxicidade , Proteína Forkhead Box O3/metabolismo , Ovário/efeitos dos fármacos , Extratos Placentários/farmacologia , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos Alquilantes/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Relação Dose-Resposta a Droga , Feminino , Hormônios/sangue , Humanos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Ovário/metabolismo , Ovário/patologia , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fosforilação/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/prevenção & controle , Proteína Companheira de mTOR Insensível à Rapamicina/antagonistas & inibidores , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Proteína de Morte Celular Associada a bcl/antagonistas & inibidores , Proteína de Morte Celular Associada a bcl/metabolismo
6.
J Biochem Mol Toxicol ; 32(11): e22213, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30152906

RESUMO

We investigated the effect of apigenin, a dietary flavonoid, on isoproterenol hydrochloride (ISO)-induced apoptotic signaling in cardiomyoblast H9C2 cells. The results showed that apigenin treatment (10 µM) prevented ISO (31.25 µM)-induced lipid peroxidative levels and antioxidants status in H9C2 cells. Furthermore, apigenin inhibited expression of inflammatory markers in ISO-treated cells. In addition, apigenin prevented ISO-induced DNA damage and apoptotic signaling through modulating the expression of Bax, caspase-3, -8 and -9, cytochrome c, and Fas proteins in H9C2 cells. It is concluded that apigenin prevents ISO-induced antioxidants depletion, oxidative DNA damage, inflammatory, and apoptotic signaling in H9C2 cells. Thus, the present results demonstrated that apigenin has a cardioprotective effect on cardiomyoblasts cells.


Assuntos
Antioxidantes/farmacologia , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Cardiotônicos/efeitos adversos , Isoproterenol/efeitos adversos , Mioblastos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Biomarcadores/metabolismo , Cardiotônicos/antagonistas & inibidores , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Isoproterenol/antagonistas & inibidores , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/imunologia , Mitocôndrias Cardíacas/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/metabolismo , Mioblastos Cardíacos/citologia , Mioblastos Cardíacos/imunologia , Mioblastos Cardíacos/metabolismo , Ratos , Proteína X Associada a bcl-2/agonistas , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo , Receptor fas/agonistas , Receptor fas/antagonistas & inibidores , Receptor fas/metabolismo
7.
Cell Death Dis ; 9(8): 781, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013101

RESUMO

Bax is a key molecule in mitochondria-apoptosis pathway, however it is not always an efficient apoptosis inducer in chemotherapeutic agents-treated cancer cells. Here, we found that specific inhibition of AURKA by MLN8237-induced calpain-mediated Bax cleavage at N-terminal 33th asparagine (c-Bax) to promote apoptosis. The c-Bax, as Bax, could also efficiently located to mitochondria but c-Bax is a stronger apoptosis inducer than Bax. Morever, c-Bax-induced apoptosis could not be blocked by the canonical Bax inhibitor, Bcl-2. Further study found p27 was degraded and subsequently Bax was transformed to c-Bax through calpain. Also, p27 efficiently inhibited Bax cleavage and p27 knockdown sensitized apoptosis through Bax cleavage when cancer cells were treated with MLN8237. It is also demonstrated that the anti-apoptotic role of p27 lies its cytoplasmic localization. Finally, we found that the positive correlation between AURKA and p27 in advanced gastric cancer patients. In conclusion, we found that MNL8237 suppressed cell growth by regulating calpain-dependent Bax cleavage and p27 dysregulation in gastric cancer cells.


Assuntos
Apoptose , Aurora Quinase A/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/genética , Azepinas/farmacologia , Calpaína/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p27/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p27/genética , Citoplasma/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Proteína X Associada a bcl-2/antagonistas & inibidores
8.
Toxicol Appl Pharmacol ; 355: 269-285, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30009776

