Input: The aim of this study was to evaluate the effects of TCDD administered to pregnant mice at two different doses (2-10 ng/kg/day), on imprinted genes in the male offspring.

TCDD


Input: The degree of methylation and the mRNA expression of Snrpn, Peg3 and Igf2r were analyzed in the sperm, skeletal muscle and liver.


Input: TCDD administration (10 ng/kg/day) decreased the sperm count in the male offspring.

TCDD


Input: It did not affect methylation but increased mRNA expression of Snrpn, Peg3, Igf2r and Air ncRNA.


Input: In muscle and liver, TCDD (10 ng/kg/day) induced increases in methylation and decreases in mRNA expression of Igf2r.

TCDD


Input: These results show that the robust effects of TCDD on the mRNA expression of Snrpn, Peg3 and Igf2r genes in the sperm and of Igf2r in the muscle and liver are unrelated to changes in methylation in their respective genes.

TCDD


Input: The 17-beta-oestradiol inhibits osteoclast activity by increasing the cannabinoid CB2 receptor expression.


Input: Bone is a highly metabolically active tissue and its formation and resorption is at the base of bone remodelling.


Input: The critical importance of a balanced bone remodelling is demonstrated by human diseases, i. e. osteoporosis, in which a net increase in bone resorption is responsible of skeleton weakening and fracture risk.


Input: Oestrogens display anti-resorptive properties on bone metabolism.

Oestrogens


Input: Indeed, the so-called post-menopausal osteoporosis occurs after interruption of gonad function and benefits from hormonal replacement treatment.


Input: Recently, an important role for the endocannabinoid system in the regulation of skeletal remodelling in human has also been shown.


Input: In particular, we showed that CB2 stimulation is able to reduce the number of human OCs in vitro.


Input: Here, we provide unprecedented evidence that 17-beta-oestradiol administration inhibits activity and formation of human OCs in vitro, demonstrating that oestrogens are able to induce an increase of CB2 expression probably through the recruitment of a putative oestrogens responsive element in the CB2 encoding for gene.

oestrogens

oestrogens


Input: Proto-oncogene PIM-1 is a novel estrogen receptor target associating with high grade breast tumors.

estrogen


Input: We searched ER alpha cistromes of MCF-7 breast cancer cells for previously unrecognized ER alpha targets and identified proto-oncogene PIM-1 as a novel potential target gene.


Input: We show that the expression of PIM-1 is induced in response to estradiol in MCF-7 cells and that the induction is mediated by ER alpha-regulated enhancers located distally upstream from the gene.

estradiol


Input: In keeping with the growth-promoting role of the PIM-1, depletion of the PIM-1 attenuated the proliferation of the MCF-7 cells, which was paralleled with up-regulation of cyclin-dependent protein kinase inhibitor CDKN1A and CDKN2B expression.


Input: Analysis of PIM-1 expression between invasive breast tumors and benign breast tissue samples showed that elevated PIM-1 expression is associated with malignancy and a higher tumor grade.


Input: In sum, identification of PIM-1 as an ER alpha target gene adds a novel potential mechanism by which estrogens can contribute to breast cancer cell proliferation and carcinogenesis.

estrogens


Input: Dichlorodiphenyltrichloroethane (DDT), DDT metabolites and pregnancy outcomes.

Dichlorodiphenyltrichloroethane

DDT

DDT


Input: Organochlorine pesticides (OCPs) are persistent endocrine disruptors.

Organochlorine


Input: OCPs cross the placenta; this prenatal exposure has been associated with adverse pregnancy outcomes.


Input: We investigated associations between prenatal exposure to OCPs and gestational age and birth weight in 600 infants born between 1960 and 1963.


Input: The primary OCP was 1, 1, 1-trichloro-2, 2-bis (p-chlorophenyl) ethane (p, p'-DDT), its primary metabolite, 1, 1'-dichloro-2, 2'-bis (p-chlorophenyl) ethylene (p, p'-DDE) and the contaminant, 1, 1, 1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane (o, p'-DDT).

1, 1, 1-trichloro-2, 2-bis (p-chlorophenyl) ethane

p, p'-DDT

1, 1'-dichloro-2, 2'-bis (p-chlorophenyl) ethylene

p, p'-DDE

1, 1, 1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane

o, p'-DDT


Input: Regression analysis indicated that for each natural log unit increase in p, p'-DDT, birth weight increased by 274 g (95% CI: 122, 425) when controlling for p, p'-DDE and o, p'-DDT.

p, p'-DDT

p, p'-DDE

o, p'-DDT


Input: At a given level of p, p'-DDT exposure, o, p'-DDT and p, p'-DDE were associated with decreased birth weight.

p, p'-DDT

o, p'-DDT

p, p'-DDE


Input: p, p'-DDE was negatively associated with length of gestation, controlling for p, p'-DDT and o, p'-DDT.

p, p'-DDE

p, p'-DDT

o, p'-DDT


Input: These findings suggest opposing associations between exposure to p, p'-DDT and p, p'-DDE and birth weight.

p, p'-DDT

p, p'-DDE


Input: We did not find evidence to support mediation by maternal thyroid hormone status nor that the association differed by sex.


Input: Longitudinal in vivo imaging of bone formation and resorption using fluorescence molecular tomography.


Input: Bone research often focuses on anatomical imaging of the bone microstructure, but in order to gain better understanding in how bone remodeling is modulated through interventions also bone formation and resorption processes should be investigated.


Input: With this in mind, the purpose of this study was to establish a longitudinal in vivo imaging approach of bone formation and resorption using fluorescence molecular tomography (FMT).


Input: In this study the reproducibility, accuracy and sensitivity of FMT for bone imaging were assessed by performing longitudinal measurements with FMT and comparing it to in vivo micro-computed tomography on a set of control mice, and mice in which load-adaptation was induced in the sixth caudal vertebra.


Input: The precision error for FMT measurements, expressed as coefficient of variation, was smaller than 16%, indicating acceptable reproducibility.


Input: A correlation was found between bone resorption measured with FMT and bone resorption rate measured with in vivo micro-computed tomography only over the first 14days (R = 0. 81, p < 0. 01), but not between bone formation measured with FMT and bone formation rate measured with in vivo micro-CT.


Input: Bone formation measured by FMT was 89-109% greater (p < 0. 05) for mice subjected to mechanical loading than control mice.


Input: Bone resorption was 5-8% lower, but did not reach a significant difference between groups, indicating moderate sensitivity for FMT.


Input: In conclusion, in vivo FMT in mouse tail bones is feasible but needs to be optimized for monitoring load adaptation in living mice.


Input: Cadmium (Cd)-induced oxidative stress down-regulates the gene expression of DNA mismatch recognition proteins MutS homolog 2 (MSH2) and MSH6 in zebrafish (Danio rerio) embryos.

Cadmium

Cd


Input: DNA mismatch repair (MMR) of simple base mismatches and small insertion-deletion loops in eukaryotes is initiated by the binding of the MutS homolog 2 (MSH2)-MSH6 heterodimer to mismatched DNA.


Input: Cadmium (Cd) is a genotoxic heavy metal that has been recognized as a human carcinogen.

Cadmium

Cd


Input: Oxidant stress and inhibition of DNA repair have been proposed as major factors underlying Cd genotoxicity.

Cd


Input: Our previous studies indicated the ability of Cd to disturb the gene expression of MSH6 in zebrafish (Danio rerio) embryos.

Cd


Input: This study was undertaken to explore if Cd-induced oxidative stress down-regulated MSH gene activities.

Cd


Input: Following the exposure of zebrafish embryos at 1 h post fertilization (hpf) to sublethal concentrations of Cd at 3-5 mu M for 4 or 9 h, a parallel down-regulation of MSH2, MSH6 and Cu/Zn superoxide dismutase (Cu/Zn-SOD) gene expression was detected by real-time RT-PCR and the expression levels were 40-50% of control after a 9-h exposure.

Cd

Cu

Zn superoxide

Cu

Zn


Input: Cd exposure also induced oxidative stress, yet no inhibition of catalase gene activity was observed.

Cd


Input: Whole mount in situ hybridization revealed a wide distribution of msh6 mRNA in the head regions of 10 hpf embryos and pretreatment of embryos with antioxidants butylhydroxytoluene (BHT), d-mannitol or N-acetylcysteine (NAC) at 1-10 mu M restored Cd-suppressed msh6 expression.

butylhydroxytoluene

BHT

d-mannitol

N-acetylcysteine

NAC

Cd


Input: QPCR confirmed the protective effects of antioxidants on Cd-suppressed msh2/msh6 mRNA production.

Cd


Input: Down-regulated MSH gene activities reaching about 50% of control were also induced in embryos exposed to paraquat, a reactive oxygen species (ROS)-generating herbicide, or hydrogen peroxide at 200 mu M.

paraquat

oxygen

hydrogen peroxide


Input: Hence, Cd at sublethal levels down-regulates msh2/msh6 expression primarily via ROS as signaling molecules.

Cd


Input: The transcriptional activation of human msh6 is known to be fully dependent on the specificity factor 1 (Sp1).


Input: Cd failed to inhibit the DNA binding activity of zebrafish Sp1 unless at lethal concentrations based on band shift assay, therefore excluding the involvement of Sp1 inactivation in Cd-induced MSH gene inhibition in zebrafish embryos.

Cd

Cd


Input: Temperature dependence of long-term cadmium toxicity in the zebrafish is not explained by liver oxidative stress: evidence from transcript expression to physiology.

cadmium


Input: Standard ecotoxicity tests are performed at species' specific standard temperatures, but temperature is known to affect chemical toxicity.


Input: A temperature increase has been shown to increase cadmium toxicity in several aquatic species but information in fish is scarce.

cadmium


Input: Based on literature we hypothesize that with increasing temperature, cadmium accumulation and oxidative stress increase, resulting in increased toxicity.

cadmium


Input: In this study zebrafish acclimated to 12, 18, 26 (standard temperature) or 34 degrees C for one month, were exposed to 5 mu M cadmium for 4 or 28 days at the respective acclimation temperature.

cadmium


Input: Cadmium toxicity (mortality) increased with increasing temperature.

