Input: After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters.

creatinine


Input: 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis.

etoposide


Input: The pharmacokinetic parameters CL and V (d) increased with increasing weight similar to BSA.


Input: Elucidation of the mechanism of ribose conjugation in a pyrazole-containing compound in rodent liver.

ribose

pyrazole


Input: Here we report on the mechanism of ribose conjugation, through NADH as a cofactor, of a pyrazole-containing compound (PT).

ribose

NADH

pyrazole


Input: Incubation of PT in rat liver microsomes supplemented with NADP +/H, NAD +/H, and beta-nicotinamide mononucleotide (NMN) resulted in complete conjugation to the adenine dinucleotide phosphate conjugate (ADP-C), adenine dinucleotide conjugate (AD-C), and 5-phosphoribose conjugate (Rib-C1), respectively.

NADP

H

NAD

H

beta-nicotinamide mononucleotide

NMN

adenine dinucleotide phosphate

ADP

adenine

Rib


Input: In hepatocytes, PT predominantly formed three ribose conjugates: Rib-C1, the ribose conjugate (Rib-C2), and the carboxylic acid of Rib-C2 (Rib-C3).

ribose

Rib

ribose

Rib

carboxylic acid

Rib

Rib


Input: Phosphatase inhibitors were added to hepatocyte incubations.


Input: AD-C was detected in this reaction, which suggests that one of the major pathways for the formation of the ribose conjugates is through NAD +/H.

ribose

NAD

H


Input: When AD-C was incubated with phosphatase, Rib-C1 and Rib-C2 formed.

Rib

Rib


Input: To understand the in vivo relevance of this metabolic pathway, rats were dosed with PT and Rib-C2 was found in the urine.

Rib


Input: Structure-activity relationship shows that replacement of the distal thiazole group in the PT to a phenyl group abolishes this conjugation.

thiazole

phenyl


Input: Three amino acid residues in the active site preferentially interact with the sulfur atom in the thiazole of PT.

amino acid

sulfur

thiazole


Input: In summary, PT forms direct AD-C in hepatocytes, which is further hydrolyzed by phosphatase to give ribose conjugates.

ribose


Input: In silico drug repositioning: what we need to know.


Input: Drug repositioning, exemplified by sildenafil and thalidomide, is a promising way to explore alternative indications for existing drugs.

sildenafil

thalidomide


Input: Recent research has shown that bioinformatics-based approaches have the potential to offer systematic insights into the complex relationships among drugs, targets and diseases necessary for successful repositioning.


Input: In this article, we propose the key bioinformatics steps essential for discovering valuable repositioning methods.


Input: The proposed steps (repurposing with a purpose, repurposing with a strategy and repurposing with confidence) are aimed at providing a repurposing pipeline, with particular focus on the proposed Drugs of New Indications (DNI) database, which can be used alongside currently available resources to improve in silico drug repositioning.


Input: Human beta-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity.


Input: The end-stage immunopathology of type 1 diabetes resulting in beta-cell destruction appears to be strongly dominated by cytotoxic CD8 T lymphocytes (CD8 T cells).


Input: However, the mechanism of cytotoxicity used by autoreactive CD8 T cells in the human setting remains unknown.


Input: Using type 1 diabetes patient-derived preproinsulin-specific CD8 T-cell clones recognizing either an HLA-A2 (A * 0201) or HLA-A24 (A * 2402)-restricted epitope (peptide of preproinsulin [PPI] (15-24), ALWGPDPAAA; or PPI (3-11), LWMRLLPLL), we assessed the use of conventional mediators of cytotoxicity in the destruction of human beta-cells in vitro compared with virus-specific cytotoxic CD8 T-cell clones.


Input: We show that PPI-specific CD8 T-cell clones are mainly reliant upon cytotoxic degranulation for inducing beta-cell death.


Input: Furthermore, we find that in comparison with virus-specific CD8 T cells, there are differences in the killing potency of PPI-specific CD8 T cells that are not due to cell-intrinsic differences, but rather are mediated by differences in strength of signaling by peptide-HLA ligands.


Input: The study highlights the regulation of beta-cell killing as a potential point for therapeutic control, including the possibility of blocking autoreactive CD8 T-cell function without impacting upon general immune competence.


Input: Osteocyte control of osteoclastogenesis.


Input: Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist sclerostin.


Input: However, the role of osteocytes in the control of bone resorption has been less clear.


Input: Recent studies have demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone.


Input: The goal of this review is to discuss these and other studies that reveal mechanisms whereby osteocytes control osteoclast formation and thus bone resorption.


Input: This article is part of a Special Issue entitled " The Osteocyte ".


Input: Relation between dynamics, activity and thermal stability within the cholinesterase family.


Input: Incoherent neutron scattering is one of the most powerful tools for studying dynamics in biological matter.


Input: Using the cold neutron backscattering spectrometer IN16 at the Institut Laue Langevin (ILL, Grenoble, France), temperature dependence of cholinesterases' dynamics (human butyrylcholinesterase from plasma: hBChE; recombinant human acetylcholinesterase: hAChE and recombinant mouse acetylcholinesterase: mAChE) was examined using elastic incoherent neutron scattering (EINS).


Input: The dynamics was characterized by the averaged atomic mean square displacement (MSD), associated with the sample flexibility at a given temperature.


Input: We found MSD values of hAChE above the dynamical transition temperature (around 200K) larger than for mAChE and hBChE, implying that hAChE is more flexible than the other ChEs.


Input: Activation energies for thermodynamical transition were extracted through the frequency window model (FWM) (Becker et al. 2004) [1] and turned out to increase from hBChE to mAChE and finally to hAChE, inversely to the MSDs relations.


Input: Between 280 and 316K, catalytic studies of these enzymes were carried out using thiocholine esters: at the same temperature, the hAChE activity was systematically higher than the mAChE or hBChE ones.

thiocholine esters


Input: Our results thus suggest a strong correlation between dynamics and activity within the ChE family.


Input: We also studied and compared the ChEs thermal inactivation kinetics.


Input: Here, no direct correlation with the dynamics was observed, thus suggesting that relations between enzyme dynamics and catalytic stability are more complex.


Input: Finally, the possible relation between flexibility and protein ability to grow in crystals is discussed.


Input: Quantum chemical investigation of the intra-and intermolecular proton transfer reactions and hydrogen bonding interactions in 4-amino-5-(2-hydroxyphenyl)-2H-1, 2, 4-triazole-3 (4H)-thione.

hydrogen

4-amino-5-(2-hydroxyphenyl)-2H-1, 2, 4-triazole-3 (4H)-thione


Input: The intramolecular thione-thiol tautomerism and intermolecular double proton transfer reaction of the hydrogen-bonded thione and thiol dimers in the title triazole compound were studied at the B3LYP level of theory using 6-311 + + G (d, p) basis function.

thione-thiol

hydrogen

thione and thiol dimers

triazole


Input: The influence of the solvent on the single and double proton transfer reactions was examined in three solvents (chloroform, methanol and water) using the polarizable continuum model (PCM) approximation.

chloroform

methanol


Input: The computational results show that the thione tautomer is the most stable isomer with a very high tautomeric energy barrier both in the gas phase and in solution phase, indicating a quite disfavored process.

thione


Input: The solvent effect is found to be sizable with increasing polarity.


Input: In the double proton transfer reaction, the thione dimer is found to be more stable than thiol dimer both in the gas phase and in solution phase.

thione dimer

thiol dimer


Input: The energetic and thermodynamic parameters of the double proton transfer process show that the double proton exchange from thione dimer to thiol dimer is thermodynamically unfavored.

thione dimer

thiol dimer


Input: However, the exchange from thiol dimer to thione dimer for the gas phase and water phase seems to be feasible with a low barrier height and with a negative value in enthalpy and free energy changes.

thiol dimer

thione dimer


Input: In addition, the hydrogen bonding interactions were analyzed in the gas phase regarding their geometries and energies.

hydrogen


Input: It is found that all complex formations are enthalpically favored, and the stability of the H-bonds comes in the order of S1-H2... N2 > N2-H2... S1 > N3-H3B... O1.

H


Input: Finally, non-linear optical properties were carried out at the same calculation level in the gas phase.


Input: Type 2 diabetes and cardiovascular disease in women.


Input: Cardiovascular disease is the leading cause of death in both men and women.


Input: This is also true for patients with diabetes.


Input: In general, differences between the sexes are present in several areas, such as epidemiology, pathophysiology, diagnostics, treatment response and prognosis, as well as the way in which disease is experienced and expressed.


Input: Cardiovascular disease presents later in life in women, who are therefore more likely to suffer from comorbidities.


Input: However, this age-related difference is attenuated in women with diabetes, who suffer their first myocardial infarction at about the same age as men with diabetes.


Input: Diabetes mellitus increases the risk of cardiovascular disease by three to four times in women and two to three times in men, after adjusting for other risk factors.


Input: This paper describes the differences in cardiovascular disease in men and women and the special situation of women with type 2 diabetes when it comes to risk factors, symptoms and the setting of acute coronary syndromes.


Input: Furthermore, it highlights the importance of sex-specific analyses in clinical research to improve our knowledge of cardiovascular disease in women in general and in women with diabetes in particular.


Input: The importance of taking sex into account when treating women and men at risk of cardiovascular disease is discussed.


Input: Methylation levels of sodium-iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression.

sodium-iodide


Input: DNA methylation regulates gene expression.


Input: Aberrant methylation plays an important role in human tumorigenesis.


Input: We have previously detected reduced NIS mRNA expression in thyroid tumors as compared to non-tumor tissues.


Input: Thus, in this study we investigated whether the methylation of the CpG-island located in the NIS gene promoter was associated with reduced mRNA expression in thyroid tumors.


Input: Methylation levels of 30 pairs of samples from 10 benign and 20 malignant thyroid tumors (T) along with matched non-tumor (NT) areas were determined by semiquantitative methylation specific-PCR.


Input: NIS methylation was detected in all samples.