RESUMO

Triptolide (TP), a major active component of Tripterygium wilfordii Hook f., is widely used in the treatment of inflammation and autoimmune disorders. Its clinical application is limited by severe adverse effects, especially cardiotoxicity. Accumulative evidences indicate that TP induces DNA damage by inhibiting RNA polymerase. Considering the relationship among DNA damage, p53, and the role of p53 in mitochondria-dependent apoptosis, we speculate that TP-induced cardiotoxicity results from p53 activation. In this study, the role of p53 in TP-induced cardiotoxicity was investigated in H9c2 cells, primary cardiomyocytes, and C57BL/6 genetic background p53-/- mice. p53 protein level was elevated by TP in vitro and in acute heart injury models. With TP administration (1.2 mg/kg), p53 deficiency prevented heart histology injury and decreased serum cardiac troponin I (cTn-I) and apoptotic proteins. Mechanistically, immunoblotting and immunofluorescence staining identified that TP-induced toxicity is dependent on p53 nuclear translocation and transactivation of Bcl2 family genes, leading to mitochondrial outer membrane permeabilization (MOMP) and mitochondria dysfunction. Consistently, p53 antagonist PFTα counteracted TP-induced p53 overexpression and regulation of Bcl2 family transcription, which improved mitochondrial membrane integrity and prevented apoptosis. Moreover, Bax antagonist Bax inhibitor peptide (BIP) V5 ameliorated TP-induced apoptosis through suppressing membrane depolarization and ROS accumulation. These results suggest that TP-induced cardiotoxicity is p53-dependent by promoting Bax-induced mitochondria-mediated apoptosis.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Diterpenos/toxicidade , Cardiopatias/induzido quimicamente , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fenantrenos/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Diterpenos/antagonistas & inibidores , Compostos de Epóxi/antagonistas & inibidores , Compostos de Epóxi/toxicidade , Cardiopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Fenantrenos/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/antagonistas & inibidores
9.
Eur Rev Med Pharmacol Sci ; 22(2): 532-539, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29424914

RESUMO

OBJECTIVE: To investigate the role and mechanism of micro ribonucleic acid (miR)-298 in myocardial apoptosis after myocardial infarction. MATERIALS AND METHODS: In vivo experiments, the rat model of myocardial infarction was established, and miR-298 was up-regulated via lentivirus with miR-298 overexpression. Cardiac function of rats was detected via echocardiography, Bcl-2 associated X protein (BAX) expressions in infarction border zone were detected via Real-time Quantitative PCR (qT-PCR) and Western blot, and TUNEL assay was used to detect the myocardial apoptosis. In vitro experiments, myocardial cells were isolated and cultured, an oxygen-glucose deprivation (OGD) model was established to mimicking the ischemic condition, the relationship between miR-298 and BAX was verified using luciferase reporter vector, lentivirus and small-interfering RNA (siRNA) in BAX. RESULTS: In vivo experiments showed that the miR-298 expression was down-regulated at 2 and 4 weeks after myocardial infarction. The up-regulation of miR-298 significantly improved the cardiac function, decreased the expressions of BAX, reduced the myocardial apoptosis and inhibit the apoptosis proteins expression including cytochrome-c and cleaved caspase-3. In vitro experiments revealed that BAX was a target gene of miR-298 and further proof that miR-298 could inhibit the cytochrome-c and cleaved caspase-3 expression and myocardial apoptosis through BAX. CONCLUSIONS: MiR-298 can improve the myocardial apoptosis through the target gene BAX.


Assuntos
Apoptose , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Caspase 3/metabolismo , Hipóxia Celular , Citocromos c/metabolismo , Regulação para Baixo , Glucose/deficiência , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
10.
Biomed Pharmacother ; 97: 213-224, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29091869

RESUMO

Lung cancer represents a significant problem for public health worldwide. Galangin (GG), a natural active compound 3, 5, 7-trihydroxyflavone, is a type of bioflavonoid, which is isolated from the Alpinia galangal root and suggested to induce apoptosis in various cancers. We investigated the ability of Galangin (GG) to attenuate the drug resistance of human lung cancer cells, resistant to treatment of cisplatin (DDP). DDP is a pyrimidine analog, widely used in cancer treatment. Galangin and DDP co-treatment resulted in a dose-dependent suppression of the cell proliferation. Decreasing of p-STAT3 was included in p65 suppression by GG with DDP in combination. Additionally, the presence of GG potentiated the effects of DDP on apoptosis induction through suppressing Bcl-2 in DDP-resistant lung cancer cells. The pro-apoptotic proteins of Bax and Bid were up-regulated, accompanied with Caspases cleavage, leading to apoptosis. Moreover, in mice xenograft models, the combined therapy inhibited tumor growth compared to the GG or DDP treatment alone. Our data indicated a novel therapeutic strategy to potentiate DDP-induced anti-tumor effect in lung cancer cells with DDP resistance by GG through inactivating p-STAT3/p65 and Bcl-2 pathways.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/fisiologia , Proteína X Associada a bcl-2/metabolismo , Células A549 , Animais , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Flavonoides/administração & dosagem , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , NF-kappa B/antagonistas & inibidores , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteína X Associada a bcl-2/antagonistas & inibidores
11.
IUBMB Life ; 70(1): 60-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29247598

