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1.
PLoS Genet ; 12(12): e1006514, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28027303

RESUMO

Mitral cells (MCs) of the mammalian olfactory bulb have a single primary dendrite extending into a single glomerulus, where they receive odor information from olfactory sensory neurons (OSNs). Molecular mechanisms for controlling dendritic arbors of MCs, which dynamically change during development, are largely unknown. Here we found that MCs displayed more complex dendritic morphologies in mouse mutants of Maml1, a crucial gene in Notch signaling. Similar phenotypes were observed by conditionally misexpressing a dominant negative form of MAML1 (dnMAML1) in MCs after their migration. Conversely, conditional misexpression of a constitutively active form of Notch reduced their dendritic complexity. Furthermore, the intracellular domain of Notch1 (NICD1) was localized to nuclei of MCs. These findings suggest that Notch signaling at embryonic stages is involved in the dendritic complexity of MCs. After the embryonic misexpression of dnMAML1, many MCs aberrantly extended dendrites to more than one glomerulus at postnatal stages, suggesting that Notch signaling is essential for proper formation of olfactory circuits. Moreover, dendrites in cultured MCs were shortened by Jag1-expressing cells. Finally, blocking the activity of Notch ligands in OSNs led to an increase in dendritic complexity as well as a decrease in NICD1 signals in MCs. These results demonstrate that the dendritic complexity of MCs is controlled by their presynaptic partners, OSNs.


Assuntos
Proteínas Nucleares/genética , Bulbo Olfatório/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Receptor Notch1/genética , Fatores de Transcrição/genética , Animais , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteína Jagged-1/biossíntese , Proteína Jagged-1/genética , Camundongos , Proteínas Nucleares/biossíntese , Bulbo Olfatório/crescimento & desenvolvimento , Neurônios Receptores Olfatórios/citologia , Receptor Notch1/biossíntese , Transdução de Sinais/genética , Fatores de Transcrição/biossíntese
2.
Pediatr Int ; 58(6): 537-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27322865

RESUMO

The incidence of ampicillin (ABPC)-resistant Escherichia coli (E. coli) infection in very low-birthweight infants has been increasing. The rate of ABPC/sulbactam (ABPC/SBT)-resistant E. coli in this population, however, is currently unknown. We encountered two cases of severe infection due to resistant E. coli and retrospectively studied the prevalence of ABPC- and ABPC/SBT-resistant E. coli in regular surveillance cultures obtained from all neonatal intensive care unit (NICU) patients between 2000 and 2013. The overall prevalence of ABPC-resistant E. coli was 39% (47/120), accounting for 63% of cases (32/51) between 2007 and 2013, compared with 22% (15/69) between 2000 and 2006. The prevalence of ABPC/SBT resistance was 17% (20/120), which was similar in both periods (16%, 8/51 vs 17%, 12/69). According to these results, not only ABPC, but also ABPC/SBT-resistant E. coli must be considered in the NICU.


Assuntos
Ampicilina/uso terapêutico , Farmacorresistência Bacteriana , Infecções por Escherichia coli/epidemiologia , Escherichia coli/isolamento & purificação , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Sulbactam/uso terapêutico , Fatores Etários , Antibacterianos/uso terapêutico , Quimioterapia Combinada , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Feminino , Humanos , Incidência , Recém-Nascido , Japão/epidemiologia , Masculino
3.
PLoS One ; 10(4): e0124081, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25879666

RESUMO

Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.


Assuntos
Carcinogênese/metabolismo , Diabetes Mellitus Experimental/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/efeitos dos fármacos , Metformina/farmacologia , Obesidade/metabolismo , Adipocinas/metabolismo , Animais , Animais Recém-Nascidos , Dietilnitrosamina , Feminino , Hipoglicemiantes/farmacologia , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Oncogênica v-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
4.
Eur J Pediatr ; 174(4): 551-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25194957

