Quantification of thermal ring flexibilities of aromatic and heteroaromatic compounds

The consequences of thermal fluctuations occurring at room temperatures on the aromatic character of a broad group of compounds were analyzed in three distinct ways. First of all, the ring deformations were modeled along normal coordinates coming from quantum thermo-chemistry computations. The amplitudes of vibrations were estimated according to absorbed energies at room temperature. Alternatively, in-plane and out-of-plane ring deformations were modeled via scanning procedure with partial relaxation of the molecular geometry. The influence of ring deformations on π–electron delocalization was expressed in terms of HOMA values. Besides, the ring deformability was defined as the averaged change of bond angles or dihedral angles constituting the ring that was associated with 1.5 kcal mol-1 increase of the system energy. The molecules structures adopted during vibrations at room temperature can lead to significant heterogeneity of structural index of aromaticity. The broad span of HOMA values was obtained for analyzed five- or six-membered aromatic and heteroaromatic rings. However, the averaged values obtained for such fluctuations almost perfectly match HOMA values of molecule in the ground state. It has been demonstrated that the ring deformability imposed by bond angle changes is much smaller than for dihedral angles with the same rise of system energy. Interestingly in the case of out-of-plane vibrations modeled by scanning procedure there is observed linear correlation between ring deformability and HOMA values. Proposed method for inclusion of thermal vibrations in the framework of π–electron delocalization provides natural shift of the way of thinking about aromaticity from a static quantity to a dynamic and heterogeneous one due to inclusion of a more realistic object of analysis – thermally deformed structures. From this perspective the thermal fluctuations are supposed to be non-negligible contributions to aromaticity phenomenon

Estradiol Regulation of Nucleotidases in Female Reproductive Tract Epithelial Cells and Fibroblasts

The use of topical and oral adenosine derivatives in HIV prevention that need to be maintained in tissues and cells at effective levels to prevent transmission prompted us to ask whether estradiol could influence the regulation of catabolic nucleotidase enzymes in epithelial cells and fibroblasts from the upper and lower female reproductive tract (FRT) as these might affect cellular TFV-DP levels. Epithelial cells and fibroblasts were isolated from endometrium (EM), endocervix (CX) and ectocervix (ECX) tissues from hysterectomy patients, grown to confluence and treated with or without estradiol prior to RNA isolation. The expression of nucleotidase (NT) genes was measurable by RT-PCR in epithelial cells and fibroblasts from all FRT tissues. To determine if sex hormones have the potential to regulate NT, we evaluated NT gene expression and NT biological activity in FRT cells following hormone treatment. Estradiol increased expression of Cytosolic 5 9 -nucleotidase after 2 or 4 h in endometrial epithelial cells but not epithelial cells or fibroblasts from other sites. In studies using a modified 5 9 - Nucleotidase biological assay for nucleotidases, estradiol increased NT activity in epithelial cells and fibroblasts from the EM, CX and ECX at 24 and 48 h. In related studies, HUVEC primary cells and a HUVEC cell line were unresponsive to estradiol in terms of nucleotidase expression or biological activity. Our findings of an increase in nucleotidase expression and biological activity induced by estradiol do not directly assess changes in microbicide metabolism. However, they do suggest that when estradiol levels are elevated during the menstrual cycle, FRT epithelial cells and fibroblasts from the EM, CX and ECX have the potential to influence microbicide levels that could enhance protection of HIV-target cells (CD4 + T cells, macrophages and dendritic cells) throughout the FRT

Arsenic Exposure and Type 2 Diabetes: A Systematic Review of the Experimental and Epidemiologic Evidence

Chronic arsenic exposure has been suggested to contribute to diabetes development. We performed a systematic review of the experimental and epidemiologic evidence on the association of arsenic and type 2 diabetes. We identified 19 in vitro studies of arsenic and glucose metabolism. Five studies reported that arsenic interfered with transcription factors involved in insulin-related gene expression: upstream factor 1 in pancreatic β-cells and peroxisome proliferative-activated receptor γ in preadipocytes. Other in vitro studies assessed the effect of arsenic on glucose uptake, typically using very high concentrations of arsenite or arsenate. These studies provide limited insight on potential mechanisms. We identified 10 in vivo studies in animals. These studies showed inconsistent effects of arsenic on glucose metabolism. Finally, we identified 19 epidemiologic studies (6 in high-arsenic areas in Taiwan and Bangladesh, 9 in occupational populations, and 4 in other populations). In studies from Taiwan and Bangladesh, the pooled relative risk estimate for diabetes comparing extreme arsenic exposure categories was 2.52 (95% confidence interval, 1.69–3.75), although methodologic problems limit the interpretation of the association. The evidence from occupational studies and from general populations other than Taiwan or Bangladesh was inconsistent. In summary, the current available evidence is inadequate to establish a causal role of arsenic in diabetes. Because arsenic exposure is widespread and diabetes prevalence is reaching epidemic proportions, experimental studies using arsenic concentrations relevant to human exposure and prospective epidemiologic studies measuring arsenic biomarkers and appropriately assessing diabetes should be a research priority

Effects of Low-Dose Drinking Water Arsenic on Mouse Fetal and Postnatal Growth and Development

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 7 (2012): e38249, doi:10.1371/journal.pone.0038249.Arsenic (As) exposure is a significant worldwide environmental health concern. Chronic exposure via contaminated drinking water has been associated with an increased incidence of a number of diseases, including reproductive and developmental effects. The goal of this study was to identify adverse outcomes in a mouse model of early life exposure to low-dose drinking water As (10 ppb, current U.S. EPA Maximum Contaminant Level). C57B6/J pups were exposed to 10 ppb As, via the dam in her drinking water, either in utero and/or during the postnatal period. Birth outcomes, the growth of the F1 offspring, and health of the dams were assessed by a variety of measurements. Birth outcomes including litter weight, number of pups, and gestational length were unaffected. However, exposure during the in utero and postnatal period resulted in significant growth deficits in the offspring after birth, which was principally a result of decreased nutrients in the dam's breast milk. Cross-fostering of the pups reversed the growth deficit. Arsenic exposed dams displayed altered liver and breast milk triglyceride levels and serum profiles during pregnancy and lactation. The growth deficits in the F1 offspring resolved following separation from the dam and cessation of exposure in male mice, but did not resolve in female mice up to six weeks of age. Exposure to As at the current U.S. drinking water standard during critical windows of development induces a number of adverse health outcomes for both the dam and offspring. Such effects may contribute to the increased disease risks observed in human populations.This work was supported by National Institute of Environmental Health Sciences at the National Institutes of Health grants 1F32 ES019070 (CDK-H) and P42 ES007373 (BPJ, JWH, RIE and CDK-H, Dartmouth Superfund Research Program Project Grant, Project 2 and Pilot Project)