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1.
Plant Cell Physiol ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32966570

RESUMO

Gibberellins (GAs) play important roles in the regulation of plant growth and development. The green revolution gene SD1 encoding gibberellin 20-oxidase 2 (GA20ox2) has been widely used in modern rice breeding. However, the molecular mechanism of how SD1/OsGA20ox2 expression is regulated remains unclear. Here we report a Cys2/His2 zinc finger protein ZFP207 acting as a transcriptional repressor of OsGA20ox2. ZFP207 was mainly accumulated in young tissues and more specifically in culm nodes. ZFP207-overexpression (ZFP207OE) plants displayed semi-dwarfism phenotype and small grains by modulating cell length. RNA interference of ZFP207 caused increased plant height and grain length. Application of exogenous GA3 could rescue the semi-dwarf phenotype of ZFP207OE rice seedlings. Moreover, ZFP207 repressed the expression of OsGA20ox2 via binding to its promoter region. Taken together, ZFP207 acts as a transcriptional repressor of SD1/OsGA20ox2 and it may play a critical role in plant growth and development through fine-tuning GA biosynthesis in rice.

2.
J Clin Invest ; 130(12): 6490-6509, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853179

RESUMO

Astrocytes have multiple functions in the brain, including affecting blood vessel (BV) homeostasis and function. However, the underlying mechanisms remain elusive. Here, we provide evidence that astrocytic neogenin (NEO1), a member of deleted in colorectal cancer (DCC) family netrin receptors, is involved in blood vessel homeostasis and function. Mice with Neo1 depletion in astrocytes exhibited clustered astrocyte distribution and increased BVs in their cortices. These BVs were leaky, with reduced blood flow, disrupted vascular basement membranes (vBMs), decreased pericytes, impaired endothelial cell (EC) barrier, and elevated tip EC proliferation. Increased proliferation was also detected in cultured ECs exposed to the conditioned medium (CM) of NEO1-depleted astrocytes. Further screening for angiogenetic factors in the CM identified netrin-1 (NTN1), whose expression was decreased in NEO1-depleted cortical astrocytes. Adding NTN1 into the CM of NEO1-depleted astrocytes attenuated EC proliferation. Expressing NTN1 in NEO1 mutant cortical astrocytes ameliorated phenotypes in blood-brain barrier (BBB), EC, and astrocyte distribution. NTN1 depletion in astrocytes resulted in BV/BBB deficits in the cortex similar to those in Neo1 mutant mice. In aggregate, these results uncovered an unrecognized pathway, astrocytic NEO1 to NTN1, not only regulating astrocyte distribution, but also promoting cortical BV homeostasis and function.

3.
Arch Biochem Biophys ; 685: 108349, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32209309

RESUMO

Breast cancer has the highest incidence and mortality in the female population. Forkhead box M1 (FOXM1) known as a transcription factor is upregulated and associated with poor prognosis in a variety of cancers. However, the molecular mechanisms of FOXM1 on breast cancer progression are poorly understood. In this study, we found that FOXM1 was up-regulated in breast cancer. FOXM1 promoted cell proliferation, clonal formation, and migration capacity in triple negative breast cancer by increasing transcriptional activity of YAP1. FOXM1 also maintained cell stemness via the Hippo pathway. The YAP1-TEAD binding inhibitor Verteporfin reduced the transcription level of OCT4 and NANOG but the Hippo pathway activator XMU-MP-1 could increase the transcription level of OCT4 and NANOG. In summary, our findings indicated that FOXM1 promoted breast cancer progression through the Hippo pathway, and it was suggested a new strategy to treat breast cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Proteína Forkhead Box M1/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Proteína Forkhead Box M1/genética , Técnicas de Silenciamento de Genes , Humanos , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Fosforilação/genética , Fatores de Transcrição/química , Regulação para Cima
4.
Life Sci ; 241: 117114, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790687