RESUMO

The aim of this study was to examine the comprehensive neuroprotective mechanism of ligustrazine, which is extracted from Ligusticum Chuanxiong Hort., against vascular dementia (VD) in rats and apoptosis in oxygen and glucose deprivation (OGD) PC12 cells. Rats were subjected to bilateral common carotid artery occlusion (BCCAO) surgery and administered ligustrazine intragastrically for 6 weeks. At the end of the experiments, the hippocampal biomarkers brain-derived neurotrophic factor (BDNF), monocyte chemotactic protein 1 (MCP-1), and homocysteine (Hcy) were examined. In experiments in vitro, OGD PC12 cells were treated with ligustrazine for 0.5, 1, 3, 6, 12, or 24 h. The cell-released biomarkers BDNF, MCP-1, and Hcy were examined. Microscopy, acridine orange-ethidium bromide (AO/EB) staining, and flow cytometry assays were performed to investigate apoptosis. Cleaved caspase-3, Bcl-2 associated X protein (Bax), and B cell lymphoma 2 (Bcl-2) expression was examined using Western blot assays. The results showed that biomarkers, including MCP-1 and Hcy, were significantly increased in both the in vivo and in vitro models, while the BDNF level was significantly decreased compared with the sham or vehicle models. Microscopy, AO/EB staining, and flow cytometry analysis showed that severe cell damage occurred in OGD PC12 cells, and apoptosis played a major role in this environment. Further Western blot studies showed that the apoptosis-related Bax/Bcl-2 protein ratio and cleaved caspase-3 were significantly increased in the experiment. However, ligustrazine profoundly suppressed the imbalance of these biomarkers, reduced cell damage, decreased the Bax/Bcl-2, and downregulated cleaved caspase-3. Pro- and anti-apoptotic biomarkers of multiple pathways including BDNF, MCP-1, and Hcy played a joint role in triggering the activation of the mitochondria-related Bax/Bcl-2 and caspase-3 apoptosis pathway in VD. Ligustrazine attenuated VD by comprehensively regulating BDNF, MCP-1, and Hcy and inactivating the Bax/Bcl-2 and caspase-3 apoptosis pathway. Our data provide novel insight into ligustrazine, which is a promising neuroprotective agent for VD disease treatment strategies. © IUBMB Life, 70(1):60-70, 2018.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/genética , Demência Vascular/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Pirazinas/farmacologia , Proteína X Associada a bcl-2/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Artéria Carótida Primitiva/cirurgia , Caspase 3/metabolismo , Hipóxia Celular , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cerebrovasculares , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Demência Vascular/genética , Demência Vascular/metabolismo , Demência Vascular/patologia , Regulação da Expressão Gênica , Glucose/deficiência , Glucose/farmacologia , Homocisteína/metabolismo , Ligusticum/química , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazinas/isolamento & purificação , Ratos , Ratos Wistar , Transdução de Sinais , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/metabolismo
12.
Med Sci Monit ; 23: 4109-4116, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28841638