RESUMO

UNLABELLED: Staphylococcal scalded skin syndrome (SSSS) demonstrates dermal symptoms due to exfoliative toxin (ET) A or ETB produced by Staphylococcus aureus. We examined the association between anti-ETA antibodies and SSSS onset in neonates. Three preterm infants carried an ETA-producing strain of S. aureus, manifesting as either SSSS or bullous impetigo; a full-term infant carrying the same strain was asymptomatic. The infants (n=106) were categorized into three groups according to their gestational age (GA) as follows: <30 weeks, 30-37 weeks, and >37 weeks. The measured levels of anti-ETA antibody in the three infants displaying SSSS were low before the onset of dermal symptoms; only the asymptomatic full-term infant displayed a high antibody level. Anti-ETA antibody levels in the preterm group with a GA of <30 weeks were statistically lower than those in the term infant group; the prevalences of anti-ETA antibodies above a cutoff value in the three groups of neonates were 55 % (18/33) among preterm infants with a GA <30 weeks, 73 % (25/34) among those with a GA of 30-37 weeks, and 90 % (35/39) among infants with a GA >37 weeks. CONCLUSION: The presence of anti-ETA antibodies below a particular cutoff level might be associated with SSSS onset in preterm infants.


Assuntos
Exfoliatinas/imunologia , Infecções Estafilocócicas/diagnóstico , Síndrome da Pele Escaldada Estafilocócica/diagnóstico , Staphylococcus aureus/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Infecções Estafilocócicas/imunologia , Síndrome da Pele Escaldada Estafilocócica/imunologia
5.
Oncol Lett ; 8(1): 223-229, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24959250

RESUMO

Metabolic syndrome (Mets), including diabetes and hypertension, increases the risk of colorectal cancer via the induction of chronic inflammation, acceleration of oxidative stress, and activation of the renin-angiotensin system. The present study examined the possible inhibitory effects of captopril, an angiotensin-converting enzyme (ACE) inhibitor and antihypertensive drug, on the development of azoxymethane (AOM)-induced colonic premalignant lesions, aberrant crypt foci (ACF), in SHRSP.Z-Leprfa /IzmDmcr (SHRSP-ZF) diabetic and hypertensive rats. Male 6-week-old SHRSP-ZF rats were administered two, weekly intraperitoneal injections of AOM (20 mg/kg body weight). Following the second injection, the rats received drinking water containing captopril (8 mg/kg/day) for two weeks. At sacrifice, captopril administration significantly lowered the blood pressure and reduced the total number and size of ACF compared with those observed in the untreated group. The serum levels of angiotensin-II and the expression levels of ACE and angiotensin-II type 1 receptor mRNA on the colonic mucosa decreased following captopril treatment. Captopril also reduced the urinary 8-hydroxy-2'-deoxyguanosine levels and the serum derivatives of reactive oxygen metabolites levels, both of which are oxidative stress markers, but increased the mRNA levels of catalase, an antioxidant enzyme, in the colonic epithelium. Moreover, the expression levels of tumor necrosis factor-α, interleukin-18, monocyte chemoattractant protein-1, inducible nitric oxide synthase, vascular endothelial growth factor and proliferating cell nuclear antigen mRNA in the colonic epithelium were decreased significantly following captopril administration. These observations suggested that captopril prevents the development of ACF by inhibiting renin-angiotensin system activation and attenuating inflammation and oxidative stress in SHRSP-ZF rats. Therefore, targeting Mets-related pathophysiological conditions, including renin-angiotensin system activation, may be an effective strategy to prevent colorectal carcinogenesis in patients with Mets, particularly those with hypertension.

6.
J Biol Chem ; 289(18): 12922-30, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24644294

RESUMO

Reelin is a secreted glycoprotein that plays essential roles in the brain. Reelin is specifically cleaved at two distinct sites, called N-t and C-t, with the former being the major one. N-t cleavage can occur both in the extracellular space and in the endosomes, although the physiological importance of endosomal N-t cleavage has not been investigated. In this study, we first determined the exact N-t cleavage site catalyzed by a protease secreted by cerebral cortical neurons. Cleavage occurred between Pro-1244 and Ala-1245 within Reelin repeat 3. A Reelin mutant in which Pro-1244 was replaced with aspartate (Reelin-PD) was resistant to a protease secreted by cultured cerebral cortical neurons, and its biological activity stayed active longer than that of wild-type Reelin. Interestingly, Reelin-PD remained in the intracellular compartments longer than wild-type Reelin and persistently activated downstream signaling. Therefore, N-t cleavage of Reelin is required for halting the signaling machinery in the extracellular space as well as within endosomes of target neurons. We established a monoclonal antibody specific to uncleaved Reelin protein and found that it is localized in the vicinity of Reelin-producing cells, whereas the N-terminal fragment diffuses, or is transported, to distant regions. These data demonstrate that N-t cleavage of Reelin plays critical roles in regulating the duration and range of Reelin functions both in the extracellular milieu and in the intracellular compartments.