RESUMO

AIMS: Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide. Over-expression of tetraspanin 8 (TSPAN8) is related to the development and progression of CRC. Whether TSPAN8 plays a role in the growth of colorectal cancer and its epigenetic mechanisms regulated by Lysine Specific Demethylase 1 (LSD1) are still unknown. MAIN METHODS: In this study, RT-PCR and western blotting were used to analyze the mRNA and protein expression, respectively; cell viability was assayed with MTS analysis; cell migration was measured with Trans-well analysis. KEY FINDINGS: In the present study, the results indicated that the mRNA levels of LSD1 and TSPAN8 in CRC were significantly higher than that in corresponding adjacent non-tumor tissue. Down-regulation of LSD1 or TSPAN8 as well as LSD1 inhibitor Tranylcypromine hemisulfate inhibited the proliferation and migration of CRC cells, while over-expression of LSD1 exhibited opposite effects. LSD1 up-regulated TSPAN8 expression and reduced H3K9me2 occupancy on the TSPAN8 promoter in CRC cells. TSPAN8 promoted epithelial-mesenchymal transition (EMT) in CRC cells in LSD1-dependent manner. SIGNIFICANCE: TSPAN8 may be considered as a promising biomarker for the diagnosis and prognosis in patients with CRC. Furthermore, TSPAN8 could be a novel therapeutic target and potent LSD1 inhibitors could be designed and developed in the treatment of CRC.


Assuntos
Neoplasias Colorretais/patologia , Histona Desmetilases/metabolismo , Tetraspaninas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilação , Regiões Promotoras Genéticas , Tetraspaninas/genética
5.
Can J Cardiol ; 35(12): 1851-1856, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813511

RESUMO

BACKGROUND: The relationship between clinical outcomes and gene mutations in Chinese pediatric patients with idiopathic and heritable pulmonary arterial hypertension (PAH) is unclear. METHODS: We retrospectively studied the clinical characteristics and outcomes of pediatric patients who visited Beijing Anzhen Hospital from September 2008 to December 2018. RESULTS: Eighty-two pediatric patients were included. Forty-two gene mutations were identified in 41 patients (50%), including 25 mutations in BMPR2, 5 mutations in ACVRL1, 3 mutations each in ABCA3 and NOTCH3, 2 mutations each in KCNK3 and HTR2B, 1 mutation in ENG, and 1 mutation in EIF2AK4. The mean age at diagnosis of PAH was 86.4 ± 55.1 months. Forty-eight patients (twenty-eight mutation carriers) underwent cardiac catheterization examinations, with acute vasodilator testing performed simultaneously. Results showed that mutation carriers demonstrated a higher pulmonary vascular resistance index (P = 0.037). Patients with gene mutations responded poorly to vasodilators (P = 0.001). The 1-, 2-, and 3-year survival rates of mutation noncarriers were 95.1%, 87.8%, and 82.5% respectively; while for mutation carriers, the proportions were 86.6% (P = 0.216), 63.8% (P = 0.021), and 52.2% (P = 0.010), respectively. Cardiac index was an independent predictor of death (P = 0.005; odds ratio [OR] 2.16, 95% confidence interval [CI] 1.258-3.704), as well as RAP (P = 0.01; OR 1.26, 95% CI 1.056-1.503). CONCLUSIONS: In our cohort of Chinese pediatric patients, those with an identified gene mutation demonstrated worse clinical outcomes. Therefore, early gene screening for pediatric patients with idiopathic and heritable PAH is recommended, and more aggressive treatment for mutation carriers may be advisable.


Assuntos
Causas de Morte , Hipertensão Pulmonar Primária Familiar/epidemiologia , Hipertensão Pulmonar Primária Familiar/genética , Predisposição Genética para Doença/epidemiologia , Hipertensão Arterial Pulmonar/epidemiologia , Hipertensão Arterial Pulmonar/genética , Criança , Pré-Escolar , China , Estudos de Coortes , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Regulação da Expressão Gênica , Testes Genéticos/métodos , Genótipo , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pediatria , Fenótipo , Prevalência , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Vasodilatadores/uso terapêutico
6.
Exp Cell Res ; 379(2): 182-190, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30978340

