Input: Improved preparation of methyl bis (2, 2, 2-trifluoroethoxy)-bromophosphonoacetate for the stereoselective synthesis of (E)-alpha-bromoacrylates.

methyl bis (2, 2, 2-trifluoroethoxy)-bromophosphonoacetate

(E)-alpha-bromoacrylates


Input: We have established an efficient method for preparing methyl bis (2, 2, 2-trifluoroethoxy) bromophosphonoacetate, which we developed for the stereoselective synthesis of (E)-alpha-bromoacrylates.

methyl bis (2, 2, 2-trifluoroethoxy) bromophosphonoacetate

(E)-alpha-bromoacrylates


Input: This improved method enables the reagent to be prepared reproducibly in one step from methyl bis (2, 2, 2-trifluoroethoxy) phosphonoacetate.

methyl bis (2, 2, 2-trifluoroethoxy) phosphonoacetate


Input: H-TiO (2) @MnO (2)//H-TiO (2) @C core-shell nanowires for high performance and flexible asymmetric supercapacitors.

H

TiO (2)

MnO (2)

H

TiO (2)

C


Input: A flexible solid-state asymmetric supercapacitor device with H-TiO (2) @MnO (2) core-shell NWs as the positive electrode and H-TiO (2) @C core-shell NWs as the negative electrode is developed.

H

TiO (2)

MnO (2)

H

TiO (2)

C


Input: This device operates in a 1. 8 V voltage window and is able to deliver a high specific capacitance of 139. 6 F g (-1) and maximum volumetric energy density of 0. 30 mWh cm (-3) with excellent cycling performance and good flexibility.


Input: Sub-lethal effects of titanium dioxide nanoparticles on the physiology and reproduction of zebrafish.

titanium dioxide


Input: There are limited data on the sub-lethal physiological effects of titanium dioxide nanoparticles (TiO (2) NPs) in adult fishes, and the consequences of TiO (2) NP exposure on reproductive success are also unclear.

titanium dioxide

TiO (2)

TiO (2)


Input: This study aimed to examine the sub-lethal effects of a 14-d aqueous TiO (2) (TiO (2) NP, 0. 1 or 1. 0 mg l (-1); TiO (2) bulk, 1. 0 mg l (-1)) exposure on the physiology and reproductive health of zebrafish.

TiO (2)

TiO (2)

TiO (2)


Input: After the 14-d exposure, fish were examined for haematology, whole body electrolyte and trace metal profiles, biochemistry, and histopathology.


Input: Then, during a 21-d post exposure recovery period, effects of the TiO (2) exposure on reproductive success were evaluated.

TiO (2)


Input: Whole body Ti concentrations increased significantly in fish exposed to both the 1. 0 mg l (-1) TiO (2) NP and bulk TiO (2) compared to controls, but concentrations returned to control levels by the end of the recovery period.

Ti

TiO (2)

TiO (2)


Input: No change in erythrocyte counts were observed, but there was a two-fold decline in leukocyte counts in all TiO (2) treatment groups relative to time-matched controls.

TiO (2)


Input: Whole body electrolyte and trace metal profiles were not affected by exposure to TiO (2), and there were no changes in Na (+) K (+)-ATPase activity in brain, gill or liver tissues.

TiO (2)

Na (+) K (+)


Input: Total glutathione (GSH) levels in brain, gill and liver tissues were higher in fish exposed to TiO (2) NP (both 0. 1 and 1. 0 mg l (-1)) compared to bulk TiO (2) and control fish.

glutathione

GSH

TiO (2)

TiO (2)


Input: Histological examination of gill, liver, brain and gonad tissues showed little evidence of treatment-related morphological change.


Input: At the end of the 14-d exposure adult zebrafish were able to reproduce; however, the cumulative number of viable embryos produced was lower in fish exposed to 1. 0 mg l (-1) TiO (2) (both NP and bulk) by the end of the 21-d recovery period.

TiO (2)


Input: Overall, this study showed limited toxicity of bulk or nano scale TiO (2) during the exposure; however reproduction was affected in both bulk and NP 1. 0 mg l (-1) groups.

