Measurements of body fat distribution: assessment of collinearity with body mass, adiposity and height in female adolescents / Medidas de localização da gordura corporal: uma avaliação da colinearidade com massa corporal, adiposidade e estatura em adolescentes do sexo feminino

OBJECTIVE : To verify the correlation between body fat location measurements with the body mass index (BMI), body fat percentage (BF%) and height, according to the nutritional status in female adolescents. METHODS : A controlled cross-sectional study was carried out with 113 adolescents (G1: 38 with normal weight, but with high body fat level, G2: 40 with normal weight and G3: 35 overweight) from public schools in Viçosa-MG, Brazil. The following measures were assessed: weight, height, waist circumference (WC), umbilical circumference (UC), hip circumference (HC), thigh circumference, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist-to-thigh ratio (WTR), conicity index (CI), sagittal abdominal diameter (SAD), coronal diameter (CD), central (CS) and peripheral skinfolds (PS). The BF% was assessed by tetrapolar electric bioimpedance. RESULTS : The increase in central fat, represented by WC, UC, WHtR, SAD, CD and CS, and the increase in peripheral fat indicated by HC and thigh circumference were proportional to the increase in BMI and BF%. WC and especially the UC showed the strongest correlations with adiposity. Weak correlation between WHR, WTR, CI and CS/PS with adiposity were observed. The height showed correlation with almost all the fat location measures, being fair or weak with waist measurements. CONCLUSIONS : The results indicate colinearity between body mass and total adiposity with central and peripheral adipose tissue. We recommend the use of UC for assessing nutritional status of adolescents, as it showed the highest capacity to predict adiposity in each group, and also showed fair or weak correlation with height. .

OBJETIVO: Verificar a correlação entre medidas de localização da gordura corporal com índice de massa corporal (IMC), percentual de gordura corporal (%GC) e estatura, de acordo com o estado nutricional em adolescentes do sexo feminino. MÉTODOS: Realizou-se estudo transversal controlado, com 113 adolescentes (G1: 38 eutróficas mas com gordura corporal elevada; G2: 40 eutróficas e G3: 35 com excesso de peso), de 14 a 19 anos, de escolas públicas de Viçosa-MG. Aferiu-se peso, estatura, circunferência da cintura (CC), circunferência umbilical (CUm), circunferência do quadril (CQ), circunferência da coxa, relação cintura/quadril (RCQ), relação cintura/estatura (RCE), relação cintura/coxa (RCC), índice de conicidade (IC), diâmetro abdominal sagital (DAS), diâmetro coronal (DC), pregas cutâneas centrais (PCC) e periféricas (PCP). Avaliou-se o %GC por bioimpedância elétrica tetrapolar. RESULTADOS: O aumento da gordura central, representada pela CC, CUm, RCE, DAS, DC e PCC, e o aumento da gordura periférica indicado pela CQ e da coxa foram proporcionais ao aumento do IMC e %GC. A CC e principalmente CUm apresentaram as correlações mais fortes com a adiposidade, enquanto RCQ, RCC, IC e PCC/PCP as mais fracas. A estatura apresentou correlação com praticamente todas as medidas de localização de gordura, sendo de fraca a regular com as medidas da cintura. CONCLUSÕES: Os resultados indicam colinearidade entre massa corporal e adiposidade total com tecido adiposo central e periférico. Recomenda-se o emprego da CUm na avaliação do estado nutricional de adolescentes, pois ela apresentou maior capacidade para predizer adiposidade em cada grupo, além de correlação fraca a regular com a estatura. .

