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1.
Genes Genet Syst ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32389919

RESUMO

Effects of environmental factors for growth of Escherichia coli on spontaneous mutagenesis and homologous recombination events are described. By analyzing rifampicin-resistant (Rifr) mutation frequencies in an E. coli strain lacking MutM and MutY repair enzymes, which suppress base substitution mutations caused by 8-oxoguanine (7,8 dihydro-8-oxoguanine; 8-oxoG) in DNA, we examined levels of oxidative DNA damage produced in normally growing cells. The level of 8-oxoG DNA damage was about 9- and 63-fold higher in cells grown in M9-glucose and M9-glycerol media, respectively, than in those grown in LB medium. We also found that about 14-fold more 8-oxoG DNA damage was produced in cells grown in about 0.1% oxygen than in those grown in the normal atmosphere. However, Rifr mutation frequency in wild-type cells was unchanged in such different growth conditions, suggesting that the capacity of repair mechanisms is sufficient to suppress mutations caused by 8-oxoG even at very high levels in cells growing in the particular conditions. On the other hand, the frequency of spontaneous homologous recombination events in wild-type E. coli cells varied with different growth conditions. When cells were grown in M9-glucose and M9-glycerol media, the spontaneous recombination frequency increased to about 4.3- and 7.3-fold, respectively, higher than that in LB medium. Likewise, the spontaneous recombination frequency was about 3.5-fold higher in cells growing in the hypoxic condition than in cells growing in the atmosphere. When cells were grown in anaerobic conditions, the recombination frequency decreased to half of that in the atmosphere. These data indicated that spontaneous homologous recombination is highly responsive to environmental factors such as nutrition and oxygen concentration.

2.
Eur Radiol ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32211964

RESUMO

OBJECTIVES: We assessed whether an association exists between myocardial oxygenation and myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM), using blood-oxygen-level-dependent (BOLD) T2* cardiac magnetic resonance imaging (T2*-CMR) and T1 mapping. METHODS: T1 mapping and T2*-CMR data were collected from 55 HCM patients using a 3-T MR and were prospectively analyzed. T2*-CMR was conducted using the black blood, breath-hold, multi-echo, and gradient echo sequence. Over 10 min, inhalation of oxygen at the flow rate of 10 L/min, T2* for mid-septum was measured following room-air and oxygen inhalation, and ΔT2* ratio (T2*oxy-T2*air/T2*air, %) was calculated. During pre- and post-gadolinium enhancement, native T1 (ms) and extracellular volume fractions (ECV, %) were calculated at sites same as the T2* measurement. Hypoxia was defined as the segment with an absolute value of the ΔT2* ratio ≥ 10%. RESULTS: ΔT2* ratio was significantly higher for segments with native T1 ≥ 1290 ms than those with native T1 < 1290 ms (21 ± 32% vs. 8 ± 6%, p = 0.005). ΔT2* ratio was also significantly higher for segments with ECV ≥ 28% than those with ECV < 28% (21 ± 32% vs. 8 ± 8%, p = 0.0003). ROC curve analysis revealed that ΔT2* ratio could detect segments with native T1 ≥ 1290 ms and ECV ≥ 28% and c-statistics of 0.72 and 0.79. According to the multivariate logistic regression analysis results, ECV is an independent factor in hypoxia (odds ratio, 1.47; 95% confidence interval, 1.02-2.13; p < 0.05). CONCLUSIONS: Analysis of BOLD T2*-CMR and T1 mapping revealed that ECV is strongly associated with ΔT2* ratio, suggesting that the onset of myocardial fibrosis is related to hypoxia in HCM patients. TRIAL REGISTRATION: Our study was approved by the ethics committee of our institute (#4036, registered on 21 July 2016) KEY POINTS: • Analysis of ΔT2* ratio and ECV with BOLD-T2* and T1 mapping revealed a strong association between myocardial fibrosis and hypoxia in HCM patients.

3.
J Diabetes Investig ; 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31916414

RESUMO

AIMS/INTRODUCTION: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue. MATERIALS AND METHODS: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study. RESULTS: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity. CONCLUSIONS: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.