TiO (2)


Input: Toxic effects of microcystin-LR on the reproductive system of male Rana nigromaculata in vitro.

microcystin-LR


Input: This study aims to demonstrate that microcystin-LR (MC-LR) has toxic effects on the reproductive system of male Rana nigromaculata in vitro.

microcystin-LR

MC-LR


Input: R. nigromaculata were treated with 0, 0. 1, 1, 10, and 100 nmol/L of MC-LR for 6 h.


Input: Results show that exposure to 1 nmol/L to 100 nmol/L of MC-LR decreased sperm motility and number of sperm cells and increased the sperm abnormality rate, whose values were significantly different from those of the control (P < 0. 01).

MC-LR


Input: Moreover, the same dosage of MC-LR increased reactive oxygen species production and malondialdehyde content.

MC-LR

oxygen

malondialdehyde


Input: At the same time, antioxidant enzyme (catalase and glutathione S-transferase) activity and glutathione reduced content rapidly increased, whereas antioxidant enzyme superoxide dismutase activity significantly decreased.

glutathione S

glutathione

superoxide


Input: These results imply that the defense system of the testes quickly responds to oxidative stress.


Input: Ultrastructural observation shows distention of the mitochondria, endoplasmic reticulum, and Golgi apparatus and changes in the mitochondrial matrix color, cristae number, and morphology.


Input: Moreover, using real-time PCR, increased relative expressions of P450 aromatase and SF-1 genes were observed.


Input: The results demonstrate for the first time that MC-LR could induce toxicity in the male reproductive system of R. nigromaculata.

MC-LR


Input: The findings in this research will provide more insights into the relationships between aquatic microcystins and amphibians.

microcystins


Input: Ultrasound-promoted coating of silk yarn with different morphology of magnesium hydroxide nanostructures.

magnesium hydroxide


Input: The growth of magnesium hydroxide nanostructures on silk yarn was achieved by sequential dipping steps in alternating bath of magnesium nitrate and potassium hydroxide under ultrasound irradiation.

magnesium hydroxide

magnesium nitrate

potassium hydroxide


Input: The effects of ultrasound irradiation, concentration, pH and sequential dipping steps on growth of the Mg (OH) (2) nanostructures have been studied.

Mg (OH) (2)


Input: Morphology of the nanostructures, depending on pH and with decreasing pH from 13 to 8, changed from nanoparticle to nanoneedle.


Input: Results show a decrease in the particles size as the concentration and sequential dipping steps increased.


Input: The physicochemical properties of the nanostructures were determined by powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and wavelength dispersive X-ray (WDX).


Input: The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone.

aconitine

buspirone


Input: Aconitum species are widely used to treat rheumatism, cardiovascular diseases, and tumors in China and other Asian countries.


Input: The herbs are always used with drugs such as paclitaxel.

paclitaxel


Input: Aconitine (AC) is one of the main bioactive/high-toxic alkaloids of Aconitum roots.

Aconitine


Input: AC is metabolized by cytochrome P450 (CYP) 3A.


Input: However, whether AC inhibits/induces CYP3A, which causes drug-drug interaction (DDI) is unclear.


Input: Our study aims to explore the potent effects of AC, as a marker component of Aconitum, on CYP3A using the probe buspirone in rats.

buspirone


Input: The effects of oral AC on pharmacokinetics of buspirone were evaluated.

buspirone


Input: CYP3A activity and protein levels in rat liver microsomes pretreated with oral AC were also measured using in vitro buspirone metabolism and Western blot.

buspirone


Input: Buspirone and its major metabolites 1-(2-pyrimidinyl) piperazine and 6'-hydroxybuspirone were determined using a newly validated UPLC-MS/MS method.

Buspirone

1-(2-pyrimidinyl) piperazine


Input: Single dose and 7-day AC administration at 0. 125mg/kg had no effect on CYP3A activity since no change in the formation of 1-(2-pyrimidinyl) piperazine and 6'-hydroxybuspirone.

1-(2-pyrimidinyl) piperazine


Input: CYP3A activity and protein levels in liver microsomes were also not affected by 7-day AC pretreatment at 0. 125mg/kg.


Input: Therefore, AC neither inhibits nor induces CYP3A in rats, indicating AC does not cause CYP3A-related DDI in the liver.


Input: Cholinesterase confabs and cousins: Approaching forty years.