Assuntos
Ácido Aspártico/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Prolina/genética , Serina Endopeptidases/genética , Transdução de Sinais/genética , Sequência de Aminoácidos , Animais , Ácido Aspártico/metabolismo , Sítios de Ligação/genética , Western Blotting , Moléculas de Adesão Celular Neuronais/metabolismo , Células Cultivadas , Endossomos/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Espaço Extracelular/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Peptídeo Hidrolases/metabolismo , Prolina/metabolismo , Proteólise , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/metabolismo
7.
J Nutr Sci Vitaminol (Tokyo) ; 60(5): 357-62, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25744425

RESUMO

The prognosis of patients with hepatocellular carcinoma (HCC) is poor and the development of effective treatments for this malignancy, including combination chemotherapy, is required. This study examined the possible combined inhibitory effects of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, and acyclic retinoid (ACR), which can prevent the development of HCC, on the growth of Huh7 human HCC cells. Xenograft tumors were produced by subcutaneously injecting Huh7 cells into nude mice. Starting 1 wk after the tumor cell injection, the mice were treated with bevacizumab alone (5 mg/kg body weight, subcutaneous injection, twice a week), ACR alone (given in a diet containing 0.03%), or their combination for 6 wk, and the effects of these regimens on xenograft growth were examined. Combined treatment with bevacizumab plus ACR significantly suppressed the growth of Huh7 xenografts. The combination of these agents significantly inhibited the phosphorylation of the Akt protein in tumor tissues. With combination therapy, the population of Ki-67-positive cells in xenografts decreased, while that of TUNEL-positive cells increased. The combination of bevacizumab and ACR exerts growth-suppressing effects on HCC cells by inhibiting cell proliferation and inducing apoptosis. This combination might be an effective regimen for the treatment of HCC.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Tretinoína/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Transplante de Neoplasias/métodos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tretinoína/administração & dosagem , Tretinoína/farmacologia
8.
Cancer Lett ; 342(1): 60-9, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23981577

RESUMO

Non-alcoholic steatohepatitis (NASH), which involves hepatic inflammation and fibrosis, is associated with liver carcinogenesis. The activation of the renin-angiotensin system (RAS), which plays a key role in blood pressure regulation, promotes hepatic fibrogenesis. In this study, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea catechins, on the development of glutathione S-transferase placental form (GST-P)-positive (GST-P(+)) foci, a hepatic preneoplastic lesion, in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP-ZF) obese and hypertensive rats. Male 7-week-old SHRSP-ZF rats and control non-obese and normotensive WKY rats were fed a high fat diet and received intraperitoneal injections of carbon tetrachloride twice a week for 8weeks. The rats were also provided tap water containing 0.1% EGCG during the experiment. SHRSP-ZF rats presented with obesity, insulin resistance, dyslipidemia, an imbalance of adipokines in the serum, and hepatic steatosis. The development of GST-P(+) foci and liver fibrosis was markedly accelerated in SHRSP-ZF rats compared to that in control rats. Additionally, in SHRSP-ZF rats, RAS was activated and inflammation and oxidative stress were induced. Administration of EGCG, however, inhibited the development of hepatic premalignant lesions by improving liver fibrosis, inhibiting RAS activation, and attenuating inflammation and oxidative stress in SHRSP-ZF rats. In conclusion, obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride displayed the histopathological and pathophysiological characteristics of NASH and developed GST-P(+) foci hepatic premalignant lesions, suggesting the model might be useful for the evaluation of NASH-related liver tumorigenesis. EGCG might also be able to prevent NASH-related liver fibrosis and tumorigenesis.


Assuntos
Anticarcinógenos/uso terapêutico , Catequina/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Hipertensão/complicações , Neoplasias Hepáticas/prevenção & controle , Obesidade/complicações , Lesões Pré-Cancerosas/tratamento farmacológico , Angiotensina II/sangue , Animais , Anticarcinógenos/farmacologia , Catequina/farmacologia , Catequina/uso terapêutico , Fígado Gorduroso/sangue , Fígado Gorduroso/etiologia , Expressão Gênica , Interleucina-6/sangue , Interleucina-6/genética , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Lesões Pré-Cancerosas/sangue , Lesões Pré-Cancerosas/etiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética
9.
BMC Cancer ; 13: 465, 2013 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-24103747

