Input: Several other coagulopathic and myotoxic high mass proteins including a class PIII snake venom metalloproteinase, C-type lectin, l-amino acid oxidase, acetylcholinesterase and phospholipase B were also identified that may contribute to the overall toxicity of A. superbus venom.

l-amino acid


Input: In conclusion, clinicians should be aware that early antivenom intervention might be necessary to prevent the onset of irreversible presynaptic neurotoxicity caused by multimeric and monomeric SPANs and that A. superbus venom is potentially capable of producing coagulopathic and myotoxic effects.


Input: Analysis by liquid chromatography-mass spectrometry of sterols and oxysterols in brain of the newborn Dhcr7 (Delta 3-5/T93M) mouse: A model of Smith-Lemli-Opitz syndrome.

sterols

oxysterols


Input: In this study the sterol and oxysterol profile of newborn brain from the Dhcr7 (Delta 3-5/T93M) mouse model of Smith-Lemli-Opitz syndrome (SLOS) has been investigated.

sterol

oxysterol


Input: This is a viable mouse model which is compound heterozygous containing one null allele and one T93M mutation on Dhcr7.


Input: We find the SLOS mouse has reduced levels of cholesterol and desmosterol and increased levels of 7-and 8-dehydrocholesterol and of 7-and 8-dehydrodesmosterol in brain compared to the wild type.

cholesterol

desmosterol

7-and 8-dehydrocholesterol

7-and 8-dehydrodesmosterol


Input: The profile of enzymatically formed oxysterols in the SLOS mouse resembles that in the wild type but the level of 24S-hydroxycholesterol, the dominating cholesterol metabolite, is reduced in a similar proportion to that of cholesterol.

oxysterols

cholesterol

cholesterol


Input: A number of oxysterols abundant in the SLOS mouse are probably derived from 7-dehydrocholesterol, however, the mechanism of their formation is unclear.

oxysterols


Input: Interrelationship between ATP-binding cassette transporters and oxysterols.

ATP

oxysterols


Input: ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of membrane proteins responsible for the translocation of several substances across membranes using the chemical energy provided by ATP hydrolysis.

ATP

ATP


Input: ABC transporters participate in many physiological and pathophysiological processes, including cholesterol and lipid transportation and multidrug resistance.

cholesterol


Input: Oxysterols are the products of cholesterol oxidation, formed by both enzymatic and non-enzymatic mechanisms.

Oxysterols

cholesterol


Input: The role of oxysterols in cholesterol metabolism and several diseases has been widely investigated, but many questions remain to be answered.

oxysterols

cholesterol


Input: Several lines of evidence link ABC transporter functions with cholesterol and oxysterol metabolism.

cholesterol

oxysterol


Input: This review discusses ABC transporters, oxysterols, and how they interact with each other.

oxysterols


Input: Donor substrate specificity of bovine kidney gamma-glutamyltransferase.


Input: The enzyme gamma-glutamyltransferase (GGT) catalyzes the hydrolysis of the gamma-glutamyl isopeptide bond of glutathione conjugates (donor substrates), releasing glutamic acid, or the transfer of the donor' s gamma-glutamyl group to an acceptor substrate, such as a dipeptide.

gamma-glutamyltransferase

glutathione

glutamic acid

gamma-glutamyl

dipeptide


Input: The specificity of GGT for xenobiotic donor substrates has not been fully characterized.


Input: The transpeptidation activity of bovine kidney GGT was measured with glycylglycine as the acceptor substrate and several glutathione conjugate donor substrates, representative of detoxication products of polycyclic aromatic xenobiotics.

glycylglycine

glutathione


Input: HPLC separation with UV detection was used for quantitation.


Input: The commonly-used chromogenic substrate gamma-glutamyl-p-nitroanilide was also tested.

gamma-glutamyl-p-nitroanilide


Input: Michaelis constants (Km) were obtained for 4-nitrobenzylglutathione (0. 075mM), 2, 4-dinitrophenylglutathione (0. 30mM), 4-methylbiphenylylglutathione (0. 12mM), 1-menaphthylglutathione (0. 23mM), and 9-methylanthracenylglutathione (0. 22mM), indicating a trend towards higher values for bulkier substrates.

2, 4-dinitrophenylglutathione


Input: These results provide insight into the capacity of GGT to act in the biotransformation of aromatic compounds, many of which are of toxicological importance.


Input: Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-gamma expression and inhibition of PI3K/Akt pathway.

puerarin


Input: Hepatic fibrosis (HF) is a chronic disease, which primarily leads to liver unregulated metabolism.


Input: In this study, we aimed to investigate the therapeutic effects of puerarin (PR), an active ingredient from kudzu root, on CCl4-induced HF rats.

puerarin


Input: PR effectively ameliorated the liver metabolic function, resulting in reduced serum enzymatic activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total-bilirubin (T-bilirubin), extracellular matrix (ECM) contents and increased levels of albumin, total-protein (T-protein) in HF rats.

alanine

aspartate

bilirubin

bilirubin


Input: Similarly, pathological examination showed that the CCl4-lesioned liver was mitigated by PR treatments.


Input: Meanwhile, we also detected significantly reduced levels of hydroxyproline (Hyp), type III precollagen (PCIII) and collagen I (Col I) in the liver tissue of HF rats, whereas the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression was effectively increased.

hydroxyproline

Hyp


Input: Moreover, the expression of tissue inhibitor of metal protease-1 (TIMP-1) was decreased, while the expression of matrix metalloproteinase-2 (MMP-2) was increased.


Input: In addition, the expression of p-PI3K and p-Akt was significantly down-regulated by PR treatments.


Input: Taken together, PR could attenuate the CCl4-induced toxicity in the hepatocytes of HF rats.


Input: It played a protective role in the liver tissue probably through regulating the PPAR-gamma expression and blocking the PI3K/Akt pathway to inhibit the excessive deposition of collagen.


Input: Dietary exposure of juvenile female mice to polyhalogenated seafood contaminants (HBCD, BDE-47, PCB-153, TCDD): Comparative assessment of effects in potential target tissues.

HBCD

TCDD


Input: Fish represents source of nutrients and major dietary vehicle of lipophilic persistent contaminants.


Input: The study compared the effects of two legacy and two emerging fish pollutants (Hexabromocyclododecane HBCD; 2, 2', 4, 4'-Tetrabromodiphenyl ether BDE-47; 2, 2', 4, 4', 5, 5'-Hexachlorobiphenyl PCB-153; 2, 3, 7, 8-Tetrachlorodibenzo-p-doxin TCDD) in juvenile female mice exposed through a salmon based rodent diet for 28days (dietary doses: HBCD 199mg/kg bw/day; BDE-47 450 mu g/kg bw/day; PCB-153 195 mu g/kg bw/day; TCDD 90ng/kg bw/day).

Hexabromocyclododecane HBCD

2, 2', 4, 4'-Tetrabromodiphenyl ether BDE-47

2, 2', 4, 4', 5, 5'-Hexachlorobiphenyl PCB-153

2, 3, 7, 8-Tetrachlorodibenzo-p-doxin TCDD

HBCD

TCDD


Input: Dose levels were comparable to previously reported developmental Lowest Observed Adverse Effect Levels.


Input: None of the treatments elicited signs of overt toxicity, but HBCD increased relative liver weight.

HBCD


Input: All compounds caused changes in liver, thymus and thyroid; spleen was affected by BDE-47 and PCB-153; no effects were seen in uterus and adrenals.


Input: Strongest effects in thyroid follicles were elicited by PCB-153, in thymus and liver by BDE-47.


Input: HBCD and BDE-47 induced liver fatty changes, but appeared to be less potent in the other tissues.

HBCD


Input: HBCD, BDE-47 and TCDD increased serum testosterone levels and the testosterone/estradiol ratio, suggesting a potential involvement of pathways related to sex steroid biosynthesis and/or metabolism.

HBCD

TCDD

testosterone

testosterone

estradiol

steroid


Input: The results support the role of toxicological studies on juvenile rodents in the hazard characterization of chemicals, due to endocrine and/or immune effects.


Input: Gambogic acid inhibits angiogenesis through inhibiting PHD2-VHL-HIF-1 alpha pathway.

Gambogic acid


Input: Our previous studies revealed that gambogic acid (GA), the major active ingredient of gamboge, possessed antiangiogenic activities.

gambogic acid


Input: In this study, we further explored the mechanism of inhibition effects of GA in tumor angiogenesis.


Input: The results of luciferase, RT-PCR, and ELISA assays indicated that GA significantly decreased transcription activation, mRNA expression, and secretion of VEGF in hypoxia.


Input: We detected that GA had no effect on mRNA level of HIF-1 alpha which targets VEGF gene, but the increase of HIF-1 alpha protein expression in hypoxia was repressed by GA, which can be reversed by proteasomal inhibitor MG132 and siRNA of VHL.


Input: But GA exhibited no effect on expression of VHL both in normoxia and hypoxia.


Input: HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis.

prolyl

oxygen


Input: Our results showed that GA potentially enhanced level of PHD2, the most important HIF hydroxylase, and showed no effect on PHD1 and PHD3.


Input: Transient transfection of siRNA of PHD2 could eliminate GA-induced VEGF secretion increase.


Input: Growth of HepG2 xenografts in BALB/cA nude mice was inhibited by GA and angiogenesis was repressed significantly in tumor xenografts by immunohistochemical staining of CD-31, a vascular endothelial marker, accompanied with decrease of HIF-1 alpha and increase of PHD2 expression in tissue extracts.


Input: This work provides the demonstration that GA shows anti-angiogenic effects via inhibiting PHD2-VHL-HIF-1 alpha pathway.


Input: Coumarins hinged directly on benzimidazoles and their ribofuranosides to inhibit hepatitis C virus.

Coumarins

benzimidazoles

ribofuranosides


Input: A new compound library that contained 20 hinged benzimidazole-coumarin hybrids and their beta-d-ribofuranosides was established.

benzimidazole

coumarin

beta-d-ribofuranosides


Input: The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested.

coumarin


Input: Two of these hybrids exhibited appealing EC50 values of as low as 3. 0 and 5. 5 mu M.


Input: The best selectivity index was 14.