4.
J Comput Assist Tomogr ; 44(1): 26-31, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31939878

RESUMO

Coronary computed tomography angiography is widely used in clinical practice. Although 3-dimensional (D) volume rendering is useful for interpretation of coronary path and territory, 2D output is common for image interpretation. Most picture archiving and communication system is incapable of manipulating 3D due to insufficient graphic specification. Thus, 2D bull's eye map display is frequently used in cardiac imaging. We developed a bull's eye map which emulated the anatomical information of individual coronary path and dominancy.


Assuntos
Vasos Coronários/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Idoso , Algoritmos , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
J Infect Chemother ; 26(3): 312-314, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31836288

RESUMO

The QuantiFERON TB Gold Plus (QFT-Plus) test is a newly approved interferon-gamma releasing assay test for detecting latent tuberculosis. Although blood samples for QFT test can be refrigerated for 48 h in lithium-heparin tubes according to package inserts, no published data are available on the effects of sample refrigeration on the test results. We conducted a clinical study that aimed to elucidate whether sample refrigeration for 48 h affects QFT-Plus test results. We collected 2 blood samples each from 40 participants for QFT-Plus; one sample was refrigerated before incubation for QFT-Plus assay, while the other sample was incubated soon after collection and treated as control. After comparing QFT-Plus test results of refrigerated samples and control samples, the concordance rate and kappa coefficient between them were 95% and 0.90, respectively. Thus, blood samples for QFT-Plus test can be refrigerated for 48 h in lithium-heparin tubes without influencing the test results.

6.
J Biochem ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722425

RESUMO

Threonine synthase catalyzes the conversion of O-phospho-L-homoserine and a water molecule to L-threonine and has the most complex catalytic mechanism among the pyridoxal 5'-phosphate-dependent enzymes. In order to study the less-characterized earlier stage of the catalytic reaction, we studied the reaction of threonine synthase with 2-amino-5-phosphonopentanoate, which stops the catalytic reaction at the enamine intermediate. The global kinetic analysis of the triphasic spectral changes showed that, in addition to the theoretically expected pathway, the carbanion is rapidly reprotonated at Cα to form an aldimine distinct from the external aldimine directly formed from the Michaelis complex. The Kd for the binding of inhibitor to the enzyme decreased with increasing pH, showing that the 2-amino-group-unprotonated form of the ligand binds to the enzyme. On the other hand, the rate constants for the proton migration steps within the active site are independent of the solvent pH, indicating that protons are shared by the active dissociative groups and are not exchanged with the solvent during the course of catalysis. This gives an insight into the role of the phosphate group of the substrate, which may increase the basicity of the ε-amino group of the catalytic lysine residue in the active site.

7.
Nutrients ; 11(7)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315223

RESUMO

Glucose/fructose in beverages/foods containing high-fructose corn syrup (HFCS) are metabolized to glyceraldehyde (GA) in the liver. We previously reported that GA-derived advanced glycation end-products (toxic AGEs, TAGE) are generated and may induce the onset/progression of non-alcoholic fatty liver disease (NAFLD). We revealed that the generation of TAGE in the liver and serum TAGE levels were higher in NAFLD patients than in healthy humans. Although we propose the intracellular generation of TAGE in the normal liver, there is currently no evidence to support this, and the levels of TAGE produced have not yet been measured. In the present study, male Wister/ST rats that drank normal water or 10% HFCS 55 (HFCS beverage) were maintained for 13 weeks, and serum TAGE levels and intracellular TAGE levels in the liver were analyzed. Rats in the HFCS group drank 127.4 mL of the HFCS beverage each day. Serum TAGE levels and intracellular TAGE levels in the liver both increased in the HFCS group. A positive correlation was observed between intracellular TAGE levels in the liver and serum TAGE levels. On the other hand, in male Wister/ST rats that drank Lactobacillus beverage for 12 weeks-a commercial drink that contains glucose, fructose, and sucrose- no increases were observed in intracellular TAGE or serum TAGE levels. Intracellular TAGE were generated in the normal rat liver, and their production was promoted by HFCS, which may increase the risk of NAFLD.