RESUMO

BACKGROUND: A malfunction of RXRα due to phosphorylation is associated with liver carcinogenesis, and acyclic retinoid (ACR), which targets RXRα, can prevent the development of hepatocellular carcinoma (HCC). Activation of PI3K/Akt signaling plays a critical role in the proliferation and survival of HCC cells. The present study examined the possible combined effects of ACR and LY294002, a PI3K inhibitor, on the growth of human HCC cells. METHODS: This study examined the effects of the combination of ACR plus LY294002 on the growth of HLF human HCC cells. RESULTS: ACR and LY294002 preferentially inhibited the growth of HLF cells in comparison with Hc normal hepatocytes. The combination of 1 µM ACR and 5 µM LY294002, in which the concentrations used are less than the IC50 values of these agents, synergistically inhibited the growth of HLF, Hep3B, and Huh7 human HCC cells. These agents when administered in combination acted cooperatively to induce apoptosis in HLF cells. The phosphorylation of RXRα, Akt, and ERK proteins in HLF cells were markedly inhibited by treatment with ACR plus LY294002. Moreover, this combination also increased RXRE promoter activity and the cellular levels of RARß and p21(CIP1), while decreasing the levels of cyclin D1. CONCLUSION: ACR and LY294002 cooperatively increase the expression of RARß, while inhibiting the phosphorylation of RXRα, and that these effects are associated with the induction of apoptosis and the inhibition of cell growth in human HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Cromonas/farmacologia , Neoplasias Hepáticas/metabolismo , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Tretinoína/análogos & derivados , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor X Retinoide alfa/metabolismo , Receptor X Retinoide beta/metabolismo , Tretinoína/farmacologia
10.
Int J Mol Sci ; 14(7): 14700-11, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23860206

RESUMO

Metabolic syndrome is associated with an increased risk of colorectal cancer. This study investigated the impact of hypertension, a component of metabolic syndrome, on azoxymethane (AOM)-induced colorectal carcinogenesis using SHRSP/Izm (SHRSP) non-diabetic/hypertensive rats and SHRSP.Z-Leprfa/IzmDmcr (SHRSP-ZF) diabetic/hypertensive rats. Male 6-week-old SHRSP, SHRSP-ZF, and control non-diabetic/normotensive Wister Kyoto/Izm (WKY) rats were given 2 weekly intraperitoneal injections of AOM (20 mg/kg body weight). Two weeks after the last injection of AOM, the SHRSP and SHRSP-ZF rats became hypertensive compared to the control WKY rats. Serum levels of angiotensin-II, the active product of the renin-angiotensin system, were elevated in both SHRSP and SHRSP-ZF rats, but only the SHRSP-ZF rats developed insulin resistance, dyslipidemia, and hyperleptinemia and exhibited an increase in adipose tissue. The development of AOM-induced colonic preneoplastic lesions and aberrant crypts foci, was significantly accelerated in both SHRSP and SHRSP-ZF hypertensive rats, compared to WKY normotensive rats. Furthermore, induction of oxidative stress and exacerbation of inflammation were observed in the colonic mucosa and systemically in SHRSP and SHRSP-ZF rats. Our findings suggest that hypertension plays a role in the early stage of colorectal carcinogenesis by inducing oxidative stress and chronic inflammation, which might be associated with activation of the renin-angiotensin system.


Assuntos
Azoximetano/toxicidade , Carcinógenos/toxicidade , Neoplasias Colorretais/patologia , Hipertensão/patologia , Estresse Oxidativo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Angiotensina II/sangue , Animais , Catalase/genética , Catalase/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/sangue , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Resistência à Insulina , Interleucina-6/sangue , Mucosa Intestinal/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Lesões Pré-Cancerosas , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Zucker , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Biomed Eng Online ; 12: 29, 2013 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-23566050

RESUMO

OBJECTIVE: The purpose of this study was to show the effects of the tracheal gas insufflation (TGI) technique on gas exchange using helium-oxygen mixtures during high-frequency oscillatory ventilation (HFOV). We hypothesized that a helium-oxygen mixture delivered into the trachea using the TGI technique (0.3 L/min) would enhance gas exchange during HFOV. METHODS: Three rabbits were prepared and ventilated by HFOV with carrier 70% helium/oxygen or 70% nitrogen/oxygen gas mixture with TGI in a crossover study. Changing the gas mixture from nitrogen70% to helium70% and back was performed three times per animal with constant ventilation parameters. RESULTS: Compared with the nitrogen-oxygen mixture, the helium-oxygen mixture of TGI reduced PaCO2 by 7.6 mmHg (p < 0.01) and improved PaO2 by 14 mmHg (p < 0.01). Amplitude during TGI was significantly lower with the helium-oxygen mixture than with the nitrogen-oxygen mixture (p < 0.01) and did not significantly affect mean airway pressure. CONCLUSIONS: This study demonstrated that a helium-oxygen mixture delivered into the trachea using the TGI technique would enhance CO2 elimination and improve oxygenation during HFOV.