Input: Methylation levels and frequencies did not differ between the groups and were not associated with BRAF mutational status.


Input: Highest methylation levels and frequencies were detected in the 5' region of the CpG-island decreasing toward the 3' end.

CpG


Input: Intraindividual analysis (T versus NT) showed high tumor methylation levels in 40% of the samples in the benign group and 30% in the malignant group, associated with low NIS mRNA expression.


Input: No quantitative correlation was detected between methylation levels and mRNA expression in any the groups.


Input: The results of this study showed that methylation of NIS promoter is a very frequent event in both benign and malignant tumors as well as in their surrounding tissues, and characterized a non-homogeneous methylation pattern along the CpG island.

CpG


Input: Therefore, further investigations involving other sites that may be implicated in methylation regulation of NIS expression are warranted.


Input: Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.


Input: The epidermis acts as a functional barrier against the external environment.


Input: Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis.


Input: Ceramides are a critical natural element of the protective epidermal barrier.


Input: The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function.


Input: When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks.


Input: Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour.


Input: Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks.


Input: Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0. 1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks.


Input: These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function.


Input: Copyright (c) 2012 John Wiley & Sons, Ltd.


Input: Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.

lysines


Input: Although biallelic mutations in non-collagen genes account for < 10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes.


Input: We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI.

prolyl


Input: These include 10 families from the Samoan Islands who share a founder mutation.


Input: Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability.


Input: In four families missense mutations result in loss of most of the protein.


Input: The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families.


Input: The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone.

lysyl


Input: The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues.

hydroxylates

lysyl


Input: These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.


Input: In vitro models for assessing the potential cardiovascular disease risk associated with cigarette smoking.


Input: Atherosclerotic cardiovascular disease is a prevalent human disorder and a significant cause of human morbidity and mortality.


Input: A number of risk factors may predispose an individual to developing atherosclerosis, and of these factors, cigarette smoking is strongly associated with the development of cardiovascular disease.


Input: Current thinking suggests that exposure to toxicants found in cigarette smoke may be responsible for this elevated disease likelihood, and this gives rise to the idea that reductions in the levels of some smoke toxicants may reduce the harm associated with cigarette smoking.


Input: To assess the disease risk of individuals who smoke cigarettes with altered toxicant levels, a weight-of-evidence approach is required examining both exposure and disease-related endpoints.


Input: A key element of such an assessment framework are data derived from the use of in vitro models of cardiovascular disease, which when considered alongside other forms of data (e. g. from clinical studies) may support evidence of potential reduced risk.


Input: Importantly, such models may also be used to provide mechanistic insight into the effects of smoking and of smoke toxicant exposure in cardiovascular disease development.


Input: In this review the use of in vitro models of cardiovascular disease and one of the contributory factors, oxidative stress, is discussed in the context of assessing the risk potential of both conventional and modified cigarettes.


Input: Practical issues concerning the use of these models for cardiovascular disease understanding and risk assessment are highlighted and areas of development necessary to enhance the power and predictive capacity of in vitro disease models in risk assessment are discussed.


Input: Can first-trimester screening program detect women at high risk for gestational diabetes mellitus?


Input: This study was designed to compare first-trimester maternal serum biochemical markers of aneuploidy and fetal nuchal translucency in pregnancies complicated by gestational diabetes mellitus and those of a control group.


Input: The study included 60 gestational diabetic and 60 control women who attended the first-trimester combined screening program for Down syndrome between 11 and 14 gestational weeks with complete follow-up data and delivered in our institution.


Input: Maternal serum free beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A and fetal nuchal translucency were investigated.


Input: The combined risks, double test risks and age risks were calculated by PRISCA software version 4. 0.


Input: Comparison of the results between the two groups yielded no significant differences in serum levels of free beta-human chorionic gonadotropin and fetal nuchal translucency.


Input: However, women who developed gestational diabetes mellitus had significantly lower pregnancy-associated plasma protein-A.


Input: And also, the combined risks and double test risks calculated by PRISCA software were statistically higher in gestational diabetic women than normal pregnant women.


Input: These results suggest that differences can be seen between diabetic and healthy pregnant women in first-trimester maternal serum biochemical markers of aneuploidy.


Input: Attenuated effect of tungsten carbide nanoparticles on voltage-gated sodium current of hippocampal CA1 pyramidal neurons.

tungsten carbide

sodium


Input: Nanomaterials and relevant products are now being widely used in the world, and their safety becomes a great concern for the general public.


Input: Tungsten carbide nanoparticles (nano-WC) are widely used in metallurgy, aeronautics and astronautics, however our knowledge regarding the influence of nano-WC on neurons is still lacking.

Tungsten carbide

WC

WC


Input: The aim of this study was to investigate the impact of nano-WC on tetrodotoxin (TTX)-sensitive voltage-activated sodium current (I (Na)) of hippocampal CA1 pyramidal neurons.

WC

tetrodotoxin

TTX

sodium


Input: Results showed that acute exposure of nano-WC attenuated the peak amplitudes of I (Na) in a concentration-dependent manner.

WC


Input: The minimal effective concentration was 10 (-5) g/ml.


Input: The exposure of nano-WC significantly decreased current amplitudes of the current-voltage curves of I (Na) from-50 to + 50 mV, shifted the steady-state activation and inactivation curves of I (Na) negatively and delayed the recovery of I (Na) from inactivation state.

WC


Input: After exposure to nano-WC, the peak amplitudes, overshoots and the V-thresholds of action potentials (APs) were markedly reduced.

WC


Input: These results suggested that exposure of nano-WC could influence some characteristics of APs evoked from the hippocampal CA1 neurons by modifying the kinetics of voltage-gated sodium channels (VGSCs).

WC

sodium


Input: IKK-beta mediates hydrogen peroxide induced cell death through p85 S6K1.

hydrogen peroxide


Input: The I kappa B kinase (IKK)/NF-kappa B pathway has been shown to be a major regulator in cell survival.


Input: However, the mechanisms through which IKK mediates cell death are not clear.


Input: In this study, we showed that IKK-beta contributed to hydrogen peroxide (H (2) O (2))-induced cell death independent of the NF-kappa B pathway.

hydrogen peroxide

H (2) O (2)


Input: Our results demonstrated that the pro-death function of IKK-beta under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism.

rapamycin

rapamycin


Input: We found that IKK-beta associated with p85, but not p70 S6K1, which was required for H (2) O (2)-induced activation of p85 S6K1.

H (2) O (2)


Input: IKK-beta and p85 S6K1 contributed to H (2) O (2)-induced phosphorylation of Mdm2 (S166) and p53 accumulation.

H (2) O (2)


Input: p85 S6K1 is critical for IKK-beta-mediated cell death.


Input: Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-beta, p85 S6K1 and Mdm2, which is response for H (2) O (2)-induced cell death.

H (2) O (2)


Input: Our results have important implications for IKK-beta and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death.


Input: Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts.

titanium dioxide


Input: Three anatase titanium dioxide (TiO (2)) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2).

titanium dioxide

TiO (2)


Input: These NPs were used to investigate the effect of NP shape and length on lung toxicity.


Input: Mice were exposed (0-30 micro g per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course.


Input: Whole lung lavage data indicated that NB1-and NB2-exposed mice, but not NS-exposed mice, had significant dose-and time-dependent pulmonary inflammation and damage.


Input: Histopathological analyses at 112 days postexposure determined no interstitial fibrosis in any NS-exposed mice, an increased incidence in 30 micro g NB1-exposed mice, and significant interstitial fibrosis in 30 micro g NB2-exposed mice.


Input: At 112 days postexposure, lung burden of NS was decreased by 96. 4% and NB2 by 80. 5% from initial deposition levels.


Input: At 112 days postexposure, enhanced dark field microscopy determined that alveolar macro-phages were the dominant deposition site, but a fraction of NB1 and NB2 was observed in the alveolar interstitial spaces.


Input: For the 30 micro g exposure groups at 112 days postexposure, confocal micro-scopy and immunofluorescent staining demonstrated that retained NB2 but not NS were present in the interstitium subjacent to the terminal bronchiole near the normal location of the smallest lymphatic capillaries in the lung.


Input: These lymphatic capillaries play a critical role in particle clearance, and the accumulation of NB2, but not NS, suggests possible impaired lymphatic clearance by the high aspect ratio particles.


Input: In summary, our data indicate that TiO (2) NP shape alters pulmonary responses, with severity of responses being ranked as NS < NB1 < NB2.

TiO (2)


Input: Effects of parabens on adipocyte differentiation.

parabens


Input: Parabens are a group of alkyl esters of p-hydroxybenzoic acid that include methylparaben, ethylparaben, propylparaben, butylparaben, and benzylparaben.

Parabens

alkyl esters

p-hydroxybenzoic acid

methylparaben

ethylparaben

propylparaben

butylparaben

benzylparaben


Input: Paraben esters and their salts are widely used as preservatives in cosmetics, toiletries, food, and pharmaceuticals.

Paraben esters and their salts


Input: Humans are exposed to parabens through the use of such products from dermal contact, ingestion, and inhalation.

parabens


Input: However, research on the effects of parabens on health is limited, and the effects of parabens on adipogenesis have not been systematically studied.

parabens

parabens


Input: Here, we report that (1) parabens promote adipogenesis (or adipocyte differentiation) in murine 3T3-L1 cells, as revealed by adipocyte morphology, lipid accumulation, and mRNA expression of adipocyte-specific markers; (2) the adipogenic potency of parabens is increased with increasing length of the linear alkyl chain in the following potency ranking order: methyl-< ethyl-< propyl-< butylparaben.

parabens

parabens

methyl

ethyl

propyl

butylparaben


Input: The extension of the linear alkyl chain with an aromatic ring in benzylparaben further augments the adipogenic ability, whereas 4-hydroxybenzoic acid, the common metabolite of all parabens, and the structurally related benzoic acid (without the OH group) are inactive in promoting 3T3-L1 adipocyte differentiation; (3) parabens activate glucocorticoid receptor and/or peroxisome proliferator-activated receptor gamma in 3T3-L1 preadipocytes; however, no direct binding to, or modulation of, the ligand binding domain of the glucocorticoid receptor by parabens was detected by glucocorticoid receptor competitor assays; and lastly, (4) parabens, butyl-and benzylparaben in particular, also promote adipose conversion of human adipose-derived multipotent stromal cells.

benzylparaben

4-hydroxybenzoic acid

parabens

benzoic acid

OH

parabens

parabens

parabens

butyl-and benzylparaben


Input: Our results suggest that parabens may contribute to obesity epidemic, and the role of parabens in adipogenesis in vivo needs to be examined further.

parabens

parabens


Input: PPTOX III: environmental stressors in the developmental origins of disease--evidence and mechanisms.