Cadmium


Input: PCA showed that the high mortality at 34 degrees C was closely correlated to an increasing tissue cadmium accumulation with increasing temperature, but not to liver oxidative damage under the form of protein carbonyl content or lipid peroxidation (measured as malondialdehyde levels) or liver antioxidative potential.

cadmium

carbonyl

malondialdehyde


Input: Instead, acclimation to 12 degrees C induced the highest oxidative damage to liver proteins and lipids, and transcript levels of glucose-6P-dehydrogenase, 6P-gluconate-dehydrogenase and glutathione peroxidase were particularly good markers of cold-induced oxidative stress.

glucose

gluconate

glutathione


Input: At this low temperature there was no interaction with cadmium exposure and there was no sign of cadmium sensitivity.

cadmium

cadmium


Input: Contrastingly, the combined effect of high temperature and cadmium exposure on mortality proved synergistic.

cadmium


Input: Therefore we conclude that interactions between temperature and cadmium toxicity increased with increasing temperature and that this probably played part in increasing cadmium sensitivity.

cadmium

cadmium


Input: Increased cadmium compartmentalization and protein carbonyl content in liver of zebrafish acclimated to the standard temperature of 26 degrees C probably played part in increased sensitivity towards the same cadmium body burden compared to lower temperatures.

cadmium

carbonyl

cadmium


Input: On the one hand we recognize and this study even confirms the importance of applying standard temperatures in standard ecotoxicity tests to ensure inter-study comparability.


Input: On the other hand temperatures in the field may deviate from standard temperatures and accounting for deviating temperatures, which can alter chemical sensitivity, in regulation can improve environmental protection.


Input: Induction of skin sensitization is augmented in Nrf2-deficient mice.


Input: Several in vitro DNA microarray studies have shown the importance of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in skin sensitization.


Input: Nevertheless, the exact in vivo role of the Nrf2-Keap1 pathway during the induction of skin sensitization remains unknown.


Input: To study the function of Nrf2, a local lymph node assay was performed in wild-type and Nrf2-deficient mice using 2, 4-dinitrochlorobenzene.

2, 4-dinitrochlorobenzene


Input: The Nrf2-deficient mice show a more pronounced response, indicating that Nrf2 is involved in dampening the induction of skin sensitization.


Input: Survivin in adrenocortical tumors-pathophysiological implications and therapeutic potential.


Input: Treatment options for adrenocortical carcinoma (ACC) are very limited.


Input: In other solid tumors, small vaccination trials targeting the anti-apoptotic molecule survivin suggested immunological and clinical benefit in selected patients.


Input: Therefore, we investigated whether survivin might be a suitable target for immunotherapy in ACC.


Input: Survivin mRNA and protein expression was assessed in adrenal tissue specimens [by real-time-PCR in 29 ACC, 24 adrenocortical adenomas (ACA) and 12 normal adrenal glands; by immunohistochemistry in 167 ACCs, 15 ACA, and 5 normal adrenal glands].


Input: Expression was correlated with clinical outcome using Kaplan-Meier and Cox regression analyses.


Input: The anti-apoptotic role of survivin was investigated in the SW13 ACC cell line using survivin siRNA.


Input: The presence of spontaneous survivin specific T-cells in peripheral blood was assessed by FACS dextramere staining in 29 ACC patients in comparison to healthy controls.


Input: Survivin mRNA in ACC was significantly overexpressed when compared with ACA or normal adrenal glands.


Input: Immunohistochemistry confirmed survivin protein expression in 97% of the ACCs.


Input: In 83% of samples, staining was moderate or high and clinical outcome in this subgroup showed a trend towards poorer prognosis [hazard ratio for death 2. 28 (95% CI 0. 99-5. 28); p = 0. 053].


Input: Survivin knockdown in SW-13 cell significantly increased the rate of apoptosis.


Input: Finally, spontaneous survivin-reactive T cells were detectable in 3 of 29 ACC patients.


Input: In conclusion, our data suggest that survivin could play an important role in the anti-apoptotic mechanisms in ACC and provide first hints that targeting survivin might be an interesting new therapeutic approach in this rare disease.


Input: Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction.


Input: Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans.


Input: Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI.


Input: Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection.

clemizole


Input: Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing.


Input: The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity.

clemizole


Input: Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor.

clemizole


Input: These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment.


Input: High-sensitivity real-time analysis of nanoparticle toxicity in green fluorescent protein-expressing zebrafish.


Input: Gold nanoparticles (AuNP) show great potential for diagnostic and therapeutic application in humans.


Input: A great number of studies have tested the cytotoxicity of AuNP using cell culture.


Input: There is, however, an urgent need to test AuNP in vertebrate animal models that interrogate biodistribution and complex biological traits like organ development, whole body metabolism, and cognitive function.


Input: The sheer number of different compounds precludes the use of small rodent model for initial screening.


Input: The extended fish embryo test (FET) is used here to bridge the gap between cell culture and small animal models.


Input: A study on the toxicity of ultrasmall AuNP in wild type and transgenic zebrafish is presented.


Input: FET faithfully reproduce all important findings of a previous study in HeLa cells and add new important information on teratogenicity and hepatotoxicity that could not be gained from studying cultured cells.


Input: Real-time fluorescence turn-on detection of alkaline phosphatase activity with a novel perylene probe.

perylene


Input: A tetracationic perylene probe (probe 1) was designed and synthesized.

perylene


Input: Probe 1 was used for the real-time fluorescence turn-on assay of alkaline phosphatase (ALP) activity and inhibitor screening.


Input: Probe 1 monomer fluorescence could be very efficiently quenched by ATP through the formation of an ATP/probe 1 complex.


Input: ALP triggered the degradation of ATP, the breakdown of the ATP/probe 1 complex, and the recovery of the probe 1 monomer fluorescence.


Input: In the presence of an ALP inhibitor, a decrease in fluorescence recovery was observed.


Input: Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action.

phorbol ester

bryostatin 1

bryostatin


Input: Bryostatin 1, like the phorbol esters, binds to and activates protein kinase C (PKC) but paradoxically antagonizes many but not all phorbol ester responses.

Bryostatin 1

phorbol esters

phorbol ester


Input: Previously, we have compared patterns of biological response to bryostatin 1, phorbol ester, and the bryostatin 1 derivative Merle 23 in two human cancer cell lines, LNCaP and U937.

bryostatin 1

phorbol ester

bryostatin 1

Merle 23


Input: Bryostatin 1 fails to induce a typical phorbol ester biological response in either cell line, whereas Merle 23 resembles phorbol ester in the U937 cells and bryostatin 1 in the LNCaP cells.

Bryostatin 1

phorbol ester

Merle 23

phorbol ester

bryostatin 1


Input: Here, we have compared the pattern of their transcriptional response in both cell lines.


Input: We examined by qPCR the transcriptional response as a function of dose and time for a series of genes regulated by PKCs.


Input: In both cell lines bryostatin 1 differed primarily from phorbol ester in having a shorter duration of transcriptional modulation.

bryostatin 1

phorbol ester


Input: This was not due to bryostatin 1 instability, since bryostatin 1 suppressed the phorbol ester response.

bryostatin 1

bryostatin 1

phorbol ester


Input: In both cell lines Merle 23 induced a pattern of transcription largely like that of phorbol ester although with a modest reduction at later times in the LNCaP cells, suggesting that the difference in biological response of the two cell lines to Merle 23 lies downstream of this transcriptional regulation.

Merle 23

phorbol ester

Merle 23


Input: For a series of bryostatins and analogs which ranged from bryostatin 1-like to phorbol ester-like in activity on the U937 cells, the duration of transcriptional response correlated with the pattern of biological activity, suggesting that this may provide a robust platform for structure activity analysis.

bryostatins

bryostatin 1

phorbol ester


Input: Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells.

resveratrol

clofarabine


Input: Dietary phytochemicals as adjuvants have been suggested to play important roles in enhancing chemotherapeutic potential owing to multitargeted chemopreventive properties and lack of substantial toxicity.


Input: Here, we investigated the efficacy of the combined treatment of various phytochemicals with the anticancer drug clofarabine in malignant mesothelioma MSTO-211H cells and normal mesothelial MeT-5A cells.

clofarabine


Input: The combined treatment of resveratrol and clofarabine produced a synergistic antiproliferative effect in MSTO-211H cells, but not in MeT-5A cells.

resveratrol

clofarabine


Input: In MSTO-211H cells, the nuclear accumulation of Sp1 and the levels of p-Akt, Sp1, c-Met, cyclin D1, and p21 were effectively decreased by the combined treatment of them.


Input: In combination with clofarabine, the ability of resveratrol to reduce the contents of Sp1 and its target gene products was also evident in a time-and dose-dependent experiment.

clofarabine

resveratrol


Input: The inhibition of phosphoinositide 3-kinase using Ly294002 augmented a decrease in the p21 level induced by their combination, but it showed no significant effects on expression of Sp1 and cyclin D1.

phosphoinositide


Input: Taken together, the data provide evidence that the synergistic antiproliferative effect of resveratrol and clofarabine is linked to the inhibition of Akt and Sp1 activities, and suggest that this combination may have therapeutic value in treatment of malignant mesothelioma.

resveratrol

clofarabine


Input: Purification and determination of two novel antioxidant peptides from flounder fish (Paralichthys olivaceus) using digestive proteases.


Input: We investigated the effects of bioactive-peptides from hydrolysates of flounder fish muscle (FFM) on antioxidant activity.


Input: The hydrolysates were prepared by enzymatic reactions of FFM using eight commercial proteases such as papain, pepsin, trypsin, neutrase, alcalase, kojizyme, protamex, and alpha-chymotrypsin.


Input: The alpha-chymotrypsin hydrolysate showed the strongest antioxidant activity among the eight enzymatic hydrolysates.


Input: Further separation of the alpha-chymotrypsin hydrolysate was performed by ultrafiltration, gel filtration, and reverse-phase high performance liquid chromatography.


Input: Consequently, two novel peptides with high antioxidant activity were purified, and their amino acid sequences were determined (Val-Cys-Ser-Val [VCSV] and Cys-Ala-Ala-Pro [CAAP], respectively).

amino acid

Val-Cys-Ser-Val

VCSV

Cys-Ala-Ala-Pro

CAAP


Input: The two peptides showed good scavenging activity against the 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical (IC (50) values, 111. 32 and 26. 89 mu M, respectively) and high cytoprotective activities against 2, 2-azobis-(2-amidino-propane) dihydrochloride (AAPH) without cytotoxicity and scavenged total reactive oxygen species in Vero cells.

1, 1-diphenyl-2-picrylhydrazyl

DPPH

2, 2-azobis-(2-amidino-propane) dihydrochloride

AAPH

oxygen


Input: In particular, apoptotic bodies produced by AAPH dose-dependently decreased following treatment with the CAAP peptide.

AAPH

CAAP


Input: These results revealed firstly the two peptides with strong antioxidative effects from FFM.


Input: Bisphenol A inhibits proliferation and induces apoptosis in micromass cultures of rat embryonic midbrain cells through the JNK, CREB and p53 signaling pathways.