Assuntos
Hélio/farmacologia , Insuflação/métodos , Oxigênio/farmacologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Respiração Artificial/métodos , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Animais , Dióxido de Carbono/metabolismo , Coelhos , Traqueia/metabolismo
12.
Carcinogenesis ; 33(12): 2499-506, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23027617

RESUMO

Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ, p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1ß, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals.


Assuntos
Aminoácidos de Cadeia Ramificada/administração & dosagem , Neoplasias Hepáticas/prevenção & controle , Lesões Pré-Cancerosas/prevenção & controle , Animais , Citocinas/genética , Suplementos Nutricionais , Resistência à Insulina , Fígado/imunologia , Fígado/metabolismo , Neoplasias Hepáticas/imunologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , PPAR gama/genética , Lesões Pré-Cancerosas/imunologia , Antígeno Nuclear de Célula em Proliferação/análise , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/análise
13.
Am J Med Genet A ; 158A(4): 772-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22407809

RESUMO

Nemaline myopathy (NM) is a group of congenital myopathies, characterized by the presence of distinct rod-like inclusions "nemaline bodies" in the sarcoplasm of skeletal muscle fibers. To date, ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2 have been found to cause NM. We have identified recessive RYR1 mutations in a patient with severe congenital NM, through high-throughput screening of congenital myopathy/muscular dystrophy-related genes using massively parallel sequencing with target gene capture. The patient manifested fetal akinesia, neonatal severe hypotonia with muscle weakness, respiratory insufficiency, swallowing disturbance, and ophthalomoplegia. Skeletal muscle histology demonstrated nemaline bodies and small type 1 fibers, but without central cores or minicores. Congenital myopathies, a molecularly, histopathologically, and clinically heterogeneous group of disorders are considered to be a good candidate for massively parallel sequencing.


Assuntos
Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Oftalmoplegia/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Fibras Musculares Esqueléticas/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Mutação
14.
Biochem Biophys Res Commun ; 417(3): 1014-7, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22209789

RESUMO

Sphingomyelin (SM) plays important roles in regulating structure and function of plasma membrane, but how intracellular localization of SM is regulated in neuronal cells is not understood. Here we show that two isoforms of SM synthase (SMS) are differentially expressed in neuronal subtypes and that only SMS2 proteins localize in neurites of hippocampal neurons. Moreover, SMS proteins induce Lysenin-binding SM clusters exclusively in their vicinity although neurons hardly contain such cluster under control condition. These findings indicate three important notions about SM metabolism in neurons. First, the activity of SMS is the rate-limiting step of SM cluster formation. Second, the SM content or clustering can be modulated by SMS activity. Third, SMS1 and SMS2 play distinct roles in regulating local SM clustering. Particularly, SMS2, rather than SMS1, is likely to be the major enzyme that is important for SM synthesis in the long neurites and its tip, the growth cone.


Assuntos
Hipocampo/enzimologia , Neurônios/enzimologia , Esfingomielinas/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Animais , Células Cultivadas , Isoenzimas/metabolismo , Microdomínios da Membrana/enzimologia , Microdomínios da Membrana/metabolismo , Camundongos
15.
Nutr Cancer ; 64(1): 72-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22172229

RESUMO

Obesity-related metabolic abnormalities include a state of chronic inflammation and adipocytokine imbalance, which increase the risk of colon cancer. Curcumin, a component of turmeric, exerts both cancer preventive and antiinflammatory properties. Curcumin is also expected to have the ability to reverse obesity-related metabolic derangements. The present study examined the effects of curcumin on the development of azoxymethane (AOM)-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Feeding with a diet containing 0.2% and 2.0% curcumin caused a significant reduction in the total number of colonic premalignant lesions compared with basal diet-fed mice. The expression levels of tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2 (COX-2) mRNAs on the colonic mucosa of AOM-treated mice were significantly decreased by curcumin administration. Dietary feeding with curcumin markedly activated AMP-activated kinase, decreased the expression of COX-2 protein, and inhibited nuclear factor-κB activity on the colonic mucosa of AOM-treated mice. Curcumin also increased the serum levels of adiponectin while conversely decreasing the serum levels of leptin and the weights of fat. In conclusion, curcumin inhibits the development of colonic premalignant lesions in an obesity-related colorectal carcinogenesis model, at least in part, by attenuating chronic inflammation and improving adipocytokine imbalance. Curcumin may be useful in the chemoprevention of colorectal carcinogenesis in obese individuals.