Assuntos
Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/toxicidade , Xarope de Milho Rico em Frutose/metabolismo , Lactobacillus , Fígado/química , Animais , Bebidas , Peso Corporal , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Ratos Wistar
8.
Sci Rep ; 9(1): 10194, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308400

RESUMO

The anhydrofructose pathway is an alternate pathway for glycogen degradation by α-1,4-glucan lyase. The sugar 1,5-anhydro-D-fructose (1,5-AF) acts as the central intermediate of this pathway, but its physiological role of in mammals is unclear. Glycation reactions forming advanced glycation end-products (AGEs) are important in the development of complications of diabetes mellitus. We hypothesized that 1,5-AF may contribute to cellular damage by forming 1,5-AF-derived AGEs (AF-AGEs) with intracellular proteins. To clarify the role of 1,5-AF in protein modification, we created a novel antibody targeting AF-AGEs. Serum albumin modified by AF-AGEs was prepared by incubating rabbit serum albumin (RSA) or bovine serum albumin (BSA) with 1,5-AF. After immunizing rabbits with AF-AGEs-RSA, affinity chromatography of anti-AF-AGE antiserum was performed on a Sepharose 4B column coupled with AF-AGEs-BSA or N-(carboxymethyl)/N-(carboxyethyl)lysine-BSA. A novel immunopurified anti-AF-AGE antibody was obtained and was characterized using a competitive enzyme-linked immunosorbent assay. Then an AF-AGEs assay was established using this immunopurified antibody. This assay was able to detect AF-AGEs in human and animal serum samples. Finally, intracellular accumulation of AF-AGEs was shown to be associated with damage to cultured hepatocytes (HepG2 cells). This is the first report about in vivo detection of AF-AGEs with a novel structural epitope.

9.
Nutrients ; 11(2)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813302

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is currently the most common feature of chronic liver disease. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD, and one of its risk factors is hyperglycemia. The chronic ingestion of excessive amounts of high-fructose corn syrup is associated with an increased prevalence of fatty liver. Under hyperglycemic conditions, advanced glycation end-products (AGEs) are generated through a non-enzymatic glycation reaction between the ketone or aldehyde groups of sugars and amino groups of proteins. Glyceraldehyde (GA) is a metabolic intermediate of sugars, and GA-derived AGEs (known as toxic AGEs (TAGE)) have been implicated in the development of NASH. TAGE accumulates more in serum or liver tissue in NASH patients than in healthy controls or patients with simple steatosis. Furthermore, the TAGE precursor, GA, causes cell damage through protein dysfunctions by TAGE modifications and induces necrotic-type hepatocyte death. Intracellular TAGE may leak outside of necrotic-type cells. Extracellular TAGE then induce inflammatory or fibrotic responses related to the pathology of NASH in surrounding cells, including hepatocytes and hepatic stellate cells. This review focuses on the contribution of TAGE to the pathology of NASH, particularly hepatic cell death related to NASH.


Assuntos
Produtos Finais de Glicação Avançada/toxicidade , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia
10.
Sci Rep ; 9(1): 2121, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765817

RESUMO

Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) and one of the largest public health issues. Risk factors for CVD correlate with an excessive intake of glucose and/or fructose, which has been shown to induce the production of advanced glycation end-products (AGEs). We previously identified AGEs derived from glyceraldehyde and named them toxic AGEs (TAGE) due to their cytotoxicities and relationship with LSRD. We also reported that extracellular TAGE in the vascular system may promote CVD and that serum TAGE levels are associated with risk factors for CVD. The mechanisms responsible for the onset and/or progression of CVD by extracellular TAGE or the above risk factors involve vascular disorders. In the present study, we revealed that rat primary cultured cardiomyocytes generated intracellular TAGE, which decreased beating rates and induced cell death. LC3-II/LC3-I, a factor of autophagy, also decreased. Although intracellular TAGE may be targets of degradation as cytotoxic proteins via autophagy, they may inhibit autophagy. Furthermore, the mechanisms by which intracellular TAGE decrease beating rates and induce cell death may involve the suppression of autophagy. The present results suggest that intracellular TAGE are generated in cardiomyocytes and directly damage them, resulting in CVD.