RESUMO

BACKGROUND In the present study, we explored the protective effect and mechanism of action of boldine (BOL) against neural apoptosis, which is a mediator of TBI. MATERIAL AND METHODS The effect of BOL on mitochondrial and cytosol proteins of extracted from cerebral cortical tissue of mice was evaluated. The grip test was used to assess the neurological deficit and brain water content of the subjects after administration of BOL to assess its effect on SOD, GSH, and MDA activity in brain ischemic tissues. To further confirm the effect of the BOL, the histopathological analysis and morphology of neurons were studied by Nissl staining. The effect of BOL against TBI-induced neural apoptosis by immuno-histochemistry and Western blotting assay were also studied. RESULTS BOL showed significant improvement against TBI in a dose-dependent manner. In the BOL-treated group, the apoptotic index was significantly reduced, but the level of caspase-3 was greatly diminished. Additionally, the level of the Bax in mitochondria (mit) and cytosol was elevated in the TBI-treated group as compared to the sham group. Further BOL at the test dose causes significant reduction in the level of mitochondrial MDA together with increase in SOD activity as compared to the TBI alone group. CONCLUSIONS BOL showed a cerebroprotective effect against TBI by attenuating the oxidative stress and the mitochondrial apoptotic pathway. It also inhibited mitochondrial Bax translocation and cytochrome c release.


Assuntos
Aporfinas/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Citocromos c/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Proteína X Associada a bcl-2/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Caspases/metabolismo , Citocromos c/metabolismo , Citosol/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
13.
Free Radic Biol Med ; 112: 336-349, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28790012

RESUMO

Aberrant modulation of mitochondrial dynamic network, which shifts the balance of fusion and fission towards fission, is involved in brain damage of various neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage, however, the underlying molecular mechanisms have remained to be elucidated. This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1 (Drp1, a dominator of mitochondrial fission) on blood-brain barrier (BBB) disruption and neuronal apoptosis following SAH and the potential mechanisms. The endovascular perforation model of SAH was performed in adult male Sprague Dawley rats. The results indicated Mdivi-1(a selective Drp1 inhibitor) reversed the morphologic changes of mitochondria and Drp1 translocation, reduced ROS levels, ameliorated the BBB disruption and brain edema remarkably, decreased the expression of MMP-9 and prevented degradation of tight junction proteins-occludin, claudin-5 and ZO-1. Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB), leading to decreased expressions of TNF-ɑ, IL-6 and IL-1ß. Moreover, Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome. To investigate the underlying mechanisms further, we determined that Mdivi-1 reduced p-PERK, p-eIF2α, CHOP, cleaved caspase-3 and Bax expression as well as increased Bcl-2 expression. Rotenone (a selective inhibitor of mitochondrial complexes I) abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1. In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Dinaminas/genética , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Quinazolinonas/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Dinaminas/antagonistas & inibidores , Dinaminas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Ocludina/genética , Ocludina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/mortalidade , Hemorragia Subaracnóidea/patologia , Espaço Subaracnóideo/efeitos dos fármacos , Espaço Subaracnóideo/metabolismo , Espaço Subaracnóideo/patologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
14.
Int J Mol Med ; 40(4): 1194-1200, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28849028

RESUMO

It is well known that Panax ginseng (PG) has various pharmacological effects such as anti-aging and anti-inflammation. In a previous study, the authors identified that PG extract induced hair growth by means of a mechanism similar to that of minoxidil. In the present study, the inhibitory effect of PG extract on Dickkopf-1 (DKK-1)-induced catagen-like changes in hair follicles (HFs) was investigated in addition to the underlying mechanism of action. The effects of PG extract on cell proliferation, anti-apoptotic effect, and hair growth were observed using cultured outer root sheath (ORS) keratinocytes and human HFs with or without DKK-1 treatment. The PG extract significantly stimulated proliferation and inhibited apoptosis, respectively, in ORS keratinocytes. PG extract treatment affected the expression of apoptosis-related genes Bcl-2 and Bax. DKK-1 inhibited hair growth, and PG extract dramatically reversed the effect of DKK-1 on ex vivo human hair organ culture. PG extract antagonizes DKK-1-induced catagen-like changes, in part, through the regulation of apoptosis-related gene expression in HFs. These findings suggested that PG extract may reduce hair loss despite the presence of DKK-1, a strong catagen inducer via apoptosis.