Calendario de inicio sexual en México: Comparación entre encuestas nacionales y tendencias en el tiempo / Sexual debut in Mexico: a comparison of household national surveys

Objetivo. Estimar el calendario de inicio sexual en México y sus tendencias a partir de encuestas poblacionales. Material y métodos. Se analizaron cinco cohortes de nacimiento con cuatro encuestas nacionales (Encuesta Nacional de Salud 2000, Encuesta Nacional de la Dinámica Demográfica 2009, Encuesta Nacional de Juventud 2010 y Encuesta Nacional de Salud y Nutrición 2012) y se identificaron las proporciones de individuos que iniciaron actividad sexual antes de los 16 y antes de los 20 años. Resultados. Las distintas encuestas son, en general, consistentes, pero difieren entre ellas en algunas cohortes. En las cohortes más jóvenes, se identificó una proporción algo mayor de individuos que iniciaron antes de los 20 años; no se advierten cambios en el inicio sexual antes de los 16 años. Conclusiones. La falta de grandes cambios en la edad de inicio de vida sexual con tendencia al adelanto del calendario en México llama a fortalecer la educación sexual integral y la oferta de servicios de salud sexual y reproductiva accesibles a los adolescentes.

Objective. To estimate calendar of sexual debut in Mexico and its trends using national representative household surveys. Materials and methods. Analysis of five birth cohorts extracted from four national population based household surveys in Mexico (National Health Survey 2000, National Survey on Demographic Dynamics 2009, National Youth Survey 2010, and National Health & Nutrition Survey 2012), using as outcome the proportion of individuals that reported sexual debut before the age of 16 and before the age of 20. Results. Overall, the four analyzed surveys produce consistent results, although some differences were found. While a larger proportion among younger cohorts reported sexual debut before the age of 20, that was not the case for sexual debut before 16 years. Conclusions. While data seems to reflect a relative stable age of sexual debut in Mexico, there is a recent trend to prepone sexual initiation that highlights the need to strengthen comprehensive sexual education and the supply of sexual & reproductive health services that are accessible and friendly to adolescents thus responding to the growing demand from this age group.

Transactivation of bad by vorinostat-induced acetylated p53 enhances doxorubicin-induced cytotoxicity in cervical cancer cells

Vorinostat (VOR) has been reported to enhance the cytotoxic effects of doxorubicin (DOX) with fewer side effects because of the lower DOX dosage in breast cancer cells. In this study, we investigated the novel mechanism underlying the synergistic cytotoxic effects of VOR and DOX co-treatment in cervical cancer cells HeLa, CaSki and SiHa cells. Co-treatment with VOR and DOX at marginal doses led to the induction of apoptosis through caspase-3 activation, poly (ADP-ribose) polymerase cleavage and DNA micronuclei. Notably, the synergistic growth inhibition induced by the co-treatment was attributed to the upregulation of the pro-apoptotic protein Bad, as the silencing of Bad expression using small interfering RNA (siRNA) abolished the phenomenon. As siRNA against p53 did not result in an increase in acetylated p53 and the consequent upregulation of Bad, the observed Bad upregulation was mediated by acetylated p53. Moreover, a chromatin immunoprecipitation analysis showed that the co-treatment of HeLa cells with VOR and DOX increased the recruitment of acetylated p53 to the bad promoter, with consequent bad transactivation. Conversely, C33A cervical cancer cells containing mutant p53 co-treated with VOR and DOX did not exhibit Bad upregulation, acetylated p53 induction or consequent synergistic growth inhibition. Together, the synergistic growth inhibition of cervical cancer cell lines induced by co-treatment with VOR and DOX can be attributed to the upregulation of Bad, which is induced by acetylated p53. These results show for the first time that the acetylation of p53, rather than histones, is a mechanism for the synergistic growth inhibition induced by VOR and DOX co-treatments.

The epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A influence adipocyte differentiation in human mesenchymal stem cells