Assuntos
Anticarcinógenos/farmacologia , Colo/patologia , Neoplasias do Colo/prevenção & controle , Curcumina/farmacologia , Obesidade/complicações , Lesões Pré-Cancerosas/patologia , Adiponectina/sangue , Tecido Adiposo/efeitos dos fármacos , Animais , Azoximetano/toxicidade , Colo/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Suplementos Nutricionais , Interleucina-6/genética , Mucosa Intestinal/efeitos dos fármacos , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , NF-kappa B/antagonistas & inibidores , Tamanho do Órgão/efeitos dos fármacos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Proteínas Quinases/metabolismo , Fator de Necrose Tumoral alfa/genética
16.
Pediatr Crit Care Med ; 13(1): 60-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21460760

RESUMO

OBJECTIVE: To investigate postnatal changes in the direction of blood flow through the ductus arteriosus in neonates with meconium-stained amniotic fluid, we measured preductal and postductal oxygen saturation in normal neonates, neonates with meconium-stained amniotic fluid, and a neonate with persistent pulmonary hypertension of the newborn. DESIGN: Prospective, observational case series report. SETTING: A single, tertiary neonatal intensive care unit. PATIENTS: Twelve normal neonates, seven neonates with meconium-stained amniotic fluid, and a neonate with persistent pulmonary hypertension of the newborn. INTERVENTIONS: SpO2 is simultaneously monitored in the right upper and lower limbs after birth. MEASUREMENTS AND MAIN RESULTS: Compared with normal neonates, three neonates with meconium-stained amniotic fluid required longer than +2 SD of the mean time for the postductal SpO2 to reach 90% and/or 95%. In a neonate with meconium-stained amniotic fluid, intense crying triggered frequent decreases to <70% in the postductal SpO2 from 25 mins after birth, while the preductal SpO2 remained at 95% or above. When the other newborn with meconium-stained amniotic fluid was held in the father's arms after 98 mins, the postductal SpO2 decreased rapidly to <80%, while the preductal SpO2 remained at 95%. Thus, 5% or greater difference between the preductal and postductal SpO2 was observed from 25 mins after birth until 120 mins in all neonates with meconium-stained amniotic fluid, whereas the difference disappeared after 25 mins in 12 normal neonates. In a neonate with persistent pulmonary hypertension of the newborn who required vigorous resuscitation, 5% or greater difference between the preductal and postductal SpO2 levels was observed until 6 hrs after birth. CONCLUSIONS: Right-to-left shunting in the ductus arteriosus may be induced readily by intense crying and rapid postural change in infants with meconium-stained amniotic fluid. It is important to monitor SpO2 at both pre- and postductal regions until 120 mins after birth in neonates with meconium-stained amniotic fluid and to subject these infants to minimal manipulations.


Assuntos
Choro/fisiologia , Canal Arterial/fisiologia , Hipertensão Pulmonar/diagnóstico , Síndrome de Aspiração de Mecônio/diagnóstico , Oxigênio/sangue , Postura/fisiologia , Líquido Amniótico , Velocidade do Fluxo Sanguíneo , Gasometria , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Prospectivos , Valores de Referência , Fluxo Sanguíneo Regional
17.
BMC Cancer ; 11: 281, 2011 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-21711565

RESUMO

BACKGROUND: Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice. METHODS: Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks. RESULTS: At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition. CONCLUSIONS: Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.