Bisphenol A


Input: Bisphenol A (BPA) has been widely used in the manufacture of polycarbonate plastic, water bottles and food containers.

Bisphenol A

BPA

polycarbonate


Input: Previous studies have established that BPA could cause developmental toxicity by inhibiting the proliferation and differentiation of rat embryonic midbrain (MB) cells in vitro.

BPA


Input: However, the underlying mechanisms have not been well studied yet.


Input: In the current study, we examined the proliferation and differentiation of MB cells treated with 10 (-12)-10 (-4) M BPA and found that only 10 (-4) M BPA inhibited proliferation and differentiation.

BPA

BPA


Input: Then, we investigated the cell cycle progression and apoptosis of MB cells; 10 (-4) M BPA caused an explicit S phase and G2/M phase arrest in the cell cycle and increased the percentage of apoptotic cells.

BPA


Input: Moreover, the phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic-AMP response binding protein (CREB) and the expression of some apoptotic regulatory genes were investigated.


Input: BPA (10 (-4) M) reduced the phosphorylation of C-Jun N-terminal kinase (JNK) and CREB, and increased the mRNA expression level of Bax and p53.

BPA

N


Input: Our findings demonstrated that BPA could cause developmental toxicity through anti-proliferation and pro-apoptosis in MB cells.

BPA


Input: Multiple signaling pathways, such as the JNK, CREB and p53-mitochondrial apoptosis pathways, participate in these effects.


Input: 1H NMR-based metabonomics approach in a rat model of acute liver injury and regeneration induced by CCl4 administration.


Input: The administration of carbon tetrachloride (CCl (4)) has been established as a model of toxin-induced acute and chronic liver injury.

carbon tetrachloride

CCl (4)


Input: In the present study, we investigate the progression of the biochemical response to acute CCl (4)-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma.

CCl (4)


Input: A single dose of CCl (4) (1 mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12h up to 72 h post treatment, while healthy animals served as controls.

CCl (4)


Input: Acquired (1) H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury.

(1) H


Input: The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36 h) and those at the regenerative phase (peaked at 48 h).


Input: At 72 h normalization of liver' s pathology similar to the controls group was apparent.


Input: Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state.


Input: A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl (4) induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions.

glucose

lactate

choline

formate

CCl (4)


Input: The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl (4) metabolism.

folate

CCl (4)


Input: Physiologically based toxicokinetics of serum aflatoxin B1-lysine adduct in F344 rats.

aflatoxin B1

lysine


Input: Aflatoxin B (1)-lysine adduct (AFB-Lys) is a reliable biomarker for aflatoxin exposure; however, a systematic toxicokinetic evaluation has not been reported.

Aflatoxin B (1)

lysine

AFB

Lys

aflatoxin


Input: In this study, male F344 rats were orally exposed to single, or repeated, doses of AFB (1) and the toxicokinetics of serum AFB-Lys that followed treatments were investigated.

AFB (1)

AFB

Lys


Input: A single-dose of AFB (1) increased serum AFB-Lys levels rapidly peaking at 4h, followed by first-order elimination, through which the half-life was estimated to be 2. 31 days.

AFB (1)

AFB

Lys


Input: A physiologically based pharmacokinetic model showed that approximately 3. 00-3. 90% and 1. 12-1. 98% of the administered AFB (1) doses were converted to serum AFB-Lys adducts at 2h and 24h post treatment, respectively.

AFB (1)

AFB

Lys


Input: Repeated AFB (1) exposure at 5-25 mu g/kg body weight linearly increased serum AFB-Lys levels for 5 weeks in animals, resulting in a 1-1. 5 times higher AFB-Lys level overall.

AFB (1)

AFB

Lys

AFB

Lys


Input: This indicates the potential of this adduct as a reliable biomarker for repeated low dose exposure.


Input: Higher dose exposure at 75 mu g/kg increased the level of AFB-Lys to a maximum at 2 weeks, followed by a gradual decrease to near plateau level up to 5 weeks.

AFB

Lys


Input: In conclusion, this study systematically evaluated the toxicokinetics of serum AFB-Lys adduct in F344 rats using a physiologically based pharmacokinetic model and robust statistical modeling analysis and provided a firm and clear understanding of the toxicokinetics of this biomarker.

AFB

Lys


Input: Influence of ovarian and non-ovarian estrogens on weight gain in response to disruption of sweet taste--calorie relations in female rats.

estrogens


Input: Regulation of energy balance in female rats is known to differ along a number of dimensions compared to male rats.


Input: Previous work from our lab has demonstrated that in female rats fed dietary supplements containing high-intensity sweeteners that may disrupt a predictive relation between sweet tastes and calories, excess weight gain is demonstrated only when females are also fed a diet high in fat and sugar, and is evidenced primarily in animals already prone to gain excess weight.

sugar


Input: In contrast, male rats show excess weight gain when fed saccharin-sweetened yogurt supplements when fed both standard chow diets and diets high in fat and sugar, and regardless of their proneness to excess weight gain.

saccharin

sugar


Input: The goal of the present experiments was to determine whether ovarian, or other sources of estrogens, contributes to the resistance to excess weight gain in female rats fed standard chow diets along with dietary supplements sweetened with yogurt.

estrogens


Input: Results of the first experiment indicated that when the ovaries were removed surgically in adult female rats, patterns of weight gain were similar in animals fed saccharin-sweetened compared to glucose-sweetened yogurt supplements.

saccharin

glucose


Input: In the second experiment, when the ovaries were surgically removed in adult female rats, and local production of estrogens was suppressed with the aromatase inhibitor anastrozole, females fed the saccharin-sweetened yogurt consumed more energy and gained more weight than females fed the glucose-sweetened yogurt.

estrogens

anastrozole

saccharin

glucose


Input: However, when the ovaries were surgically removed prior to the onset of puberty (at 24-25 days of age), females given saccharin-sweetened yogurt along with vehicle gained excess weight.

saccharin


Input: In contrast, weight gain was similar in those given saccharin-sweetened and glucose-sweetened yogurt along with anastrozole.

saccharin

glucose

anastrozole


Input: The results suggest that behavioral differences between males and females in response to disruption of sweet --> calorie relations may result from differences in patterns of local estrogen production.

estrogen


Input: These differences may be established developmentally during the pubertal period in females.


Input: Manganese transport via the transferrin mechanism.

Manganese


Input: Excessive manganese (Mn) uptake by brain cells, particularly in regions like the basal ganglia, can lead to toxicity.

manganese

Mn


Input: Mn (2 +) is transported into cells via a number of mechanisms, while Mn (3 +) is believed to be transported similarly to iron (Fe) via the transferrin (Tf) mechanism.

Mn (2 +)

Mn (3 +)

iron

Fe


Input: Cellular Mn uptake is therefore determined by the activity of the mechanisms transporting Mn into each type of cell and by the amounts of Mn (2 +), Mn (3 +) and their complexes to which these cells are exposed; this complicates understanding the contributions of each transporter to Mn toxicity.

Mn

Mn

Mn (2 +)

Mn (3 +)

Mn


Input: While uptake of Fe (3 +) via the Tf mechanism is well understood, uptake of Mn (3 +) via this mechanism has not been systematically studied.

Fe (3 +)

Mn (3 +)


Input: The stability of the Mn (3 +) Tf complex allowed us to form and purify this complex and label it with a fluorescent (Alexa green) tag.

Mn (3 +)

Alexa green


Input: Using purified and labeled Mn (3 +) Tf and biophysical tools, we have developed a novel approach to study Mn (3 +) Tf transport independently of other Mn transport mechanisms.

Mn (3 +)

Mn (3 +)

Mn


Input: This approach was used to compare the uptake of Mn (3 +) Tf into neuronal cell lines with published descriptions of Fe (3 +) uptake via the Tf mechanism, and to obtain quantitative information on Mn uptake via the Tf mechanism.

Mn (3 +)

Fe (3 +)

Mn


Input: Results confirm that in these cell lines significant Mn (3 +) is transported by the Tf mechanism similarly to Fe (3 +) Tf transport; although Mn (3 +) Tf transport is markedly slower than other Mn transport mechanisms.

Mn (3 +)

Fe (3 +)

Mn (3 +)

Mn


Input: This novel approach may prove useful for studying Mn toxicity in other systems and cell types.

Mn


Input: Organization of the BcgI restriction-modification protein for the cleavage of eight phosphodiester bonds in DNA.

phosphodiester


Input: Type IIB restriction-modification systems, such as BcgI, feature a single protein with both endonuclease and methyltransferase activities.


Input: Type IIB nucleases require two recognition sites and cut both strands on both sides of their unmodified sites.


Input: BcgI cuts all eight target phosphodiester bonds before dissociation.

phosphodiester


Input: The BcgI protein contains A and B polypeptides in a 2: 1 ratio: A has one catalytic centre for each activity; B recognizes the DNA.


Input: We show here that BcgI is organized as A (2) B protomers, with B at its centre, but that these protomers self-associate to assemblies containing several A (2) B units.


Input: Moreover, like the well known FokI nuclease, BcgI bound to its site has to recruit additional protomers before it can cut DNA.


Input: DNA-bound BcgI can alternatively be activated by excess A subunits, much like the activation of FokI by its catalytic domain.


Input: Eight A subunits, each with one centre for nuclease activity, are presumably needed to cut the eight bonds cleaved by BcgI.


Input: Its nuclease reaction may thus involve two A (2) B units, each bound to a recognition site, with two more A (2) B units bridging the complexes by protein-protein interactions between the nuclease domains.


Input: Understanding the role of gut microbes and probiotics in obesity: how far are we?


Input: Obesity has been associated with structural alterations in the gut microbiota, suggesting potential causality between specific microbial taxa and this disorder.


Input: Studies in animal models have also provided evidence for plausible gut microbiota mechanisms of action underlying body weight regulation.


Input: Yet evidence identifying which specific microbes contribute to or predict obesity is not completely consistent across studies.


Input: More recently, diet has also been shown to be primarily involved in regulating the microbiota structure initially related to obesity, suggesting that the role of microbes in energy balance is under the influence of diet.


Input: Controversy over the role of components of the gut microbiota in obesity has extended to bacteria, which although weakly related to body weight in observational and human intervention studies, are of interest due to their use as probiotics.


Input: This review focuses exclusively on human observational studies and probiotic intervention trials, excluding animal studies and studies in infants at early developmental stages, since such results cannot be extrapolated to human obesity at later stages in life.


Input: In this context, evidence for relationships between the gut microbiota composition and obesity and the possible role of probiotics is reviewed, discussing the strengths and weaknesses of the studies conducted to date.