Assuntos
Folículo Piloso/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Queratinócitos/efeitos dos fármacos , Panax/química , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Minoxidil/farmacologia , Extratos Vegetais/química , Raízes de Plantas/química , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Vasodilatadores/farmacologia , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
15.
Eur J Cancer ; 83: 154-165, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28738256

RESUMO

Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors. Indeed, drug combinations targeting both mutant BRAF and MITF or one of its important targets Bcl-2 were effective in mutant BRAF melanoma but had no effect on acquired resistance. Therefore, we aimed to further investigate the downstream MITF targets that can explain this anti-apoptotic effect and to evaluate in parallel the effect of p53 reactivation on the promotion of apoptosis under MEK inhibition in a panel of Q61NRAS-mutant melanoma cells. First, we showed that MEK inhibition (pimasertib) led to a significant inhibition of cell proliferation but with a limited effect on apoptosis that could be explained by the systematic MITF upregulation. Mimicking the MITF effect via cyclic adenosine monophosphate activation conferred resistance to MEK inhibition and upregulated Bcl-2 expression. In addition, acquired resistance to MEK inhibition was associated with a strong activation of the anti-apoptotic signalling MITF/Bcl-2. More importantly, selective Bcl-2 inhibition by ABT-199 or Bcl-2 knockout using CRISPR/Cas9 system annihilated the acquired resistance and restored the sensitivity of NRAS-mutant melanoma cells to MEK inhibition. Strikingly and similarly, direct p53 reactivation (PRIMA-1Met, APR-246) also broke resistance and synergised with MEK inhibition to induce massive apoptosis in NRAS-mutant melanoma cells with wild-type or mutant p53. Hence, our data identify MITF/Bcl-2 as a key mechanism underlying resistance of NRAS-mutant melanoma cells to apoptosis by MEK inhibitors and paves the way for a promising drug combination that could prevent or reverse anti-MEK resistance in this group of patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , GTP Fosfo-Hidrolases/genética , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Fator de Transcrição Associado à Microftalmia/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Supressora de Tumor p53/fisiologia , Proteína X Associada a bcl-2/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Melanoma/genética , Prognóstico
16.
Sci Rep ; 7(1): 2552, 2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28566720

RESUMO

Human umbilical cord mesenchymal stem cells (huMSCs) can treat primary ovarian insufficiency (POI) related to ovarian granulosa cell (OGC) apoptosis caused by cisplatin chemotherapy. Exosomes are a class of membranous vesicles with diameters of 30-200 nm that are constitutively released by eukaryotic cells. Exosomes mediate local cell-to-cell communication by transferring microRNAs and proteins. In the present study, we demonstrated the effects of exosomes derived from huMSCs (huMSC-EXOs) on a cisplatin-induced OGC model in vitro and discussed the preliminary mechanisms involved in these effects. We successfully extracted huMSC-EXOs from huMSC culture supernatant and observed the effective uptake of exosomes by cells with fluorescent staining. Using flow cytometry (with annexin-V/PI labelling), we found that huMSC-EXOs increased the number of living cells. Western blotting showed that the expression of Bcl-2 and caspase-3 were upregulated, whilst the expression of Bax, cleaved caspase-3 and cleaved PARP were downregulated to protect OGCs. These results suggest that huMSC-EXOs can be used to prevent and treat chemotherapy-induced OGC apoptosis in vitro. Therefore, this work provides insight and further evidence of stem cell function and indicates that huMSC-EXOs protect OGCs from cisplatin-induced injury in vitro.


Assuntos
Cisplatino/antagonistas & inibidores , Exossomos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Substâncias Protetoras/farmacologia , Animais , Anexina A5/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Cisplatino/farmacologia , Feminino , Citometria de Fluxo , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Cultura Primária de Células , Substâncias Protetoras/química , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Cordão Umbilical/citologia , Cordão Umbilical/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
17.
J Huazhong Univ Sci Technolog Med Sci ; 37(3): 401-406, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28585136