RESUMO

Lysine demethylase 5B (KDM5B) is up-regulated in many cancers, including breast cancer. However, the underlying metabolic mechanisms of KDM5B on breast cancer progression are poorly understood. Here, we showed that KDM5B expression positively correlates with metastasis in breast cancer. Cell functional analyses were demonstrated that KDM5B knockdown and KDM5B inhibitor AS-8351 inhibited breast cancer cell proliferation and migration. Furthermore, we reported that KDM5B knockdown and AS-8351 reversed epithelial-mesenchymal transition (EMT) and decreased the protein levels of fatty acid synthase (FASN) and ATP citrate lyase (ACLY) in MCF-7 and MDA-MB-231 cells. Interestingly, we found that activation of AMP-activated protein kinase (AMPK) signaling pathway is involved in KDM5B-mediated EMT and lipid metabolism reprogramming in breast cancer cells. As a result, silencing of KDM5B-induced activation of AMPK signaling pathway inhibited breast cancer cell proliferation and migration. Taken together, our findings indicated that KDM5B was a novel regulator of lipid metabolism reprogramming, and it was suggested a new strategy to treat breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Metabolismo dos Lipídeos/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos
8.
J Cell Mol Med ; 23(5): 3451-3463, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30809937

RESUMO

Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF-E2-related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch-like ECH-associated protein 1 (Keap1) reduced the expression of glucose-6-phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia-inducing factor 1α (HIF-1α) in MCF-7 and MDA-MB-231 cells. Overexpression of Nrf2 up-regulated the expression of Notch1 via G6PD/HIF-1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES-1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2-driven breast cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular , Glucosefosfato Desidrogenase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Receptor Notch1/metabolismo , Regulação para Cima , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Modelos Biológicos , Via de Pentose Fosfato , Transdução de Sinais
9.
Plant Physiol ; 179(4): 1330-1342, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30617050

RESUMO

Magnaporthe oryzae is a fungal pathogen that causes rice (Oryza sativa) blast. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are key components in vesicle trafficking in eukaryotic cells and are known to contribute to fungal pathogen resistance. Syntaxin of Plants121 (SYP121), a Qa-SNARE, has been reported to function in nonhost resistance in Arabidopsis (Arabidopsis thaliana). However, the functions of SYP121 in host resistance to rice blast are largely unknown. Here, we report that the rice SYP121 protein, OsSYP121, accumulates at fungal penetration sites and mediates host resistance to rice blast. OsSYP121 is plasma membrane localized and its expression was obviously induced by the rice blast in both the blast-resistant rice landrace Heikezijing and the blast-susceptible landrace Suyunuo (Su). Overexpression of OsSYP121 in Su resulted in enhanced resistance to blast. Knockdown of OsSYP121 expression in Su resulted in a more susceptible phenotype. However, knockdown of OsSYP121 expression in the resistant landrace Heikezijing resulted in susceptibility to the blast fungus. The POsSYP121 ::GFP-OsSYP121 accumulated at rice blast penetration sites in transgenic rice, as observed by confocal microscopy. Yeast two-hybrid results showed that OsSYP121 can interact with OsSNAP32 (Synaptosome-associated protein of 32 kD) and Vesicle-associated membrane protein714/724. The interaction between OsSYP121 and OsSNAP32 may contribute to host resistance to rice blast. Our study reveals that OsSYP121 plays an important role in rice blast resistance as it is a key component in vesicle trafficking.


Assuntos
Interações Hospedeiro-Patógeno , Magnaporthe/fisiologia , Oryza/metabolismo , Imunidade Vegetal , Proteínas de Plantas/fisiologia , Oryza/imunologia , Oryza/microbiologia , Plantas Geneticamente Modificadas
10.
Biomed Pharmacother ; 109: 71-83, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30396094

