Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
iScience ; 23(11): 101684, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33196019

RESUMO

Cancer cells alter their nutrition metabolism to cope the stressful environment. One important metabolism adjustment is that cancer cells activate glutaminolysis in response to the reduced carbon from glucose entering into the TCA cycle due to inactivation of several enzymes in glycolysis. An important question is how the cancer cells coordinate the changes of glycolysis and glutaminolysis. In this report, we demonstrate that the pyruvate kinase inactive dimer PKM2 facilitates activation of glutaminolysis. Our experiments show that growth stimulations promote PKM2 dimer. The dimer PKM2 plays a role in regulation of glutaminolysis by upregulation of mitochondrial glutaminase I (GLS-1). PKM2 dimer regulates the GLS-1 expression by controlling internal ribosome entry site (IRES)-dependent c-myc translation. Growth stimulations promote PKM2 interacting with c-myc IRES-RNA, thus facilitating c-myc IRES-dependent translation. Our study reveals an important linker that coordinates the metabolism adjustment in cancer cells.

2.
Menopause ; 27(3): 326-332, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31834159

RESUMO

OBJECTIVE: To determine the effect of metformin on marrow adiposity in postmenopausal women with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: We enrolled 25 postmenopausal T2DM women who satisfied the requirement of having been on 1 year of metformin therapy and 26 age-matched healthy women receiving a placebo. All participants were analyzed for marrow fat fraction (FF) by magnetic resonance spectroscopy, vertebral volumetric bone mineral density (vBMD) by quantitative computed tomography, blood glucose, lipid profiles, and bone biomarkers to compare values before and after the interventions. Differences between groups were assessed using a Student's t test and chi-square test or an analysis of covariance adjusted for covariates. Twelve-month change in within-group difference was assessed using paired t tests. Correlations were determined by Pearson's correlation. RESULTS: Vertebral vBMD was lower in T2DM than in nondiabetic controls (105.6 ±â€Š13.8 vs 112.8 ±â€Š15.2 mg/cm; P = 0.029). T2DM women had a higher marrow FF than those without diabetes (66.3 ±â€Š7.2% vs 58.9 ±â€Š7.5%; P < 0.001), even after adjusting for covariates. From baseline to month 12 in the T2DM group, metformin was associated with a reduction in marrow FF (-12.0%; P < 0.001) and an increase in vBMD (3.7%; P = 0.020). For metformin-treated T2DM women, the 12-month change in marrow FF was inversely associated with change in vBMD (r = -0.771, P < 0.001), but not with changes in bone biomarkers, whereas change in vBMD or FF was not significant in the control group. CONCLUSION: Postmenopausal women with newly diagnosed T2DM have a higher marrow fat content compared with nondiabetic women. Metformin treatment reduced marrow adiposity in T2DM.

3.
Nat Commun ; 10(1): 4777, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664017

RESUMO

Early diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences. Here we report a collagen type I targeting protein-based contrast agent (ProCA32.collagen1) with strong collagen I affinity. ProCA32.collagen1 possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage (Ishak stage 3 of 6) liver fibrosis and nonalcoholic steatohepatitis (Ishak stage 1 of 6 or 1 A Mild) in animal models via dual contrast modes. ProCA32.collagen1 also demonstrates vasculature changes associated with intrahepatic angiogenesis and portal hypertension during late-stage fibrosis, and heterogeneity via serial molecular imaging. ProCA32.collagen1 mitigates metal toxicity due to lower dosage and strong resistance to transmetallation and unprecedented metal selectivity for Gd3+ over physiological metal ions with strong translational potential in facilitating effective treatment to halt further chronic liver disease progression.


Assuntos
Meios de Contraste/química , Gadolínio/química , Hipertensão Portal/diagnóstico por imagem , Fígado/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Doença Crônica , Diagnóstico Precoce , Humanos
4.
Zhonghua Nei Ke Za Zhi ; 55(2): 121-6, 2016 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-26875581

RESUMO

OBJECTIVE: To explore the clinical manifestations, antimicrobial therapy, and risk factors of mortality in patients with Acinetobacter baumannii bloodstream infection. METHODS: Clinical data of 153 patients with Acinetobacter baumannii bloodstream infection hospitalized in First Affiliated Hospital of Zhejiang University from January 2013 to September 2014 were analyzed retrospectively.According to the 28-day survival after diagnosis, the patients were divided into death group (n=76) and survival group (n=77). Data related to demographic and clinical characteristics, underlying diseases, treatment, invasive procedures, bacterial resistance to antibiotics, acute physiology and chronic health evaluation Ⅱ(APACHEⅡ )scores at onset, and antimicrobial therapy were collected.The index as an independent risk factor of mortality was demonstrated by multivariate logistic regression analysis. RESULTS: This study included 153 patients with Acinetobacter baumannii bloodstream infection. The 28-day mortality was 49.7%. The independent risk factors of mortality were APACHE Ⅱ score ≥ 22 at onset (OR=15.7, 95%CI 5.1-48.1, P<0.001), septic shock(OR=6.3, 95%CI 1.9-21.3, P=0.003), and administration of steroids(OR=3.6, 95%CI 1.0-12.3, P=0.043). Compared with subjects treated with non-cefoperazone-sulbactam-based regimen , those treated with cefoperazone-sulbactam for multidrug-resistant Acinetobacter baumannii(MDR-AB) had significantly lower mortality on day7, day14 and day28(8.9% vs 59.2%, 31.1% vs 65.8%, 44.4% vs 72.4% respectively). CONCLUSIONS: The patients with Acinetobacter baumannii bloodstream infection have high mortality within one month. Administration of steroids and septic shock are associated with poor prognosis. APACHEⅡ score ≥ 22 at onset predicts adverse outcome. Cefoperazone-sulbactam-based antimicrobial therapy improves patients' survival.