11.
Dev Growth Differ ; 60(8): 473-482, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30368782

RESUMO

During brain development, once primary neural networks are formed, they are largely sculpted by environmental stimuli. The juvenile brain has a unique time window termed the critical period, in which neuronal circuits are remodeled by experience. Accumulating evidence indicates that abnormal rewiring of circuits in early life contributes to various neurodevelopmental disorders at later stages of life. Recent studies implicate two important aspects for activation of the critical period, both of which are experience-dependent: (a) proper excitatory/inhibitory (E/I) balance of neural circuit achieved during developmental trajectory of inhibitory interneurons, and (b) epigenetic regulation allowing flexible gene expression for neuronal plasticity. In this review, we discuss the molecular mechanisms of juvenile brain plasticity from the viewpoints of transcriptional and chromatin regulation, with a focus on Otx2 homeoprotein. Depending on experience, Otx2 is transported into cortical parvalbumin-positive interneurons (PV cells), where it induces PV cell maturation to activate the critical period. Understanding the unique behavior and function of Otx2 as a "messenger" of experience should therefore provide insights into mechanisms of juvenile brain development. Recently identified downstream targets of Otx2 suggest novel roles of Otx2 in homeostasis of PV cells, and, moreover, in regulation of chromatin state, which is important for neuronal plasticity. We further discuss epigenetic changes during postnatal brain development spanning the critical period. Different aspects of chromatin regulation may underlie experience-dependent neuronal development and plasticity.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Transcrição Genética , Metilação de DNA/genética , Humanos , Fatores de Transcrição Otx/metabolismo
12.
Sci Rep ; 7(1): 13717, 2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29057960

RESUMO

Recent studies of Asian glaciers have shown that glaciers in eastern Karakoram and West Kunlun have been slightly gaining mass while those in nearby Jammu Kashmir and Himalayas are losing mass, at rates of more than 0.5 m w.e.yr-1 and about 0.3 m w.e.yr-1, respectively. Two possible explanations have been proposed for this difference in glacier behaviour: spatial heterogeneity in climate change (climatic forcing) or differing glacier responses to climate change (glacier response). However, neither explanation has strong supporting evidence. Here, we examine the glacial response by calculating the mass-balance sensitivity to temperature change in high-mountain Asia. In support of the glacier-response explanation, we find a strong correlation between observed glacier surface-elevation changes and mass-balance sensitivity of glaciers. The high coefficient of determination (R2 = 0.61) suggests that spatially heterogeneous mass-balance sensitivity has more explanatory power than regionally different climate change for the recent contrasting glacier fluctuations in the high mountain Asia.

13.
Sci Rep ; 7(1): 12646, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28974755

RESUMO

Ocular dominance plasticity is easily observed during the critical period in early postnatal life. Chondroitin sulfate (CS) is the most abundant component in extracellular structures called perineuronal nets (PNNs), which surround parvalbumin-expressing interneurons (PV-cells). CS accumulates in PNNs at the critical period, but its function in earlier life is unclear. Here, we show that initiation of ocular dominance plasticity was impaired with reduced CS, using mice lacking a key CS-synthesizing enzyme, CSGalNAcT1. Two-photon in vivo imaging showed a weaker visual response of PV-cells with reduced CS compared to wild-type mice. Plasticity onset was restored by a homeoprotein Otx2, which binds the major CS-proteoglycan aggrecan and promotes its further expression. Continuous CS accumulation together with Otx2 contributed bidirectionally to both onset and offset of plasticity, and was substituted by diazepam, which enhances GABA function. Therefore, CS and Otx2 may act as common inducers of both onset and offset of the critical period by promoting PV-cell function throughout the lifetime.


Assuntos
Sulfatos de Condroitina/metabolismo , N-Acetilgalactosaminiltransferases/genética , Fatores de Transcrição Otx/genética , Córtex Visual/metabolismo , Agrecanas/genética , Animais , Sulfatos de Condroitina/genética , Diazepam/administração & dosagem , Dominância Ocular/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Interneurônios/metabolismo , Camundongos Knockout , Plasticidade Neuronal/genética , Parvalbuminas/genética , Ligação Proteica , Córtex Visual/crescimento & desenvolvimento , Córtex Visual/patologia , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismo
14.
Sci Rep ; 7(1): 14282, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29079763