Input: The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the beta configuration, one of which inhibited HCV replication with an EC50 value of 20 mu M.

d-ribofuranose

nucleosides


Input: Additionally, the structure-activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids.

benzimidazole

coumarin

ribofuranose


Input: The protective role of l-carnitine against cylindrospermopsin-induced oxidative stress in tilapia (Oreochromis niloticus).

l-carnitine

cylindrospermopsin


Input: Cylindrospermopsin (CYN) is one of the most important cyanotoxins in terms of both human health and environmental quality and is produced by several different species of cyanobacteria, including Aphanizomenon ovalisporum.

Cylindrospermopsin

CYN


Input: The principal mechanisms of action of CYN involve inhibition of protein and glutathione synthesis.

CYN

glutathione


Input: In addition, CYN-mediated genotoxicity results from DNA fragmentation.

CYN


Input: The results of both in vivo and in vitro studies suggest that oxidative stress also plays a significant role in CYN pathogenesis in fish.

CYN


Input: We investigated the protective effects of l-carnitine (LC) pre-treatment on A. ovalisporum-induced oxidative stress in cells containing CYN and deoxy-CYN, or pure standard CYN, in tilapia (Oreochromis niloticus) that had been acutely exposed via oral administration.

l-carnitine

CYN

deoxy-CYN

CYN


Input: Various oxidative stress markers, including lipid peroxidation (LPO), protein oxidation, DNA oxidation, and the ratio of reduced glutathione to oxidised glutathione (GSH/GSSG), and the activities of NADPH oxidase, superoxide dismutase (SOD), catalase (CAT), and gamma-glutamyl-cysteine synthetase (gamma-GCS), were evaluated in the livers and kidneys of fish in the absence and presence of 400 or 880mgLC/kgfish/day during a 21 day period prior to CYN-intoxication.

reduced glutathione

oxidised glutathione

GSH

GSSG

NADPH

superoxide

gamma-glutamyl-cysteine

CYN


Input: The results of our study demonstrated for the first time the beneficial antioxidant effects of LC dietary supplementation on oxidative stress status in fish.


Input: No pro-oxidant effects were detected at any of the LC doses assayed, suggesting that LC is a chemoprotectant that reduces hepatic and renal oxidative stress and may be effective when used for the prophylaxis and treatment of CYN-related intoxication in fish.

CYN


Input: A child exposed to primidone not prescribed for her.

primidone


Input: A 7. 5-year-old girl who was treated with phenobarbital (PHB) for epilepsy was admitted with decreased levels of consciousness.

phenobarbital

PHB


Input: She had been known to have high PHB levels of unknown cause, without symptoms.

PHB


Input: Her PHB levels were very high, as expected, but primidone levels were also detected although she and her parents denied history of primidone administration.

PHB

primidone

primidone


Input: We wished to rule out intentional unprescribed use of primidone.

primidone


Input: Our retrospective review showed 3 other children with high PHB concentrations where primidone was also detected when PHB levels were over 130 mu mol/L.

PHB

primidone

PHB


Input: Complementary studies confirmed that high-dose PHB can convert to its prodrug primidone, which has not been reported previously.

PHB

primidone


Input: Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes.

imatinib


Input: Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects.

imatinib


Input: The present analysis offers a systematic qualitative and quantitative summary and comparison of those.


Input: Its primary objective was to provide useful information for evaluating the expectedness of imatinib plasma concentration measurements in the frame of therapeutic drug monitoring.

imatinib


Input: The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitability of plasma concentration values.


Input: Nine PPK models describing total imatinib plasma concentration were identified.

imatinib


Input: Parameter estimates were standardized to common covariate values whenever possible.


Input: Predicted median exposure (C min) was derived by simulations and ranged between models from 555 to 1388 ng/mL (grand median: 870 ng/mL and interquartile " reference " range: 520-1390 ng/mL).


Input: Covariates of potential clinical importance (up to 30% change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, alpha 1 acid glycoprotein, and white blood cell count.


Input: Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial.


Input: Concentration-response relationships had more importance below the average reference range and concentration-toxicity relationships above.


Input: Therapeutic drug monitoring-guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials.

imatinib


Input: To evaluate the expectedness of a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics.


Input: For future research, external PPK model validation or meta-model development should be considered.


Input: Enteropathogenic Escherichia coli-induced macrophage inhibitory cytokine 1 mediates cancer cell survival: an in vitro implication of infection-linked tumor dissemination.


Input: Mucosally adherent Escherichia coli is frequently observed in intestinal surface of patients with colorectal cancer, but rarely in healthy control.


Input: Particularly, enteropathogenic Escherichia coli (EPEC) is known to be closely associated with colorectal carcinogenesis in human.


Input: In this study, one consequence of EPEC infection in human intestinal cancer cells was induction of macrophage inhibitory cytokine 1 (MIC-1), which is a multifunctional cytokine with biological activities involved in cancer cell growth, differentiation and migration.


Input: The present investigation assessed the involvement of MIC-1 protein in EPEC infection-mediated cancer cell survival.


Input: The challenge with EPEC induced cancer cell detachment via cytoskeleton rearrangement, which was positively associated with induced MIC-1 expression.


Input: Moreover, MIC-1 also mediated RhoA GTPase-linked survival of the detached cancer cells.


Input: Blocking of MIC-1 or RhoA activity increased cellular apoptosis of the detached cancer cells.


Input: In terms of signaling pathway, MIC-1 triggered transforming growth factor beta-activated kinase 1 (TAK1), which enhanced expression of RhoA GTPase.


Input: We conclude that EPEC enhances MIC-1 gene expression in the human intestinal cancer cells, which can be associated with enhanced tumor cell resistance to anchorage-dependent tumor cell death via enhanced TAK1 and RhoA GTPase. Oncogene advance online publication, 18 March 2013; doi: 10. 1038/onc. 2012. 508.


Input: The regulatory roles of phosphatases in cancer.


Input: The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology.


Input: Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied.


Input: Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking.

phosphatidylinositol


Input: In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. Oncogene advance online publication, 18 March 2013; doi: 10. 1038/onc. 2013. 80.


Input: Sol-gel nanoglues for an organic binder-free TiO2 nanofiber anode for lithium ion batteries.

lithium


Input: A TiO2 nanofiber anode is glued using a sol-gel reaction to improve cycle performance and Coulombic efficiencies.


Input: The hydrolysis-condensation process produces TiO2 nanoglues consisting of TiO2 nanoparticles, providing strong adhesion between nanofibers and the current collector as well as between nanofibers, rendering favourable transporting properties of electrons and Li ions in the TiO2 nanofiber electrode, and eventually leading to the excellent performance of Li ion batteries exhibiting an excellent initial Coulombic efficiency (~ 85%), cycle performance up to 100 cycles, and high rate capability (60% at 5 C).

Li

Li


Input: Cellular effects of manufactured nanoparticles: effect of adsorption ability of nanoparticles.


Input: Nanoparticles are important industrial materials.


Input: However, many nanoparticles show biological effects, including toxic activity.


Input: Metal ion release is the most important factor affecting the biological effects of nanoparticles.


Input: In addition, nanoparticles have large adsorption ability.


Input: The adsorption ability, in particular protein adsorption to nanoparticles, has an effect on cellular uptake and cellular metabolisms.


Input: Moreover, the adsorption ability of nanoparticles causes artificial effects in in vitro systems.


Input: Consequently, accurate determination of released or secreted proteins such as lactate dehydrogenase and cytokines adsorbed to nanoparticles is affected.

lactate


Input: In addition, artificial effects cause overestimation or underestimation of the cytotoxicity of nanoparticles.


Input: Therefore, measurement of the protein adsorption of nanoparticles is important.


Input: Some methods for the determination of the adsorption to nanoparticles have been suggested.


Input: The flow field-flow fractionation method is one of the efficient techniques for determining proteins on the surface of nanoparticles.


Input: The cellular effects caused by nanoparticles should be carefully considered.


Input: Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis.

Xanthohumol


Input: Health beneficial effects of xanthohumol have been reported, and basic research provided evidence for anti-cancer effects.

xanthohumol


Input: Furthermore, xanthohumol was shown to inhibit the migration of endothelial cells.

xanthohumol


Input: Therefore, this study investigated the anti-metastatic potential of xanthohumol.

xanthohumol


Input: MCF-7 breast cancer spheroids which are placed on lymphendothelial cells (LECs) induce " circular chemorepellent-induced defects " (CCIDs) in the LEC monolayer resembling gates for intravasating tumour bulks at an early step of lymph node colonisation.


Input: NF-kappa B reporter-, EROD-, SELE-, 12 (S)-HETE-and adhesion assays were performed to investigate the anti-metastatic properties of xanthohumol.

12 (S)-HETE

xanthohumol


Input: Western blot analyses were used to elucidate the mechanisms inhibiting CCID formation.


Input: Xanthohumol inhibited the activity of CYP, SELE and NF-kB and consequently, the formation of CCIDs at low micromolar concentrations.

Xanthohumol


Input: More specifically, xanthohumol affected ICAM-1 expression and adherence of MCF-7 cells to LECs, which is a prerequisite for CCID formation.

xanthohumol


Input: Furthermore, markers of epithelial-to-mesenchymal transition (EMT) and of cell mobility such as paxillin, MCL2 and S100A4 were suppressed by xanthohumol.

xanthohumol


Input: Xanthohumol attenuated tumour cell-mediated defects at the lymphendothelial barrier and inhibited EMT-like effects thereby providing a mechanistic explanation for the anti-intravasative/anti-metastatic properties of xanthohumol.

Xanthohumol

xanthohumol


Input: Gas-phase structures and thermochemistry of neutral histidine and its conjugated acid and base.

histidine


Input: Extensive exploration of the conformational space of neutral, protonated and deprotonated histidine has been conducted at the G4MP2 level.

histidine


Input: Theoretical protonation and deprotonation thermochemistry as well as heats of formation of gaseous histidine and its ionized forms have been calculated at the G4 level considering either the most stable conformers or an equilibrium population of conformers at 298 K.

histidine


Input: These theoretical results were compared to evaluated experimental determinations.


Input: Recommended proton affinity and protonation entropy deduced from these comparisons are PA (His) = 980 kJ mol (-1) and Delta pS (His) ~ 0 J mol (-1) K (-1), thus leading to a gas-phase basicity value of GB (His) = 947. 5 kJ mol (-1).

His

His

His


Input: Similarly, gas phase acidity parameters are Delta acidH (o) (His) = 1373 kJ mol (-1), Delta acidS (His) ~ 10 J mol (-1) K (-1) and Delta acidG (o) (His) = 1343 kJ mol (-1).