Epigenetic mechanisms such as DNA methylation and histone modification are important in stem cell differentiation. Methylation is principally associated with transcriptional repression, and histone acetylation is correlated with an active chromatin state. We determined the effects of these epigenetic mechanisms on adipocyte differentiation in mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSCs) and adipose tissue (ADSCs) using the chromatin-modifying agents trichostatin A (TSA), a histone deacetylase inhibitor, and 5-aza-2′-deoxycytidine (5azadC), a demethylating agent. Subconfluent MSC cultures were treated with 5, 50, or 500 nM TSA or with 1, 10, or 100 µM 5azadC for 2 days before the initiation of adipogenesis. The differentiation was quantified and expression of the adipocyte genes PPARG and FABP4 and of the anti-adipocyte gene GATA2 was evaluated. TSA decreased adipogenesis, except in BM-MSCs treated with 5 nM TSA. Only treatment with 500 nM TSA decreased cell proliferation. 5azadC treatment decreased proliferation and adipocyte differentiation in all conditions evaluated, resulting in the downregulation of PPARG and FABP4 and the upregulation of GATA2. The response to treatment was stronger in ADSCs than in BM-MSCs, suggesting that epigenetic memories may differ between cells of different origins. As epigenetic signatures affect differentiation, it should be possible to direct the use of MSCs in cell therapies to improve process efficiency by considering the various sources available.

Pharmacological Unmasking Microarray Approach-Based Discovery of Novel DNA Methylation Markers for Hepatocellular Carcinoma

DNA methylation is one of the main epigenetic mechanisms and hypermethylation of CpG islands at tumor suppressor genes switches off these genes. To find novel DNA methylation markers in hepatocellular carcinoma (HCC), we performed pharmacological unmasking (treatment with 5-aza-2'-deoxycytidine or trichostatin A) followed by microarray analysis in HCC cell lines. Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues. Thirty-three loci showed a 20% higher methylation frequency in tumors than in adjacent nonneoplastic tissues. Correlation of individual cancer-related methylation markers with clinicopathological features of HCC patients (n = 95) revealed that the number of hypermethylated genes in HCC tumors was higher in older than in younger patients. Univariate and multivariate survival analysis revealed that the HIST1H2AE methylation status is closely correlated with the patient's overall survival (P = 0.022 and P = 0.010, respectively). In conclusion, we identified 221 novel DNA methylation markers for HCC. One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.

ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response

Chromatin structure has a crucial role in a diversity of physiological processes, including development, differentiation and stress responses, via regulation of transcription, DNA replication and DNA damage repair. Histone deacetylase (HDAC) inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving Ataxia-telangiectasia mutated (ATM). Herein, we investigated the impact of histone acetylation/deacetylation modification on the ATM-mediated transcriptional modulation to provide a better understanding of the transcriptional function of ATM. The prototype HDAC inhibitor trichostain A (TSA) reprograms expression of the myeloid cell leukemia-1 (MCL1) and Gadd45alpha genes via the ATM-mediated signal pathway. Transcription of MCL1 and Gadd45alpha is enhanced following TSA treatment in ATM+ cells, but not in isogenic ATM- or kinase-dead ATM expressing cells, in the ATM-activated E2F1 or BRCA1-dependent manner, respectively. These findings suggest that ATM and its kinase activity are essential for the TSA-induced regulation of gene expression. In summary, ATM controls the transcriptional upregulation of MCL1 and Gadd45alpha through the activation of the ATM-mediated signal pathway in response to HDAC inhibition. These findings are important in helping to design combinatory treatment schedules for anticancer radio- or chemo-therapy with HDAC inhibitors.

Proteomic analysis of cervical cancer cells treated with suberonylanilide hydroxamic acid.

Suberonylanilide hydroxamic acid (SAHA)is an orally administered histone deacetylase inhibitor (HDACI) that has shown significant antitumour activity in a variety of tumour cells.To identify proteins involved in its antitumour activity,we utilized a proteomic approach to reveal protein expression changes in the human cervical cancer cell line HeLa following SAHA treatment.Protein expression profiles were analysed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument.As a result,a total of nine differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue (CBB) staining.Further,all the changed proteins were positively identified via mass spectrometry (MS)/MS analysis. Of these,PGAM1 was significantly downregulated in HeLa cells after treatment with SAHA. Moreover,PGAM1 has been proven to be downregulated in another cervical cancer cell line (CaSki) by western blot analysis.Together,using proteomic tools,we identified several differentially expressed proteins that underwent SAHA-induced apoptosis. These changed proteins may provide some clues to a better understanding of the molecular mechanisms underlying SAHA-induced apoptosis in cervical cancer.