Input: In the past four decades of cholinesterase (ChE) research, we have seen substantive evolution of the field from one centered around substrate and inhibitor kinetic profiles and compound characterizations to the analysis of ChE structure, first through the gene families and then by X-ray crystallographic determinations of the free enzymes and their complexes and conjugates.


Input: Indeed, these endeavors have been facilitated by recombinant DNA technologies, structure determinations and parallel studies in related proteins in the alpha/beta-hydrolase fold family.


Input: This approach has not only contributed to a fundamental understanding of structure and function of a large family of hydrolase-like proteins possessing functions other than catalysis, but also has been used to develop new practical strategies for scavenging and antidotal activity in cases of organophosphate insecticide or nerve agent exposure.

organophosphate


Input: Timing of decontamination and treatment in case of percutaneous VX poisoning: A mini review.


Input: Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin.

organophosphorous


Input: The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent.

oximes

atropine

diazepam


Input: Repeated administration of these drugs showed to improve treatment efficacy compared to a single injection treatment.


Input: Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure.

carbamate

pyridostigmine

physostigmine

procyclidine

scopolamine


Input: Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs.

scopolamine


Input: These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen.


Input: Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure.


Input: To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4 x LD50 VX in IPA.

IPA


Input: The results showed that RSDL decontamination at 15min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment.


Input: A similar decontamination regimen with RSDL at 90min showed that it still might effectively increase the time window of opportunity for treatment.


Input: In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment.


Input: The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment.


Input: Molecular analyses of dinosaur osteocytes support the presence of endogenous molecules.


Input: The discovery of soft, transparent microstructures in dinosaur bone consistent in morphology with osteocytes was controversial.


Input: We hypothesize that, if original, these microstructures will have molecular features in common with extant osteocytes.


Input: We present immunological and mass spectrometry evidence for preservation of proteins comprising extant osteocytes (Actin, Tubulin, PHEX, Histone H4) in osteocytes recovered from two non-avian dinosaurs.


Input: Furthermore, antibodies to DNA show localized binding to these microstructures, which also react positively with DNA intercalating stains propidium iodide (PI) and 4', 6'-diamidino-2-phenylindole dihydrochloride (DAPI).

propidium iodide

4', 6'-diamidino-2-phenylindole dihydrochloride

DAPI


Input: Each antibody binds dinosaur cells in patterns similar to extant cells.


Input: These data are the first to support preservation of multiple proteins and to present multiple lines of evidence for material consistent with DNA in dinosaurs, supporting the hypothesis that these structures were part of the once living animals.


Input: We propose mechanisms for preservation of cells and component molecules, and discuss implications for dinosaurian cellular biology.


Input: Effect of amorphization method on telmisartan solubility and the tableting process.

telmisartan


Input: Telmisartan (TLM), a poorly water-soluble angiotensin II receptor antagonist in crystalline form, was transformed into the amorphous state by the melt quench technique, as well as a cryogenic grinding method, in order to improve its physiochemical properties.

Telmisartan

TLM


Input: The chemical stability of TLM, that is, the tendency of the material to resist change or decomposition due to internal reaction, or due to the effects of air, heat, light, pressure, etc., during formation of the amorphous phase was assessed by monitoring high performance liquid chromatography.

TLM


Input: The existence of the amorphous state was confirmed by differential scanning calorimetry and X-ray powder diffraction.


Input: The glass transition occurred at T (g) = 401K.


Input: In the next stage, the solubility of TLM in 0. 1M HCl, phosphate buffer, pH = 6. 8, and water (25 degrees C and 37 degrees C) was determined.

TLM

HCl


Input: Both amorphous forms of TLM (vitrified and cryogrinded) had a higher solubility (mu g/ml) than their crystalline counterpart.

TLM


Input: An important and interesting problem of the study was to evaluate how the tableting process was affected by the choice of either a crystalline or an amorphous form of TLM.

TLM


Input: Eight different tablet formulations were evaluated using both the crystalline and the amorphous form of TLM.

TLM


Input: Measurements of the physical properties and dissolution tests of G4 formulations tablets with telmisartan in crystalline and amorphous form after different storage periods were also performed.

telmisartan


Input: Binding of Gq protein stabilizes the activated state of the muscarinic receptor type 1.