His

His

His


Input: Computed G4 heats of formation values are equal to-290, 265 and-451 kJ mol (-1) for gaseous neutral histidine and its protonated and deprotonated forms, respectively.

histidine


Input: The present computational data correct, and complete, previous thermochemical parameter estimates proposed for gas-phase histidine and its acido-basic properties.


Input: Maternal perinatal diet induces developmental programming of bone architecture.


Input: Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming.


Input: This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength.


Input: We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation.


Input: Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet.


Input: Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance.

glucose


Input: Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P < 0. 05 for both).

glucose


Input: WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P < 0. 05 for all).


Input: Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P < 0. 05 for both).

glucose


Input: Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P < 0. 05).


Input: Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P < 0. 05 for both).


Input: These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.


Input: LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice.


Input: In addition to the well known regulating effects of leptin on energy balance and glucose homeostasis through the central nervous system, circulating leptin has a direct effect on pancreatic islet and insulin secretion through its receptor (OBRb).

glucose


Input: The LIM-homeodomain transcription factor Isl-1 is expressed in all classes of pancreatic endocrine cells and is involved in regulating both islet development and insulin secretion.


Input: Both OBRb and Isl-1 mutations result in obesity-related diabetes.


Input: However, the interactions and physiological significance of leptin and Isl-1 in pancreatic islets remain to be established.


Input: Here, we show that most of leptin target cells in pancreatic islets and NIT beta cells express Isl-1.


Input: Both in vivo and in vitro results demonstrate that leptin suppresses Isl-1 expression and insulin secretion in islet in physiological and pathophysiological conditions, e. g. high fat diet.


Input: This effect of leptin on insulin secretion is lost in leptin receptor-defective db/db and Isl-1-inducible knock-out mice.


Input: We conclude that the action of leptin on insulin secretion is at least partly mediated by Isl-1.


Input: Another new finding of this study is that Isl-1 acts as a direct downstream target of leptin signaling molecule STAT3 to influence the effect of leptin on insulin secretion, whereas inversely, insulin has feedback regulating effects on Isl-1 expression through JAK-STAT3 pathway.


Input: These findings are crucial for understanding the mechanisms regulating insulin secretion and metabolism in related diseases, such as obesity and type 2 diabetes.


Input: Testicular function and fertility in men with Klinefelter syndrome: a review.


Input: Klinefelter syndrome, 47, XXY (KS), is the most frequent sex chromosome aberration in males, affecting 1 in 660 newborn boys.


Input: The syndrome is characterized by testicular destruction with extensive fibrosis and hyalinization of the seminiferous tubules resulting in small testes, hypergonadotropic hypogonadism, and azoospermia in the majority of cases.


Input: Until recently, infertility was considered an untreatable condition in KS.


Input: However, with the development of new advanced assisted reproductive techniques such as testicular sperm extraction (TESE) combined with ICSI it seems that KS patients should no longer be labelled as infertile.


Input: Especially, microdissection (micro)-TESE has proved to be an advantageous procedure for the identification of testicular spermatozoa in KS.


Input: The aim of this review was to describe current knowledge on the testicular changes occurring in KS, the associated changes in reproductive hormones and spermatogenesis, and the existing possibilities of biological fatherhood in 47, XXY patients.


Input: Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases.

Polyglutamine

Polyglutamine


Input: Protein misfolding and aggregation in the brain have been recognized to be crucial in the pathogenesis of various neurodegenerative diseases, including Alzheimer' s, Parkinson' s, and the polyglutamine (polyQ) diseases, which are collectively called the " protein misfolding diseases ".

polyglutamine

polyQ


Input: In the polyQ diseases, an abnormally expanded polyQ stretch in the responsible proteins causes the proteins to misfold and aggregate, eventually resulting in neurodegeneration.

polyQ

polyQ


Input: Hypothesizing that polyQ protein misfolding and aggregation could be inhibited by molecules specifically binding to the expanded polyQ stretch, we identified polyQ binding peptide 1 (QBP1).

polyQ

polyQ

polyQ


Input: We show that QBP1 does, indeed, inhibit misfolding and aggregation of the expanded polyQ protein in vitro.

polyQ


Input: Furthermore overexpression of QBP1 by the crossing of transgenic animals inhibits neurodegeneration in Drosophila models of the polyQ diseases.

polyQ


Input: We also introduce our attempts to deliver QBP1 into the brain by administration using viral vectors and protein transduction domains.


Input: Interestingly, recent data suggest that QBP1 can also inhibit the misfolding/aggregation of proteins responsible for other protein misfolding diseases, highlighting the potential of QBP1 as a general therapeutic molecule for a wide range of neurodegenerative diseases.


Input: We hope that in the near future, aggregation inhibitor-based drugs will be developed and bring relief to patients suffering from these currently intractable protein misfolding diseases.


Input: The Pharmacokinetics and Pharmacodynamics of Zaleplon Delivered as a Thermally Generated Aerosol in a Single Breath to Volunteers.

Zaleplon


Input: Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers.

zaleplon


Input: Forty participants received 0. 5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study.

zaleplon


Input: Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours.


Input: Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1. 89 (1. 45, 3. 08) minutes and the mean (SD) elimination half-life was 1. 24 (0. 24) hours.


Input: The equilibration half-life for sedation (t1/2 ke0) was 1. 16 (0. 62, 2. 17) minutes.


Input: The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0. 92 (0. 82, 1. 02).

zaleplon


Input: No clinically significant changes were noted in laboratory values, vital signs, or spirometry.


Input: The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance.


Input: Zaleplon inhalation represents a safe, well-tolerated means of rapidly achieving effective plasma concentrations.

Zaleplon


Input: Exposure-Exposure Relationship of Tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis.


Input: Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies.


Input: Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers.


Input: A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies.


Input: An indirect-response model with a sigmoid Emax (maximal drug effect) inhibitory drug effect on DAS28 " production " rate adequately described the relationship between tocilizumab concentration and DAS28.


Input: Mean minimum serum tocilizumab concentration at steady state was greater than the EC50 (concentration at which 50% of Emax on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose.


Input: Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg.


Input: Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant.


Input: Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships.


Input: These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.


Input: Sclerostin and bone strength in women in their 10 (th) decade of life.


Input: Sclerostin is a potent inhibitor of bone formation but has been shown to correlate positively with areal bone mineral density (aBMD).


Input: Little is known about its relationship to parameters of bone strength and volumentric BMD (vBMD) as measured by peripheral quantitative computed tomography (pQCT).


Input: We measured both serum sclerostin and parameters of tibial bone size and strength by pQCT to characterize this relationship.


Input: Our study population consisted of 223 Caucasian and 35 African American women (mean age 87) from the Study of Osteoporotic Fractures (SOF) cohort, who had usable pQCT scans of the tibia at sites 4% (T4%), 33% (T33%), and 66% (T66%) from the ankle.


Input: Analysis of covariance was used to test for differences in age-adjusted means of aBMD, pQCT variables, and serum biomarkers across sclerostin quartiles.


Input: Black women had significantly lower median sclerostin (34. 3 pmol/L) than white women (48. 5 pmol/L) (p = 0. 05).


Input: Women in the highest sclerostin quartile had 7-14. 5% higher hip aBMD and pQCT parameters of vBMD and bone size than those in the lowest quartile in multivariate models adjusting for age, race, weight, height and diabetes.


Input: The association of sclerostin with parameters of bone strength differed dramatically between T33% and T66% sites.


Input: At T66%, women in the highest sclerostin quartile had pQCT strength parameters 9. 4-15. 3% greater than the lowest quartile, whereas no trend was found for the T33% site.


Input: Our results suggest paradoxical associations between circulating sclerostin and bone size, density and strength.


Input: (c) 2013 American Society for Bone and Mineral Research.


Input: Interplay of Octahedral Tilts and Polar Order in BiFeO3 Films.


Input: Heterointerface stabilization of a distinct nonpolar BiFeO3 phase occurs simultaneously with changes in octahedral tilts.


Input: The resulting phase arises via suppression of polarization by a structural order parameter and can thus be identified as anti-ferroelectric (Fe displacements-bottom panel).

Fe


Input: The phase is metastable and can be switched into a polar ferroelectric state (top panel) under an applied electric bias.


Input: Cobalt chloride speciation, mechanisms of cytotoxicity on human pulmonary cells, and synergistic toxicity with zinc.

Cobalt chloride

zinc


Input: Cobalt is used in numerous industrial sectors, leading to occupational diseases, particularly by inhalation.

Cobalt


Input: Cobalt-associated mechanisms of toxicity are far from being understood and information that could improve knowledge in this area is required.

Cobalt


Input: We investigated the impact of a soluble cobalt compound, CoCl (2). 6H (2) O, on the BEAS-2B lung epithelial cell line, as well as its impact on metal homeostasis.

cobalt

CoCl (2). 6H (2) O


Input: Cobalt speciation in different culture media, in particular soluble and precipitated cobalt species, was investigated via theoretical and analytical approaches.

Cobalt

cobalt


Input: The cytotoxic effects of cobalt on the cells were assessed.

cobalt


Input: Upon exposure of BEAS-2B cells to cobalt, intracellular accumulation of cobalt and zinc was demonstrated using direct in situ microchemical analysis based on ion micro-beam techniques and analysis after cell lysis by inductively coupled plasma mass spectrometry (ICP-MS).

cobalt

cobalt

zinc


Input: Microchemical imaging revealed that cobalt was rather homogeneously distributed in the nucleus and in the cytoplasm whereas zinc was more abundant in the nucleus.

cobalt

zinc


Input: The modulation of zinc homeostasis led to the evaluation of the effect of combined cobalt and zinc exposure.

zinc

cobalt

zinc


Input: In this case, a clear synergistic increase in toxicity was observed as well as a substantial increase in zinc content within cells.

zinc


Input: Western blots performed under the same coexposure conditions revealed a decrease in ZnT1 expression, suggesting that cobalt could inhibit zinc release through the modulation of ZnT1.

cobalt

zinc


Input: Overall, this study highlights the potential hazard to lung function, of combined exposure to cobalt and zinc.

cobalt

zinc


Input: Boosting Immunity to Small Tumor-Associated Carbohydrates with Bacteriophage Q beta Capsids.