Input: Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards.


Input: Subtle effects during development can lead to functional deficits and increased disease risk later in life.


Input: The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies.


Input: Similar observations have been made on the long-term impact of nutritional unbalance during early development.


Input: In an effort to bridge the fields of nutritional and environmental developmental toxicity, the Society of Toxicology sponsored this work.


Input: This report summarizes novel findings in developmental toxicity as reported by select invited experts and meeting attendees.


Input: Recommendations for the application and improvement of current and future research efforts are also presented.


Input: Increased responses to the actions of fibroblast growth factor 21 on energy balance and body weight in a seasonal model of adiposity.


Input: The present study aimed to investigate the actions of fibroblast growth factor 21 (FGF21) on energy balance in a natural model of relative fatness, the Siberian hamster.


Input: Hamsters were studied under long days (LD) to promote weight gain, or short days to induce weight loss, and treated with rhFGF21 (3 mg/kg/day) via s. c. minipumps for 14 days.


Input: On days 7-9, detailed assessments of ingestive behaviour, metabolic gas exchange and locomotor activity were made.


Input: FGF21 caused substantial (P < 0. 0001) weight loss in the fat LD state but not in the lean SD state: at the end of the study, FGF21-treated hamsters in LD lost 18% of body weight compared to vehicle controls, which is comparable to the natural body weight loss observed in SD.


Input: Epididymal fat pads, a correlate of total carcass fat content, were reduced by 19% in FGF21 treated hamsters in LD, whereas no difference was found in SD.


Input: Body weight loss in LD was associated with a reduction in food intake (P < 0. 001) and a decreased respiratory exchange ratio (P < 0. 001), indicating increased fat oxidation.


Input: Treatment with FGF21 maintained the normal nocturnal increase in oxygen consumption and carbon dioxide production into the early light phase in hamsters in LD, indicating increased energy expenditure, although locomotor activity was unaffected.

oxygen

carbon dioxide


Input: These data suggest a greater efficacy of FGF21 in hamsters in LD compared to those in SD, which is consistent with both the peripheral and possibly central actions of FGF21 with respect to promoting a lean phenotype.


Input: The observed differences in FGF21 sensitivity may relate to day length-induced changes in adipose tissue mass.


Input: Differential cell-specific cytotoxic responses of oral cavity cells to tobacco preparations.


Input: To examine the effects of standardized (reference) tobacco preparations on human oral cavity cells, two oral squamous cell carcinoma cell lines (101A, 101B) and normal human gingival epithelial cells (HGEC) were treated with cigarette smoke total particulate matter (TPM), smokeless tobacco extracted with complete artificial saliva (ST/CAS), or whole-smoke conditioned media (WS-CM).


Input: EC-50 values, as determined by sulforhodamine B assays, varied among the cell types and agents.

sulforhodamine B


Input: When normalized to nicotine content, cytotoxicity for WS-CM and TPM was higher compared to that observed with ST/CAS.

nicotine


Input: Nicotine alone had no or only minimal cytotoxicity for all cell types in the applied range.

Nicotine


Input: Activation of pro-apoptotic caspase-3 was examined in all cell types at their respective EC-50 doses for the three agents.


Input: TPM, but not ST/CAS or WS-CM significantly activated caspase-3 in all three cell types.


Input: Fluorescence-activated cell sorting (FACS) for expression of the early apoptosis marker Annexin V and for nuclear staining by 7-aminoactinomycin (7-AAD) revealed different extents of apoptosis versus non-apoptotic cell death for the three agents.


Input: These data characterize differential responses of normal and malignant oral cells after exposure to TPM, ST/CAS, or WS-CM.


Input: They assist in understanding differential effects of combustible versus non-combustible tobacco products, and in identifying novel biomarkers for tobacco smoke exposure and effect in the oral cavity.


Input: Loss of TDAG51 results in mature-onset obesity, hepatic steatosis, and insulin resistance by regulating lipogenesis.


Input: Regulation of energy metabolism is critical for the prevention of obesity, diabetes, and hepatic steatosis.


Input: Here, we report an important role for the pleckstrin homology-related domain family member, T-cell death-associated gene 51 (TDAG51), in the regulation of energy metabolism.


Input: TDAG51 expression was examined during adipocyte differentiation.


Input: Adipogenic potential of preadipocytes with knockdown or absence of TDAG51 was assessed.


Input: Weight gain, insulin sensitivity, metabolic rate, and liver lipid content were also compared between TDAG51-deficient (TDAG51 (-/-)) and wild-type mice.


Input: In addition to its relatively high expression in liver, TDAG51 was also present in white adipose tissue (WAT).


Input: TDAG51 was downregulated during adipogenesis, and TDAG51 (-/-) preadipocytes exhibited greater lipogenic potential.


Input: TDAG51 (-/-) mice fed a chow diet exhibited greater body and WAT mass, had reduced energy expenditure, displayed mature-onset insulin resistance (IR), and were predisposed to hepatic steatosis.


Input: TDAG51 (-/-) mice had increased hepatic triglycerides and SREBP-1 target gene expression.

triglycerides


Input: Furthermore, TDAG51 expression was inversely correlated with fatty liver in multiple mouse models of hepatic steatosis.


Input: Taken together, our findings suggest that TDAG51 is involved in energy homeostasis at least in part by regulating lipogenesis in liver and WAT, and hence, may constitute a novel therapeutic target for the treatment of obesity and IR.


Input: A convective replica-exchange method for sampling new energy basins.


Input: Replica-exchange is a powerful simulation method for sampling the basins of a rugged energy landscape.


Input: The replica-exchange method' s sampling is efficient because it allows replicas to perform round trips in temperature space, thereby visiting both low and high temperatures in the same simulation.


Input: However, replicas have a diffusive walk in temperature space, and the round trip rate decreases significantly with the system size.


Input: These drawbacks make convergence of the simulation even more difficult than it already is when bigger systems are tackled.


Input: Here, we present a simple modification of the exchange method.


Input: In this method, one of the replicas steadily raises or lowers its temperature.


Input: We tested the convective replica-exchange method on three systems of varying complexity: the alanine dipeptide in implicit solvent, the GB1 beta-hairpin in explicit solvent and the A beta (25-35) homotrimer in a coarse grained representation.

alanine dipeptide


Input: For the highly frustrated A beta (25-35) homotrimer, the proposed " convective " replica-exchange method is twice as fast as the standard method.


Input: It discovered 24 out of 27 free-energy basins in less than 500 ns.


Input: It also prevented the formation of groups of replicas that usually form on either side of an exchange bottleneck, leading to a more efficient sampling of new energy basins than in the standard method.


Input: Oriented electrophoretic deposition of GdOCl nanoplatelets.

GdOCl


Input: Electrophoretic deposition has emerged as a versatile and precisely tunable approach for the rapid deposition of conformal thin films of colloidal nanocrystals.


Input: The electrophoretic deposition of phosphor particles has assumed special significance in recent years as a commercially viable means toward the fabrication of large-area, ultrathin high-resolution emissive display screens.


Input: Here, we demonstrate that the anisotropic shape of colloidal ligand-passivated GdOCl nanoplatelets enables their assembly with remarkable substrate alignment and a high packing density upon electrophoretic deposition.

GdOCl


Input: GdOCl nanocrystals are promising candidates for phosphor applications given their low maximum phonon cutoff energy, robust chemical stability over prolonged periods of operation, and ability to promote efficacious phonon energy transfer to dopant ions.

GdOCl


Input: Potentiostatic deposition of GdOCl nanoplatelets from cyclohexane dispersions allows the deposition of individual nanoplatelets with their basal planes parallel to the electrode surface.

GdOCl

cyclohexane


Input: Tuning the applied voltage and solution concentration allows control of film thickness, ranging up to several tens of micrometers.


Input: The high degree of particle alignment is attributed to anisotropic charge distribution and entrainment within electroosmotic flows established in the vicinity of the electrode surface.


Input: The oriented high-particle-density GdOCl nanoplatelet thin films are possible candidates for phosphor applications, which is illustrated by the green emission from a Tb-doped GdOCl thin film on indium tin oxide (ITO)-coated glass.

GdOCl

Tb-doped GdOCl

indium tin oxide

ITO


Input: Inhaled Muscarinic Acetylcholine Receptor Antagonists for Treatment of COPD.


Input: Bronchodilators, generally administered via metered dose or dry powder inhalers, are the mainstays of pharmacological treatment of stable COPD.


Input: Inhaled long-acting beta-agonists (LABA) and anticholinergics are the bronchodilators primarily used in the chronic treatment of COPD.


Input: Anticholinergics act as muscarinic acetylcholine receptor antagonists and are frequently preferred over beta-agonists for their minimal cardiac stimulatory effects and greater efficacy in most studies.


Input: Their therapeutic efficacy is based on the fact that vagally mediated bronchoconstriction is the major reversible component of airflow obstruction in patients with COPD.


Input: However, bronchodilators are effective only on the reversible component of airflow obstruction, which by definition is limited, as COPD is characterized by a fixed or poorly reversible airflow obstruction.


Input: Inhaled anticholinergic antimuscarinic drugs approved for the treatment of COPD include ipratropium bromide, oxitropium bromide and tiotropium bromide.

ipratropium bromide

oxitropium bromide

tiotropium bromide


Input: Ipratropium bromide, the prototype of anticholinergic bronchodilators, is a short-acting agent.