Input: Influence of experimental type 1 diabetes on the pulmonary effects of diesel exhaust particles in mice.


Input: Epidemiologically, exposure to particulate air pollution is associated with increases in morbidity and mortality, and diabetics are especially vulnerable to effects of particles.


Input: This study was carried out to determine the respiratory effect of diesel exhaust particles (DEP; 0. 4mg/kg) on mice rendered diabetic by the injection of streptozotocin or vehicle (control).

streptozotocin


Input: Four weeks following induction of diabetes, the animals were intratracheally instilled (i. t.) with DEP (0. 4mg/kg) or saline.


Input: 24h later, the measurement of airway reactivity to methacholine in vivo by a forced oscillation technique showed a significant and dose-dependent increase in airway resistance in non-diabetic mice exposed to DEP versus non-diabetic mice exposed to saline.

methacholine


Input: Similarly, the airway resistance was significantly increased in diabetic mice exposed to DEP versus diabetic mice exposed to saline.


Input: Nevertheless, there was no difference in the airway resistance between diabetic and non-diabetic mice after i. t. administration of DEP.


Input: Following DEP administration there were neutrophil polymorphs infiltration of pulmonary interalveolar septae and the alveolar spaces with many macrophages containing DEP in both diabetic and non-diabetic mice.


Input: Interestingly, apoptotic cells were only found in the examined lung sections from diabetic mice exposed to DEP.


Input: Total proteins and albumin concentrations in bronchoalveolar lavage (BAL) fluid, markers for increase of epithelial permeability, were significantly increased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice.


Input: Superoxide dismutase activity and reduced glutathione concentration in BAL were significantly decreased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice.

Superoxide


Input: Moreover, tumor necrosis factor alpha (TNF alpha) concentrations were significantly increased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice.


Input: We conclude that, at the dose and time point investigated, DEP equally increased airway resistance and caused infiltration of inflammatory cells in the lung of both diabetic and non-diabetic mice.


Input: However, the occurrence of oxidative stress, the presence lung apoptotic cells and the increase of total proteins, albumin and TNF alpha in BAL fluid were only seen in DEP-exposed diabetic mice suggesting an increased respiratory susceptibility to particulate air pollution.


Input: Iron oxide particles modulate the ovalbumin-induced Th2 immune response in mice.

Iron oxide


Input: This study was designed to investigate the modulatory effects of submicron and nanosized iron oxide (Fe (2) O (3)) particles on the ovalbumin (OVA)-induced immune Th2 response in BALB/c mice.

iron oxide

Fe (2) O (3)


Input: Particles were intratracheally administered four times to mice before and during the OVA sensitization period.


Input: For each particle type, three different doses, namely 4 x 100, 4 x 250 or 4 x 500 mu g/mouse, were used and for each dose, four groups of mice, i. e. group saline solution (1), OVA (2), particles (3), and OVA plus particles (4), were constituted.


Input: Mice exposed to OVA alone exhibited an allergic Th2-dominated response with a consistent increase in inflammatory scores, eosinophil numbers, specific IgE levels and IL-4 production.


Input: When the mice were exposed to OVA and to high and intermediate doses of iron oxide submicron-or nanoparticles, the OVA-induced allergic response was significantly inhibited, as evidenced by the decrease in eosinophil cell influx and specific IgE levels.

iron oxide


Input: However, the low dose (4 x 100 mu g) of submicron particles had no significant effect on the OVA allergic response while the same dose of nanoparticles had an adjuvant effect on the Th2 response to OVA.


Input: In conclusion, these data demonstrate that the pulmonary immune response to OVA is a sensitive target for intratracheally instilled particles.


Input: Depending on the particle dose and size, the allergic response was suppressed or enhanced.


Input: Mice heterozygous for AChE are more sensitive to AChE inhibitors but do not respond to BuChE inhibition.


Input: An impaired central cholinergic system is at least partly involved in Alzheimer' s disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses.


Input: AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain.


Input: The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity.


Input: In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold.

choline

choline


Input: We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BuChE) inhibition (bambuterol).

bambuterol


Input: HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil.

donepezil

physostigmine

glucose

donepezil


Input: Behavioural tests show comparable cognitive function in both mouse strains.


Input: Our results are discussed in relation to the use of AChE/BuChE inhibitors in AD patients.


Input: Decreased pain responses of C-C chemokine receptor 5 knockout mice to chemical or inflammatory stimuli.


Input: Chemokines are small chemotactic cytokines that elicit many physiological and pathological effects through binding to their corresponding receptors.


Input: Recent studies have suggested that C-C chemokine receptor (CCR) 5 interacts with mu-opioid receptor and modifies a nociceptive reaction.


Input: We examined effects of CCR5 deficiency on pain responses by employing CCR5 knockout (KO) mice.


Input: We found that pain responses of CCR5 KO mice to chemical or inflammation stimuli were milder than those of CCR5 wild type (WT) mice.


Input: However, there was no remarkable change in thermal nociception.


Input: To prove the involvement of CCR5 deletion in lowered nociception, we examined pain reactions with CCR5 WT mice following treatment of a CCR5 antagonist (D-Ala (1)-peptide T-NH (2,) DAPTA).

D-Ala (1)-peptide T-NH (2,) DAPTA


Input: Chemical or inflammatory pain behavior was significantly relieved by intracerebroventricular infusion of the inhibitor.


Input: When we assessed expression level of mu-opioid receptor (MOR) in the periaqueductal gray where the receptors are critical for analgesic effects, immunoreactivity of MOR was significantly higher in CCR5 KO mice than WT mice without change in phosphorylation level of the receptor.


Input: Reduced nociceptive responses in CCR5 KO mice were moderated by administration of naloxone and d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), MOR antagonists.

naloxone

CTAP


Input: Our data indicate that CCR5 deficiency is related to up-regulation of MOR without an increase in the receptor desensitization which might result in increased analgesic effects against chemical or inflammatory stimuli.


Input: Alternatively, higher amount of opioid ligands in CCR5 mice might be linked to these results.


Input: Therefore, CCR5 appears to be a therapeutic target for treatment of pain related diseases such as inflammatory hyperalgesia.


Input: First-principles simulation of the absorption bands of fluorenone in zeolite L.

fluorenone

zeolite L


Input: The absorption spectrum of fluorenone in zeolite L is calculated from first-principles simulations.

fluorenone

zeolite L


Input: The broadening of each band is obtained from the explicit treatment of the interactions between the chromophore and its environment in the statistical ensemble.


Input: The comparison between the simulated and measured spectra reveals the main factors affecting the spectrum of the chromophore in hydrated zeolite L.

zeolite L


Input: Whereas each distinguishable band is found to originate from a single electronic transition, the bandwidth is determined by the statistical nature of the environment of the fluorenone molecule.

fluorenone


Input: The K (+)... O = C motif is retained in all conformations.

K (+)

O = C


Input: Although the interactions between K (+) and the fluorenone carbonyl group result in an average lengthening of the C [double bond, length as m-dash] O bond and in a redshift of the lowest energy absorption band compared to gas phase or non-polar solvents, the magnitude of this shift is noticeably smaller than the total shift.

K (+)

fluorenone carbonyl

C

O


Input: An important factor affecting the shape of the band is fluorenone' s orientation, which is strongly affected by the presence of water.

fluorenone


Input: The effect of direct interactions between fluorenone and water is, however, negligible.

fluorenone


Input: Uptake and toxicity of polycyclic aromatic hydrocarbons in terrestrial springtails--studying bioconcentration kinetics and linking toxicity to chemical activity.

polycyclic aromatic hydrocarbons


Input: Passive dosing applies a polymer loaded with test compound (s) to establish and maintain constant exposure in laboratory experiments.


Input: Passive dosing with the silicone poly (dimethylsiloxane) was used to control exposure of the terrestrial springtail Folsomia candida to six polycyclic aromatic hydrocarbons (PAHs) in bioconcentration and toxicity experiments.

poly (dimethylsiloxane)

polycyclic aromatic hydrocarbons

PAHs


Input: Folsomia candida could move freely on the PAH-loaded silicone, resulting in exposure via air and direct contact.

PAH

silicone


Input: The bioconcentration kinetics indicated efficient uptake of naphthalene, anthracene, and pyrene through air and (near) equilibrium partitioning of these PAHs to lipids and possibly the waxy layer of the springtail cuticle.

naphthalene

anthracene

pyrene


Input: Toxicities of naphthalene, phenanthrene, and pyrene were related to chemical activity, which quantifies the energetic level and drives spontaneous processes including diffusive biouptake.

naphthalene

phenanthrene

pyrene


Input: Chemical activity-response relationships yielded effective lethal chemical activities (La50s) well within the expected range for baseline toxicity (0. 01-0. 1).


Input: Effective lethal body burdens for naphthalene and pyrene exceeded the expected range of 2 to 8 mmol kg (-1) fresh weight, which again indicated the waxy layer to be a sorbing phase.

naphthalene

pyrene


Input: Finally, chemical activities were converted into equilibrium partitioning concentrations in lipids yielding effective lethal concentrations for naphthalene and phenanthrene in good correspondence with the lethal membrane burden for baseline toxicity (40-160 mmol kg (-1) lipid).

naphthalene

phenanthrene


Input: Passive dosing was a practical approach for tightly controlling PAH exposure, which in turn provided new experimental possibilities and findings.


Input: Gamma-radiation induced formation of chromium oxide nanoparticles from dissolved dichromate.

chromium oxide

dichromate


Input: The formation of chromium oxide nanoparticles by gamma radiolysis of Cr (VI) (CrO (4) (2-) or Cr (2) O (7) (2-)) solutions was investigated as a function of pH and initial Cr (VI) concentration by measuring [Cr (VI)], the particle concentration ([Cr (III) (col)]) and [H (2)], and by characterizing the particles using TEM, Raman, FTIR and XPS.

chromium oxide

Cr (VI)

CrO (4) (2-)

Cr (2) O (7) (2-)

Cr (VI)

Cr (VI)

Cr (III)

H (2)


Input: The results show that Cr (VI) is easily reduced to Cr (III) by a homogeneous aqueous reaction with. e (aq) (-), but, due to the stability of Cr (III) colloids, the growth of the Cr (OH) (3) particles is very slow.

Cr (VI)

Cr (III)

Cr (III)

Cr (OH) (3)


Input: As the particles grow the interior of the particle dehydrates to form Cr (2) O (3) while the outer layer remains hydrated.

Cr (2) O (3


Input: When most of the Cr (VI) that is initially present in the solution is converted to Cr (OH) (3) further redox reactions of chromium species occur on the particle surfaces.