RESUMO

Doxorubicin (DOX) is a wide spectrum antitumor drug. However, its clinical application is limited due to the cardiotoxicity. Carvedilol (CAR) is a ß-blocker used to treat high blood pressure and heart failure. Accordingly, supplementation with natural antioxidants or plant extracts exerts protective effects against various injury in vivo. Carnosic acid (CAA), the principal constituent of rosemary, has various biological activities, including antioxidant, antitumor, and anti-inflammatory. Here, heart injury mouse model was established using DOX (20 mg/kg) in vivo. And cardiac muscle cell line of H9C2 was subjected to 0.5 µM of DOX for 24 h in vitro. Then, the protective effects of CAA and CAR alone, or the two in combination on DOX-induced cardiotoxicity in vivo and in vitro were explored. The results indicated that both CAA and CAR, when used alone, were moderately effective in attenuating DOX-induced cardiotoxicity. The combination of two drugs functioned synergistically to ameliorate cardiac injury caused by DOX, as evidenced by the significantly reduced collagen accumulation and improved dysfunction of heart. CAA and CAR exhibited stronger anti-oxidative role in DOX-treated mice partly by augmenting the expression and activities of the anti-oxidative enzymes. In addition, inflammatory response was significantly suppressed by the two in combination, proved by the decreased pro-inflammatory cytokines (COX2, TNF-α, IL-6, IL-1ß and IL-18), which was associated with the inactivation of nuclear factor κB (NF-κB). Furthermore, DOX-stirred apoptosis and autophagy were dramatically attenuated by the co-treatments of CAA and CAR through down-regulating cleaved Caspase-3 and LC3B signaling pathways. The effects of CAA and CAR combination against cardiotoxicity were observed in H9C2 cells with DOX stimulation. Our findings above suggested that the use of CAR and CAA in combination could be expected to have synergistic efficacy and significant potential against cardiotoxicity induced by DOX.


Assuntos
Abietanos/farmacologia , Cardiotoxicidade/prevenção & controle , Carvedilol/farmacologia , Doxorrubicina/toxicidade , Abietanos/administração & dosagem , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cardiotoxicidade/etiologia , Carvedilol/administração & dosagem , Linhagem Celular , Citocinas/metabolismo , Sinergismo Farmacológico , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
11.
J Cell Physiol ; 234(6): 9663-9672, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30362561

RESUMO

Colorectal cancer (CRC) is the third-leading cause of cancer mortality worldwide. HACE1 function as a tumor-suppressor gene and is downregulated in several kinds of cancers. However, the distribution and clinical significance of HACE1 in CRC is still not clarified. In this study, we found that the HACE1 expression is greatly downregulated in CRC tissues and cell lines. Moreover, the HACE1 expression was significantly associated with inhibition of CRC cell proliferation, metastasis, and invasion. HACE1 inhibited epithelial-mesenchymal transition in CRC cells. Furthermore, we found that HACE1 altered the protein expression of the Hippo pathway by downregulation of YAP1. HACE1 suppresses the invasive ability of CRC cells by negatively regulating the YAP1 pathway. Our data indicates that HACE1 directly targets YAP1 and induces downregulation of YAP1, thereby increasing the activity of the Hippo pathway. In summary, these findings demonstrated that HACE1-YAP1 axis had an important part in the CRC development and progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Movimento Celular/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/deficiência , Regulação para Cima/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
12.
Oxid Med Cell Longev ; 2018: 1640804, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30116474

RESUMO

Myocardial diseases are prevalent syndromes with high mortality rate. The exploration of effective interference is important. Anti-ß1-adrenergic receptor autoantibody (ß1-AAB) is highly correlated with myocardial dysfunction. The actions and underlying mechanisms of honokiol (HNK) in ß1-AAB-positive patients await to be unraveled. In this study, we established a rat model of ß1-AAB positive with myocardial dysfunction. Cardiac function following ß1-AR-ECII administration was analyzed using the VisualSonics Vevo 770 High-Resolution In Vivo Imaging System. The levels of autophagy-related proteins were detected by Western blotting. Our data revealed that HNK reversed ß1-AAB-induced effects and protected myocardial tissues from dysfunction. After HNK treatment, the cardiac contractile ability increased and the LDH activity decreased. HNK attenuated myocardial degeneration. In addition, HNK promoted the activation of the AMP-dependent protein kinase/Unc-51-like autophagy activating kinase (AMPK/ULK) pathway and activated autophagy. These results suggest that HNK protects against ß1-AAB-induced myocardial dysfunction via activation of autophagy and it may be a potentially therapeutic compound for ß1-AAB-positive myocardial diseases.