Ipratropium bromide


Input: Oxitropium bromide is administered twice a day.

Oxitropium bromide


Input: Tiotropium bromide, the only long-acting antimuscarinic agent (LAMA) currently approved, is administered once a day.

Tiotropium bromide


Input: Newer LAMAs including aclidinium bromide and glycopyrrolate bromide are currently in phase III development for treatment of COPD.

aclidinium bromide

glycopyrrolate bromide


Input: Some new LAMAs, including glycocpyrrolate, are suitable for once daily administration and, unlike tiotropium, have a rapid onset of action.

tiotropium


Input: New LAMAs and their combination with ultra-LABA and, possibly, inhaled corticosteroids, seem to open new perspectives in the management of COPD.


Input: Dual-pharmacology muscarinic antagonist-beta2 agonist (MABA) molecules present a novel approach to the treatment of COPD by combining muscarinic antagonism and beta2 agonism in a single molecule.


Input: Development of New Drugs for COPD.


Input: Chronic obstructive pulmonary disease (COPD) is an increasing global health problem and cause of death.


Input: COPD is a chronic inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction.


Input: However, current therapies fail to prevent either disease progression or mortality.


Input: The mainstay of current drug therapy is long-acting bronchodilators.


Input: Several once daily inhaled beta 2-agonists and muscarinic antagonists (and combinations) are now in development.


Input: No treatments effectively suppress chronic inflammation in COPD lungs.


Input: With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified.


Input: Several mediator antagonists or inhibitors tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment are more promising.


Input: Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus kinases, NF-kappa B kinase and PI3 kinase-gamma and-delta, but side effects after oral administration are a major limitation so that in future inhaled delivery may be necessary.


Input: A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity.

corticosteroid


Input: This might be achieved by existing treatments such as theophylline, nortriptyline and macrolides, or more selectively by PI3 kinase-delta inhibitors.

theophylline

nortriptyline

macrolides


Input: Thus although there have been major advances in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are safe and effective.


Input: A comparative study of two novel nanosized radiolabeled analogues of methionine for SPECT tumor imaging.

methionine


Input: It has been reported that most tumor cells show an increased uptake of variety of amino acids specially methionine when compared with normal cells and amino acid transport is generally increased in malignant transformation.

amino acids

methionine

amino acid


Input: Based on the evidences, two novel nanosized analogues of methionine (Anionic Linear Globular Dendrimer G (2), a biodigredabale anionic linear globular-Methionin, and DTPA-Methionine (1) conjugates) were synthesized and labeled with (99m) Tc and used in tumor imaging/therapy in vitro and in vivo.

methionine

Methionin

DTPA

Methionine

(99m) Tc


Input: The results showed marked tumor SPECT molecular imaging liabilities for both compounds but with a better performance by administration of (99m) Tc-Dendrimer G (2)-Methionin.

(99m) Tc

Methionin


Input: The results also showed a good anticancer activity for 99mTc-DTPA-Methionine.

DTPA

Methionine


Input: Based on the present study (99m) Tc-Dendrimer G (2)-Methionin or 99mTc-DTPA-(Methionine) (1) have potentials to be used in tumor molecular imaging as well as cancer therapy in future.

(99m) Tc

Methionin

DTPA

Methionine


Input: Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei.


Input: Mutation of tub gene in mice induces obesity, suggesting that tub could be an important regulator of energy balance.


Input: In the current study, we investigated whether insulin, leptin, and obesity can modulate Tub in vivo in hypothalamic nuclei, and we investigated possible consequences on energy balance, neuropeptide expression, and hepatic glucose metabolism.

glucose


Input: Food intake, metabolic characteristics, signaling proteins, and neuropeptide expression were measured in response to fasting and refeeding, intracerebroventricular insulin and leptin, and Tub antisense oligonucleotide (ASO).


Input: Tub tyrosine phosphorylation (Tub-p-tyr) is modulated by nutritional status.

tyrosine

tyr


Input: Tub is a substrate of insulin receptor tyrosine kinase (IRTK) and leptin receptor (LEPR)-Janus kinase 2 (JAK2) in hypothalamic nuclei.

tyrosine


Input: After leptin or insulin stimulation, Tub translocates to the nucleus.


Input: Inhibition of Tub expression in hypothalamus by ASO increased food intake, fasting blood glucose, and hepatic glucose output, decreased O (2) consumption, and blunted the effect of insulin or leptin on proopiomelanocortin, thyroid-releasing hormone, melanin-concentrating hormone, and orexin expression.

glucose

glucose

O (2)


Input: In hypothalamus of mice administered a high-fat diet, there is a reduction in leptin and insulin-induced Tub-p-tyr and nuclear translocation, which is reversed by reducing protein tyrosine phosphatase 1B expression.

tyr

tyrosine


Input: These results indicate that Tub has a key role in the control of insulin and leptin effects on food intake, and the modulation of Tub may contribute to insulin and leptin resistance in DIO mice.


Input: Anti-obesity effects of glabridin-rich supercritical carbon dioxide extract of licorice in high-fat-fed obese mice.

glabridin

carbon dioxide


Input: Licorice (Glycyrrhiza glabra Linne) is a well-known medicinal plant and glabridin is an isoflavan isolated from licorice.

glabridin

isoflavan


Input: In this study, we investigated the anti-obesity effect of glabridin and glabridin-rich supercritical fluid extract of licorice (LSC).

glabridin

glabridin


Input: Glabridin effectively inhibited adipogenesis in 3T3-L1 cells.

Glabridin


Input: Moreover, LSC showed inhibitory effect on adipogenesis in a dose-dependent manner.


Input: The inhibitory effect of LSC resulted from inhibiting the induction of the transcriptional factors CCAAT enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma.


Input: Then we fed mice with high-fat diet containing none, 0. 1% and 0. 25% LSC for 8weeks to explore the anti-obesity effect of LSC in vivo.


Input: LSC significantly reduced weight gain by high-fat diet in a dose-dependent manner.


Input: The reductions of the hypertrophy of white adipose tissue and of fat cell size were also observed.


Input: In the liver, LSC supplementation effectively inhibited high-fat diet-induced hepatic steatosis through downregulation of gluconeogenesis related phosphoenolpyruvate carboxykinase and glucose 6-phosphatase and upregulation of the beta-oxidation related carnitine palmitoyltransferase 1.

phosphoenolpyruvate

glucose

carnitine


Input: Taken together, our results suggest that glabridin and glabridin-rich licorice extract would be effective anti-obesity agents.

glabridin

glabridin


Input: Effects of metabotropic glutamate receptor ligands on male sexual behavior in rats.

glutamate


Input: Metabotropic glutamate receptors (mGluRs), particularly mGluR2/3, mGluR5 and mGluR7, have received much attention in medication development for the treatment of drug addiction and other neuropsychiatric diseases.

glutamate


Input: However, little is known as to whether mGluR ligands also alter natural sexual behavior, a possible unwanted effect when used in humans.


Input: In the present study, we used classical copulatory behaviors to evaluate the effects of LY379268 (a selective mGluR2/3 agonist), MPEP (a selective mGluR5 antagonist) and AMN082 (a selective mGluR7 agonist), on male sexual performance in rats.

MPEP


Input: We found that systemic administration of LY379268 (1, 3 mg/kg, i. p.) had no effect, while MPEP (20 mg/kg, but not 10 mg/kg, i. p.) and AMN082 (10, 20 mg/kg, but not 3 mg/kg) produced a significant and dose-dependent reduction in both sex-seeking and sex-performance behaviors, manifested as an increase in mount or intromission latency and time required for ejaculation, and a reduction in mount or intromission frequency.

MPEP


Input: This inhibition lasted for about 30-60 min.


Input: These findings suggest that compounds that target mGluR5 or mGluR7, but not mGluR2/3, may have short-term inhibitory effects on male sexual performance.


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.


Input: Public support and consent preference for biomedical research and biobanking in Jordan.


Input: The success of any biobank depends on a number of factors including public' s view of research and the extent to which it is willing to participate in research.


Input: As a prototype of surrounding countries, public interest in research and biobanking in addition to the influence and type of informed consent for biobanking were investigated in Jordan.


Input: Data were collected as part of a national survey of 3196 individuals representing the Jordanian population.


Input: The majority of respondents (88. 6%) had a positive perception of the level of research in Jordan and they overwhelmingly (98. 2%) agreed to the concept of investing as a country in research.


Input: When respondents were asked if the presence of an informed consent would influence their decision to participate in biobanking, more individuals (19. 8%) considered having an informed consent mechanism as a positive factor than those who considered it to have negative connotations (13. 1%).


Input: However, a substantial portion (65%) did not feel it affected their decision.


Input: The majority of survey participants (64%) expressed willingness to participate in biobanking and over 90% of them preferred an opt-in consent form whether general (75. 2%) or specific for disease or treatment (16. 9%).


Input: These results indicate a promising ground for research and biobanking in Jordan.


Input: Educational programs or mass awareness campaigns to promote participation in biobanking and increase awareness about informed consent and individual rights in research will benefit both the scientific community as well as the public.


Input: GH and cortisol responses following an acute session of respiratory muscle endurance training in severely obese patients.

cortisol


Input: It is well established that obese patients are hypo-responsive to classical GH-releasing stimuli, including aerobic exercise.


Input: Recently, we have demonstrated that whole body vibration was able to markedly stimulate GH secretion in obese patients, thus suggesting that this refractoriness is not absolute but dependent on the GH-releasing stimulus.


Input: Furthermore, we have shown the ability of a respiratory muscle endurance training (RMET) to stimulate GH and cortisol secretion in healthy subjects.

cortisol


Input: The objective of this study was to evaluate the effects of RMET on GH and cortisol responses in severely obese patients.

cortisol


Input: Eight severely obese patients (4 M/4 F, mean age +/- SEM: 22. 8 +/- 1. 6 years, body mass index, BMI: 39. 9 +/- 1. 1 kg/m2) underwent an incremental progressive RMET protocol of 11 daily sessions, obtained through the use of a specifically designed respiratory device (Spiro Tiger (R)).