RESUMO

Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH); however, the pathogenesis of NASH currently remains unclear. We aimed to investigate the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (GA-AGEs) on human hepatocyte cell death. The accumulation of intracellular GA-AGEs has been associated with the induction of DNA damage and hepatocyte necrotic cell death. Among intracellular GA-AGEs, caspase-3 has been identified as a GA-AGE-modified protein with abrogated protein function. Furthermore, the activation of caspase-3 and induction of hepatocyte apoptosis by camptothecin, a DNA-damaging agent, was suppressed by a treatment with GA. These results suggest the inhibitory effects of GA-AGE-modified caspase-3 on the induction of DNA-damage-induced apoptosis, which is associated with hepatocyte necrosis. Therefore, the suppression of necrosis, the inflammatory form of cell death, by the accumulation of GA-AGEs and GA-AGE-modified caspase-3 may represent a novel therapeutic target for the pathogenesis of NASH.


Assuntos
Morte Celular/fisiologia , Produtos Finais de Glicação Avançada/metabolismo , Gliceraldeído/metabolismo , Hepatócitos/metabolismo , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Produtos Finais de Glicação Avançada/administração & dosagem , Gliceraldeído/administração & dosagem , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Substâncias Protetoras/administração & dosagem
15.
World J Gastroenterol ; 23(27): 4910-4919, 2017 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-28785145

RESUMO

AIM: To determine the possibility that diabetes mellitus promotes pancreatic ductal adenocarcinoma via glyceraldehyde (GA)-derived advanced glycation-end products (GA-AGEs). METHODS: PANC-1, a human pancreatic cancer cell line, was treated with 1-4 mmol/L GA for 24 h. The cell viability and intracellular GA-AGEs were measured by WST-8 assay and slot blotting. Moreover, immunostaining of PANC-1 cells with an anti-GA-AGE antibody was performed. Western blotting (WB) was used to analyze the molecular weight of GA-AGEs. Heat shock proteins 90α, 90ß, 70, 27 and cleaved caspase-3 were analyzed by WB. In addition, PANC-1 cells were treated with GA-AGEs-bovine serum albumin (GA-AGEs-BSA), as a model of extracellular GA-AGEs, and proliferation of PANC-1 cells was measured. RESULTS: In PANC-1 cells, GA induced the production of GA-AGEs and cell death in a dose-dependent manner. PANC-1 cell viability was approximately 40% with a 2 mmol/L GA treatment and decreased to almost 0% with a 4 mmol/L GA treatment (each significant difference was P < 0.01). Cells treated with 2 and 4 mmol/L GA produced 6.4 and 21.2 µg/mg protein of GA-AGEs, respectively (P < 0.05 and P < 0.01). The dose-dependent production of some high-molecular-weight (HMW) complexes of HSP90ß, HSP70, and HSP27 was observed following administration of GA. We considered HMW complexes to be dimers and trimers with GA-AGEs-mediated aggregation. Cleaved caspase-3 could not be detected with WB. Furthermore, 10 and 20 µg/mL GA-AGEs-BSA was 27% and 34% greater than that of control cells, respectively (P < 0.05 and P < 0.01). CONCLUSION: Although intracellular GA-AGEs induce pancreatic cancer cell death, their secretion and release may promote the proliferation of other pancreatic cancer cells.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Diabetes Mellitus Tipo 2/patologia , Produtos Finais de Glicação Avançada/metabolismo , Gliceraldeído/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/etiologia , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Ductal Pancreático/etiologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Proteínas de Choque Térmico/metabolismo , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/etiologia , Sais de Tetrazólio/farmacologia , Regulação para Cima
16.
Front Neurosci ; 11: 307, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28620275

RESUMO

Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin-positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondrial function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as KV3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2-deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

17.
Nutrients ; 9(6)2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28632197

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA), while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA) in the liver. GA and AA are known to react non-enzymatically with the ε- or α-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively) in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE) and a related novel theory for preventing the onset/progression of NAFLD and ALD.