Assuntos
Anti-Infecciosos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Lignanas/uso terapêutico , Animais , Anti-Infecciosos/farmacologia , Autofagia , Compostos de Bifenilo/farmacologia , Cardiomiopatias/patologia , Modelos Animais de Doenças , Humanos , Lignanas/farmacologia , Masculino , Ratos , Ratos Wistar
13.
J Cell Physiol ; 233(2): 1359-1369, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28513825

RESUMO

Epigenetic modifications such as histone modifications and cytosine hydroxymethylation are linked to tumorigenesis. Loss of 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation 1 (TET1) down-regulation facilitates tumor initiation and development. However, the mechanisms by which loss of TET1 knockdown promotes malignancy development remains unclear. Here, we report that TET1 knockdown induced epithelial-mesenchymal transition (EMT) and increased cancer cell growth, migration, and invasion in DLD1 cells. Loss of TET1 increased EZH2 expression and reduced UTX-1 expression, thus increasing histone H3K27 tri-methylation causing repression of the target gene E-cadherin. Ectopic expression of the H3K27 demethylase UTX-1 or EZH2 depletion both impeded EZH2 binding caused a loss of H3K27 methylation at epithelial gene E-cadherin promoter, thereby suppressing EMT and tumor invasion in shTET1 cells. Conversely, UTX-1 depletion and ectopic expression of EZH2 enhanced EMT and tumor metastasis in DLD1 cells. These findings provide insight into the regulation of TET1 and E-cadherin and identify EZH2 as a critical mediator of E-cadherin repression and tumor progression.


Assuntos
Caderinas/metabolismo , Movimento Celular , Neoplasias do Colo/metabolismo , Histonas/metabolismo , Oxigenases de Função Mista/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Antígenos CD , Caderinas/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Metilação de DNA , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Oxigenases de Função Mista/genética , Invasividade Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Transfecção
14.
Int J Biochem Cell Biol ; 95: 85-92, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29275212

RESUMO

High aerobic glycolysis not only provides energy to breast cancer cells, but also supports their anabolic growth. The redox sensitive transcription factor NRF2 is over-expressed in multiple cancers, including breast cancer. It is unclear whether NRF2 could promote breast cancer cell growth through enhancing glycolysis. In this study, we found that NRF2 and HIF1α mRNA and protein levels were significantly increased in MCF-7 and MDA-MB-231 breast cancer cells as compared to MCF-10A benign breast epithelial cells. Down-regulation of NRF2 decreased MCF7 and MBA-DA-231 breast cell proliferation, while it reversed by hypoxia inducible factor 1α (HIF1α). Knockdown of NRF2 inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including HK2, PFKFB3, PKM2 and LDHA. Our results further indicated that the AKT activation and AMPK inhibition were required for NRF2-mediated up-regulation of glycolytic enzymes. Consistent with these results, a positive correlation existed between NRF2 or HIF1α and several key glycolytic genes in human breast cancer cell samples and breast cancer patients with high NRF2 or HIF1α expression had poorer overall survival. In conclusion, our study demonstrates that NRF2 promotes breast cancer progression by enhancing glycolysis through coactivation of HIF1α, implicating that NRF2 is a potential molecular target for breast cancer treatment.


Assuntos
Neoplasias da Mama/metabolismo , Mama/metabolismo , Reprogramação Celular , Regulação Neoplásica da Expressão Gênica , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Mama/citologia , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Registros Eletrônicos de Saúde , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Análise de Sobrevida
15.
Arch Biochem Biophys ; 625-626: 17-23, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28583828

RESUMO

Considerable evidence has shown that autophagy has an important role in HIV-1 infection. However, it is still unknown whether metabolism-regulated autophagy pathway is involved in Tat-mediated HIV-1 transactivation. This study demonstrated that treatment of Tat in TZM-bl cells significantly down-regulated protein levels of Beclin-1, Atg-5, Atg-7, and LC3B-II and up-regulated of p62 levels. Blockage of autophagy enhanced Tat-induced HIV-1 transactivation in TZM-bl cells. Moreover, we found that Tat activated the Akt/mTOR and inhibited AMPK signaling pathway that was related to its up-regulation of PKM2 expression. In addition, we showed that PI3K/AKT activation and AMPK inhibtion was required for the PKM2-mediated inhibition of autophagy in Tat-treated TZM-bl cells. In conclusion, our data reveals that PKM2-mediated autophagy inhibition is required for Tat-mediated HIV-1 transactivation. Metabolism-related autophagic pathway may act as a promising diagnostic and therapeutic tool for HIV-1 infection in the future.