Carbohydrates


Input: The development of an effective immunotherapy is an attractive strategy toward cancer treatment.


Input: Tumor associated carbohydrate antigens (TACAs) are overexpressed on a variety of cancer cell surfaces, which present tempting targets for anticancer vaccine development.

carbohydrate


Input: However, such carbohydrates are often poorly immunogenic.

carbohydrates


Input: To overcome this challenge, we show here that the display of a very weak TACA, the monomeric Tn antigen, on bacteriophage Q beta virus-like particles elicits powerful humoral responses to the carbohydrate.

carbohydrate


Input: The effects of adjuvants, antigen display pattern, and vaccine dose on the strength and subclasses of antibody responses were established.


Input: The local density of antigen rather than the total amount of antigen administered was found to be crucial for induction of high Tn-specific IgG titers.


Input: The ability to display antigens in an organized and high density manner is a key advantage of virus-like particles such as Q beta as vaccine carriers.


Input: Glycan microarray analysis showed that the antibodies generated were highly selective toward Tn antigens.


Input: Furthermore, Q beta elicited much higher levels of IgG antibodies than other types of virus-like particles, and the IgG antibodies produced reacted strongly with the native Tn antigens on human leukemia cells.


Input: Thus, Q beta presents a highly attractive platform for the development of carbohydrate-based anticancer vaccines.

carbohydrate


Input: Cell Durotaxis on Polyelectrolyte Multilayers with Photogenerated Gradients of Modulus.


Input: Behaviors of rat aortic smooth muscle (A7r5) and human osteosarcoma (U2OS) cells on photo-cross-linked polyelectrolyte multilayers (PEMUs) with uniform, or gradients of, moduli were investigated.


Input: The PEMUs were built layer-by-layer with the polycation poly (allylamine hydrochloride) (PAH) and a polyanion poly (acrylic acid) (PAA) that was modified with photoreactive 4-(2-hydroxyethoxy) benzophenone (PAABp).

poly (allylamine hydrochloride)

PAH

poly (acrylic acid)

PAA

4-(2-hydroxyethoxy) benzophenone


Input: PEMUs with different uniform and gradients of modulus were generated by varying the time of uniform ultraviolet light exposure and by exposure through optical density gradient filters.


Input: Analysis of adhesion, morphology, cytoskeletal organization, and motility of the cells on the PEMUs revealed that A7r5 cells established a polarized orientation toward increasing modulus on shallow modulus gradients (approximately 4. 7 MPa mm (-1)) and durotaxed toward stiffer regions on steeper gradients (approximately 55 MPa mm (-1)).


Input: In contrast, U2OS cells exhibited little orientation or durotaxis on modulus gradients.


Input: These results demonstrate the utility of photo-cross-linked PEMUs to direct vascular and osteoblast cell behavior, a potential application for PEMU coatings on biomedical implants.


Input: New selective inhibitors of MMP-13 for inflammatory diseases: a patent evaluation (W02012151158).


Input: A series of compounds incorporating an aromatic scaffold based on isoxazolines were prepared in the patent application (WO2012151158).

isoxazolines


Input: The new compounds from the patent are defined to be biologically active metabolites, prodrugs, isomers, stereoisomers, solvates, hydrates and pharmaceutically acceptable salts, they are claimed to be useful for treating immunological conditions because of their inhibitory activities on matrix metalloproteinase (MMP-13), although no specific MMP-13 inhibition data or other rationale to explain their biological effects is provided.


Input: The compounds have a broad potential utility with osteoarthritis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, degenerative joint disease or systemic lupus erythematosus among the likely preferred indications.


Input: Increased Levels of Inosine in a Mouse Model of Inflammation.

Inosine


Input: One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation.

oxygen

nitrogen

halogen


Input: To determine the most biologically deleterious chemistries of inflammation, we previously assessed products across the spectrum of DNA damage arising in inflamed tissues in the SJL mouse model nitric oxide overproduction (Pang et al. (2007) Carcinogenesis 28, 1807-1813).

nitric oxide


Input: Among the anticipated DNA damage chemistries, we observed significant changes only in lipid peroxidation-derived etheno adducts.

etheno


Input: We have now developed an isotope-dilution, liquid chromatography-coupled, tandem quadrupole mass spectrometric method to quantify representative species across the spectrum of RNA damage products predicted to arise at sites of inflammation, including nucleobase deamination (xanthosine and inosine), oxidation (8-oxoguanosine), and alkylation (1, N (6)-ethenoadenosine).

nucleobase

xanthosine

inosine

1, N (6)-ethenoadenosine


Input: Application of the method to the liver, spleen, and kidney from the SJL mouse model revealed generally higher levels of oxidative background RNA damage than was observed in DNA in control mice.


Input: However, compared to control mice, RcsX treatment to induce nitric oxide overproduction resulted in significant increases only in inosine and only in the spleen.

nitric oxide

inosine


Input: Further, the nitric oxide synthase inhibitor, N-methylarginine, did not significantly affect the levels of inosine in control and RcsX-treated mice.

nitric oxide

N-methylarginine

inosine


Input: The differences between DNA and RNA damage in the same animal model of inflammation point to possible influences from DNA repair, RcsX-induced alterations in adenosine deaminase activity, and differential accessibility of DNA and RNA to reactive oxygen and nitrogen species as determinants of nucleic acid damage during inflammation.

adenosine

oxygen

nitrogen


Input: Comprehensive Experimental and Computational Analysis of Binding Energy Hot Spots at the NF-kappa B Essential Modulator/IKK beta Protein-Protein Interface.


Input: We report a comprehensive analysis of binding energy hot spots at the protein-protein interaction (PPI) interface between nuclear factor kappa B (NF-kappa B) essential modulator (NEMO) and I kappa B kinase subunit beta (IKK beta), an interaction that is critical for NF-kappa B pathway signaling, using experimental alanine scanning mutagenesis and also the FTMap method for computational fragment screening.


Input: The experimental results confirm that the previously identified NEMO binding domain (NBD) region of IKK beta contains the highest concentration of hot-spot residues, the strongest of which are W739, W741, and L742 (Delta Delta G = 4. 3, 3. 5, and 3. 2 kcal/mol, respectively).


Input: The region occupied by these residues defines a potentially druggable binding site on NEMO that extends for ~ 16 A to additionally include the regions that bind IKK beta L737 and F734.


Input: NBD residues D738 and S740 are also important for binding but do not make direct contact with NEMO, instead likely acting to stabilize the active conformation of surrounding residues.


Input: We additionally found two previously unknown hot-spot regions centered on IKK beta residues L708/V709 and L719/I723.


Input: The computational approach successfully identified all three hot-spot regions on IKK beta.


Input: Moreover, the method was able to accurately quantify the energetic importance of all hot-spot residues involving direct contact with NEMO.


Input: Our results provide new information to guide the discovery of small-molecule inhibitors that target the NEMO/IKK beta interaction.


Input: They additionally clarify the structural and energetic complementarity between " pocket-forming " and " pocket-occupying " hot-spot residues, and further validate computational fragment mapping as a method for identifying hot spots at PPI interfaces.


Input: Targeting TRP Channels in Airway Disorders.


Input: Novel effective therapeutic agents are actively sought for the treatment of a broad spectrum of respiratory diseases which collectively significantly impact on mortality, morbidity and quality of life of hundreds of millions of people world-wide.


Input: These include asthma, allergic rhinitis, chronic obstructive pulmonary disease, cough, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis and acute lung injury.


Input: TRP channels are broadly distributed throughout the respiratory tract and play an important physiological role in sensing and subsequently responding to a wide variety of stimuli, for example temperature, osmolarity and oxidant stress.


Input: In the context of respiratory disease however TRP channel function may be altered, eg: under conditions of oxidative stress, inflammation, hypoxia and mechanical stress.


Input: In addition there is evidence that the expression/activity of TRP channels can be affected in the disease setting.


Input: Modulators of TRP channel function are therefore under investigation for a range of diseases including disorders of the respiratory system.


Input: Several excellent review articles have discussed in detail evidence that modulation of specific TRP channels may be of benefit in specific respiratory diseases.


Input: In this article we have taken the approach of reviewing evidence that modulation of TRP channel function may be able to affect common and over-lapping characteristic features of respiratory diseases, for example bronchoconstriction, airways hyper-responsiveness, cough, airways inflammation, mucus hyper-secretion, exacerbations, lung injury, hypoxia and airways re-modelling.


Input: The therapeutic potential of TRP channel modulators, the status of these agents in the clinic along with the challenges posed in this rapidly advancing field are also discussed in this review.


Input: The hemodynamics of septic shock: a historical perspective.


Input: In the late 19th century, it was already known that severe infections could be associated with cardiovascular collapse, a fact essentially attributed to cardiac failure.


Input: A major experimental work in the rabbit, published by Romberg and P a ssler in 1899, shifted attention to disturbed peripheral vascular tone as the mechanism of hypotension in these conditions.


Input: In the first half of the 20th century, great progresses were made in the pathophysiologic understanding of hemorrhagic and traumatic shocks, while researchers devoted relatively little attention to septic shock.


Input: Progress in the hemodynamic understanding of septic shock resumed with the advent of critical care units.


Input: The hyperdynamic state was recognized in the late fifties and early sixties.


Input: The present short review ends with landmark studies by Max Harry Weil, demonstrating the importance of venous pooling, and John H. Siegel, which introduced the concept of deficient peripheral utilization of oxygen, inspiring later work on the microvascular disturbances of septic shock.

oxygen


Input: Effect of Enzyme Concentration of the Morphology and Properties of Enzymatically Triggered Peptide Hydrogels.


Input: We have recently shown that thermolysine, a protease enzyme obtained from Bacillus thermoproteolyticus rokko, can be used to trigger the gelation of FEFK (F, phenylalanine; E, glutamic acid; K, lysine) tetrapeptides through reverse hydrolysis and formation of longer peptide sequences, mainly octapeptides, that self-assemble readily.

phenylalanine

glutamic acid

lysine


Input: In this article we investigate the effect of enzyme concentration on the morphology and properties of enzymatically triggered peptide hydrogels using HPLC, FTIR, real-time SAXS, TEM, and shear rheology.


Input: We have shown that the enzyme concentration, Cenz, does not affect the final composition of the samples.


Input: Instead, this is dictated by the initial tetrapeptide concentration, C0, suggesting the existence of a chemical equilibrium.