Input: Activation of G protein coupled receptors (GPCRs) induces various cellular responses through interactions with G proteins.


Input: The key trigger of GPCR activation is agonist binding.


Input: It is reportedly known that the agonist-bound active conformation of the GPCRs, such as the muscarinic acetylcholine receptor type 1 (M (1) R), can be affected by the coupling of G proteins and by depolarization of the membrane potential.


Input: Here we aimed at investigating their effects on the structural rearrangements of the M (1) Rs between the active and quiescent states, using the fluorescence resonance energy transfer (FRET) technique.


Input: For this purpose, fluorescent M (1) R constructs that maintained intact activation of the Gq pathway and interaction with Gq were used.


Input: We captured the agonist-induced conformational changes of the M (1) R as the FRET decreases and found that the FRET decreases were enhanced by co-expression of the Gq subunits.


Input: In addition, co-expression of the Gq subunits decelerated the recovery of the declined FRET upon removal of the agonists, which was slower than the dissociation of the Gq subunits from the receptor.


Input: These results suggested that Gq binding stabilizes the agonist-induced activated conformation of the M (1) R.


Input: We also found that depolarization of the membrane potential slightly but significantly enhanced the agonist-induced FRET decrease, by accelerating the agonist-induced conformational changes.


Input: Thus, structural rearrangement analyses by FRET revealed that Gq coupling stabilizes the active conformation of the M (1) R and also suggested that depolarization accelerates the transition from quiescent to activation conformation.


Input: What is behind the non-antibiotic properties of minocycline?

minocycline


Input: Minocycline is a second-generation, semi-synthetic tetracycline that has been in use in therapy for over 30 years for its antibiotic properties against both Gram-positive and Gram-negative bacteria.

Minocycline

tetracycline


Input: It displays antibiotic activity due to its ability to bind to the 30S ribosomal subunit of bacteria and thus inhibit protein synthesis.


Input: More recently, it has been described to exert a variety of biological actions beyond its antimicrobial activity, including anti-inflammatory and anti-apoptotic activities, inhibition of proteolysis, as well as suppression of angiogenesis and tumor metastasis, which have been confirmed in different experimental models of non-infectious diseases.


Input: There are also many studies that have focused on the mechanisms involved in these non-antibiotic properties of minocycline, including anti-oxidant activity, inhibition of several enzyme activities, inhibition of apoptosis and regulation of immune cell activation and proliferation.

minocycline


Input: This review summarizes the current findings in this topic, mainly focusing on the mechanisms underlying the immunomodulatory and anti-inflammatory activities of minocycline.

minocycline


Input: Target promiscuity and physicochemical properties contribute to pharmacologically induced ER-stress.


Input: In vivo toxicity of drug candidates remains a major problem in the pharmaceutical industry, and is a significant cause of late stage attrition.


Input: As a consequence predictive in vitro assays are developed and put in place early in the discovery pipeline to aid compound selection.


Input: Endoplasmic reticulum stress (ER-stress) has been implicated in many disease states, as well as compound-induced organ toxicities.


Input: We explored the role of ER-stress as a general mechanism of toxicity by utilizing a high-throughput in vitro assay to screen 316 chemically diverse Pfizer proprietary compounds with known in vivo toxicity outcome for nuclear accumulation of spliced x-box binding protein 1 (XBP1s), a key transcription factor of the unfolded protein response (UPR).


Input: We examined the correlation between physicochemical properties, such as molecular weight, pKA, lipophilicity, topological polar surface area, and passive permeability, as well as target promiscuity, between XBP1s hits and non-hits and found that lipophilicity, target promiscuity and low passive permeability significantly contributed to ER-stress.


Input: In addition, we have shown that compounds which cause ER-stress in the form of XBP1s activation at concentrations below 40 mu M have a more than four times greater chance of causing in vivo toxicity at 10 mu M plasma exposure.


Input: Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice.


Input: The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively.


Input: Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0. 001), body weight (p < 0. 01), circulating insulin and LDL-cholesterol (p < 0. 001) and improved insulin sensitivity (p < 0. 001) as well as oral and intraperitoneal (p < 0. 001) glucose tolerance.

cholesterol

glucose


Input: Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls.

glucose


Input: In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle.

triacylglycerol


Input: Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0. 001) elevated pancreatic glucagon content.