Cr (VI)

Cr (OH) (3)

chromium


Input: The redox system reaches a pseudo-equilibrium state due to cyclic reactions of Cr (III) with. OH and H (2) O (2), and reactions of Cr (VI) with. e (aq) (-) and H (2) O (2).

Cr (III)

OH

H (2) O (2)

Cr (VI)

H (2) O (2)


Input: The size distribution of the particles that are formed is controlled by these solution-solid interface reactions.


Input: Assessing causation of the extirpation of stream macroinvertebrates by a mixture of ions.


Input: Increased ionic concentrations are associated with the impairment of benthic invertebrate assemblages.


Input: However, the causal nature of that relationship must be demonstrated so that it can be used to derive a benchmark for conductivity.


Input: The available evidence is organized in terms of six characteristics of causation: co-occurrence, preceding causation, interaction, alteration, sufficiency, and time order.


Input: The inferential approach is to weight the lines of evidence using a consistent scoring system, weigh the evidence for each causal characteristic, and then assess the body of evidence.


Input: Through this assessment, the authors found that a mixture containing the ions Ca (+), Mg (+), HCO 3 (-), and SO 4 (-), as measured by conductivity, is a common cause of extirpation of aquatic macroinvertebrates in Appalachia where surface coal mining is prevalent.

Ca (+)

Mg (+)

HCO 3 (-)

SO 4 (-)

coal


Input: The mixture of ions is implicated as the cause rather than any individual constituent of the mixture.


Input: The authors also expect that ionic concentrations sufficient to cause extirpations would occur with a similar salt mixture containing predominately HCO 3 (-), SO 4 (2-), Ca (2 +), and Mg (2 +) in other regions with naturally low conductivity.

HCO 3 (-)

SO 4 (2-)

Ca (2 +)

Mg (2 +)


Input: This case demonstrates the utility of the method for determining whether relationships identified in the field are causal.


Input: Experimental exposure of eggs to polybrominated diphenyl ethers BDE-47 and BDE-99 in red-eared sliders (Trachemys scripta elegans) and snapping turtles (Chelydra serpentina) and possible species-specific differences in debromination.

polybrominated diphenyl ethers BDE-47


Input: Polybrominated diphenyl ethers (PBDEs) are a bioaccumulative, persistent, and toxic class of flame retardants that can potentially impact turtles in natural habitats via exposure through maternal transfer.

Polybrominated diphenyl ethers

PBDEs


Input: To simulate maternal transfer in the present study, PBDE congeners BDE-47 and BDE-99 were topically applied to the eggshell and were allowed to diffuse into the egg contents of the red-eared slider (Trachemys scripta elegans) and snapping turtle (Chelydra serpentina).

PBDE


Input: Eggs were topically dosed over 8 d to achieve a target concentration of 40 ng/g in the egg contents.


Input: Transfer efficiency was higher for BDE-47 than for BDE-99 in the red-eared sliders (25. 8 +/- 1. 9% vs 9. 9 +/- 1. 1%) and snapping turtles (31. 3 +/- 1. 6% vs 12. 5 +/- 1. 4%), resulting in greater BDE-47 and lower BDE-99 egg content concentrations relative to the 40 ng/g target.


Input: However, only 25. 8 and 31. 3% of the total BDE-47 and 9. 9 and 12. 5% of the total BDE-99 dose applied could be accounted for in the red-eared slider and snapping turtle egg contents, respectively.


Input: Additionally, increased BDE-47 in red-eared slider egg contents dosed with only BDE-99 indicate that BDE-99 might have been debrominated to BDE-47.


Input: The efficacy of topical dosing for administering desired embryonic exposures is clearly affected by the chemical properties of the applied compounds and was more successful for BDE-47 in both species.


Input: Gs-coupled adenosine receptors differentially limit antigen-induced mast cell activation.

adenosine


Input: Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes.


Input: Allergen-induced mast cell activation is central to the pathogenesis of asthma and other allergic diseases.


Input: Presently, most pharmacological agents for the treatment of allergic disease target receptors for inflammatory mediators.


Input: Many of these mediators, such as histamine, are released by mast cells.

histamine


Input: Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell.


Input: In vitro studies using cultured human and mouse mast cells, and studies of mice lacking A (2B) receptors, suggest that adenosine receptors, specifically the G (s)-coupled A (2A) and A (2B) receptors, might provide such a target.

adenosine


Input: Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo.

adenosine

adenosine


Input: We identify A (2B) as the primary receptor limiting mast cell degranulation, whereas the combined activity of A (2A) and A (2B) is required for the inhibition of cytokine synthesis.


Input: QT dispersion in patients with acromegaly.


Input: Acromegaly is a rare condition caused by a pituitary adenoma that secretes growth hormone.


Input: The mortality rate is 72% higher in patients with acromegaly than in the general population according to meta-analyses.


Input: Mortality analysis has shown as many as 60% of acromegalic patients die due to cardiovascular disease.


Input: Sudden cardiac death may occur in patients with acromegaly and malignant ventricular arrhythmia may play an important role in this fatal complication; however, the precise mechanism is not fully known.


Input: QT dispersion (dQT) is an electrophysiological factor known to be associated with a tendency for ventricular arrhythmia and sudden cardiac death.


Input: This study aimed to evaluate dQT as an early predictor of ventricular tachyarrhythmia, as sudden cardiac death commonly occurs in acromegalic patients.


Input: This cross-sectional case-control study enrolled 20 patients (10 female and 10 male) with acromegaly and 20 healthy controls (11 female and 9 male) after exclusion criteria were applied.


Input: Each participant underwent 12-lead electrocardiography, including >= 3 QRS complexes, at a speed of 25 mm/s after a 15-min rest.


Input: In each participant, the QT interval (beginning of the Q wave to the end of the T wave) was corrected (QTc) for heart rate using Bazett' s formula [Formula: see text] QTc dispersion (dQTc) (QTc max-QTc min) was also calculated.


Input: There was no significant difference in median dQTc between the acromegalic patients (0. 79 s) and the controls (0. 45 s) (p > 0. 05).


Input: Active acromegalic patients (n = 14) were estimated to have a median dQTc of 0. 82 s, after excluding from the analysis six patients that were under full biochemical control, and that had randomly obtained growth hormone levels < 0. 4 ng/mL, GH < 1 ng/mL based on oral glucose tolerance test, and normal IGF-I for age and gender.

glucose


Input: A significant difference was noted in median dQTc between the active acromegalic patients and the controls (p = 0. 015).


Input: The dQT in active acromegalic patients was longer than that in the control group, which indicates that patients with active acromegaly might have an elevated risk for ventricular arrhythmia.


Input: We think that a non-invasive, simple and inexpensive marker-measurement of dQT-as part of cardiac monitoring could be valuable for screening complications in acromegalic patients.


Input: Longitudinal cystic fibrosis care.


Input: Cystic fibrosis is a complex disease entity that presents considerable lifelong challenges.


Input: Implementation of medical and surgical treatment options involves multisystem interventions to prevent and treat lung and gastrointestinal manifestations of cystic fibrosis and associated comorbidities.


Input: From birth through adulthood, cystic fibrosis care entails a longitudinal regimen aimed at achieving relief of disease symptoms and enhanced life expectancy.


Input: With increased knowledge of the molecular behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) in health and disease, clinical practice has been enriched by the prospect of novel strategies, including mutation-specific drug and gene therapy targeting restoration of corrupted transepithelial ion transport.


Input: Emerging paradigms of comprehensive care increasingly enable personalized solutions to address the root cause of disease-transforming management options for individuals with cystic fibrosis.


Input: Maternal and fetal exposure to bisphenol a is associated with alterations of thyroid function in pregnant ewes and their newborn lambs.

bisphenol a


Input: The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human.

bisphenol A

BPA


Input: The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption.

BPA

BPA-glucuronide


Input: Ewes were treated with BPA [5 mg/(kg. d) sc] or vehicle from d 28 until the end of pregnancy.

BPA


Input: Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0. 13 +/- 0. 02 and 0. 18 +/- 0. 03 nmol/ml in cord and maternal blood, respectively).

BPA


Input: In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA.

BPA-Gluc

BPA


Input: Total T (4) concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease).

BPA


Input: A similar difference was observed for free T (4) plasma concentrations in the jugular blood of the newborns.


Input: Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns.

BPA


Input: If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment.

BPA


Input: Molecular modeling and simulation of membrane lipid-mediated effects on GPCRs.


Input: Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding of the modulation of GPCR by membrane lipids is not available.


Input: However, specific receptor-lipid interactions as well as unspecific effects mediated by the bulk properties of the membrane (thickness, curvature, etc.) have been proposed to be key regulators of GPCR modulation.


Input: In this review, we examine computational efforts made towards modeling and simulation of (i) the complex behavior of membrane lipids, (ii) membrane lipid-GPCR interactions as well as membrane lipid-mediated effects on GPCRs and (iii) GPCR oligomerization in a native-like membrane environment.


Input: We propose that, from the perspective of computational modeling, all three of these components need to be addressed in order to achieve a deeper understanding of GPCR functioning.


Input: Presently, we are able to simulate numerous lipid properties applying advanced computational techniques, although some barriers, such as the time-length of these simulations, need to be overcome.


Input: Implementing three-dimensional structures of GPCRs in such validated membrane systems can give novel insights in membrane-dependent receptor modulation and formation of higher order receptor complexes.


Input: Finally, more realistic GPCR-membrane models would provide a very useful tool in studying receptor behavior and its modulation by small drug-like ligands, a relevant issue for drug discovery.


Input: Metabotropic purinergic receptors in lipid membrane microdomains.


Input: There is broad evidence that association of transmembrane receptors and signalling molecules with lipid rafts/caveolae provides an enriched environment for protein-protein interactions necessary for signal transduction, and a mechanism for the modulation of neurotransmitter and/or growth factor receptor function.


Input: Several receptors translocate into submembrane compartments after ligand binding, while others move in the opposite direction.


Input: The role of such a dynamic localization and functional facilitation is signalling modulation and receptor desensitization or internalization.


Input: Purine and pyrimidine nucleotides have been viewed as primordial precursors in the evolution of all forms of intercellular communication, and they are now regarded as fundamental extracellular signalling molecules.

Purine

pyrimidine nucleotides


Input: They propagate the purinergic signalling by binding to ionotropic and metabotropic receptors expressed on the plasma membrane of almost all cell types, tissues and organs.


Input: Here, we have illustrated the localization in lipid rafts/caveolae of G protein-coupled P1 receptors for adenosine and P2Y receptors for nucleoside tri-and di-phosphates.

adenosine

nucleoside tri-and di-phosphates


Input: We have highlighted that microdomain partitioning of these purinergic GPCRs is cell-specific, as is the overall expression levels of these same receptors.