Input: The 12th session of RMET (15 min duration: 1 min at a respiration rate of 28 acts/min, 5 min at 32 acts/min, 5 min at 34 acts/min, 4 min at 36 acts/min) was associated with blood samplings for determination of GH, cortisol, and lactate (LA) levels.

cortisol

lactate


Input: An age-and sex-matched normal-weighted control group (n = 7, 4 M/3 F, age: 26. 1 +/- 3. 1 years, BMI: 22. 4 +/- 0. 6 kg/m2) was also recruited.


Input: In both normal-weighted subjects and obese patients, GH secretion significantly increased after a 15-min RMET session.


Input: Although serum GH levels at 30 min were higher in normal-weighted subjects than in obese patients, there was no statistically significant difference in either GH peaks or net GH areas under the curve between the 2 groups.


Input: RMET significantly increased serum cortisol levels in normal-weighted subjects, but was associated to a progressive cortisol decline in obese patients.

cortisol

cortisol


Input: RMET stimulated LA production, with no significant differences in normal-weighted subjects and in obese patients.


Input: A 15-min RMET session was capable to induce a GH response in severely obese patients, which was comparable to that recorded in normal-weighted subjects.


Input: A progressive decline in serum cortisol levels occurred in obese patients after RMET, while an opposite pattern (i. e., a significant cortisol increase) was found in normal-weighted subjects.

cortisol

cortisol


Input: Optimization of long-term RMET protocols could represent a valid strategy to (physiologically) stimulate GH/IGF-I system in those GH hyposecretory states such as obesity.


Input: Energy depletion of bovine mammary epithelial cells activates AMPK and suppresses protein synthesis through inhibition of mTORC1 signaling.


Input: The molecular mechanisms by which cellular energy status regulates global protein synthesis in mammary epithelial cells have not been characterized.


Input: The objective of this study was to examine the effect of AMP-activated protein kinase (AMPK) activation by 2-deoxyglucose on protein synthesis and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in bovine mammary epithelial cells.

rapamycin


Input: Phosphorylation of AMPK at Thr172 increased by 1. 4-fold within 5 min, and remained elevated throughout a 30-min time course, in response to 2-deoxyglucose.


Input: Global rates of protein synthesis declined by 78% of control values.


Input: The decline in protein synthesis was associated with repression of mTORC1 signaling, as indicated by reduced phosphorylation of ribosomal protein S6 kinase 1 and eIF4E binding protein-1 (4E-BP1).


Input: Phosphorylation of ER-stress marker eIF2 alpha was also increased but only at 30 min of 2-deoxyglucose exposure.


Input: 2-Deoxyglucose increased phosphorylation of tuberous sclerosis complex 2 (TSC2) on AMPK consensus sites but did not change the amount of TSC1 bound to TSC2.


Input: Activation of AMPK did not result in changes in the amount of raptor bound to mTOR.


Input: The inhibitory effects of AMPK activation on mTORC1 signaling were associated with a marked increase in Ser792 phosphorylation on raptor.


Input: Collectively, the results suggest that activation of AMPK represses global protein synthesis in mammary epithelial cells through inhibition of mTORC1 signaling.


Input: Factors associated with the glucose-lowering effect of vildagliptin identified from the results of the oral glucose tolerance test in Japanese patients with type 2 diabetes.

glucose

vildagliptin

glucose


Input: In order to investigate the factors contributing to the glucose-lowering effect of vildagliptin, we analyzed the results of the oral glucose tolerance test together with several clinical parameters in Japanese patients with type 2 diabetes before and after 24 weeks of treatment with vildagliptin.

glucose

vildagliptin

glucose

vildagliptin


Input: The data of the 13 patients who satisfactorily completed the follow-up examinations were included.


Input: After 24 weeks treatment with vildagliptin, the patients were classified into a responder group (69. 2%) and a non-responder group (30. 8%); the responders consisting of subjects whose HbA1c decreased following 24 weeks treatment with vildagliptin, and the non-responders consisting of subjects who did not show any significant decrease of HbA1c.

vildagliptin

vildagliptin


Input: There were no differences in baseline characteristics between the two groups before administration of vildagliptin.

vildagliptin


Input: After 24 weeks of treatment, HbA1c was significantly reduced from 7. 3 +/- 0. 5% to 6. 7 +/- 0. 5% in the responder group (P = 0. 0077), while it tended to rather increased from 7. 1 +/- 0. 6% to 7. 5 +/- 0. 7% in the non-responder group (P = 0. 0679).


Input: Also, parameters reflecting the glucose-stimulated insulin secretion, such as the insulinogenic index and oral disposition index, were significantly higher in the responder group than in the non-responder group, whereas insulin sensitivity was similar between the two groups.

glucose


Input: These results suggest that the difference in the degree of improvement of the glucose tolerance between the responder group and non-responder group in this study could be associated with the effect of vildagliptin on the glucose-stimulated insulin secretion, but not on the insulin sensitivity.

glucose

vildagliptin

glucose


Input: Luminescent neutral platinum complexes bearing an asymmetric N (^) N (^) N ligand for high-performance solution-processed OLEDs.

platinum


Input: The synthesis and full characterization of new platinum complexes bearing a bulky asymmetric dianionic tridentate ligand is reported.

platinum


Input: The hindrance of the ligand prevents detrimental intermolecular interactions yielding to highly emitting species in both crystalline state and thin-film.


Input: Such properties prompted their successful use in solution-processed OLEDs, showing remarkable external quantum efficiency up to 5. 6%.


Input: Alpha-asarone from Acorus gramineus alleviates epilepsy by modulating A-type GABA receptors.

Alpha-asarone

GABA


Input: Alpha (alpha)-asarone is a major effective compound isolated from the Chinese medicinal herb Acorus gramineus, which is widely used in clinical practice as an antiepileptic drug; however, its mechanism of action remains unclear.

(alpha)-asarone


Input: In this study, we have characterized the action of alpha-asarone on the excitability of rat hippocampal neurons in culture and on the epileptic activity induced by pentylenetetrazole or kainate injection in vivo.

alpha-asarone

pentylenetetrazole

kainate


Input: Under cell-attached configuration, the firing rate of spontaneous spiking was inhibited by application of alpha-asarone, which was maintained in the Mg (2 +)-free solution.

alpha-asarone

Mg (2 +)


Input: Under whole-cell configuration, alpha-asarone induced inward currents in a concentration-dependent manner with an EC (50) of 248 +/- 33 mu M, which was inhibited by a GABA (A) receptor blocker picotoxin and a competitive GABA (A) receptor antagonist bicuculline but not a specific glycine receptor inhibitor strychnine.

GABA

picotoxin

GABA

bicuculline

glycine

strychnine


Input: Measurement of tonic GABA currents and miniature spontaneous inhibitory postsynaptic currents indicated that alpha-asarone enhanced tonic GABAergic inhibition while left phasic GABAergic inhibition unaffected.

GABA

alpha-asarone


Input: In both pentylenetetrazole and kainate seizure models, alpha-asarone suppressed epileptic activity of mice by prolonging the latency to clonic and tonic seizures and reducing the mortality as well as the susceptibility to seizure in vivo presumably dependent on the activation of GABA (A) receptors.

pentylenetetrazole

kainate

alpha-asarone

GABA


Input: In summary, our results suggest that alpha-asarone inhibits the activity of hippocampal neurons and produces antiepileptic effect in central nervous system through enhancing tonic GABAergic inhibition.

alpha-asarone


Input: Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates.


Input: A library of more than 200 novel uncharged oxime reactivators was used to select and refine lead reactivators of human acetylcholinesterase (hAChE) covalently conjugated with sarin, cyclosarin, VX, paraoxon and tabun.

oxime

sarin

cyclosarin

paraoxon

tabun


Input: N-substituted 2-hydroxyiminoacetamido alkylamines were identified as best reactivators and reactivation kinetics of the lead oximes, RS41A and RS194B, were analyzed in detail.

N-substituted 2-hydroxyiminoacetamido alkylamines

oximes


Input: Compared to reference pyridinium reactivators, 2PAM and MMB4, molecular recognition of RS41A reflected in its Kox constant was compromised by an order of magnitude on average for different OP-hAChE conjugates, without significant differences in the first order maximal phosphorylation rate constant k2.

pyridinium


Input: Systematic structural modifications of the RS41A lead resulted in several-fold improvement with reactivator, RS194B.


Input: Kinetic analysis indicated Kox reduction for RS194B as the main kinetic constant leading to efficient reactivation.


Input: Subtle structural modifications of RS194B were used to identify essential determinants for efficient reactivation.


Input: Computational molecular modeling of RS41A and RS194B interactions with VX inhibited hAChE, bound reversibly in Michaelis type complex and covalently in the pentacoordinate reaction intermediate suggests that the faster reactivation reaction is a consequence of a tighter RS194B interactions with hAChE peripheral site (PAS) residues, in particular with D74, resulting in lower interaction energies for formation of both the binding and reactivation states.


Input: Desirable in vitro reactivation properties of RS194B, when coupled with its in vivo pharmacokinetics and disposition in the body, reveal the potential of this oxime design as promising centrally and peripherally active antidotes for OP toxicity.

oxime


Input: Emerging opportunities for allosteric modulation of G-protein coupled receptors.


Input: Their ubiquitous nature, wide cellular distribution and versatile molecular recognition and signalling help make G-protein binding receptors (GPCRs) the most important class of membrane proteins in clinical medicine, accounting for ~ 40% of all current therapeutics.


Input: A large percentage of current drugs target the endogenous ligand binding (orthosteric) site, which are structurally and evolutionarily conserved, particularly among members of the same GPCR subfamily.


Input: With the recent advances in GPCR X-ray crystallography, new opportunities for developing novel subtype selective drugs have emerged.