Assuntos
Autofagia , Proteínas de Transporte/metabolismo , Infecções por HIV/metabolismo , HIV-1/fisiologia , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Ativação Transcricional , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas de Transporte/genética , Linhagem Celular , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Hormônios Tireóideos/genética
16.
Proc Natl Acad Sci U S A ; 114(5): 1177-1182, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28096412

RESUMO

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.


Assuntos
Transtornos Cognitivos/genética , Giro Denteado/fisiologia , Filtro Sensorial/genética , Proteínas de Transporte Vesicular/fisiologia , Animais , Animais Recém-Nascidos , Transtornos Cognitivos/fisiopatologia , Giro Denteado/metabolismo , Modelos Animais de Doenças , Eletroporação , Potenciais Pós-Sinápticos Excitadores/fisiologia , Medo , Genes Reporter , Ácido Glutâmico/fisiologia , Células HEK293 , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Neurônios/ultraestrutura , Densidade Pós-Sináptica/química , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de AMPA/biossíntese , Esquizofrenia/genética , Filtro Sensorial/fisiologia , Transmissão Sináptica/fisiologia , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/genética
17.
Int J Biochem Cell Biol ; 80: 51-56, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27671333

RESUMO

Epigenetic modifications are thought to be important for gene expression changes during HIV-1 transcription and replication. The removal of histone H3 lysine27 (H3K27) trimethylation mark by UTX-1 is important for the robust induction of many specific genes during Tat-mediated HIV-1 transactvation. We found that UTX-1 enzymatic activity is needed for Tat to remove a repressive mark H3K27me3 in the HIV-1 long terminal repeat (LTR). UTX-1 converted the chromatin structure to a more transcriptionally active state by up-regulation of H3K4 methylation and down-regulation of H3K27 methylation on the specific regions of HIV-1 LTR. The increase in H3K27me3 and the decrease in H3K4me3 induced by UTX-1 knockdown was detected on the HIV-1 LTR, but not by control siRNA. Additionally, UTX-1 promotes HIV-1 gene expression by enhancing both the NF-κB p65's nuclear translocation and its p65 binding to HIV-1 LTR. And we further demonstrated that H3K27 demethylase activity was required for increased HIV-1 transactivation induced by UTX-1. Together, our data reveal key roles for UTX-1 in a timely transition from poised to active chromatin in HIV-1 LTR during HIV-1 transcription and a fundamental mechanism by which a H3K27 demethylase triggers tissue-specific chromatin changes. Our findings provide a mechanistic link between UTX-1 and enhanced HIV-1 replication, and suggest that targeting at epigenetic mechanism may have a therapeutic benefit for HIV-1 patients.


Assuntos
HIV-1/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Ativação Transcricional , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Transporte Ativo do Núcleo Celular , Núcleo Celular/metabolismo , Células HeLa , Histonas/química , Humanos , Lisina/metabolismo , Metilação , NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismo , Regulação para Cima
18.
Biosci Rep ; 36(3)2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27166426

RESUMO

Catalpol, an iridoid glucoside, has been reported to inhibit apoptosis of neuron and endothelial cells. In the present study, we investigated the mechanism of catalpol-mediated cardioprotection. The rat embryonic ventricular myocardial cell line (H9c2) cells were first incubated with catalpol, and then exposed to hydrogen peroxide (H2O2). The concentration of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were all determined by using commercially available kits. Apoptotic cells were assessed by Hoechst 33258 and Annexin V-fluorescein isothiocyanate binding assay. Synthesis of Bcl-2, Bax, cytochrome c and caspase-3 were analysed by real-time semiquantitative reverse transcription-PCR and Western blotting. We observed that apoptosis in H9c2 was associated with increased Bax, cytochrome c, caspase-3, decreased Bcl-2 activity after 24 h of H2O2 exposure. Catalpol pretreatment afforded a marked protection against the above H2O2-mediated cytotoxicity and apoptosis in H9c2 cells. Moreover, the catalpol pretreatment led to a great reduction in H2O2-induced MDA release and increased SOD. These findings indicated for the first time that pretreatment of H9c2 cells with catalpol can be against H2O2-induced apoptosis, and the protective effect of catalpol involves the mitochondrial-dependent caspase pathway and is associated with increased Bcl-2 and decreased Bax expression.