Input: Moreover, we have described that disruption of submembrane compartments can shift the purinergic receptors from raft/caveolar to non-raft/non-caveolar fractions, and then abolish their ability to activate lipid signalling pathways and to integrate with additional lipid-controlled signalling events.


Input: This modulates the biological response to purinergic ligands and most of all indicates that the topology of the various purinergic components at the cell surface not only organizes the signal transduction machinery, but also controls the final cellular response.


Input: Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity.


Input: An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their alpha-helical conformation, for example, stabilized BimBH3 peptides (BimSAHB) designed to induce apoptosis.


Input: Unexpectedly, we found that such modified peptides have reduced affinity for their targets, the pro-survival Bcl-2 proteins.


Input: We attribute this loss in affinity to disruption of a network of stabilizing intramolecular interactions present in the bound state of the native peptide.


Input: Altering this network may compromise binding affinity, as in the case of the BimBH3 stapled peptide studied here.


Input: Moreover, cells exposed to these peptides do not readily undergo apoptosis, strongly indicating that BimSAHB is not inherently cell permeable.


Input: Effect of Australian elapid venoms on blood coagulation: Australian Snakebite Project (ASP-17).


Input: Snake venoms contain toxins that activate the coagulation network and cause venom-induced consumption coagulopathy.


Input: A previously developed mathematical model of the coagulation network was refined and used to describe and predict the time course of changes in the coagulation factors following envenomation by Brown snake (Pseudonaja spp.), Tiger snake (Notechis scutatus), Rough-scaled snake (Tropidechis carinatus) and Hoplocephalus spp.


Input: (Stephens banded, Pale headed and Broad headed).


Input: Simulations of the time course of the change in coagulation factors were compared to data obtained from a large prospective study of Australian snake bites-the Australian Snakebite Project.


Input: The model predictions were also compared against data for partial and complete VICC obtained from the same study.


Input: The model simulations were used to understand the differences in consumption and recovery of clotting factors in partial versus complete VICC as well as among bites from different snake types.


Input: The model suggested that the venoms were absorbed almost instantaneously and provided a reasonable prediction of the observed concentration of clotting factors over time in patients bitten by Australian elapid snakes.


Input: The model predictions suggested a higher consumption of factors (fibrinogen, II and IX in particular) in patients with complete VICC compared to those with partial VICC.


Input: The model also predicted that snakes with " Xa-like " venoms may produce a less severe VICC than snakes with " Xa: Va-like " venoms.


Input: One hundred years of helicene chemistry.

helicene


Input: Part 2: stereoselective syntheses and chiral separations of carbohelicenes.

carbohelicenes


Input: Carbohelicenes generally incorporate a helical, distorted, conjugated, polyaromatic system with ortho-fused benzenoid rings, which is a fundamental molecular characteristic of this class of compounds.

Carbohelicenes

benzenoid


Input: They have been described as " molecules in distress " due to their distortion.


Input: The generation of a chiral helicity in helicenes was observed because of a severe intramolecular steric strain.

helicenes


Input: Helicity is a molecular necessity in the higher series of carbohelicenes, when at some point, a helical pitch occurs when a second coil is formed.

carbohelicenes


Input: The most interesting properties resulting from such molecular distortion are the very high chiroptical and circular dichroism values.


Input: For instance, the resolution of some helicene racemates by " hand picking " of a few homochiral single enantiomeric crystals allowed for a measurement of their optical rotation.

helicene


Input: Due to that intrinsic chirality spanned over a large polyaromatic template, preliminary results clearly established the efficiency of carbohelicenes to induce asymmetry and chirality in organic synthesis and in supramolecular chemistry.

carbohelicenes


Input: Additionally, they have some potential uses in several fields: materials science, nanoscience, chemical biology and supramolecular chemistry.


Input: It has encouraged many attempts to develop new asymmetric syntheses of carbohelicenes, as well as some chiral separations of enantiomers and diastereoisomers.

carbohelicenes


Input: This review is thus dedicated to carbohelicene chirality.

carbohelicene


Input: It gathered a substantial collection of data, and a comprehensive review on the preparations of enantioenriched helicenes, either from an asymmetric synthesis or from a chiral separation.

helicenes


Input: Utilizations of non-racemic helicenes and their applications will be treated in the following review (Part 3), and will not be the subject of this manuscript.

helicenes


Input: Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test.

oleanolic acid


Input: The study aimed to explore the antidepressant-like effect of oleanolic acid and its possible mechanism related to the monoaminergic system and neurotrophin in mice exposed to the repeated forced swimming test (FST).

oleanolic acid


Input: Both the duration and the latency of immobility affected by oleanolic acid (10, 20 and 40 mg/kg) were evaluated in the FST repeated at intervals on days 1, 7 and 14, followed by neurochemical and brain-derived neurotrophic factor (BDNF) analyses in the mouse brain regions of frontal cortex and whole hippocampus.

oleanolic acid


Input: A repeated analysis of variance (ANOVA) indicated that over retesting the immobility time increased, whereas latency to immobility tended to decrease.


Input: Minute-by-minute analysis showed that immobility time also increased during the 4-min course of the test.


Input: In addition, post-hoc Dunnett' s test demonstrated that sub-chronic and chronic, but not acute, oleanolic acid treatment reduced the immobility time (sub-chronic: 20 mg/kg, 43. 5%; chronic: 10 mg/kg, 19. 3%; 20 mg/kg, 31. 8%) and increased the latency to immobility (sub-chronic: 10 mg/kg, 60. 6%; 20 mg/kg, 80. 1%; chronic: 10 mg/kg, 121. 8%; 20 mg/kg, 140. 8%; 40 mg/kg, 80. 0%).

oleanolic acid


Input: Furthermore, chronic administration of oleanolic acid significantly increased serotonin (5-HT) levels (frontal cortex: 44. 5%, 41. 9%, 27. 5% for 10, 20, 40 mg/kg; hippocampus: 57. 2%, 80. 9% for 10, 20 mg/kg), decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio (frontal cortex: 31. 6%, 30. 1%, 23. 5%; hippocampus: 40. 6%, 47. 7%, 29. 2% for 10, 20, 40 mg/kg) and elevated norepinephrine (NE) levels (hippocampus: 20 mg/kg, 45. 4%) but did not alter dopamine (DA) levels.

oleanolic acid

serotonin

5-hydroxyindoleacetic acid

norepinephrine

dopamine


Input: Moreover, BDNF levels in the two brain regions were also elevated by chronic oleanolic acid treatment (frontal cortex: 20 mg/kg, 67. 2%; hippocampus: 10 mg/kg, 36. 4%; 20 mg/kg, 55. 1%).

oleanolic acid


Input: Taken together, these findings imply that functions of 5-HT, NE and BDNF may be involved in the antidepressant-like effect of oleanolic acid.

oleanolic acid


Input: A review of anti-inflammatory agents for symptoms of schizophrenia.


Input: Schizophrenia is a chronic debilitating mental disorder that affects about 1% of the US population.


Input: The pathophysiology and etiology remain unknown, thus new treatment targets have been challenging and few novel treatments with new mechanisms of action have come to market in the past few decades.


Input: Increasing attention has been paid to the role of inflammation in schizophrenia and new data suggests that decreasing inflammation and inflammatory biomarkers may play some role in schizophrenia treatment.


Input: This review summarizes the clinical trial literature regarding medications that possess anti-inflammatory properties that have been tested for schizophrenia symptoms and covers such medications as non-steroidal anti-inflammatory agents, such as the cyclo-oxygenase-2 (COX-2) inhibitors and aspirin, omega-3 fatty acids, neurosteroids and minocycline.

steroidal

aspirin

omega-3 fatty acids

neurosteroids

minocycline


Input: Overall, there is accumulating evidence, albeit mostly adjunctive treatments, that agents working on inflammatory pathways have some benefits in people with schizophrenia.


Input: In the next few years the field will begin to see data on many treatments with anti-inflammatory properties that are currently under study.


Input: Hopefully advancements in understanding inflammation and effective treatments having anti-inflammatory properties may help revolutionize our understanding and provide new targets for prevention and treatment in schizophrenia.


Input: Arsenic activates endothelin-1 Gi protein-coupled receptor signaling to inhibit stem cell differentiation in adipogenesis.

Arsenic


Input: Dysfunctional lipid and glucose metabolism contribute to metabolic syndrome-a major public health concern that enhances cardiovascular disease risk.

glucose


Input: Arsenic (As (III)) exposure may increase metabolic syndrome and cardiovascular disease risk by impairing adipose tissue differentiation, function, and insulin sensitivity through pathogenic mechanisms that remain unclear.

Arsenic

As (III)


Input: We hypothesized that As (III) signals through the Pertussis toxin (Ptx) sensitive, Gi protein-coupled receptor (GPCR) to impair adipogenesis, as previously demonstrated for its stimulation of vascular oxidant generation, angiogenesis, and remodeling.

As (III)


Input: Because both As (III) and GPCR ligands inhibit progenitor cell differentiation into adipocytes, we investigated the hypothesis in a model of low-passage human mesenchymal stem cells (hMSC).

As (III)


Input: As (III) (0. 1-1. 0 micro M) suppressed dexamethasone/insulin-induced hMSC adipogenesis, as indicated by decreased transcriptional promoters of differentiation, decreased fat droplet formation, and decreased expression of differentiated adipocyte markers, such as adiponectin and perilipin.

As (III)

dexamethasone


Input: Preincubating hMSC with Ptx prevented 90% of the suppressive effect of As (III).

As (III)


Input: Selective competitive antagonists of Gi-coupled endothelin-1 type A and B receptors were ~ 60% effective in blocking As (III) inhibition and combination of antagonists to both receptors were 85% effective.

As (III)


Input: In contrast, antagonists to the sphingosine-1-phosphate type 1 receptor (previously shown to mediate As (III) vascular effects) or the angiotensin II type 1 receptor were ineffective in blocking As (III) effects.

As (III)

As (III)


Input: These studies suggest a majority of arsenic-inhibited adipocyte differentiation, and metabolism requires endothelin-1 GPCRs and that As (III) effects on GPCR signaling are tissue and context specific.

arsenic

As (III)


Input: This may represent a significant mechanism for the contribution of arsenic exposure to increased metabolic and cardiovascular diseases.

arsenic


Input: The progesterone positive feedback effect in women after ovariectomy.

progesterone


Input: Various ovarian substances regulate the secretion of gonadotrophins during the menstrual cycle, but there are still several unclarified issues.