Input: We went on to show that Cenz does not affect the self-assembly of these peptides at a molecular level either nor the structure of the fibrillar network formed at the nanometer scale.


Input: Interestingly, the mechanical properties were found to be affected by Cenz, where the shear moduli of the hydrogels were found to increase with increasing Cenz.


Input: These results suggest that morphological differences between the hydrogels at the microscale are at the origin of their difference in mechanical properties.


Input: In this paper, we propose a morphological model in which denser network regions are found around the enzymes, resulting in the creation of heterogeneous networks.


Input: These were confirmed by TEM measurements.


Input: The existence of these denser network regions will result in the reinforcement of the hydrogels, thus, explaining the high shear moduli obtained increasing Cenz.


Input: Evaluation of Constituents of Piper retrofractum Fruits on Neurotrophic Activity.


Input: Three new compounds, 1-3, together with 22 known compounds, were isolated from the fruits of Piper retrofractum.


Input: The structures of the new compounds were elucidated on the basis of spectroscopic data analysis and comparison with literature values.


Input: Compound 1 was found to enhance the neurite outgrowth of NGF-mediated PC12 cells at concentrations ranging from 0. 1 to 10 mu M.


Input: ' Bacoside B'-the need remains for establishing identity.

Bacoside B


Input: Bacopa monnieri is fast gaining popularity for its beneficial effects on cognition and memory.


Input: The active constituents of the plant were putatively identified as' bacosides A and B' in older publications.

bacosides A and B


Input: Subsequently' bacoside A' was identified as a mixture of four saponins [bacoside A3 (1), bacopaside II (2), bacopasaponin C (3) and the jujobogenin isomer of the latter (4)] and was considered as part of major constituents of the herb along with bacopaside I (5).

bacoside A

saponins

bacoside A3

bacopaside II

bacopasaponin C

jujobogenin

bacopaside I


Input: These major saponins now form part of analytical monographs in many Pharmacopoeia.

saponins


Input: However identity of' bacoside B' still appears controversial with seemingly contradictory information available in the scientific literature.

bacoside B


Input: At the same time quality of many extracts and herbal products derived from the plant is still being determined based on the content of' bacosides A and B'.

bacosides A and B


Input: We have elaborated these issues in this article along with our recommendations to move forward towards achieving scientific clarity on the subject.


Input: Interpretation of the margin of exposure for genotoxic carcinogens-Elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.


Input: The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to " as low as reasonably achievable/practicable " (ALARA/P).


Input: However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary.


Input: To address this, the " Margin of Exposure " (MOE) approach has been proposed.


Input: The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure.


Input: However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures.


Input: In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens.


Input: This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens.


Input: Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship.


Input: Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia.


Input: There is evidence that high-density lipoproteins (HDLs) may regulate platelet function, but disparate results exist regarding the effects of oxidized HDLs on platelets.


Input: The objective of our study was to determine the role of in vivo oxidized HDLs on platelet aggregation.


Input: Platelet aggregation and redox status were investigated in 5 patients with abetalipoproteinemia (ABLP) or homozygous hypobetalipoproteinemia, two rare metabolic diseases characterized by the absence of apolipoprotein B-containing lipoproteins, compared to 5 control subjects.


Input: Platelets isolated from plasma of patients with ABLP aggregated 4 to 10 times more than control platelets, depending on the agonist.


Input: By contrast, no differences in the extent of platelet aggregation were observed between ABLP platelet-rich plasma (PRP) and control PRP, suggesting the presence of a protective factor in ABLP plasma.


Input: ABLP HDLs inhibited agonist-induced platelet aggregation by binding to SR-BI, while control HDLs had no effect.


Input: On the other hand, lipoprotein-deficient plasma from patients with ABLP did not inhibit platelet aggregation.


Input: Severe oxidative stress was evidenced in patients with ABLP.


Input: Compared to control HDLs, ABLP HDLs showed a 40% decrease of alpha-tocopherol and an 11-fold increased malondialdehyde concentration.

alpha-tocopherol

malondialdehyde


Input: These results demonstrate that in vivo oxidized HDLs do not lose their antiaggregatory properties despite oxidation.-Calzada, C., V e ricel, E., Colas, R., Guillot, N., El Khoury, G., Drai, J., Sassolas, A., Peretti, N., Ponsin, G., Lagarde, M., Moulin, P.


Input: Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia.


Input: A genome-wide association study of bronchodilator response in asthmatics.


Input: Reversibility of airway obstruction in response to beta 2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors.


Input: In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations.

albuterol

nucleotide


Input: The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n = 764).


Input: The second replication phase tested 13 SNPs in three additional asthma populations (n = 241, n = 215 and n = 592).


Input: An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P = 1. 98 x 10 (-7)) in the primary replication trials.


Input: An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P = 8. 51 x 10 (-6)).


Input: This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics. The Pharmacogenomics Journal advance online publication, 19 March 2013; doi: 10. 1038/tpj. 2013. 5.


Input: Differential tolerance to copper, but no evidence of population-level genetic differences in a widely-dispersing native barnacle.

copper


Input: Despite many estuaries having high levels of metal pollution, species are found to persist in these stressful environments.


Input: Populations of estuarine invertebrates exposed to toxic concentrations of such metals may be under selection.


Input: However, in species with a wide-dispersal potential, any short-term results of localized selection may be counteracted by external recruitment from populations not under selection.


Input: The barnacle Amphibalanus variegatus is found in nearshore coastal environments as well as sheltered embayments and estuaries, including metal-impacted estuaries, from New South Wales, Australia to Western Australia.


Input: The fertilised eggs of A. variegatus are brooded internally and released as larvae (nauplii), which remain in the water-column for ~ 14 days before settling.


Input: Hence the species has a considerable dispersal capacity.


Input: The purpose of this study was to examine whether populations of A. variegatus from metal-impacted sites, displayed a greater tolerance to a toxicant (copper) than reference populations.

copper


Input: Adult barnacles where collected from twenty sites within two metal-impacted and fourteen sites within two reference estuaries.


Input: Within 24 h, adults were induced to spawn and the offspring were exposed to copper in a laboratory assay.

copper


Input: Larvae collected from the metal-impacted estuaries demonstrated a greater tolerance to copper compared to those from reference sites.

copper


Input: To determine if selection/localised in the metal impacted sites was occurring, the genetic structure of populations at three sites was examined using an AFLP methodology.


Input: No evidence of unique population identity and or selection (outlier loci) was detected suggesting that: (1) the tolerance displayed in the assay was derived from acclimation during development; and/or (2) that the populations are open preventing the fixation of any unique alleles.


Input: Diurnal pituitary-adrenal activity during schedule-induced polydipsia of water and ethanol in cynomolgus monkeys (Macaca fascicularis).

ethanol


Input: RATIONALE: Intermittent delivery of an important commodity (e. g., food pellets) generates excessive behaviors as an adjunct to the schedule of reinforcement (adjunctive behaviors) that are hypothesized to be due to conflict between engaging and escaping a situation where reinforcement is delivered, but at suboptimal rates.


Input: OBJECTIVES: This study characterized the endocrine correlates during schedule-induced polydipsia of water and ethanol using a longitudinal approach in non-human primates.

ethanol


Input: METHODS: Plasma adrenocorticotropic hormone (ACTH) and cortisol were measured in samples from awake cynomolgus monkeys (Macaca fascicularis, 11 adult males) obtained at the onset, mid-day, and offset of their 12-h light cycle.

cortisol


Input: The monkeys were induced to drink water and ethanol (4% w/v, in water) using a fixed time (FT) 300-s interval schedule of pellet delivery.

ethanol


Input: The induction fluid changed every 30 sessions in the following order: water, 0. 5 g/kg ethanol, 1. 0 g/kg ethanol, and 1. 5 g/kg ethanol.

ethanol

ethanol

ethanol


Input: Following induction, ethanol and water were concurrently available for 22 h/day.

ethanol


Input: RESULTS: The FT 300-s schedule gradually increased ACTH, but not cortisol, during water induction to a plateau sustained throughout ethanol induction in every monkey.

cortisol

ethanol


Input: Upon termination of the schedule, ACTH decreased to baseline and cortisol below baseline.

cortisol


Input: Diurnal ACTH and cortisol were unrelated to the dose of ethanol, but ACTH rhythm flattened at 0. 5 g/kg/day and remained flattened.

cortisol

ethanol


Input: CONCLUSIONS: The coincidence of elevated ACTH with the initial experience of drinking to intoxication may have altered the mechanisms involved in the transition to heavy drinking.


Input: Repressive Epigenetic Changes at the Mglu2 Promoter in Frontal Cortex of 5-HT2A Knockout Mice.


Input: Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders such as schizophrenia, depression and suicide.

Serotonin

glutamate


Input: Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice.


Input: However, the molecular mechanism responsible for this alteration remains unknown.


Input: We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT2A-KO mice.


Input: Disruption of 5-HT2A receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac), and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter-epigenetic changes that correlate with transcriptional repression.

lysine


Input: Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected.

lysine

lysine


Input: We found that Egr1, a transcription factor whose promoter activity was positively regulated by the 5-HT2A receptor agonist TCB-2, binds less to the mGlu2 promoter in frontal cortex of 5-HT2A-KO as compared to wild-type mice.


Input: Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of Flag-tagged Egr1 in mouse frontal cortex.


Input: Together, these observations suggest that 5-HT2A receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.


Input: Relationship of Dehydroepiandrosterone Sulfate with Overweight and Insulin Sensitivity in 12-16-Year-old Spanish Children.

Dehydroepiandrosterone Sulfate


Input: DHEA-S is the most abundant steroid hormone in human circulation.

DHEA-S

steroid


Input: Although a relationship of DHEA-S with obesity-related diseases has been reported, the metabolic role of this hormone remains unclear, particularly in children.

DHEA-S


Input: In our study, we have investigated the relationship of DHEA-S levels with anthropometric variables, insulin, HOMA, and free fatty acids in adolescents.

DHEA-S

free fatty acids


Input: The study sample included 812 healthy 12-16-year-old children (383 boys and 429 girls).


Input: Plasma DHEA-S was determined by RIA, insulin concentrations by IRMA, and free fatty acids by using a commercial kit.

DHEA-S

free fatty acids


Input: Insulin resistance was estimated using the HOMA index.


Input: No significant differences in plasma DHEA-S levels were found between sexes.