Input: Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0. 001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1.


Input: Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0. 05), body weight (p < 0. 05 to p < 0. 01), circulating glucose (p < 0. 05 to p < 0. 01) and insulin (p < 0. 05 to p < 0. 001) and improved glucose tolerance (p < 0. 05) and insulin sensitivity (p < 0. 001).

glucose

glucose


Input: Notably, these beneficial effects were still evident 18 days following cessation of treatment.


Input: These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes.


Input: Evaluating the neurotoxic effects of lactational exposure to persistent organic pollutants (POPs) in Spanish children.


Input: Although the brain continues developing in the postnatal period, epidemiological studies on the effects of postnatal exposure to neurotoxic POPs through breast-feeding remain mostly inconclusive.


Input: Failure to detect associations between postnatal exposure and health outcomes may stem from the limitations of commonly employed approaches to assess lactational exposure.


Input: The aim of the present study was to assess whether lactational exposure to polychlorinated biphenyl-153 (PCB-153), dichlorodiphenyldichloroethylene (DDE), or hexachlorobenzene (HCB) as estimated with a physiologically based pharmacokinetic (PBPK) model, is associated with decrements in mental and psychomotor development scores of the Bayley Scales of Infant Development (BSID) test in children aged around 14-months of a subsample (N = 1175) of the Spanish INMA birth cohort, and to compare this with the effects of prenatal exposure.

polychlorinated biphenyl-153

dichlorodiphenyldichloroethylene

DDE

hexachlorobenzene

HCB


Input: Although in the present study population PCB-153, DDE and HCB exposure increased within the first months of postnatal life, no associations were found between different periods of postnatal exposure to these compounds and mental or psychomotor scores.

DDE

HCB


Input: Increasing prenatal PCB-153 concentrations were associated with worse mental and psychomotor scores, although significance was only reached for psychomotor development (beta [95% CI] =-1. 36 [-2. 61,-0. 11]).


Input: Indeed, the association between exposure and effects observed during prenatal life weakened gradually across periods of postnatal life.


Input: Results of the present study suggest that, although breastfeeding increases children' s blood persistent organic pollutants (POPs) levels during postnatal life, deleterious effects of PCB-153 on neuropsychological development are mainly attributable to prenatal exposure.


Input: Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology.


Input: Wet media milling by top down method has proved to be an effective method to prepare nanosuspension of poorly soluble drugs/APIs.


Input: Few or no attempts have been made so far to understand the feasibility of nanosuspension formulation in terms of the mechanism of stabilization as a function of drug properties.


Input: The objective of this study was to understand the effect of drug substance and stabilizer properties to form a successful nanosuspension product.


Input: From this study, logP and enthalpy were concluded to have a direct correlation on the feasibility of formation of a stable nanosuspension.


Input: The most likely candidate for media milling was a drug substance with a high enthalpy and hydrophobicity which can be stabilized either electrostatically or sterically.


Input: The least likely candidate will be one that is hydrophilic and having a very low enthalpy value.


Input: Also the choice of an ideal stabilizer/surfactant was found to be influenced by the degree of hydrophobicity of the drug itself.


Input: Finally the morphology of the starting drug was found to significantly affect the milling time required to produce submicron particles.


Input: Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes.


Input: Despite the recent attention focused on the roles of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of type 2 diabetes, little is known about the ex vivo profile of inflammasome activation in type 2 diabetic patients.

nucleotide


Input: In this study, we investigated patterns of NLRP3 inflammasome activation in monocyte-derived macrophages (MDMs) from drug-na i ve patients with newly diagnosed type 2 diabetes.


Input: Type 2 diabetic subjects had significantly increased mRNA and protein expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and proinflammatory cytokines in MDMs cultured with autologous sera compared with healthy controls.


Input: Upregulated interleukin (IL)-1 beta maturation, IL-18 secretion, and caspase-1 cleavage were observed in MDMs from type 2 diabetic patients after stimulation with various danger molecules (ATP, high-mobility group protein B1, free fatty acids, islet amyloid polypeptide, and monosodium uric acid crystals).