Input: The aim of this study was to investigate the positive feedback effect of progesterone during the immediate period following ovariectomy.

progesterone


Input: Experiments were performed in 12 normally cycling women (aged 39-49 years).


Input: Following abdominal hysterectomy plus bilateral ovariectomy performed on cycle day 3 (day 0), the women received either estradiol via skin patches (days 0-7, n = 6, group 1) or estradiol as above plus vaginal progesterone (days 1-7, n = 6, group 2).

estradiol

estradiol


Input: Serum estradiol values increased similarly in the two groups.

estradiol


Input: After the operation, serum progesterone levels decreased significantly in group 1, while in group 2 they remained stable becoming higher than in group 1 (p < 0. 05).

progesterone


Input: An LH and an FSH surge occurred in group 2 with the values after the peak returning to the pre-surge baseline.


Input: In contrast, in group 1 LH and FSH levels following an initial decrease, increased gradually until the end of the experiment.


Input: These results demonstrate that, despite a variable response to estrogens, the positive feedback effect of progesterone remained intact immediately after ovariectomy in women.

estrogens

progesterone


Input: It is suggested that it is the combining action of estradiol and progesterone that can ensure the expression of a positive feedback mechanism in women.

estradiol

progesterone


Input: A new approach to predicting human hepatic clearance of CYP3A4 substrates using monkey pharmacokinetic data.


Input: Focusing on the genetic similarity of CYP3A subfamily enzymes (CYP3A4 and CYP3A5) between monkeys and humans, we have attempted to provide a single-species approach to predicting human hepatic clearance (CLh) of CYP3A4 substrates using pharmacokinetic parameters in cynomolgus monkeys following intravenous administrations.


Input: Hepatic intrinsic clearance (CLint, h) of six CYP3A4 substrates (alprazolam, clonazepam, diltiazem, midazolam, nifedipine, and quinidine), covering a wide range of clearance, in monkeys correlated well with that cited in literature for humans (R = 0. 90) with a simple equation of Y = 0. 165X (Y: human CLint, h, X: monkey CLint, h, represented in mL/min/kg).

alprazolam

clonazepam

diltiazem

midazolam

nifedipine

quinidine


Input: To verify the predictability of human CLint, h, monkey CLint, h of a test set of CYP3A4 substrates cited in literature (dexamethasone, nifedipine, midazolam, quinidine, tacrolimus, and verapamil) was applied to the equation and human CLint, h was calculated.

dexamethasone

nifedipine

midazolam

quinidine

tacrolimus

verapamil


Input: The human CLint, h of all the substrates was predicted within 3-fold error (fold error: 0. 35-2. 77).


Input: The predictability of human CLh by our method was superior to common in vivo prediction methods (allometry and liver blood flow method).


Input: These results suggest that human hepatic clearance of CYP3A4 substrates can be predicted by applying cynomolgus monkey CLint, h obtained following intravenous administrations in each laboratory to the simple equation.


Input: Assessment of cytochrome P450 (1A2, 2B6, 2C9 and 3A4) induction in cryopreserved human hepatocytes cultured in 48-well plates using the cocktail strategy.


Input: 1. A fast, straightforward and cost-effective assay was validated for the assessment of CYP induction in cryopreserved human hepatocytes cultured in 48-well plates.


Input: The cocktail strategy (in situ incubation) was used to assess the induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 by using the recommended probe substrate, i. e. phenacetin, bupropion, diclofenac and midazolam, respectively.

phenacetin

bupropion

diclofenac

midazolam


Input: 2. Cryopreserved human hepatocytes were treated for 72 h with prototypical reference inducers, beta-naphthoflavone (25 micro M), phenobarbital (500 micro M) and rifampicin (10 micro M) as positive controls for CYP induction.

beta-naphthoflavone

phenobarbital

rifampicin


Input: The use of a cocktail strategy has been validated and compared to the classical approach (single incubation).


Input: The need of using phase II inhibitor (salicylamide) in CYP induction assay was also investigated.

salicylamide


Input: 3. By using three different batches of cryopreserved human hepatocytes and our conditions of incubations, we showed that there was no relevant drug-drug interaction using the cocktail strategy.


Input: The same conclusions were observed when a broad range of enzyme activity has to be assessed (wide range of reference inducers, i. e. EC50-Emax experiment).


Input: In addition, the interassay reproducibility assessment showed that the day-to-day variability was minimal.


Input: 4. In summary, the study showed that the conditions used (probe substrates, concentration of probe substrate and time of incubation) for the cocktail approach were appropriate for investigations of CYP induction potential of new chemical entities.


Input: In addition, it was also clear that the use of salicylamide in the incubation media was not mandatory and could generate drug-drug interactions.

salicylamide


Input: For this reason, we recommend to not use salicylamide in CYP induction assay.

salicylamide


Input: Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre-and postablation scintigraphies and their relation to xerostomia symptoms.

radioactive iodine


Input: Background: Chronic sialadenitis is one of the most frequent chronic complications after radioactive iodine (RAI) therapy for thyroid cancer.

radioactive iodine

RAI


Input: To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGSs) taken before and at 5 years after an RAI ablation.

RAI

RAI


Input: Methods: SGS was performed just before RAI ablation (pre-SGS) and ~ 5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer.

RAI

RAI


Input: The uptake score (U score) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS.


Input: Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in U score and EF between the two SGSs.


Input: Xerostomia was assessed and compared with the SGS findings.


Input: Results: Worsening of the U score was observed in 182 of 852 salivary glands (total: 21. 3%; mild: 4. 2%, moderate: 7. 4%, severe: 9. 7%), and 47. 4% of the patients had a worsening U score for at least one of four salivary glands.


Input: A decrease in EF was observed in 173 of 852 salivary glands (total: 20. 3%; mild: 5. 4%, moderate: 6. 8%, severe: 8. 1%), and 43. 7% of the patients experienced a decrease in the EF of at least one of the four salivary glands.


Input: Bilateral parotid gland dysfunction was the most commonly observed condition.


Input: Thirty-five (16. 4%) patients complained of xerostomia at 5 years after RAI ablation.

RAI


Input: Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5. 55 GBq, compared with 3. 7 GBq.


Input: Xerostomia was more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68. 8% vs. 33. 3%, p < 0. 05).


Input: The number of dysfunctional salivary glands was correlated with xerostomia (p < 0. 01).


Input: Conclusion: About 20% of the salivary glands were dysfunctional on SGS 5 years after a single RAI ablation, especially in patients who received higher doses of RAI.

RAI

RAI


Input: While parotid glands are more susceptible to (131) I-related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands.


Input: IFN alpha converts IL-22 into a cytokine efficiently activating STAT1 and its downstream targets.


Input: Besides their antiviral activity, type I Interferons (IFN) display context-specific immunomodulation.


Input: In contrast to long-known IFN alpha/beta, Interleukin (IL)-22 is an anti-bacterial, largely tissue protective cytokine that recently gained attention.


Input: Herein, cellular IFN alpha/IL-22 interactions are investigated.


Input: We report that pre-conditioning of epithelial cells with IFN alpha initiated dramatic changes in IL-22 signaling normally dominated by signal transducer and activator of transcription (STAT)-3.


Input: Specifically, by using human DLD1 colon epithelial/carcinoma cells we demonstrate that, upon IFN alpha, IL-22 converts into a cytokine robustly activating STAT1 and its downstream pro-inflammatory targets CXCL9, CXCL10, and inducible nitric oxide synthase (iNOS).

nitric oxide


Input: Accordingly, only after IFN alpha pre-incubation was IL-22-induced STAT1 binding to the CXCL10 promoter detectable.


Input: Using the viral mimic polyinosinic: polycytidylic acid and the IFN alpha/beta antagonist B18R we furthermore demonstrate the capability of endogenous IFN to promote IL-22-induced STAT1 activation and expression of CXCL10.

polyinosinic: polycytidylic acid


Input: IL-22-induced STAT1 activation subsequent to IFN alpha priming became likewise apparent in human Caco2 colon epithelial/carcinoma cells, HepG2 hepatoma cells, and primary keratinocytes.


Input: Current observations may relate to characteristics of IFN alpha/beta in clinical therapy and expose margins of tissue protection by IL-22 application.


Input: Proposed model for in vitro interaction between fenitrothion and DNA, by using competitive fluorescence, (31) P NMR, (1) H NMR, FT-IR, CD and molecular modeling.

fenitrothion

(31) P

(1) H


Input: In this work we proposed a model for in vitro interaction of fenitrothion (FEN) with calf thymus-DNA by combination of multispectroscopic and two dimensional molecular modeling (ONIOM) methods.

fenitrothion

FEN


Input: The circular dichroism results showed that FEN changes the conformation of B-DNA and caused some changes to C-DNA form.

FEN


Input: The FT-IR results confirmed a partial intercalation between FEN and edges of all base pairs.

FEN


Input: The competitive fluorescence, using methylene blue as fluorescence probe, in the presence of increasing amounts of FEN, revealed that FEN is able to release the non-intercalated methylene blue from the DNA.

methylene blue

FEN

FEN

methylene blue


Input: The weak chemical shift and peak broadening of (1) H NMR spectrum of FEN in the presence of DNA confirmed a non-intercalation mode.

(1) H

FEN


Input: The (31) P NMR showed that FEN interacts more with DNA via its-NO2 moiety.

(31) P

FEN


Input: The ONIOM, based on the hybridization of QM/MM (DFT, 6. 31 + + G (d, p)/UFF) methodology, was also performed by Gaussian 2003 package.


Input: The results revealed that the interaction is base sequence dependent, and FEN interacts more with AT base sequences.

FEN


Input: Three-dimensional imaging of collagen fibril organization in rat circumferential lamellar bone using a dual beam electron microscope reveals ordered and disordered sub-lamellar structures.


Input: Lamellar bone is a major component of most mammalian skeletons.


Input: A prominent component of individual lamellae are parallel arrays of mineralized type I collagen fibrils, organized in a plywood like motif.


Input: Here we use a dual beam microscope and the serial surface view (SSV) method to investigate the three dimensional collagen organization of circumferential lamellar bone from rat tibiae after demineralization and osmium staining.


Input: Fast Fourier transform analysis is used to quantitatively identify the mean collagen array orientations and local collagen fibril dispersion.


Input: Based on collagen fibril array orientations and variations in fibril dispersion, we identify 3 distinct sub-lamellar structural motifs: a plywood-like fanning sub-lamella, a unidirectional sub-lamella and a disordered sub-lamella.


Input: We also show that the disordered sub-lamella is less mineralized than the other sub-lamellae.