DHEA-S


Input: DHEA-S levels in overweight children were significantly higher than in normal-weight children.

DHEA-S


Input: DHEA-S levels were significantly correlated with weight and BMI after adjusting for age.

DHEA-S


Input: Significant positive correlations between DHEA-S and free fatty acids levels were found after adjusting for age and BMI, particularly in boys, but not between DHEA-S levels and insulin or HOMA in either gender.

DHEA-S

free fatty acids

DHEA-S


Input: DHEA-S levels in 12-16-year-old children are correlated with weight and BMI independently of age.

DHEA-S


Input: We failed to find any association between DHEA-S and insulin levels, but we did find a-significant correlation between DHEA-S and free fatty acids levels, suggesting that its association with free fatty acids may be related to the onset of the association of DHEA-S with insulin resi-stance.

DHEA-S

DHEA-S

free fatty acids

free fatty acids

DHEA-S


Input: Dammarane-type saponins from heat-processed Gynostemma pentaphyllum show fortified activity against A549 cells.

Dammarane

saponins


Input: An ethanol extract from heat-processed Gynostemma pentaphyllum showed more potent cytotoxic activity against human lung adenocarcinoma A549 cells than that of raw G. pentaphyllum.

ethanol


Input: Four constituents were isolated from heat-processed G. pentaphyllum using resin HP-20, silica gel and reversed ODS column chromatography.

silica gel


Input: They were identified by mass and NMR spectra as damulin A and damulin B, gypenoside L and gypenoside LI, respectively.

damulin A

damulin B

gypenoside L

gypenoside LI


Input: To evaluate the efficacy of these four constituents, the MTT cytotoxicity assay was performed using A549 cells.

MTT


Input: Based on the structure of these four constituents, the results indicate that the hydroxyl group in C-2 and double bond in C20 (21) and C20 (22) positions are of importance in inhibition of A549 cell proliferation.

hydroxyl


Input: Two new tirucallane triterpenoids from the leaves of Aquilaria sinensis.

tirucallane triterpenoids


Input: Two new tirucallane triterpenoids, aquilacallanes A-B (1-2), together with 15 known compounds (3-17) were isolated from the leaves of Aquilaria sinensis.

tirucallane triterpenoids

aquilacallanes A-B


Input: The structures of these new compounds were elucidated on the basis of extensive spectroscopic analyses.


Input: All compounds were evaluated for their cytotoxic activity against five human cancer cell lines.


Input: The known compounds, ursolic acid (7) and 5, 7, 4'-trimethoxyflavone (14), exhibited weak cytotoxic activity against some cells.

ursolic acid

5, 7, 4'-trimethoxyflavone


Input: Free radical reactions in two dimensions: a case study on photochlorination of graphene.

graphene


Input: Graphene, a two-dimensional giant-molecule of sp (2)-bonded carbon atoms, provides a perfect platform for studying free radical reaction chemistry in two-dimensions, which holds promise to control the chemical functionality of graphene.

Graphene

carbon

graphene


Input: Free-radical photochlorination of graphene is used as an example to investigate the thickness, stacking order, and single-and double-side dependent reactivity in graphene.

graphene

graphene


Input: Anomalously low reactivity is observed in the photochlorination of AB-stacked bilayer graphene in comparison with that of few-layer graphene.

graphene

graphene


Input: Double-sided chlorination of graphene shows higher reactivity and chlorine coverage than single-sided reaction.

graphene

chlorine


Input: It is also experimentally and theoretically demonstrated that chlorine free radicals at low coverage prefer to form a stable charge-transfer complex with graphene, which highly enhances graphene' s conductivity and simultaneously generates a pseudo-bandgap through noninvasive doping.

chlorine

graphene

graphene


Input: Moreover, the initial accumulation of chlorine radicals is considered as the rate-determining step of photochlorination of graphene.

chlorine

graphene


Input: Enhanced Replication of R5 HIV-1 Isolates in vitro by a Small-Molecule Reagent Targeting HIV-1 Protease.


Input: Chemical enhancement: Designed to target HIV-1 protease, a novel gamma-hydroxyphosphonate has been found to significantly enhance viral replication in a panel of clinically relevant R5 HIV-1 isolates.

gamma-hydroxyphosphonate


Input: This unexpected result constitutes the first instance of a small molecule capable of doing this, and it has implications for the preparation and use of R5 isolates in vaccine and drug development.


Input: Synthesis and evaluation of stable substrate analogs as potential modulators of cyclodiphosphate synthase IspF.

cyclodiphosphate


Input: Stable IspF substrate analogs were synthesized.


Input: In the presence of substrate analogs, the E. coli IspF-MEP complex shows activities distinct from IspF, and bisphosphonates (BP) behave differently than their diphosphate (DP) counterparts.

MEP

bisphosphonates

diphosphate


Input: Bisphosphonate analogs activate and/or stabilize IspF, and only the closest structural substrate analog weakly inhibits the IspF-MEP complex.

Bisphosphonate

MEP


Input: Scopoletin and Scopolin Isolated from Artemisia iwayomogi Suppress Differentiation of Osteoclastic Macrophage RAW 264. 7 Cells by Scavenging Reactive Oxygen Species.

Scopoletin

Scopolin

Oxygen


Input: Artemisia iwayomogi has been used as a folk medicine for treating various diseases including inflammatory and immune-related diseases.


Input: Scopoletin (1) and scopolin (2) were isolated from this species.

Scopoletin

scopolin


Input: Scopoletin (1) showed more potent peroxyl radical-scavenging capacity, reducing capacity, and cellular antioxidant capacity compared to scopolin (2).

Scopoletin

peroxyl

scopolin


Input: The inhibitory effect of 1 on the receptor activator of nuclear factor kappa B ligand-induced osteoclastic differentiation of RAW 264. 7 macrophage cells was also more potent than that of 2.


Input: The production of general reactive oxygen species (ROS) and superoxide anions during differentiation of preosteoclastic RAW 264. 7 cells into osteoclasts was attenuated by compounds 1 and 2.

oxygen

superoxide


Input: These findings indicate that the suppressive effects of 1 and 2 on the differentiation of preosteoclastic RAW 264. 7 cells is partially due to their intracellular antioxidant capacity, as they can scavenge ROS and play an important signaling role in the differentiation process.


Input: Acoustics as a Tool for Better Characterization of Ionic Liquids: A Comparative Study of 1-Alkyl-3-methylimidazolium Bis [(trifluoromethyl) sulfonyl] imide Room-Temperature Ionic Liquids.

1-Alkyl-3-methylimidazolium Bis [(trifluoromethyl) sulfonyl] imide


Input: Acoustic properties of three (1-ethyl-, 1-butyl-, and 1-octyl-) 1-alkyl-3-methylimidazolium bis [(trifluoromethyl) sulfonyl] imide room-temperature ionic liquids are reported and discussed.

1-alkyl-3-methylimidazolium bis [(trifluoromethyl) sulfonyl] imide


Input: The speeds of sound in RTILs were measured as a function of temperature in the range 288-323 K by means of a sing around method.


Input: The densities and isobaric heat capacities were determined from 288. 15 to 363. 15 K and from 293. 15 to 323. 15 K, respectively.


Input: The related properties, like isentropic and isothermal compressibilities, isobaric coefficients of thermal expansion, molar isochoric heat capacities, and internal pressures, were calculated.


Input: It was found that for some ionic liquids, temperature dependence of isobaric coefficients of thermal expansion is small and negative.


Input: All investigations were completed by the ultrasound absorption coefficient measurements in 1-ethyl-and 1-octyl-3-methylimidazolium bis [(trifluoromethyl) sulfonyl] imide as a function of frequency from 10 to 300 MHz at temperatures 293. 15-298. 15 K.

1-ethyl-and 1-octyl-3-methylimidazolium bis [(trifluoromethyl) sulfonyl] imide


Input: The ultrasound absorption spectra indicate relaxation frequencies in the megahertz range.


Input: Ectopic Thyroid Tissue in the Adrenal Gland: Report of 2 Cases with Pathogenetic Implications.


Input: Background: Ectopic thyroid tissue is usually found anywhere along the embryonic descent pathway of the medial thyroid anlage from the tongue to the trachea (W o lfler area).


Input: However, ectopic thyroid tissue in the adrenal gland (ETTAG) is not easy to understand on the basis of thyroid embryology; because it is so rare, the possibility of metastasis should first be considered.


Input: Here, we describe 2 cases of ETTAG with pathogenetic implications and review the literature.


Input: Patient findings: Two cases of ETTAG presented as incidental cystic adrenal masses in adult females, one having a congenital hernia of Morgagni.


Input: The ETTAG was histologically indistinguishable from normal orthotopic thyroid tissue, and its follicular nature was confirmed by immunohistochemical positivity for thyroglobulin, thyroperoxidase, thyroid transcription factor-1 (TTF-1/Titf-1/Nkx2. 1), cytokeratin (CK) AE1/AE3, CK 7, pendrin, human sodium iodide symporter (hNIS), paired box gene 8 (PAX8) and FOXE1 (TTF-2), as well as positivity for the messenger RNA of the thyroglobulin gene by in situ hybridization analysis.

sodium iodide


Input: No C cells (negativity for calcitonin, cromogranin and synaptophysin) were present.


Input: Neither BRAF nor KRAS mutations were detected with real-time polymerase chain reaction analysis.


Input: Further work-up did not show evidence of thyroid malignancy.


Input: Summary: ETTAG is a rare finding, with only 7 cases reported; women are much more frequently affected than men (8: 1) and it usually clinically presents in the fifth decade (mean age: 54, range: 38-67) as a cystic adrenal mass incidentally discovered on abdominal ultrasonography and/or in computed tomography images.


Input: ETTAG is composed of normal follicular cells without C cells.


Input: The expression of some transcription factors (TTF-1, PAX8 and FOXE1) involved in development and/or migration of the medial thyroid anlage is preserved.


Input: Coexistence of a congenital hernia of Morgagni in one patient suggests an over-descent of medial thyroid anlage derived cells in its pathogenesis.


Input: Conclusion: Although ETTAG pathogenesis remains unknown, the lack of C cells together with the coexistence of a congenital defect of the anterior diaphragm (hernia of Morgagni) in one of our patients could suggest an over-descent of medial thyroid anlagen derived cells in the origin of this heterotopia.