ATP

fatty acids

monosodium uric acid


Input: Mitochondrial reactive oxygen species and NLRP3 were required for IL-1 beta synthesis in MDMs.

oxygen


Input: Finally, 2 months of therapy with the antidiabetic drug metformin significantly inhibited the maturation of IL-1 beta in MDMs from patients with type 2 diabetes through AMP-activated protein kinase (AMPK) activation.

metformin

AMP


Input: Taken together, these data suggest that NLRP3 inflammasome activation is elevated in myeloid cells from type 2 diabetic patients and that antidiabetic treatment with metformin contributes to modulation of inflammasome activation in type 2 diabetes.

metformin


Input: Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic-pituitary-adrenal axis response to acute stress.


Input: The neuropeptide apelin is expressed in hypothalamic paraventricular and supraoptic nuclei and mediates its effects via activation of the apelin receptor (APJ).


Input: Evidence suggests a role for apelin and APJ in mediating the neuroendocrine response to stress.


Input: To understand the physiological role of APJ in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, we measured ACTH and corticosterone (CORT) plasma levels in male and female mice lacking APJ (APJ knockout, APJ KO) and in wild-type controls, in response to a variety of acute stressors.

corticosterone

CORT


Input: Exposure to mild restraint, systemic injection of lipopolysaccharide (LPS), insulin-induced hypoglycaemia and forced swim (FS) stressors, elevated plasma ACTH and CORT levels in wild-type mice.

CORT


Input: Acute mild restraint significantly increased plasma ACTH and CORT to a similar level in APJ KO mice as in wild-type mice.

CORT


Input: However, an intact APJ was required for a conventional ACTH, but not CORT, response to LPS administration in male mice and to insulin-induced hypoglycaemia in male and female mice.

CORT


Input: In contrast, APJ KO mice displayed an impaired CORT response to acute FS stress, regardless of gender.

CORT


Input: These data indicate that APJ has a role in regulation of the HPA axis response to some acute stressors and has a gender-specific function in peripheral immune activation of the HPA axis.


Input: Assessing bioavailability and toxicity of permethrin and DDT in sediment using matrix solid phase microextraction.

permethrin

DDT


Input: Matrix solid phase microextraction (matrix-SPME) was evaluated as a surrogate for the absorbed dose in organisms to estimate bioavailability and toxicity of permethrin and dichlorodiphenyltrichloroethane (DDT) in laboratory-spiked sediment.

permethrin

dichlorodiphenyltrichloroethane

DDT


Input: Sediments were incubated for 7, 28, and 90 days at room temperature to characterize the effect of aging on bioavailability and toxicity.


Input: Sediment toxicity was assessed using two freshwater invertebrates, the midge Chironomus dilutus and amphipod Hyalella azteca.


Input: Disposable polydimethylsiloxane fibers were used to estimate the absorbed dose in organisms and to examine bioavailability and toxicity.

polydimethylsiloxane


Input: The equilibrium fiber concentrations substantially decreased with an increase in sediment aging time, indicating a reduction in bioavailability.


Input: Based on median lethal fiber concentrations (fiber LC50), toxicity of permethrin was not significantly different among the different aging times.

permethrin


Input: Due to the substantial degradation of DDT to dichlorodiphenyldichloroethane (DDD) in sediment, sediment toxicity to C. dilutus increased, while it decreased for H. azteca with extended aging times.

DDT

dichlorodiphenyldichloroethane

DDD


Input: A toxic unit-based fiber LC50 value represented the DDT mixture (DDT and DDD) toxicity for both species.

DDT

DDT

DDD


Input: Significant linear relationships were found between organism body residues and the equilibrium fiber concentrations for each compound, across aging times.


Input: The study suggested that the matrix-SPME fibers mimicked bioaccumulation in the organisms, and enabled estimation of body residues, and could potentially be used in environmental risk assessment across matrices (e. g. sediment and water) to measure bioavailability and toxicity of hydrophobic pesticides.


Input: Effects of DMSA-coated Fe3O4 nanoparticles on the transcription of genes related to iron and osmosis homeostasis.

DMSA

iron


Input: In this article, we checked the effect of 2, 3-dimercaptosuccinic acid-coated Fe (3) O (4) nanoparticles on gene expression of mouse macrophage RAW264. 7 cells and found that the transcription of several important genes related to intracellular iron homeostasis were significantly changed.