Input: Given the increasing recognition that the extracellular surface conformation changes in response to ligand binding, it is likely that all GPCRs possess an allosteric site (s) capable of regulating GPCR signalling.


Input: Allosteric sites are less structurally conserved than their corresponding orthosteric site and thus provide new opportunities for the development of more selective drugs.


Input: Constitutive oligomerisation (dimerisation) identified in many of the GPCRs investigated, adds another dimension to the structural and functional complexity of GPCRs.


Input: In this review, we compare 60 crystal structures of nine GPCR subtypes (rhodopsin, beta 2-AR, beta 1-AR, A (2a)-AR, CXCR4, D 3 R, H 1 R, M 2 R, M 3 R) across four subfamilies of Class A GPCRs, and discuss mechanisms involved in receptor activation and potential allosteric binding sites across the highly variable extracellular surface of these GPCRs.


Input: This analysis has identified a new extracellular salt bridge (ESB-2) that might be exploited in the design of allosteric modulators.


Input: Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging.


Input: mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi.


Input: Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death.


Input: Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age.


Input: These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues.


Input: Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals.


Input: CTNNA3 (alpha-catenin) gene variants are associated with diisocyanate asthma: a replication study in a caucasian worker population.

diisocyanate


Input: Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, and rs4378283) associated with diisocyanate-induced occupational asthma (DA).

diisocyanate


Input: The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions.


Input: We conducted a candidate gene association study to replicate these findings in Caucasian workers.


Input: Genotyping was performed on DNA using a 5' nuclease PCR assay collected from 410 diisocyanate-exposed and predominantly Canadian workers including 132 workers with DA confirmed by a specific inhalation challenge (DA +); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA-); and 147 hexamethylene diisocyanate-exposed asymptomatic workers (AWs).

diisocyanate

hexamethylene diisocyanate


Input: As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA + when compared with AWs but not in comparison with DA-workers (p <= 0. 05).


Input: After adjusting for potentially confounding variables of age, smoking status, and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs (OR = 9. 05 [95% CI: 1. 69, 48. 54] and OR = 6. 82 [95% CI: 1. 65, 28. 24], respectively).


Input: In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA.


Input: These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of catenins in the disease process.


Input: Something' s got to give: psychiatric disease on the rise and novel drug development on the decline.


Input: Research and development of drugs for psychiatric disease is currently in a state of decline.


Input: Despite the increasing prevalence and healthcare costs of psychiatric disease, the costly and unpredictable drug development process has led to decreased public and investor confidence in the abilities of companies to develop safe and efficacious drugs.


Input: Industrial research in this disease area is therefore being scaled back owing to various scientific, corporate, financial and legal factors.


Input: This review will consider how these factors contribute to the current status of psychiatric drug development and offer several avenues forward to spur reinvestment in this type of research.


Input: Such a shift is needed to reduce the burden psychiatric disease imposes on the healthcare system and its patient populations.


Input: Oral delivery of anticancer drugs III: formulation using drug delivery systems.


Input: In the past few years, the growth of nanometric size drug delivery systems (DDS) has burst into challenging innovations enabling real progresses to achieve oral delivery of anticancer drugs.


Input: DDS, such as polymeric nanoparticles, micelles, dendrimers and lipid-based formulations enable physico-chemical properties of cytotoxic agents to be improved and oral bioavailability to be enhanced.


Input: In this review we highlight current DDS used for the oral delivery of anticancer drugs.


Input: Orphan drugs: the regulatory environment.


Input: The definition of a rare disease is not universal and depends on the legislation and policies adopted by each region or country.


Input: The main objective of this article is to describe and discuss the legal framework and the regulatory environment of orphan drugs worldwide.


Input: Some reflections and discussions on the need for specific orphan drug legislation or policies are described at length.


Input: Furthermore, some aspects of the history of each region in respect of the orphan drug legislation evolution are outlined.


Input: This article describes and compares the orphan drug legislation or policies of the following countries or regions: United Sates of America (US), European Union (EU), Japan, Australia, Singapore, Taiwan and Canada.


Input: The incentives described in the orphan drug legislations or policies, the criteria for designation of orphan status and the authorisation process of an orphan drug are also described and compared.


Input: The legislations and policies are to some extent similar but not the same.


Input: It is important to understand the main differences among all available legislative systems to improve the international collaboration in the field of orphan drugs and rare diseases.


Input: Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis.


Input: Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ) in the form of asymmetric AChE (AChE/ColQ).


Input: The C-terminal domain of ColQ binds to MuSK, the muscle-specific receptor tyrosine kinase, that mediates a signal for acetylcholine receptor (AChR) clustering at the NMJ.

C

tyrosine

acetylcholine


Input: ColQ also binds to heparan sulfate proteoglycans including perlecan.


Input: Congenital defects of ColQ cause endplate AChE deficiency.


Input: A single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq-/-mice rescued motor functions, synaptic transmission, and the ultrastructure of NMJ.


Input: We also injected AAV1-COLQ-IRES-EGFP to the left tibialis anterior and observed colocalization of AChE/ColQ at all the examined NMJs of the non-injected limbs.


Input: Additionally, injection of purified recombinant AChE/ColQ protein complex into gluteus maximus accumulated AChE in non-injected forelimbs.


Input: These observations suggest that the tissue-targeting signal of ColQ can be exploited to specifically deliver the transgene product to the target tissue.


Input: MuSK antibody-positive myasthenia gravis (MG) accounts for 5-15% of autoimmune MG.


Input: As AChR deficiency is typically mild and as cholinesterase inhibitors are generally ineffective or worsen myasthenic symptoms, we asked if the patient' s MuSK-IgG interferes with binding of ColQ to MuSK.


Input: In vitro overlay of AChE/ColQ to muscle sections of Colq-/-mice revealed that MuSK-IgG blocks binding of ColQ to the NMJ.


Input: In vitro plate-binding of MuSK to ColQ disclosed that MuSK-IgG exerts a dose-dependent block of MuSK-ColQ interaction.


Input: In addition, passive transfer of MuSK-IgG to mice reduced the size and density of ColQ to ~ 10% of controls and had a lesser effect on the sizes and densities of AChR and MuSK.


Input: Elucidation of molecular mechanisms of specific binding of ColQ to the NMJ enabled us to ameliorate devastating myasthenic symptoms of Colq-/-mice and to reveal bases of anti-MuSK MG.


Input: Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2 alpha/CHOP-dependent manner.

Verrucarin A


Input: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics.


Input: However, resistance to TRAIL in some cancers remains a current problem in recent.


Input: The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis.


Input: Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress.

verrucarin A


Input: We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells.


Input: Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis.


Input: Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2 alpha), which is a common cellular response of ER stress.


Input: Furthermore, salubrinal, a specific eIF2 alpha phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA.

salubrinal


Input: In contrast, transfection of mutant-eIF2 alpha significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression.


Input: Therefore, VA-induced eIF2 alpha phosphorylation seemed to be important for CHOP and DR5 upregulation and TRAIL-induced apoptosis.


Input: In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress.

oxygen


Input: We concluded that VA triggers TRAIL-induced apoptosis by eIF2 alpha/CHOP-dependent DR5 induction via ROS generation.


Input: A chemistry wiki to facilitate and enhance compound design in drug discovery.


Input: At AstraZeneca a focus on hypothesis-driven design and the formation of drug design teams has placed a greater emphasis on collaboration in the drug discovery process.


Input: We have created a novel software tool based on the principles of wikis and social networks to facilitate collaborative working, visual planning and incorporation of predictive science to improve design capability.


Input: Monitoring the design and make process via the tool enabled the identification of bottlenecks and delays.


Input: Solutions to these problems were implemented, reducing the time taken from the initial idea stage to the generation of the synthesised compound by more than 50%.


Input: A common mechanism for resistance to oxime reactivation of acetylcholinesterase inhibited by organophosphorus compounds.

oxime

organophosphorus


Input: Administration of oxime therapy is currently the standard approach used to reverse the acute toxicity of organophosphorus (OP) compounds, which is usually attributed to OP inhibition of acetylcholinesterase (AChE).

oxime

organophosphorus


Input: Rate constants for reactivation of OP-inhibited AChE by even the best oximes, such as HI-6 and obidoxime, can vary > 100-fold between OP-AChE conjugates that are easily reactivated and those that are difficult to reactivate.

obidoxime


Input: To gain a better understanding of this oxime specificity problem for future design of improved reactivators, we conducted a QSAR analysis for oxime reactivation of AChE inhibited by OP agents and their analogues.

oxime

oxime


Input: Our objective was to identify common mechanism (s) among OP-AChE conjugates of phosphates, phosphonates and phosphoramidates that result in resistance to oxime reactivation.

phosphates

phosphonates

phosphoramidates

oxime


Input: Our evaluation of oxime reactivation of AChE inhibited by a sarin analogue, O-methyl isopropylphosphonofluoridate, or a cyclosarin analogue, O-methyl cyclohexylphosphonofluoridate, indicated that AChE inhibited by these analogues was at least 70-fold more difficult to reactivate than AChE inhibited by sarin or cyclosarin.

oxime

O-methyl isopropylphosphonofluoridate

cyclosarin

O-methyl cyclohexylphosphonofluoridate

sarin

cyclosarin


Input: In addition, AChE inhibited by an analogue of tabun (i. e., O-ethyl isopropylphosphonofluoridate) was nearly as resistant to reactivation as tabun-inhibited AChE.

tabun

O-ethyl isopropylphosphonofluoridate

tabun


Input: QSAR analysis of oxime reactivation of AChE inhibited by these OP compounds and others suggested that the presence of both a large substituent (i. e., <= the size of dimethylamine) and an alkoxy substituent in the structure of OP compounds is the common feature that results in resistance to oxime reactivation of OP-AChE conjugates whether the OP is a phosphate, phosphonate or phosphoramidate.

dimethylamine

alkoxy

oxime

phosphate

phosphonate

phosphoramidate


Input: The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons.

amphetamines


Input: 3, 4-Methylenedioxymethamphetamine (MDMA or " Ecstasy ") and 2, 5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties.