Input: Dendrimer Driven Self-Assembly of SPR Active Silver-Gold Nanohybrids.

Silver


Input: A fourth generation PAMAM dendrimer has been successfully employed for the development of a single step synthesis strategy for self-assembled Ag-Au nanohybrid structures.

PAMAM

Ag

Au


Input: The surface plasmon resonance properties and the degree of self-assembly of the nanohybrid are strongly correlated with the stoichiometry of the metals which gives rise to enhanced plasmonic properties.


Input: The enhanced plasmonic response of the nanohybrids is modeled and is validated experimentally in a model HRP (horseradish peroxidise) bioassay carried out on an SPR-based biochip platform.


Input: H3O2 Bridging Ligand in a Metal-Organic Framework.


Input: Insight into the Aqua-Hydroxo <--> Hydroxyl Equilibrium: A Combined Experimental and Theoretical Study.

Aqua-Hydroxo

Hydroxyl


Input: A metal-organic framework (MOF) bearing the aqua-hydroxo species (O2H3) (-) in the framework, as well as the processes that govern the equilibrium aqua-hydroxo (O2H3) (-) <--> hydroxyl (OH) in Sc-MOFs, are studied experimentally and theoretically.

aqua-hydroxo

(O2H3) (-)

aqua-hydroxo (O2H3) (-)

hydroxyl

OH

Sc


Input: Computational studies were employed to determine the relative energies for the two compounds that coexist under certain hydrothermal conditions at pH < 2. 8.


Input: The thermodynamically more stable [Sc3 (3, 5-DSB) 2 (mu-O2H3) (mu-OH) 2 (H2O) 2] (from now on, (O2H3) Sc-MOF; 3, 5-DSB = 3, 5-disulfobenzoic acid) was obtained as a pure and stable phase.

[Sc3 (3, 5-DSB) 2 (mu-O2H3) (mu-OH) 2 (H2O) 2]

(O2H3) Sc

3, 5-DSB

3, 5-disulfobenzoic acid


Input: It was impossible to isolate [Sc3 (3, 5-DSB) 2 (mu-OH) 3 (H2O) 4] as a pure phase, as it turned out to be the precursor of (O2H3) Sc-MOF.

[Sc3 (3, 5-DSB) 2 (mu-OH) 3 (H2O) 4]

(O2H3) Sc


Input: Additionally, a third compound that appears at pH between 3. 5 and 4, [Sc3 (3, 5-DSB) (mu-OH) 6 (H2O)] and a fourth, [Sc (3, 5-DSB) (Phen) (H2O)] (H2O), in whose formula neither OH groups nor H3O2 (-) anions appear, are reported for comparative purposes.

[Sc3 (3, 5-DSB) (mu-OH) 6 (H2O)]

[Sc (3, 5-DSB) (Phen) (H2O)] (H2O)

OH

H3O2 (-)


Input: A study of the (O2H3) Sc-MOF electronic structure, and some heterogeneous catalytic tests in cyanosilylation of aldehydes reactions, are also reported.

(O2H3) Sc

aldehydes


Input: Identification of benzofurano [3, 2-d] pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors.

benzofurano [3, 2-d] pyrimidin-2-ones

nucleotide


Input: Screening of our sample collection led to the identification of a set of benzofurano [3, 2-d] pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI).

benzofurano [3, 2-d] pyrimidine-2-one

nucleotide


Input: Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold.

benzofuranopyrimidone


Input: The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency.


Input: Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.


Input: Is there a link between neutrophil-lymphocyte ratio and microvascular complications in geriatric diabetic patients?


Input: Background: Chronic inflammation plays an important role on development and progression of type 2 diabetes through immunologic inflammatory mechanisms.


Input: Neutrophil to lymphocyte ratio (NLR) is a new, simple and cheap marker of subclinical inflammation.


Input: NLR has recently been used as a systemic inflammation marker in chronic diseases as well as a predictor of prognosis in cardiovascular diseases and malignancies.


Input: Aim: The objective of the present study was to investigate the relationship between NLR and microvascular complications of diabetes mellitus in elderly population.


Input: Subjects and methods: Two hundred and forty-two patients with DM (145 diabetic patients with complications, 97 diabetic patients without complications) and 218 control subjects were enrolled in this study.


Input: NLR and microvascular complications because of diabetes mellitus were evaluated and compared with other inflammatory markers.


Input: Results: NLR was higher in the diabetic group (2. 21 +/- 1. 14) than in the controls (2. 18 +/- 0. 76).


Input: Furthermore, there was a statistically significant difference between NLR levels in diabetic patients with and without complications (2. 46 +/- 1. 26 vs. 2. 04 +/- 0. 51, respectively; P < 0. 001).


Input: The results of the multiple logistic regression analysis depicted that NLR is also an independent predictor for microvascular complications (OR = 2. 217; 95% = 1. 086-4. 526, P = 0. 029).


Input: ROC curve analysis suggested that the optimum NLR cut-off point for microvascular complication was 2. 89 with 96. 72% specificity, 94. 4% positive predictive value.


Input: Conclusion: Increased NLR levels may be associated with microvascular complications of diabetes mellitus in the elderly population.


Input: High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C.

cholesterol


Input: Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans.

cholesterol

steroid


Input: While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis.


Input: To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin: cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations.

steroid hormone

ATP

cholesterol

cholesterol


Input: HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0. 001).


Input: In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0. 04).

17-ketogenic steroids


Input: In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls.


Input: In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin.


Input: These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.

cholesterol


Input: Redox-and pH-Responsive Cysteamine-Modified Poly (aspartic acid) Showing a Reversible Sol-Gel Transition.

Cysteamine

Poly (aspartic acid)


Input: Synthesis and characterization of a pH-and redox-sensitive hydrogel of poly (aspartic acid) are reported.

poly (aspartic acid)


Input: Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol-disulphide interconversion in the side chain of the polymers.

dimethylformamide

thiol-disulphide


Input: Structural changes are confirmed by Raman microscopy and rheological measurements.


Input: Injectable aqueous solutions of thiolated poly (aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery.

thiolated poly (aspartic acid)


Input: Reduction-facilitated release of an entrapped drug from disulphide cross-linked hydrogels is studied.

disulphide


Input: Diarylheptanoids from Alnus glutinosa Bark and Their Chemoprotective Effect on Human Lymphocytes DNA.

Diarylheptanoids


Input: A study of secondary metabolites from the bark of Alnus glutinosa led to the isolation of fourteen diarylheptanoids: oregonin (1), platyphylloside (2), rubranoside A (3), rubranoside B (4), hirsutanonol (5), hirsutenone (6), hirsutanonol-5-O-beta-D-glucopyranoside (7), platyphyllonol-5-O-beta-D-xylopyranoside (8), aceroside VII (9), alnuside A (10), alnuside B (11), 1, 7-bis-(3, 4-dihydoxyphenyl)-5-hydroxy-heptane-3-O-beta-D-xylopyranoside (12), (5S)-1-(4-hydroxyphenyl)-7-(3, 4-dihydroxyphenyl)-5-O-beta-D-glucopyranosyl-heptan-3-one (13), and (5S)-1, 7-bis-(3, 4-dihydroxyphenyl)-5-O-beta-D-[6-(3, 4-dimethoxycinnamoylglucopyranosyl)]-heptan-3-one (14).

diarylheptanoids

oregonin

platyphylloside

rubranoside A

rubranoside B

hirsutanonol

hirsutenone

platyphyllonol-5-O-beta-D-xylopyranoside

aceroside VII

alnuside A

alnuside B

1, 7-bis-(3, 4-dihydoxyphenyl)-5-hydroxy-heptane-3-O-beta-D-xylopyranoside

(5S)-1-(4-hydroxyphenyl)-7-(3, 4-dihydroxyphenyl)-5-O-beta-D-glucopyranosyl-heptan-3-one

(5S)-1, 7-bis-(3, 4-dihydroxyphenyl)-5-O-beta-D-[6-(3, 4-dimethoxycinnamoylglucopyranosyl)]-heptan-3-one


Input: All of the diarylheptanoids, except 1 and 5, were found in A. glutinosa for the first time, while 13 and 14 were new compounds.

diarylheptanoids


Input: The structures were determined by spectroscopic techniques: 1D and 2D NMR, HR-ESI-MS, FTIR, UV, and CD.


Input: All isolated compounds were analyzed for an in vitro protective effect on chromosome aberrations in peripheral human lymphocytes using the cytokinesis-block micronucleus assay.


Input: The majority of them, including the new compounds 13 and 14, exerted a pronounced effect in decreasing DNA damage in human lymphocytes.


Input: Diarylheptanoids 1, 2, 5, 13, and 14 at a concentration of 1 micro g/mL decreased the frequency of micronuclei by 52. 8%, 43. 8%, 63. 6%, 44. 4%, and 56. 0%, respectively, exerting a much stronger effect than the synthetic protector amifostine (17. 2%, c = 1 micro g/mL).

Diarylheptanoids

amifostine


Input: Edge-to-Edge Assembled Graphene Oxide Aerogels with Outstanding Mechanical Performance and Superhigh Chemical Activity.

Graphene Oxide


Input: Aerogels, an extremely important aggregation state of various self-assembled nanoscale building blocks, have great potential in fields ranging from energy storage to thermal insulation.


Input: However, the porosity of aerogels makes them mechanically weak in most cases, and the chemical activity of the resulting aerogel needs consideration.


Input: Herein, chemically crosslinked graphene oxide (GO) 3D aerogels with large specific surface areas (up to 850 m (2) g (-1)), outstanding mechanical performance (up to 20 MPa Young' s modulus, 1 MPa yield strength and 45 J g (-1) specific energy adsorption), and superhigh chemical activity (toward some reducing gases such as H2 S, HI, and SO2), are fabricated by assembling 2D GO sheets edge-to-edge into uniform, 3D hydrogel networks with subsequent supercritical fluid drying.

graphene oxide

H2 S

HI


Input: These aerogels are superior to other 3D frameworks (e. g. graphene aerogels) assembled via partial overlapping of the basal planes of the 2D building blocks.

graphene


Input: Mastoid Obliteration Using Three-Dimensional Composite Scaffolds Consisting of Polycaprolactone/beta-Tricalcium Phosphate/Collagen Nanofibers: An In Vitro and In Vivo Study.