Transcriptional induction of DLC-1 gene through Sp1 sites by histone deacetylase inhibitors in gastric cancer cells

We previously reported that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, induced DLC-1 mRNA expression and accumulated acetylated histones H3 and H4 associated with the DLC-1 promoter in DLC-1 non-expressing gastric cancer cells. In this study, we demonstrated the molecular mechanisms by which TSA induced the DLC-1 gene expression. Treatment of the gastric cancer cells with TSA activates the DLC-1 promoter activity through Sp1 sites located at -219 and -174 relative to the transcription start site. Electrophoretic mobility-shift assay (EMSA) revealed that Sp1 and Sp3 specifically interact with these Sp1 sites and showed that TSA did not change their binding activities. The ectopic expression of Sp1, but not Sp3, enhances the DLC-1 promoter responsiveness by TSA. Furthermore, the TSA-induced DLC-1 promoter activity was increased by p300 expression and reduced by knockdown of p300. These results demonstrated the requirement of specific Sp1 sites and dependence of Sp1 and p300 for TSA-mediated activation of DLC-1 promoter.

Computational characteristics of valproic acid binding to histone deacetylase

Recently, the antiepileptic drug valproic acid [VPA] has also demonstrated efficacy in the management of cancer and bipolar disorders. These actions are largely mediated by inhibition of the HDAC enzyme/induction of certain genes. Relative to other HDAC inhibitors such as trichostatin-A [TSA], VPA offers higher selectivity on cancer cells with virtually no detrimental effects on normal cells. The molecular underpinnings of these biological profiles for VPA remain undefined. We currently propose for and attempt to identify differences in the binding of VPA and TSA to HDAC. In this paper, conformational changes and energy calculations have been derived. VPA had to accomplish conformational changes in its structure for best accommodation at the HDAC binding site. Energy computations showed that VPA has a lower binding affinity than TSA [-53.80 vs. -66.30 Kcal/mol]. These findings demonstrate that VPA binding to HDAC confers catalytic, conformational, and computational characteristics that are distinct from those of TSA. These findings for VPA are consistent with a moderate inhibition of HDAC, a low toxicity on normal cells, and a higher selectivity on cancer cells than TSA. Accordingly, these newly identified binding properties of VPA can state a framework strategy for the rational design of VPA-related anticancer drugs with superior cytodifferentiating- and/or safety-profiles

Trichostatin A-mediated upregulation of p21

Histone deacetylase inhibitors (HDIs), a new class of anti-cancer agents, have been reported to suppress formation of osteoclast precursors and their fusion into multinucleated cells. However, little is known about the effect of HDIs on mature osteoclasts, which may have significance for their therapeutic use. Here, we demonstrate a novel action of HDIs on osteoclast apoptosis. Primary multinucleated mature osteoclasts were prepared from mouse bone marrow cells. Treatment of osteoclasts with the HDI trichostatin A (TSA) caused apoptosis, as confirmed by annexin V staining and caspase activation. TSA caused the upregulation of p21WAF1 in osteoclasts. To understand the role of p21(WAF1) upregulation in TSA-treated osteoclasts, shRNA against p21(WAF1)-containing lentivirus was introduced into osteoclasts. The suppression of p21(WAF1) decreased TSA-directed osteoclast apoptosis. Collectively, our results provide evidence that TSA causes osteoclast apoptosis, which involves, in part, TSA-induced upregulation of p21(WAF1), and strongly supports HDIs as potential therapeutic agents for excessive bone resorption.