Input: The hubs and junctions of the canalicular network, which connect radially oriented canaliculi, are intimately associated with the disordered sub-lamella.


Input: We also note considerable variations in the proportions of these 3 sub-lamellar structural elements among different lamellae.


Input: This new application of Serial Surface View opens the way to quantitatively compare lamellar bone from different sources, and to clarify the 3-dimensional structures of other bone types, as well as other biological structural materials.


Input: Modulation of the cellular redox status by the Alternaria toxins alternariol and alternariol monomethyl ether.

alternariol

alternariol monomethyl ether


Input: The mycotoxin alternariol (AOH) has been reported to possess genotoxic properties, inducing enhanced levels of DNA damage after only 1 h of incubation.

alternariol

AOH


Input: In the present study we addressed the question whether the induction of oxidative stress might contribute to the genotoxic effects of AOH or its naturally occurring monomethylether (AME).

AOH

monomethylether

AME


Input: In the dichlorofluorescein (DCF) assay, treatment of HT29 cells for 1 h enhanced the formation of dichlorofluorescein, indicative for ROS formation.

dichlorofluorescein

DCF

dichlorofluorescein


Input: The total glutathione (tGSH) was transiently decreased.

glutathione


Input: In accordance with the results of the DCF assay, AOH and AME enhanced the proportion of the transcription factor Nrf2 in the nucleus.

DCF

AOH

AME


Input: Concomitantly, the Nrf2/ARE-dependent genes gamma-glutamylcysteine ligase (gamma-GCL) and glutathione-S-transferase (GSTA1/2) showed enhanced transcript levels.

gamma-glutamylcysteine

glutathione

S


Input: After 24 h of incubation this effect was also reflected on the protein level by an increase of GST activity.


Input: However, in spite of the positive DCF assay and the activation of the redox-sensitive Nrf2/ARE-pathway, the level of oxidative DNA damage, measured in the comet assay by the addition of formamidopyrimidine-DNA-glycosylase (fpg) remained unaffected.

DCF

formamidopyrimidine


Input: Of note, after 3 h of incubation no significant DNA damaging potential of AOH and AME was detectable, indicating either inactivation of the compounds or enhanced DNA repair.

AOH

AME


Input: In summary, the mycotoxins AOH and AME were found to modulate the redox balance of HT29 cells but without apparent negative effect on DNA integrity.

AOH

AME


Input: Sensory gating, Cannabinoids and Schizophrenia.


Input: Sensory gating, a mandatory process in early information processing, has been found to be defective in neuropsychiatric diseases such as schizophrenia.


Input: Understanding the neurobiology of sensory gating may provide insight into unravelling the neurobiology of information processing and to yet unanswered queries on the pathophysiology of disabling neuropsychiatric diseases.


Input: The endocannabinoid system has been linked to the pathophysiology of schizophrenia.


Input: Furthermore, cannabinoids disrupt sensory gating in animals and humans which supports the hypothesis that the disruption of sensory gating by alterations in the endocannabinoid system is a significant factor in the etiology of schizophrenia.


Input: Based on the above hypothesis this article reviews the sensory gating process in relation to the auditory conditioning-test paradigm with an emphasis on its association with the endocannabinoid system and schizophrenia.


Input: Synthesis of novel indole hydrazone derivatives and evaluation of their antiplatelet aggregation activity.

indole hydrazone


Input: Based on the existing reports regarding the antiplatelet aggregation activity of hydrazone derivatives, a series of indole hydrazone derivatives were considered as potential antiplatelet agents and synthesized.

hydrazone

indole hydrazone


Input: The structures of the synthesized compounds were confirmed by spectral data and elemental analysis.


Input: The new indole hydrazone derivatives were evaluated for their ability to inhibit platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA).

indole hydrazone

adenosine diphosphate

ADP

arachidonic acid


Input: Compounds 1h and 3h exhibited remarkable activity against arachidonic acid induced platelet aggregation with IC (50) values comparable to that of indomethacin and compound 1i efficiently inhibited platelet aggregation induced by both ADP and AA.

arachidonic acid

indomethacin

ADP


Input: Applications of asymmetric organocatalysis in medicinal chemistry.


Input: In the last decade, organocatalysis, the use of small chiral organic molecules as catalysts, has proven to be a valuable and attractive tool for the synthesis of enantiomerically enriched molecules.


Input: A number of organocatalysts and processes, such as one-pot, tandem, cascade or multicomponent reactions, have been reported to date.


Input: Furthermore, the many advantages of organocatalysis-robust, non-toxic, affordable, inert atmosphere, easy reaction manipulation, etc.


Input: -allow the preparation of bioactive compounds using simple and metal-free procedures, thus avoiding false positives in the biological evaluation.


Input: This mini-review focuses on medicinal chemistry programs that have synthesized biologically active compounds using one or more organocatalytic steps.


Input: In this respect, the potential of organocatalytic methods for enabling the chemical synthesis of important medicinal targets will be highlighted.


Input: Enhanced heterodimerization of Bax by Bcl-2 mutants improves irradiated cell survival.


Input: B Cell Lymphoma-2 (Bcl-2) protein suppresses ionizing radiation-induced apoptosis in hemato-lymphoid system.


Input: To enhance the survival of irradiated cells, we have compared the effects and mechanism of Bcl-2 and its functional variants, D34A (caspase-3 resistant) and S70E (mimics phosphorylation on S70).


Input: Bcl-2 and its mutants were transfected into hematopoietic cell line and assessed for cell survival, clonogenicity and cell cycle perturbations upon exposure to ionizing radiation.


Input: The electrostatic potential of BH3 cleft of Bcl-2/mutants and their heterodimerization with Bcl-2 associated X protein (Bax) were computationally evaluated.


Input: Correspondingly, these results were verified by co-immunoprecipitation and western blotting.


Input: The mutants afford higher radioprotective effect than Bcl-2 in apoptotic and clonogenic assays at D (0) (radiation dose at which 37% cell survival was observed).


Input: The computational and functional analysis indicates that mutants have higher propensity to neutralize Bax protein by heterodimerization and have increased caspase-9 suppression capability, which is responsible for enhanced survival.


Input: This study implies potential of Bcl-2 mutants or their chemical/peptide mimics to elicit radioprotective effect in cells exposed to radiation.


Input: Inferring population histories using genome-wide allele frequency data.


Input: The recent development of high-throughput genotyping technologies has revolutionized the collection of data in a wide range of both model and nonmodel species.


Input: These data generally contain huge amounts of information about the demographic history of populations.


Input: In this study, we introduce a new method to estimate divergence times on a diffusion time scale from large single-nucleotide polymorphism (SNP) data sets, conditionally on a population history that is represented as a tree.


Input: We further assume that all the observed polymorphisms originate from the most ancestral (root) population; that is, we neglect mutations that occur after the split of the most ancestral population.


Input: This method relies on a hierarchical Bayesian model, based on Kimura' s time-dependent diffusion approximation of genetic drift.


Input: We implemented a Metropolis-Hastings within Gibbs sampler to estimate the posterior distribution of the parameters of interest in this model, which we refer to as the Kimura model.


Input: Evaluating the Kimura model on simulated population histories, we found that it provides accurate estimates of divergence time.


Input: Assessing model fit using the deviance information criterion (DIC) proved efficient for retrieving the correct tree topology among a set of competing histories.


Input: We show that this procedure is robust to low-to-moderate gene flow, as well as to ascertainment bias, providing that the most distantly related populations are represented in the discovery panel.


Input: As an illustrative example, we finally analyzed published human data consisting in genotypes for 452, 198 SNPs from individuals belonging to four populations worldwide.


Input: Our results suggest that the Kimura model may be helpful to characterize the demographic history of differentiated populations, using genome-wide allele frequency data.


Input: Matrix metalloproteinase-1-mediated up-regulation of vascular endothelial growth factor-2 in endothelial cells.


Input: Matrix metalloproteinase-1 (MMP-1) is a collagenase that is highly active in extracellular matrix and vascular remodeling, angiogenesis, and tumor progression.


Input: Vascular endothelial growth factor receptor-2 (VEGFR2), the main receptor for VEGF-A, is expressed on endothelial cells and promotes cell survival, proliferation, and other functions.


Input: Although MMP-1 and VEGFR2 co-exist in many normal and pathophysiological conditions, the effect of MMP-1 on cellular VEGFR2 that can promote the above processes is unknown.


Input: In this study we test the hypothesis that stimulation of endothelial cells with MMP-1 increases their levels of VEGFR2.


Input: The increased VEGFR2 is then available to bind VEGF-A, resulting in increased response.


Input: Indeed we found that endothelial cells incubated with active MMP-1 had higher mRNA and protein levels of VEGFR2.


Input: Furthermore, VEGF-A-dependent phosphorylation of intracellular signaling molecules and endothelial proliferation were elevated after MMP-1 treatment.


Input: MMP-1 caused activation of the nuclear factor-kappa B (NF-kappa B) pathway (p65/RelA) in endothelial cells, and this response was dependent upon activation of protease activated receptor-1 (PAR-1).


Input: Chromatin immunoprecipitation was used to confirm NF-kappa B-mediated active transcription of the VEGFR2 (KDR) gene.


Input: Elevation in VEGFR2 after MMP-1 stimulation was inhibited by PAR-1 knockdown and NF-kappa B specific inhibition.


Input: We conclude that MMP-1 promotes VEGFR2 expression and proliferation of endothelial cells through stimulation of PAR-1 and activation of NF-kappa B.


Input: These results suggest a mechanism by which MMP-1 may prime or sensitize endothelial cell functions.


Input: The scintigraphic evaluation and genetic correlation of joint involvements in pediatric patients with familial Mediterranean fever.


Input: Purpose: We aimed to evaluate the articular involvements in pediatric patients with familial Mediterranean fever (FMF) with joint symptoms by bone scintigraphy and to correlate the involved joints with the gene mutations.


Input: Materials and methods: A total of 41 newly diagnosed patients in pediatric age group (28 girls and 13 boys; mean age 9. 14 +/- 2. 91 years) with joint involvement symptoms were included in this study.


Input: Scintigraphic images were obtained at 5th min (blood pool or early phase) and starting at 3 h (late phase) after (after tracer injection) intravenous administration of technetium-99m (99mTc)-methylendiphosphonate (MDP).

methylendiphosphonate

MDP


Input: Genomic DNA was isolated from leukocytes using standard salting out procedure.


Input: The sequencing data were analyzed.


Input: Results: Of the 41 patients, arthritis was found in 21 (51. 2%) patients.


Input: Of the 21 patients, there was single joint involvement in 15 (71. 4%) patients and multiple joint involvement in six (28. 6%) patients.