RESUMO

The effect and underlying mechanism of Bu-Shen-An-Tai recipe on ovarian apoptosis in mice with controlled ovarian hyperstimulation (COH) implantation dysfunction were studied. The COH implantation dysfunction model in mice was established by intraperitoneal injection of 7.5 IU pregnant mare's serum gonadotrophin (PMSG), followed by 7.5 IU human chorionic gonadotrophin (HCG) 48 h later. Then the female mice were mated with male at a ratio of 2:1 in the same cage at 6:00 p.m. The female mice from normal group were injected intraperitoneally with normal saline and mated at the corresponding time. Day 1 of pregnancy was recorded by examining its vaginal smears at 8:00 a.m. of the next day. Fifty successfully pregnant mice were equally randomly divided into 5 groups: normal control pregnant group (NC), COH implantation dysfunction model group (COH), low dosage of Bu-Shen-An-Tai recipe group (LOW), middle dosage of Bu-Shen-An-Tai recipe group (MID) and high dosage of Bu-Shen-An-Tai recipe group (HIGH). Then from day 1, the mice in different groups were respectively intragastrically given corresponding treatments at 9:00 a.m. for 5 consecutive days. The concentrations of 17ß-estradiol (E2) and progesterone (P4) were determined by radioimmunoassay (RIA). The ultrastructural changes of ovarian tissues were observed by transmission electron microscope (TEM). The histopathological changes of ovarian tissues were observed by HE staining. The number of atretic follicles and pregnant corpus luteum were also recorded. TUNEL was applied to measure apoptotic cells of ovarian tissues. Western blotting was used to detect the protein expression of apoptosis- related factors like Bax, Bcl-2 and cleaved-caspase-3 in ovarian tissue of mice. The results showed that ovarian weight, the concentrations of E2 and P4, the number of atretic follicles and pregnant corpus luteum, as well as the apoptosis of granulosa cells were significantly increased in the COH group. The ultrastructures of ovarian tissues in the COH group showed that chromatin in granulosa cells was increased, agglutinated, aggregated or crescent-shaped. The focal cavitation and the typical apoptotic bodies could be seen in granulosa cells in the late stage of apoptosis. After the treatment with different doses of Bu-Shen-An-Tai recipe, the ultrastructural changes of ovarian granulosa cells apoptosis were dramatically improved and even disappeared under TEM. Visible mitochondria and mitochondrial cristae were increased and vacuoles were significantly reduced. The lipid dropltes were shown in a circluar or oval shape. The protein expression levels of Bax and cleaved-caspase-3 were decreased, and the expression of Bcl-2 protein was increased after treatment. It was concluded that Bu-Shen-An-Tai recipe can inhibit the apoptosis of ovarian granulosa cells, probably by up-regulating the protein expression of Bcl-2 and down-regulating Bax and cleaved-caspase-3, which contributes to the formation and maintenance of ovarian corpus luteum. It's helpful to promote the embryonic implantation, to reduce embryo loss and ultimately to improve the success rate of pregnancy.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Implantação do Embrião/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células da Granulosa/efeitos dos fármacos , Síndrome de Hiperestimulação Ovariana/prevenção & controle , Substâncias para o Controle da Reprodução/farmacologia , Animais , Caspase 3/genética , Caspase 3/metabolismo , Gonadotropina Coriônica/administração & dosagem , Corpo Lúteo/citologia , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Esquema de Medicação , Implantação do Embrião/fisiologia , Estradiol/sangue , Feminino , Absorção Gástrica/fisiologia , Gonadotropinas Equinas/administração & dosagem , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Cavalos , Camundongos , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Síndrome de Hiperestimulação Ovariana/induzido quimicamente , Síndrome de Hiperestimulação Ovariana/genética , Síndrome de Hiperestimulação Ovariana/patologia , Indução da Ovulação/métodos , Gravidez , Progesterona/sangue , Proteínas Proto-Oncogênicas c-bcl-2/agonistas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
18.
Cell Death Dis ; 8(6): e2858, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28569794