Assuntos
Produtos Finais de Glicação Avançada/toxicidade , Hepatopatias Alcoólicas/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Humanos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Estresse Oxidativo
18.
Acta Med Okayama ; 71(1): 59-68, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28238011

RESUMO

Human RAD17 acts as an activator of checkpoint signals in response to DNA damage. Here we evaluated the association of hRAD17 Leu546Arg (rs1045051), a missense single nucleotide polymorphism, with the risk of colorectal cancer (CRC) in relation to smoking and alcohol consumption habits in 212 CRC patients and 1,142 cancer-free controls in a case-control study conducted in Japan. The results showed that the hRAD17 Leu/Arg genotype compared to the Leu/Leu genotypes was significantly associated with the protective effect on CRC risk with the adjusted odds ratio (OR) of 0.68 [95% confidence interval (CI): 0.49-0.95, p=0.024], and the males with the Arg/Arg genotype had a greater risk of CRC compared to those with the Leu/Leu and Leu/Arg genotypes (OR=1.87, 95%CI 1.03-3.40, p=0.04). In stratified studies, the protective effect of the Leu/Arg genotype on CRC risk was markedly higher in the light smokers (< 20 pack years) (OR=0.61, 95%CI 0.40-0.94, p=0.024) and the rectal cancer patients (OR=0.49, 95%CI 0.31-0.78, p=0.003). The risk of the Arg/Arg genotype was associated with heavy smoking (≥ 20 pack-years) (OR=2.24, 95%CI 1.09-4.61, p=0.03). These findings suggest that the genetic variant of hRAD17 Leu546Arg polymorphism has a significant effect on CRC susceptibility in Japanese.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Genótipo , Fumar/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Códon , Neoplasias Colorretais/etiologia , Intervalos de Confiança , Dano ao DNA , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Adulto Jovem
19.
Clin Anat ; 30(3): 413-420, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28192858

RESUMO

The in-plane lateral to medial approach is a standard technique for ultrasound-guided femoral nerve block (USG-FNB). The first bifurcation of the femoral artery, which consists of the deep artery of the thigh (DAT) or occasionally the lateral circumflex femoral artery (LCFA), is regarded as the distal border for this procedure. We sometimes detect arteries along the estimated needle trajectory for USG-FNB. The superficial (SCIA) and deep (DCIA) circumflex iliac arteries run laterally parallel to the inguinal ligament from the femoral or external iliac artery. The relationship between the SCIA and DCIA and other anatomical structures related to USG-FNB around the femoral triangle region was studied by gross anatomical examination of 100 formalin-fixed adult cadavers. At least one SCIA and one DCIA were identified around each femoral triangle; 81.8% of SCIA and 58% of DCIA originated from the femoral artery. All DCIA coursed between the fascia lata and fascia iliaca and 80% of SCIA penetrated the fascia lata. In 94% of femoral triangles, at least one arterial branch heading towards the lateral part of the thigh originated from the femoral artery from the level of the inguinal ligament to the first bifurcation of the femoral artery. The presence of SCIA and DCIA should be considered during USG-FNB using the in-plane lateral to medial approach to avoid inadvertently injuring them, as they are occasionally located along the presumed needle trajectory superficial to the fascia iliaca. Clin. Anat. 30:413-420, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Fascia Lata/anatomia & histologia , Artéria Femoral/anatomia & histologia , Artéria Ilíaca/anatomia & histologia , Bloqueio Nervoso/métodos , Adulto , Cadáver , Feminino , Nervo Femoral , Humanos , Masculino , Cirurgia Assistida por Computador , Ultrassonografia
20.
Oncol Lett ; 13(1): 289-295, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28123557

RESUMO

Paclitaxel is widely used to treat various cancers; however, resistance to this drug is a major obstacle to breast cancer chemotherapy. To identify the proteins involved in paclitaxel resistance, the present study compared the proteomes of MCF-7 human breast cancer cells and its paclitaxel-resistant subclone MCF-7/PTX. Using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry, 11 upregulated and 12 downregulated proteins were identified in MCF-7/PTX cells compared with the parental cell line. These 23 proteins were functionally classified as stress-induced chaperones, metabolic enzymes and cytoskeletal proteins. The anti-apoptotic proteins, stress-70 protein, 78-kD glucose-regulated protein, peptidyl-prolyl cis-trans isomerase A (PPIA) and heterogeneous nuclear ribonucleoprotein H3, were also upregulated in MCF-7/PTX cells. Notably, knockdown of the stress-response chaperone PPIA using small interfering RNA in MCF-7/PTX cells restored their sensitivity to paclitaxel. These findings indicated that PPIA may have an important role in paclitaxel resistance in MCF-7/PTX cells.

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