2, 3-dimercaptosuccinic acid

Fe (3) O (4)

iron


Input: We thus speculated that the cellular iron homeostasis might be disturbed by this nanoparticle through releasing iron ion in cells.

iron

iron


Input: To verify this speculation, we first confirmed the transcriptional changes of several key iron homeostasis-related genes, such as Tfrc, Trf, and Lcn2, using quantitative PCR, and found that an iron ion chelator, desferrioxamine, could alleviate the transcriptional alterations of two typical genes, Tfrc and Lcn2.

iron

iron

desferrioxamine


Input: Then, we designed and validated a method based on centrifugation for assaying intracellular irons in ion and nanoparticle state.

irons


Input: After extensive measures of intracellular iron in two forms and total iron, we found that the intracellular iron ion significantly increased with intracellular total iron and nanoparticle iron, demonstrating degradation of this nanoparticle into iron ion in cells.

iron

iron

iron

iron

iron

iron


Input: We next mimicked the intralysosomal environment in vitro and verified that the internalized iron nanoparticle could release iron ion in lysosome.


Input: We found that as another important compensatory response to intracellular overload of iron ion, cells significantly downregulated the expressions of genes belonging to solute carrier family which are responsible for transferring many organic solutes into cells, such as Slc5a3 and Slc44a1, in order to prevent more organic solutes into cells and thus lower the intracellular osmosis.

iron


Input: Based on these findings, we profiled a map of gene effects after cells were treated with this iron nanoparticle and concluded that the iron nanoparticles might be more detrimental to cell than iron ion due to its intracellular internalization fashion, nonspecific endocytosis.

iron

iron

iron


Input: Developmental consequences of the ColQ/MuSK interactions.


Input: CollagenQ (ColQ) is a specific collagen that anchors acetylcholinesterase (AChE) in the synaptic basal lamina of the neuromuscular junction (NMJ).


Input: Over 30 mutations in the COLQ gene have been identified that are responsible for a congenital myasthenic syndrome with AChE deficiency, highlighting the importance of this collagen in the physiology of the NMJ.


Input: The anchoring of AChE at the synapse requires the interaction of ColQ with MuSK (Muscle-Specific Kinase), a tyrosine kinase expressed on the muscle membrane that is necessary for the formation and the maintenance of the NMJ.

tyrosine


Input: MuSK forms with its co-receptor LRP4, a member of the Low-density Related Protein family, a receptor complex for agrin and Wnts, representing the core system from which the postsynaptic domain is built, the growth cone attracted and the presynaptic element instructed for some aspects of its differentiation.


Input: Therefore, the discovery that ColQ binds to MuSK prompted us to study a possible regulatory function of ColQ during NMJ development.


Input: In this review, after a brief survey on ColQ, we summarize our recent data demonstrating that ColQ, in addition to its anchoring role, exerts signaling functions and controls some aspects of postsynaptic differentiation such as the clustering of acetylcholine receptors.


Input: Our results also strengthen the hypothesis that the defects observed in synaptic congenital myasthenic syndromes might be linked, at least in part, to alterations of ColQ signaling functions and not only to AChE deficiency.


Input: Finally, we discuss future research directions to understand how ColQ may modulate the action of the other ligands of the MuSK/LRP4 complex and cooperate with them to coordinate the different steps of NMJ formation and maintenance.


Input: Redox control of teratogenesis.


Input: A number of human teratogens elicit their deleterious effects through mechanisms involving the generation of reactive oxygen species (ROS) and oxidative stress.

oxygen


Input: However, classic definitions of oxidative stress do not fully coincide with basic fundamental principles of teratology.


Input: Newer definitions of oxidative stress focus on the targeted redox modification of cysteine/thiol functional groups found in the regulatory domains of critical signaling pathway proteins, suggesting that the targeted disruption of signaling through specific redox couples may account for the specificity of teratogen-induced malformations which previously could not be rationalized.

cysteine

thiol


Input: Here, we review examples of teratogens that induce ROS and oxidative injury, describe oxidative stress-related teratogenic mechanisms, and provide rationale for developmental periods of sensitivity and species susceptibility.


Input: Understanding how chemicals disrupt redox status, induce oxidative stress leading to dysmorphogenesis becomes important to identify potential teratogens and develop therapeutic interventions for attenuation of harmful chemical effects in utero following exposure.