RESUMO

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Although its pathogenesis remains unclear, mitochondrial dysfunction plays a vital role in the pathology of PD. P7C3, an aminopropyl carbazole, possesses a significant neuroprotective ability in several neurodegenerative disorders, including PD. Here, we showed that P7C3 stabilized mitochondrial membrane potential, reduced reactive oxygen species production, and inhibited cytochrome c release in MES23.5 cells (a dopaminergic (DA) cell line) exposed to 1-methyl-4-phenylpyridinium (MPP+). In MES23.5 cells, P7C3 inhibited glycogen synthase kinase-3 beta (GSK3ß) activation induced by MPP+. P7C3 also inhibited p53 activity and repressed Bax upregulation to protect cells from MPP+ toxicity. In addition, the activation of p53 was significantly attenuated with the inhibition of GSK3ß activity by P7C3. Furthermore, P7C3 blocked GSK3ß and p53 activation in the midbrain, and prevented DA neuronal loss in the substantia nigra in 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine mice. Thus, our study demonstrates that P7C3 protects DA neurons from neurotoxin-induced cell death by repressing the GSK3ß-p53-Bax pathway both in vitro and in vivo, thus providing a theoretical basis for P7C3 in the potential clinical treatment of PD.


Assuntos
Antiparkinsonianos/farmacologia , Carbazóis/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Substância Negra/efeitos dos fármacos , 1-Metil-4-fenilpiridínio/antagonistas & inibidores , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Linhagem Celular Tumoral , Quimera , Citocromos c/antagonistas & inibidores , Citocromos c/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Substância Negra/metabolismo , Substância Negra/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Int J Radiat Oncol Biol Phys ; 99(2): 353-361, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28479002

RESUMO

PURPOSE: Ionizing radiation (IR)-induced pulmonary fibrosis (PF) is an irreversible and severe late effect of thoracic radiation therapy. The goal of this study was to determine whether clearance of senescent cells with ABT-263, a senolytic drug that can selectively kill senescent cells, can reverse PF. METHODS AND MATERIALS: C57BL/6J mice were exposed to a single dose of 17 Gy on the right side of the thorax. Sixteen weeks after IR, they were treated with 2 cycles of vehicle or ABT-263 (50 mg/kg per day for 5 days per cycle) by gavage. The effects of ABT-263 on IR-induced increases in senescent cells; elevation in the expression of selective inflammatory cytokines, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinases; and the severity of the tissue injury and fibrosis in the irradiated lungs were evaluated 3 weeks after the last treatment, in comparison with the changes observed in the irradiated lungs before treatment or after vehicle treatment. RESULTS: At 16 weeks after exposure of C57BL/6 mice to a single dose of 17 Gy, thoracic irradiation resulted in persistent PF associated with a significant increase in senescent cells. Treatment of the irradiated mice with ABT-263 after persistent PF had developed reduced senescent cells and reversed the disease. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that PF can be reversed by a senolytic drug such as ABT-263 after it becomes a progressive disease. Therefore, ABT-263 has the potential to be developed as a new treatment for PF.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Senescência Celular , Pneumonite por Radiação/tratamento farmacológico , Sulfonamidas/uso terapêutico , Proteína X Associada a bcl-2/antagonistas & inibidores , Células Epiteliais Alveolares/patologia , Animais , Antineoplásicos/administração & dosagem , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citocinas/análise , Hidroxiprolina/análise , Mediadores da Inflamação/metabolismo , Pulmão/química , Pulmão/enzimologia , Pulmão/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/análise , Pneumonite por Radiação/genética , Pneumonite por Radiação/patologia , Radiação Ionizante , Proteína X Associada a bcl-2/metabolismo , beta-Galactosidase/análise
20.
Biomed Pharmacother ; 92: 33-38, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28528183

RESUMO

Quercetin is a flavonoid that has been shown to have anti-oxidation, anti-inflammation, anti-allergic, anti-viral, and anti-cancer activities. Here, we examined the effects of quercetin on cell viability, cell cycle progression, and migration in U251 cells, a human glioblastoma cell line. We found that quercetin inhibited cell proliferation after treating cells for 24 (IC50 of 113.65µg/ml) or 48h (IC50 of 48.61µg/ml). Quercetin treatment also induced apoptosis via deregulating the expression of apoptotic genes, including Bax and Bcl-2, and arrested cell cycle at G2/M phases. We further found that quercetin impaired cell migration and invasion via downregulating the expression of matrix metallopeptidases MMP9 and MMP2. Our results provide evidences that quercetin has inhibitory effects on glioblastoma cell proliferation and invasion, and suggest a potential clinical application for glioblastoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Neurônios/efeitos dos fármacos , Quercetina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/química , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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