Polycaprolactone

beta-Tricalcium Phosphate


Input: Two different composite scaffolds, solid-freeform-fabricated PCL/beta-TCP supplemented with and without collagen nanofibers are fabricated.

PCL

beta-TCP


Input: These scaffolds are evaluated whether a combination of collagen nanofibers with PCL/beta-TCP can promote osteogenesis in a mastoid obliteration.

PCL

beta-TCP


Input: To assess the effects of the cellular activities of osteoblast-like-cells (MG63), SEM images and MTT assays are conducted.

MTT


Input: Experimental mastoid obliteration is performed using guinea pigs that are divided group A (PCL/beta-TCP/collagen-nanofiber scaffold) and group B (PCL/beta-TCP scaffold).

PCL

beta-TCP

PCL

beta-TCP


Input: The results reveal that PCL/beta-TCP/collagen scaffold provide much broader cell attachment sites than PCL/beta-TCP scaffold.

PCL

beta-TCP

PCL

beta-TCP


Input: The micro-CT and fluorescent microscopy results reveal that the acceleration of early new bone formation within the pores and scaffold itself at week 4 post-operation is more effective in group A.


Input: In addition, based on the results of the histological and micro-CT at 12 weeks post-surgery, the effective regeneration of bone in the PCL/beta-TCP/collagen scaffold is appeared.

PCL

beta-TCP


Input: Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review.


Input: Introduction: An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.


Input: The International League Against Epilepsy classifies seizures in two broad categories: partial (localized to one cerebral hemisphere) and generalized (localized to both cerebral hemispheres).


Input: One indirect pathway for the treatment of epilepsy includes the inhibition of carbonic anhydrase (CA), thereby increasing CO2 levels in the brain.


Input: Areas covered: Carbonic anhydrases (EC 4. 2. 1. 1) are ubiquitous metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3 (-), respectively.

HCO3 (-)


Input: CA inhibitors (CAIs) such as acetazolamide, methazolamide, topiramate, zonisamide, and sulthiame can reduce seizures through perturbation of the CO2 equilibrium and/or the inhibition of ion channels.

acetazolamide

methazolamide

topiramate

zonisamide

sulthiame


Input: This review focuses on the mechanism of epilepsy, CA catalysis, and recent developments in the treatment of epilepsy using CAIs.


Input: Expert opinion: Based on the observed active-site binding interactions of CAIs in crystal structures and their respective inhibition constants, structure-activity relationships can be mapped.


Input: Various CAIs along with novel techniques to administer them have been patented in the last four years.


Input: However, epilepsy continues to be a path less traveled when it comes to CAIs.


Input: A major area of research must focus toward the design of isoform-specific inhibitors using analogs of existing CAIs.


Input: Serotonin-kynurenine hypothesis of depression: historical overview and recent developments.

Serotonin

kynurenine


Input: This mini-review focuses on the studies of late Prof.


Input: IP Lapin (1903-2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect.

methoxyindole

kynurenine

KYN

tryptophan

TRP


Input: In the late 60s of the last century Prof.


Input: IP Lapin suggested that " intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component " while " activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect ".


Input: The cause of serotonin deficiency in depression was attributed to the shunt of TRP " metabolism away from serotonin production towards KYN production " due to cortisol-induced activation of liver enzyme, tryptophan 2, 3-dioxygenase, the rate-limiting enzyme of TRP-KYN pathway.

serotonin

TRP

serotonin

KYN

cortisol

tryptophan

TRP

KYN


Input: Prof.


Input: Lapin suggested and discovered that KYN and its metabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect (kynurenine hypothesis).

KYN


Input: Further research suggested the antidepressant and cognition-enhancing effects of post-serotonin metabolite, N-acetylserotonin (NAS), an agonist to tyrosine kinase B (TrkB) receptor; and link between depression and chronic inflammation-associated disorders (e. g., insulin resistance, hepatitis C virus) via inflammation-induced activation of indoleamine 2, 3-dioxygenase, brain located rate-limiting enzyme of TRY-KYN metabolism.

serotonin

N-acetylserotonin

NAS

tyrosine

indoleamine

TRY

KYN


Input: NAS and kynurenines might be the targets for prevention and treatment of depression and associated conditions.

NAS

kynurenines


Input: Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) Promotes Growth and Survival of Breast Epithelial Cells: Novel Regulation of the Estrogen Receptor.

Estrogen


Input: In breast tumors IGF binding protein-2 (IGFBP-2) is elevated, and the presence of IGFBP-2 has been shown to correlate with malignancy.


Input: However, how IGFBP-2 contributes to the malignant state is still unclear.


Input: Silencing IGFBP-2 blocked cell proliferation and in MCF-7 cells increased cell death, indicating that IGFBP-2 was acting in both a mitogenic and a survival capacity.


Input: Exogenous IGFBP-2 acting via integrin receptors to reduce phosphatase and tensin homolog deleted from chromosome 10 (PTEN) levels protected these cells against death induced by various chemotherapeutic agents.


Input: This was dependent on a functional estrogen receptor (ER)-alpha because silencing ER-alpha blocked the ability of IGFBP-2 to confer cell survival.

estrogen


Input: Loss of IGFBP-2 increased levels of PTEN and improved chemosensitivity of the cells, confirming its role as a survival factor.


Input: Silencing IGFBP-2 had no effect on the response to IGF-II, but responses to estrogen and tamoxifen were no longer observed due to loss of ER-alpha, which could be prevented by the inhibition of PTEN.

estrogen

tamoxifen


Input: Conversely, exogenous IGFBP-2 increased ER-alpha mRNA and protein in both normal and cancer cells via its interaction with integrin receptors.


Input: These actions of IGFBP-2 on ER-alpha involved the IGF-I receptor and activation of phosphatidylinositol 3-kinase in the cancer cells but were independent of this in normal breast cells.

phosphatidylinositol


Input: The production of IGFBP-2 by breast cancer cells enhances their proliferative potential, increases their survival, and protects them against chemotherapy-induced death.


Input: IGFBP-2 not only modulates IGFs and directly regulates PTEN but also has a role in maintaining ER-alpha expression.


Input: Involvement of serotonin mechanism in methamphetamine-induced chronic pulmonary toxicity in rats.

serotonin

methamphetamine


Input: The widest distribution and the highest uptake of methamphetamine (MA) in the human body occurred in the lungs, so that more and more attention should be paid to MA-induced pulmonary toxicity.

methamphetamine


Input: MA induces the release of serotonin, which is an important mediator in pulmonary disease.

serotonin


Input: The purpose of this study is to investigate the chronic response of the lung to MA and its potential mechanism in rats.


Input: Models of the chronic toxicity of MA were established with MA of 5 mg/kg and 10 mg/kg (intraperitoneally, twice per day) for 5 weeks.


Input: It was found that the high dose of MA induced rat pulmonary toxicity: crowded lung parenchyma, thickened septum, reduced number of alveolar sacs, inflammatory cell infiltration, and pulmonary arteriolar remodeling.


Input: In addition, MA resulted in a significant increase in the lung serotonin concentration and the marked upregulation of tryptophan hydroxylase 1, vesicular monoamine transporter 2, serotonin transporter, and downregulation of monoamine oxidase-A.

serotonin

tryptophan

serotonin

monoamine


Input: These findings suggest that MA induced chronic pulmonary toxicity, which is concerned with the elevated serotonin concentration in rat lungs by increased synthesis, reduced metabolism, augmented accumulation, and promoted release of serotonin.

serotonin

serotonin


Input: Transforming growth factor beta 1 and monocyte chemoattractant protein-1 as prognostic markers of diabetic nephropathy.


Input: We aimed to find the relationship between serum transforming growth factor beta 1 (TGF-beta 1) and urinary monocyte chemoattractant protein-1 (MCP-1) throughout the course of diabetic nephropathy (DN) and to assess the relationship between both levels and other parameters of renal injury such as albumin/creatinine ratio and estimated glomerular filtration rate (eGFR).

creatinine


Input: Serum TGF-beta 1, urinary MCP-1, eGFR, and glycosylated hemoglobin (HbA1c) were measured in 60 patients with type II diabetes mellitus with different degrees of nephropathy (20 patients with normoalbuminuria, 20 patients with microalbuminuria, and 20 patients with macroalbuminuria) and compared with 20 matched healthy control subjects.


Input: Both the levels of serum TGF-beta 1 and urinary MCP-1 were significantly higher in patients with micro-and macroalbuminuria (137. 8 +/- 69. 5 and 329. 25 +/- 41. 46 ng/dl, respectively, for TGF-beta 1 and 167. 41 +/- 50. 23 and 630. 87 +/- 318. 10 ng/g creatinine, respectively, for MCP-1) compared with normoalbuminuric patients and healthy controls (33. 25 +/- 17. 5 and 29. 64 +/- 10. 57 ng/dl, respectively, for TGF-beta 1 and 63. 85 +/- 21. 15 and 61. 50 +/- 24. 81 ng/g creatinine, respectively, for MCP-1; p < 0. 001).

creatinine

creatinine


Input: There was a positive significant correlation between the levels of serum TGF-beta 1 and those of urinary MCP-1 (r = 0. 73, p < 0. 001).


Input: Also, serum TGF-beta 1 and urinary MCP-1 correlated positively with HbA1c (r = 0. 49 and 0. 55, respectively, p < 0. 05 for both) and inversely with eGFR (r =-0. 69 and-0. 60, respectively, p < 0. 001 for both).


Input: We can conclude that serum TGF-beta 1 and urinary MCP-1 can be used as the markers for detection of progression of DN.


Input: Antagonizing TGF-beta 1 and MCP-1 might be helpful in attenuating the progression of nephropathy in diabetic patients.


Input: Efficacy of D-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats.

D-penicillamine

acetaldehyde

alcohol


Input: RATIONALE: Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate.


Input: An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents.

acetaldehyde


Input: Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as D-penicillamine (DP), in relapse prevention has not been studied yet.

ethanol

acetaldehyde

D-penicillamine


Input: OBJECTIVES: The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment.

alcohol

ethanol


Input: METHODS: Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0. 25, or 1 mg/h of DP during 1 week.


Input: The efficacy to prevent ADE was determined.


Input: DP plasma and brain levels achieved during its subcutaneous administration were measured.


Input: In a second experiment, animals received bilateral infusions of 0 or 1. 5 mu g/h of DP directly into pVTA, and the appearance of ADE was evaluated.