3, 4-Methylenedioxymethamphetamine

MDMA

Ecstasy

2, 5-dimethoxy-4-iodoamphetamine hydrochloride

DOI

amphetamines


Input: The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine' s neurotoxicity.

amphetamine


Input: We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19).

DOI

MDMA


Input: Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M).

MDMA

DOI


Input: Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration-and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs.

lactate

tetrazolium

MTT


Input: Both drugs promoted a significant increase in caspase-8 and caspase-3 activities.


Input: At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA.

DOI

MDMA


Input: In the mitochondrial fraction of neurons exposed 24h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot.

DOI

MDMA


Input: Moreover, 24h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons.

DOI


Input: Pre-treatment with an antibody raised against the 5-HT (2A)-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA.

DOI

MDMA


Input: In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators.

amphetamines


Input: Death was dependent, at least in part, on the stimulation of the 5-HT (2A)-receptors.


Input: A DFT study on the initial stage of thermal degradation of Poly (methyl methacrylate)/carbon nanotube system.

Poly (methyl methacrylate)

carbon


Input: DFT calculations, with VWN exchange correlation functional and double numeric basis set, were used to evaluate the energies required for the scission reactions taking place in the initial stage of the thermal degradation of Poly (methyl methacrylate) (PMMA) in the presence of a carbon nanotube (CNT).

Poly (methyl methacrylate)

PMMA

carbon


Input: Side group and main chain scissions were investigated.


Input: The results averaged from five configurations of pure PMMA (DP = 5) were used as references and compared to the results obtained for the five same configurations of PMMA grafted on three carbon nanotubes of similar diameter (1. 49 nm).

PMMA

PMMA

carbon


Input: The bond dissociation energies (BDE) of main chain scission evaluated for grafted PMMA was 4% less endothermic than for pure PMMA.

PMMA

PMMA


Input: These results seemed independent of the tested chirality (11, 11); (12, 10) and (16, 5) of the carbon nanotubes.

carbon


Input: Comparisons with the BDE of the weakest bonds due to intrinsic defaults (head to head and unsaturated end chain) were performed.


Input: Ectopic acromegaly due to growth hormone releasing hormone.


Input: Acromegaly secondary to extra-pituitary tumors secreting growth hormone releasing hormone (GHRH) is rarely encountered.


Input: We review the literature on ectopic acromegaly and present the index report of ectopic acromegaly secondary to GHRH secretion from a mediastinal paraganglioma.


Input: Clinical and pathological manifestations and therapeutic management of 99 patients with ectopic acromegaly are reviewed.


Input: Acromegaly secondary to ectopic GHRH secretion is usually caused by a neuroendocrine tumor in the lung and pancreas.


Input: We report an additional cause of ectopic acromegaly from a mediastinal paraganglioma.


Input: Diagnostic criteria of ectopic GHRH syndrome include biochemical and pathologic tumoral confirmation of GHRH secretion and expression.


Input: Management of ectopic acromegaly consists of surgical resection of the primary tumor and biochemical normalization, with possible adjuvant use of somatostatin analogs.


Input: The review demonstrates that there are several tumor types, including paragangliomas which may secrete GHRH, leading to acromegaly.


Input: Clinical and laboratory manifestations of the syndrome and challenges in diagnosis and management of these rarely encountered patients require early diagnosis and appropriate treatment to prevent long-term morbidity and mortality with ectopic acromegaly.


Input: Comparative cytological responses of lung epithelial and pleural mesothelial cells following in vitro exposure to nanoscale SiO2.


Input: Due to unique surface chemistries and the ability to easily functionalize their surface, amorphous silica nanoparticles are being assimilated into medicinal and consumer products at an increasing rate.

silica


Input: Subsequently, there is an emergent need to understand the interactions of these particulates with biological systems in an attempt to mitigate toxicity.


Input: The identification of susceptible or resistant cell types of the pulmonary system remains a critical step in the development of toxicity assessments for nanoparticle-based platforms.


Input: Specific to this study, the cellular responses of A549 lung epithelial and MeT-5A pleural mesothelial cell lines as a means of detecting nanoparticle-induced oxidative stress were examined.


Input: Basal expression and cellular antioxidant activity, including SOD, CAT, and GSH, were examined prior to H (2) O (2) and ~ 30 nm SiO (2) (0. 01-100mg/L) exposures.

GSH

H (2) O (2)

SiO (2)


Input: Dose-response observations were made regarding oxidant production, cytotoxicity, GSH depletion and NRF2 transcription factor activation.

GSH


Input: Results indicated that, while both cell types exhibited susceptibility to H (2) O (2) and SiO (2)-induced oxidative stress and damage, the A549 cell line was relatively more resilient.

H (2) O (2)

SiO (2)


Input: Ultrasonic treatment and synthesis of sugar alcohol modified Na +-montmorillonite clay.

sugar alcohol

Na +

montmorillonite


Input: Na (+)-montmorillonite clay (generally referred to as MMT) is very useful for reinforcing polymeric matrix at very low concentrations (typically, 2-5% wt).

Na (+)

montmorillonite

MMT


Input: These clay particles are typically exfoliated before they can demonstrate the significant gains in heat deflection temperature, modulus, and elongation properties.


Input: In the case of hydrophilic biopolymer based matrices, such as carbohydrates and chitosan, exfoliating these nanoclay particles needs greater attention because the exfoliation is typically carried out using hydrophobic oligomers through ion-exchange.

carbohydrates


Input: This study reports a new method of synthesizing completely hydrophilic MMT-assemblages using hydrophilic plasticizers for biopolymers.

MMT


Input: We used sugar alcohols (glycerol, xylitol with 3 and 5 hydroxyl groups) and polysaccharide maltodextrin to exfoliate the MMT.

sugar alcohols

glycerol

xylitol

hydroxyl

MMT


Input: Sonication was conducted for MMT nanoclay and plasticizers at different weight ratios.

MMT


Input: It was confirmed that all plasticizer/modifier led to expansion of MMT gallery spacing (d-spacing) and the change in d-spacing could be related to the molecular structure of the plasticizer.

MMT


Input: Meanwhile, the extent of exfoliation was maximum with maltodextrin (fully exfoliation with 1: 10 and 1: 20 ratio of MMT: plasticizer) across all test samples and interestingly, glycerol and xylitol samples quickly established within the MMT galleries and exhibited minimal influence with further increase in relative concentrations.

MMT

glycerol

xylitol

MMT


Input: Soy isoflavones modulate adipokines and myokines to regulate lipid metabolism in adipose tissue, skeletal muscle and liver of male Huanjiang mini-pigs.

isoflavones


Input: Although a growing body of evidence suggests that soy isoflavones help regulate lipid metabolism, the underlying mechanism has not yet been thoroughly clarified.

isoflavones


Input: The present study was undertaken to determine the effects of soy isoflavones on the expression of genes involved in lipid metabolism in different adipose tissue depots, skeletal muscle and liver of male Huanjiang mini-pigs, as well as the expression of adipokines and myokines.

isoflavones


Input: A total of 36 male Huanjiang mini-pigs were fed basal diet (control, Con), low-dose soy isoflavones (LSI) and high-dose soy isoflavones (HSI).

isoflavones

isoflavones


Input: The results showed that LSI and HSI regulated the expression of genes involved in the anabolism and catabolism of fatty acids in dorsal subcutaneous (DSA), abdominal subcutaneous (ASA) and perirenal (PRA) adipose tissue depots, as well as longissimus dorsi muscle (LDM) and liver.

fatty acids


Input: LSI and HSI also regulated the expression of adipokines in DSA, ASA and PRA, and the expression of myokines in LDM in male Huanjiang mini-pigs.


Input: In addition, soy isoflavones regulated plasma glucose, leptin and adiponectin contents after treatment for two months.

isoflavones

glucose


Input: Our results indicate that soy isoflavones, by regulating the expression of adipokines and myokines, may regulate the metabolism of lipids and could have potential therapeutic applications in lipid abnormalities.

isoflavones


Input: Decreased serum chemerin levels in male Japanese patients with type 2 diabetes: sex dimorphism.


Input: Chemerin, a recently discovered adipocytokine plays an important role in obesity and obesity-associated metabolic complications.


Input: However, the role of chemerin in the pathogenesis of type 2 diabetes mellitus (T2DM) has not fully been elucidated.


Input: We compared the serum chemerin levels and metabolic parameters between 88 control subjects, 86 patients with metabolic syndrome (MS), and 147 patients with T2DM in a Japanese population and further analyzed their correlation.


Input: Enzyme-linked immunosorbent assay was used to measure the serum chemerin levels.


Input: The chemerin levels were significantly higher in male than in female control subjects (p < 0. 005), with significant decreases in patients with T2DM compared with those with MS and control subjects (164. 9 +/- 6. 3 ng/mL vs. 209. 8 +/- 7. 7 and 218. 7 +/- 7. 3 ng/mL; p < 0. 0001 vs. p < 0. 0001, respectively) but no significant differences in female subjects.


Input: The multiple regression analysis revealed that the chemerin levels negatively correlated with the fasting glucose and HbA1c levels in total and male subjects.

glucose


Input: In the patients with T2DM, the chemerin levels negatively correlated with fasting glucose and high-density lipoprotein cholesterol but positively correlated with body mass index (BMI), and total cholesterol and triglyceride levels.

glucose

cholesterol

cholesterol

triglyceride


Input: The negative correlation between the chemerin and fasting glucose levels remained significant after adjustment for age, sex, and BMI in the total and male subjects and those with T2DM.

glucose


Input: These results suggest the role of chemerin in sex dimorphism and a potential link between chemerin levels and T2DM pathogenesis in a Japanese population.