Assuntos
Infecções por Acinetobacter/patologia , Bacteriemia/patologia , APACHE , Infecções por Acinetobacter/diagnóstico , Infecções por Acinetobacter/mortalidade , Acinetobacter baumannii , Antibacterianos/uso terapêutico , Bacteriemia/diagnóstico , Bacteriemia/mortalidade , Cefoperazona/uso terapêutico , Humanos , Estudos Retrospectivos , Fatores de Risco , Choque Séptico/diagnóstico , Choque Séptico/patologia , Sulbactam/uso terapêutico
5.
Wound Repair Regen ; 24(2): 328-36, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26808610

RESUMO

Neutrophils infiltration/activation following wound induction marks the early inflammatory response in wound repair. However, the role of the infiltrated/activated neutrophils in tissue regeneration/proliferation during wound repair is not well understood. Here, we report that infiltrated/activated neutrophils at wound site release pyruvate kinase M2 (PKM2) by its secretive mechanisms during early stages of wound repair. The released extracellular PKM2 facilitates early wound healing by promoting angiogenesis at wound site. Our studies reveal a new and important molecular linker between the early inflammatory response and proliferation phase in tissue repair process.


Assuntos
Neovascularização Fisiológica , Neutrófilos/metabolismo , Piruvato Quinase/metabolismo , Cicatrização/fisiologia , Ferimentos e Lesões/enzimologia , Ferimentos e Lesões/patologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Matriz Extracelular/patologia , Imuno-Histoquímica , Inflamação/enzimologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/enzimologia
6.
J Cell Biochem ; 116(8): 1595-601, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25649741

RESUMO

1-(3,5-Dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl)aminocarbonyl] piperazine (RX-5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX-5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of (3) H-labeled RX-5902 to Y593 phospho-p68 RNA helicase. We further demonstrated RX-5902 inhibited the ß-catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX-5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the ß-catenin pathway, such as c-Myc, cyclin D1 and p-c-Jun. Therefore, our study indicates that the inhibition of Y593 phospho-p68 helicase - ß-catenin interaction by direct binding of RX-5902 to Y593 phospho-p68 RNA helicase may contribute to the anti-cancer activity of this compound.


Assuntos
Antineoplásicos/farmacologia , RNA Helicases DEAD-box/metabolismo , Neoplasias/tratamento farmacológico , Piperazinas/farmacologia , Quinoxalinas/farmacologia , beta Catenina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , RNA Helicases DEAD-box/química , Humanos , Neoplasias/metabolismo , Fosforilação , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
7.
J Biol Chem ; 289(37): 25812-21, 2014 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-25070887

RESUMO

It is long known that pyruvate kinase isoform M2 (PKM2) is released into the circulation of cancer patients. The PKM2 levels in patients have been suggested as a diagnostic marker for many types of cancers. However, it is not known how PKM2 is released in the blood, and whether the circulating PKM2 has any physiological function(s) in tumor progression. In this report, we demonstrate that PKM2 in the blood facilitates tumor growth by promoting tumor angiogenesis. Our experiments show that PKM2 promotes tumor angiogenesis by increasing endothelial cell proliferation, migration, and cell-ECM adhesion. Only the dimeric PKM2 possess the activity in promoting tumor angiogenesis, which is consistent with the observations that PKM2 in circulation of cancer patients is a dimer form.


Assuntos
Proteínas de Transporte/sangue , Proliferação de Células/genética , Proteínas de Membrana/sangue , Neovascularização Patológica/patologia , Isoformas de Proteínas/sangue , Hormônios Tireóideos/sangue , Animais , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Glicólise/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Neoplasias/sangue , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Neovascularização Patológica/sangue , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Biol Chem ; 288(22): 15971-9, 2013 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-23576436

RESUMO

Pyruvate kinase isoform M2 (PKM2) is an enzyme-catalyzing conversion of phosphoenolpyruvate to pyruvate in the glycolysis pathway. It was demonstrated that PKM2 interacts with tyrosine phosphopeptide, and the interaction with the tyrosine phosphopeptide affects the pyruvate kinase activity of PKM2. Our experiments suggest that PKM2 is also an active protein kinase (Gao, X., Wang, H., Yang, J. J., Liu, X., and Liu, Z. R. (2012) Mol. Cell 45, 598-609). We report here that growth signals reciprocally regulate the pyruvate kinase and protein kinase activities of PKM2 by different mechanisms. On the one hand, growth signals induce protein tyrosine phosphorylations. The tyrosine-phosphorylated protein(s) regulates the conversion of pyruvate kinase and protein kinase of PKM2 by directly interacting with PKM2. Binding of the tyrosyl-phosphorylated proteins at the fructose 1,6-bisphosphate-binding site converts the tetrameric PKM2 to a dimer. On the other hand, growth stimulations also lead to PKM2 phosphorylation, which consequently regulates the conversion of protein kinase and pyruvate kinase activities. Growth factor stimulations significantly increase the dimer/tetramer PKM2 ratio in cells and consequently activate the protein kinase activity of PKM2. Our study suggests that the conversion between the pyruvate kinase and protein kinase activities of PKM2 may be an important mechanism mediating the effects of growth signals in promoting cell proliferation.


Assuntos
Proliferação de Células , Multimerização Proteica/fisiologia , Proteínas Tirosina Quinases/metabolismo , Piruvato Quinase/metabolismo , Transdução de Sinais/fisiologia , Sítios de Ligação , Linhagem Celular , Humanos , Fosforilação/fisiologia , Proteínas Tirosina Quinases/genética , Piruvato Quinase/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...