Assuntos
Apoptose/efeitos dos fármacos , Glucosídeos Iridoides/administração & dosagem , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Animais , Caspase 3/genética , Citocromos c/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Peróxido de Hidrogênio/toxicidade , Mitocôndrias/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética
19.
Arch Biochem Biophys ; 598: 50-6, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27040384

RESUMO

Pyruvate kinase M2 (PKM2) plays a pivotal role in the growth, survival and metabolic reprogramming of cancer cells. Here, we presented for the first time that tanshinone ⅡA inhibited human esophagus cancer cell growth through miR-122-mediated PKM2 down-regulation pathway. Tanshinone ⅡA inhibited cell proliferation and induced cell cycle arrest in S phase in human Ec109 cells. As expected, tanshinone ⅡA down-regulated PKM2 mRNA and protein expression in Ec109 cells. Given these findings, we further investigated microRNAs regulation of PKM2 and confirmed miR-122 for targeting PKM2. Moreover, we found that tanshinone ⅡA-induced up-regulation of miR-122 expression inhibited PKM2 expression in Ec109 cells. Meanwhile, tanshinone ⅡA inhibited proliferation through miR122-medated PKM2 down-regulation. It was demonstrated that the anticancer activity of tanshinone ⅡA was targeted at metabolic regulation of miR-122/PKM2 in human esophagus cancer cells. Taken together, our results revealed tanshinone ⅡA targeting at PKM2-mediated metabolic reprogramming play an important role in inhibition of esophageal cancer cell growth.


Assuntos
Abietanos/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , Piruvato Quinase/biossíntese , RNA Neoplásico/biossíntese , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Células HeLa , Humanos
20.
Clin Lab ; 61(10): 1471-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26642709

RESUMO

BACKGROUND: DNA methylation has been proposed as a potential biomarker for cervical cancer detection. This study aimed to evaluate the diagnostic role of paired boxed gene 1 (PAX1) methylation for cervical cancer screening in Asians. METHODS: Eligible studies were retrieved by searching the electronic databases, and the quality of the enrolled studies was assessed via the quality assessment for studies of diagnostic accuracy (QUADAS) tool. The bivariate meta-analysis model was employed to generate the summary receiver operator characteristic (SROC) curve using Stata 12.0 software. Cochran's Q test and I2 statistics were applied to assess heterogeneity among studies. Publication bias was evaluated by the Deeks' funnel plot asymmetry test. RESULTS: A total of 9 articles containing 15 individual studies were included. The SROC analysis showed that single PAX1 methylation allowed for the discrimination between cancer/high-grade squamous intraepithelial lesion (HSIL) patients and normal individuals with a sensitivity (95% confidence interval) of 0.80 (0.70 - 0.87) and specificity of 0.89 (0.86 - 0.92), corresponding to an area under curve (AUC) of 0.92. Notably, our subgroup analysis suggested that combing parallel testing of PAX1 methylation and HPV DNA (AUC, sensitivity, and specificity of 0.90, 0.82, and 0.84, respectively) seemed to harbor higher accuracy than single HPV DNA testing (AUC, sensitivity, and specificity of 0.81, 0.86, and 0.67, respectively). CONCLUSIONS: PAX1 methylation hallmarks a potential diagnostic value for cervical cancer screening in Asians, and parallel testing of PAX1 methylation and HPV in cervical scrapings confers an improved accuracy than single HPV DNA testing.


Assuntos
Biomarcadores Tumorais/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/genética , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Carcinoma de Células Escamosas/patologia , Detecção Precoce de Câncer , Feminino , Humanos , Metilação , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Software , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico
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