Input: Comparative antioxidant effects of lycopene, apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in human macrophages exposed to H2O2 and cigarette smoke extract.

apo-10'-lycopenoic acid

apo-14'-lycopenoic acid


Input: Much of the beneficial effects of tomato lycopene in the prevention of chronic diseases has been attributed to its antioxidant properties, which could be mediated by its metabolites and/or oxidation products.

lycopene


Input: However, the biological functions of these lycopene derivatives remain still unknown.

lycopene


Input: In the present study, we evaluated and compared the antioxidant efficacy of the lycopene eccentric cleavage products apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in counteracting the oxidative effects of H (2) O (2) and cigarette smoke extract (CSE) in THP-1 macrophages.

lycopene

apo-10'-lycopenoic acid

apo-14'-lycopenoic acid

H (2) O (2)


Input: Both apo-10'-lycopenoic acid and apo-14'-lycopenoic acid were able to inhibit spontaneous and H (2) O (2)-induced ROS production in a dose-dependent manner.

apo-10'-lycopenoic acid

apo-14'-lycopenoic acid

H (2) O (2)


Input: Such an effect was accompanied by an inhibition of MAPK phosphorylation, by NF-kappa B inactivation, and by inhibition of hsp-70 and hsp-90 expressions.


Input: Both apo-lycopenoic acids also decreased CSE-induced ROS production, 8-OHdG formation and reduced the increase in NOX-4 and COX-2 expressions caused by CSE.

apo-lycopenoic acids


Input: However, in both the models of oxidative stress, apo-14'-lycopenoic acid was much more potent as an antioxidant than apo-10'-lycopenoic acid, showing antioxidant properties similar to lycopene.

apo-14'-lycopenoic acid

apo-10'-lycopenoic acid

lycopene


Input: These data strongly suggest that apo-lycopenoic acids, and particularly apo-14'-lycopenoic acid, may mediate some of the antioxidant functions of lycopene in cells.

apo-lycopenoic acids

apo-14'-lycopenoic acid


Input: Efficacy of all-trans retinoid acid in preventing nickel induced cardiotoxicity in myocardial cells of rats.

all-trans retinoid acid

nickel


Input: Nickel, a metal commonly found in battery plants and welding factories, has potential cardiotoxicity, while all-trans retinoid acid (atRA) can promote cardiovascular repair and myocardial recovery.

Nickel

all-trans retinoid acid

atRA


Input: The purpose of this study was to investigate whether atRA could prevent cardiotoxicity induced by nickel both in vitro and in vivo.

atRA

nickel


Input: In the study, a rat myocardial cell line (H9c2) exposed to different concentrations of nickel chloride (NiCl (2)) displayed apoptotic features accompanied by reactive oxygen species generation.

nickel chloride

NiCl (2)

oxygen


Input: In addition, NiCl (2) also caused obvious apoptosis and systolic dysfunction in primary myocardial cells.

NiCl (2)


Input: Treatment with atRA efficiently attenuated the cytotoxicities triggered by NiCl (2) as it significantly mitigated ROS generation and decreased MAP kinases activity in NiCl (2)-treated cardiomyocytes.

atRA

NiCl (2)

NiCl (2)


Input: Additionally, NiCl (2) exposure caused obvious arrhythmia in Sprague-Dawley rats with the maximum tolerance dose of NiCl (2) between 2 and 3mg/kg.

NiCl (2)

NiCl (2)


Input: A combinational intragastric administration of 40mg/kg atRA can partially reverse NiCl (2)-induced arrhythmia in rats.

atRA

NiCl (2)


Input: Our results suggested that atRA might have therapeutic potential in alleviating the adverse effects of nickel on the cardiovascular system.

atRA

nickel


Input: Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines.

Pioglitazone

cisplatin


Input: Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment.

Cisplatin


Input: The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin-induced nephrotoxicity.

pioglitazone

cisplatin


Input: The underlying suggested mechanism (s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated.

cisplatin


Input: Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator-activated receptor gamma (PPAR-gamma) antagonist), or their combination were administered to rats one hour before cisplatin injection.

Pioglitazone

Bisphenol A diglycidyl ether

BADGE

cisplatin


Input: Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied.


Input: The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-alpha), nuclear factor kappa B (NF-kappa B) genes expression in cisplatin injected rats.

pioglitazone

malondialdehyde

MDA

cisplatin


Input: It increased both renal reduced glutathione (GSH) content and PPAR-gamma gene expression.

glutathione

GSH


Input: In contrast to the data obtained by prior administration of BADGE.

BADGE


Input: Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration.

Pioglitazone

cisplatin

BADGE


Input: In conclusion, these results suggested that pioglitazone protected against cisplatin-induced nephrotoxicity through its interaction with PPAR-gamma receptors and antioxidant effects.

pioglitazone

cisplatin


Input: Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.

pioglitazone

cisplatin


Input: Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo.


Input: The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins.


Input: However, a new role for apoE as a regulator of bone metabolism in mice has recently been established.


Input: In contrast to mice, the human APOE gene is characterized by three common isoforms APOE epsilon 2, epsilon 3, and epsilon 4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans.


Input: To clarify this, we investigated bone phenotypes of apoE knock-in (k. i.) mice, which express one human isoform each (apoE2 k. i., apoE3 k. i., apoE4 k. i.) in place of the mouse apoE.


Input: Analysis of 12-week-old female k. i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k. i. animals as compared to apoE3 k. i. and apoE4 k. i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) ratio in apoE2 k. i., indicating increased turnover with prevailing resorption in apoE2 k. i.


Input: Accordingly, histomorphometric and micro-computed tomography (micro CT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k. i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance.


Input: Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms.


Input: To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for epsilon 2/epsilon 2, epsilon 3/epsilon 3, and epsilon 4/epsilon 4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers.


Input: In analogy to apoE2 k. i. mice, a lower OPG/RANKL ratio was observed in the serum of epsilon 2/epsilon 2 carriers as compared to epsilon 3/epsilon 3 and epsilon 4/epsilon 4 individuals (p = 0. 02 for epsilon 2/epsilon 2 versus epsilon 4/epsilon 4).


Input: In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE epsilon 2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans.


Input: Acute effect of calcium citrate on serum calcium and cardiovascular function.

calcium citrate

calcium


Input: Calcium supplements have been associated with an increased risk of cardiovascular events.

Calcium


Input: However, the validity of these findings has been questioned.


Input: A major concern is that the mechanism underlying an increase in cardiovascular events has not been demonstrated.


Input: Calcium initiates cardiac and vascular contraction following influx of calcium into cardiac and smooth muscle from extracellular fluid.

Calcium

calcium


Input: We have investigated whether the acute rise in serum calcium following calcium supplement administration is associated with adverse changes in cardiovascular function.

calcium

calcium


Input: In an open interventional study, we recruited 25 volunteers (16 female, age 60. 3 +/- 6. 5 years, body mass index 25. 7 +/- 2. 7 kg/m2) from the community who were not taking calcium supplements.

calcium


Input: Participants were studied before and 3 hours after a single oral dose of 1000 mg calcium citrate.

calcium citrate


Input: We assessed well-validated markers of arterial stiffness (pulse wave velocity [PWV]), arterial wave reflection (augmentation index [AIx]), and myocardial perfusion (subendocardial viability ratio [SEVR]) by pulse wave analysis and endothelial function (reactive hyperemia index [RHI]) by peripheral arterial tonometry.


Input: Total and ionized serum calcium were acutely increased by 0. 10 +/- 0. 07 and 0. 06 +/- 0. 03 mmol/L, respectively, 3 hours after calcium citrate administration (p < 0. 0001 for both comparisons).

calcium

calcium citrate


Input: Following administration of calcium citrate there was a fall in AIx from a median of 29. 7% (23. 8% to 34. 0%) to 26. 4% (22. 7% to 34. 0%, p = 0. 03) and an increase in SEVR from 163% (148% to 174%) to 170% (149% to 185%, p = 0. 007).

calcium citrate


Input: PWV and RHI were not significantly altered.


Input: The change in total calcium was negatively correlated with the change in AIx (r =-0. 48, p = 0. 02).

calcium


Input: In summary, the acute increase in serum calcium following calcium supplement administration is associated with reduced arterial wave reflection and a marker of increased myocardial perfusion.

calcium

calcium


Input: If maintained long-term, these changes would be expected to reduce cardiovascular risk.


Input: Acute serum calcium-mediated changes in these parameters of cardiovascular function are unlikely to underlie an association between calcium supplementation and cardiovascular events.

calcium

calcium


Input: Can peripheral blood gamma delta T cells predict osteonecrosis of the jaw?


Input: An immunological perspective on the adverse drug effects of aminobisphosphonate therapy.

aminobisphosphonate


Input: Nitrogen-bisphosphonates (n-BP), often referred to as aminobisphosphonates, are the most commonly prescribed drugs for the treatment of disorders of bone fragility.

Nitrogen-bisphosphonates

n-BP

aminobisphosphonates


Input: However, long-term continuous treatment predisposes certain individuals to serious rare side effects, such as bisphosphonate-associated osteonecrosis of the jaw (BAONJ).

bisphosphonate


Input: n-BP use is known to unintentionally activate a subset of innate T cells called V gamma 9V delta 2 T cells, but the consequence of this chronic immune stimulation has remained unexplored.

n-BP


Input: The primary objectives of this study were to 1) determine the fate of V gamma 9V delta 2 T cells in osteoporotic patients on n-BP therapy as a function of time and type of therapy; 2) evaluate the proportion of V gamma 9V delta 2 T cells in patients who had recently experienced n-BP-associated ONJ.

n-BP

n-BP


Input: We found there is a notable loss of V gamma 9V delta 2 T cells over time in osteoporotic patients on n-BP therapy, particularly those on intravenous (iv) therapy (Spearman r =-0. 55, p < 0. 0001 iv; r =-0. 3, p < 0. 03 oral) (n = 68); no difference was observed in total T cells, monocytes, or granulocytes.

n-BP


Input: Importantly, the observed negative effect on V gamma 9V delta 2 T cells coincides with the reported route of administration and timing of the rare occurrence of BAONJ.