Assuntos
Dislipidemias/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hepatopatias/prevenção & controle , Neoplasias Hepáticas Experimentais/prevenção & controle , Obesidade/complicações , Lesões Pré-Cancerosas/prevenção & controle , Quinolinas/uso terapêutico , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Adiponectina/sangue , Animais , Apoptose/efeitos dos fármacos , Cocarcinogênese , Cruzamentos Genéticos , Dietilnitrosamina/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/biossíntese , Interleucina-6/genética , Leptina/sangue , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/etiologia , Hepatopatias/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/sangue , Obesidade/genética , Tamanho do Órgão/efeitos dos fármacos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Proteína de Morte Celular Associada a bcl/biossíntese , Proteína de Morte Celular Associada a bcl/genética
18.
Nat Cell Biol ; 13(6): 668-75, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21532585

RESUMO

Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2-ARID5B. PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. These findings suggest that the PHF2-ARID5B complex is a signal-sensing modulator of histone methylation and gene transcription, in which phosphorylation of PHF2 enables subsequent formation of a competent and specific histone demethylase complex.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Enzimológica da Expressão Gênica , Histona Desmetilases/metabolismo , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Deleção de Genes , Histona Desmetilases/química , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fatores de Transcrição/genética
19.
Cancer Prev Res (Phila) ; 4(3): 396-403, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21372039

RESUMO

Obesity and related metabolic abnormalities, including insulin resistance and a state of chronic inflammation, increase the risk of hepatocellular carcinoma. Abnormal activation of the insulin-like growth factor (IGF)/ IGF-1 receptor (IGF-1R) axis is also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of (-)-epigallocatechin gallate (EGCG), a major biologically active component of green tea, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks and then they received drinking water containing 0.1% EGCG for 34 weeks. At sacrifice, drinking water with EGCG significantly inhibited the development of liver cell adenomas in comparison with the control EGCG-untreated group. EGCG inhibited the phosphorylation of the IGF-1R, ERK (extracellular signal-regulated kinase), Akt, GSK-3ß (glycogen synthase kinase-3ß), Stat3, and JNK (c-Jun NH(2)-terminal kinase) proteins in the livers of experimental mice. The serum levels of insulin, IGF-1, IGF-2, free fatty acid, and TNF-α were all decreased by drinking EGCG, which also decreased the expression of TNF-α, interleukin (IL)-6, IL-1ß, and IL-18 mRNAs in the livers. In addition, EGCG improved liver steatosis and activated the AMP-activated kinase protein in the liver. These findings suggest that EGCG prevents obesity-related liver tumorigenesis by inhibiting the IGF/IGF-1R axis, improving hyperinsulinemia, and attenuating chronic inflammation. EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals. Cancer Prev Res; 4(3); 396-403. ©2011 AACR.


Assuntos
Catequina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Dietilnitrosamina/farmacologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/prevenção & controle , Obesidade/complicações , Adenoma/metabolismo , Animais , Anticarcinógenos/farmacologia , Carcinógenos , Catequina/farmacologia , Diabetes Mellitus Experimental/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo
20.
Int J Syst Evol Microbiol ; 61(Pt 9): 2215-20, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20935083

RESUMO

Three chitin-degrading strains representing two novel species were isolated from mangrove forests in Okinawa, Japan. The isolates, ABABA23(T), ABABA211 and ABABA212(T), were Gram-negative, non-spore-forming, strictly aerobic chemo-organotrophs. The novel strains produced Q-8 as the major isoprenoid quinone component. The predominant fatty acids were iso-C15:0 and C16:0. On the basis of 16S rRNA gene sequence analysis, the isolates were closely affiliated with members of the genus Microbulbifer. The DNA G+C contents of strains ABABA23(T) and ABABA212(T) were 57.8 and 60.2 mol%, respectively. DNA-DNA relatedness values between these two strains and Microbulbifer reference strains were significantly lower than 70 %, the generally accepted threshold level below which strains are considered to belong to separate species. Based on differences in taxonomic characteristics, the three isolates represent two novel species of the genus Microbulbifer, for which the names Microbulbifer chitinilyticus sp. nov. (type strain, ABABA212(T) = JCM 16148(T) = NCIMB 14577(T)) and Microbulbifer okinawensis sp. nov. (type strain, ABABA23(T) = JCM 16147(T) = NCIMB 14576(T); reference strain, ABABA211) are proposed.


Assuntos
Alteromonadaceae/classificação , Alteromonadaceae/isolamento & purificação , Quitina/metabolismo , Plantas/microbiologia , Aerobiose , Alteromonadaceae/genética , Alteromonadaceae/metabolismo , Técnicas de Tipagem Bacteriana , Composição de Bases , Análise por Conglomerados , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Ácidos Graxos/análise , Japão , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Filogenia , Quinonas/análise , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Árvores
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