Inhibition of trichostatin A-induced antiangiogenesis by small-interfering RNA for thrombospondin-1

Expression of thrombospondin-1 (TSP-1), which is a known inhibitor of tumor growth and angiogenesis, is reciprocally regulated by positive regulators, such as VEGF. Additionally, trichostatin A (TSA) suppresses tumor progression by altering VEGF levels and VEGF-mediated signaling. Thus, understanding TSA-regulated TSP-1 expression and the effects of altered TSP-1 levels might provide insights into the mechanism of action of TSA in anti-tumorigenesis, and provide an approach to cancer therapy. Here, we examined the effect of TSA on TSP-1 expression, and the effects of TSA-induced TSP-1 on cell motility and angiogenesis, in HeLa and bovine aortic endothelial cells. TSA remarkably increased TSP-1 expression at the mRNA and protein levels, by controlling the TSP-1 promoter activity. Both TSA and exogenous TSP-1 reduced cell migration and capillary-like tube formation and these activities were confirmed by blocking TSP-1 with its neutralizing antibody and small-interfering RNA. Our results suggest that TSP-1 is a potent mediator of TSA-induced anti- angiogenesis.

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Trichostatin A (TSA), originally developed as an antifungal agent, is one of potent histone deacetylase (HDAC) inhibitors, which are known to cause growth arrest and apoptosis induction of transformed cells, including urinary bladder, breast, prostate, ovary, and colon cancers. However, the effect of HDAC inhibitors on human non-small cell lung cancer cells is not clearly known yet. Herein, we demonstrated that treatment of TSA resulted in a significant decrease of the viability of H157 cells in a dose-dependent manner, which was revealed as apoptosis accompanying with nuclear fragmentation and an increase in sub-G0/G1 fraction. In addition, it induced the expression of Fas/FasL, which further triggered the activation of caspase-8. Catalytic activation of caspase-9 and decreased expression of anti-aptototic Bcl-2 and Bcl-XL proteins were observed in TSA-treated cells. Catalytic activation of caspase-3 by TSA was further confirmed by cleavage of pro-caspase-3 and intracellular substrates, including poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, a characteristic phenomenon of mitochondrial dysfunction, including mitochondrial membrane potential transition and release of mitochondrial cytochrome c into the cytosol was apparent in TSA-treated cells. Taken together, our data indicate that inhibition of HDAC by TSA induces the apoptosis of H157 cells through signaling cascade of Fas/FasL-mediated extrinsic and mitocondria-mediated intrinsic caspases pathway.

Regulation of histone acetylation and apoptosis by trichostatin in HL-60 cells / 华中科技大学学报（医学）（英德文版）

In order to examine the strong anticancer action and low toxicity of Trichostatin A (TSA), the effect of TSA was examined on the growth inhibition, acetylation of histone H3 and apoptosis in HL-60 cells by employing MTT, immunocytochemical techniques, and Annexin-V-FITC/ PI assay. Our results showed that TSA could inhibit proliferation of HL- 60 cells in a time- and dose-dependent manner, and the IC50 at the 36th h was 100 ng/ml. The apoptosis-inducing effect of TSA on HL-60 cells was also time- and dose-dependent. But it didn't demonstrate apparent apoptosis induction in NPBMNCs within specific dose and time range. Both of the acetylation of histone H3 in HL-60 cells and NPBMNCs increased significantly (P0.05). It is concluded that TSA can inhibit growth and induce apoptosis of HL-60 cells in a time- and dose-dependent manner, and is able to selectively induce apoptosis in HL-60 cells but does not respond in NPBMNCs under the same conditions. The difference of TSA between HL-60 cells and NPBMNCs can't be explained by the regulation of histone acetylation.

Acidos hidroxâmicos: aspectos químicos e atividade biológica / Hydroxamic acids: chemical aspects and biological activity

Foi feita uma revisäo extensiva da literatura recente relativa aos principais aspectos da química e das propriedades biológicas de ácidos hidroxâmicos. Foram enfatizados os métodos gerais de preparaçäo desses ácidos, porém outros aspectos como reatividade e estrutura também foram discutidos. Relativamente aos aspectos biológicos, foram abordados os seguintes: inibiçäo da enzima urease, propriedades anti-hipertensivas, inibiçäo da síntese do DNA, efeito carcinogênico, açäo contra tripanossomas, inibiçäo de zinco-metaloproteases, atividade fungicida etc