Input: Cholesterol ester droplets and steroidogenesis.

Cholesterol ester


Input: Intracellular lipid droplets (LDs) are dynamic organelles that contain a number of associated proteins including perilipin (Plin) and vimentin.


Input: Cholesteryl ester (CE)-rich LDs normally accumulate in steroidogenic cells and their mobilization is the preferred initial source of cholesterol for steroidogenesis.

Cholesteryl ester

cholesterol


Input: Plin1a, 1b and 5 were found to preferentially associate with triacylglycerol-rich LDs and Plin1c and Plin4 to associate with CE-rich LDs, but the biological significance of this remains unanswered.

triacylglycerol


Input: Vimentin null mice were found to have decreased ACTH-stimulated corticosterone levels, and decreased progesterone levels in females, but normal hCG-stimulated testosterone levels in males.

corticosterone

progesterone

testosterone


Input: Smaller LDs were seen in null cells.


Input: Lipoprotein cholesterol delivery to adrenals and ovary was normal, as was the expression of steroidogenic genes; however, the movement of cholesterol to mitochondria was reduced in vimentin null mice.

cholesterol

cholesterol


Input: These results suggest that vimentin is important in the maintenance of CE-rich LDs and in the movement of cholesterol for steroidogenesis.

cholesterol


Input: The interactive effects of selenomethionine and methylmercury on their absorption, disposition, and elimination in juvenile white sturgeon.

selenomethionine

methylmercury


Input: Selenium (Se) and mercury (Hg) are prevalent pollutants of industrialized watersheds.

Selenium

Se

mercury

Hg


Input: However, when co-administered, Se has protective effects on organisms from Hg.

Se

Hg


Input: The mechanism is not fully understood, but it is thought that Se reduces Hg availability, either by forming biologically inert complexes and/or associating with selenoproteins.

Se

Hg


Input: Despite concerns with aquatic contaminations, relatively little information is available on the interaction in aquatic organisms.


Input: In the present study, the interactive effects of Se and Hg on their absorption, disposition, and elimination were examined in juvenile white sturgeon, a benthic fish species at high risk to exposures of both contaminants.

Se

Hg


Input: Selenium and Hg were provided as L-selenomethionine (SeMet) and methylmercury (MeHg), respectively.

Selenium

Hg

L-selenomethionine

SeMet

methylmercury

MeHg


Input: Groups of 10 sturgeon were orally intubated with a single dose of either 0 (control), SeMet (500 mu g Se/kg body weight; BW), MeHg (850 mu g Hg/kg BW), or their combination (Se/Hg; 500 mu g Se/kg and 850 mu g Hg/kg BW).

SeMet

Se

MeHg

Hg

Se

Hg

Se


Input: The blood was repeatedly sampled and urine collected from the fish, over a 48 h post intubation period.


Input: At 48 h, the fish were sacrificed for Se and Hg tissue concentration and distribution.

Se

Hg


Input: The co-administration of SeMet and MeHg significantly (p < 0. 05) lowered blood concentrations of both Se and Hg and tissue Se concentrations.

SeMet

MeHg

Se

Hg

Se


Input: Similarly, assimilation of Se and Hg was also reduced significantly.

Se

Hg


Input: The interaction has a more quantitative effect on Se metabolism because the reduction in the overall tissue Se is a consequence of reduced Se absorption at the gut and not from the metabolic effects after absorption.

Se

Se

Se


Input: In contrast, given the pulse increase in blood Hg concentration, tissue redistribution, and increased urinary elimination, the interactive effect on tissue Hg concentration is likely to be post-absorption.

Hg

Hg


Input: Even in the absence of exogenous SeMet, Se and Hg co-accumulated in tissue at a Se: Hg molar ratio greater than 1.

SeMet

Se

Hg

Se

Hg


Input: Thus, similar to mammals, maintaining at least a 1: 1 molar ratio of Se and Hg is of great physiological importance in the white sturgeon.

Se

Hg


Input: Interestingly, SeMet did not divert Hg from the brain.

SeMet

Hg


Input: Allocation of Se from the kidneys may have occurred in order to maintain the high Se: Hg molar ratios in the brain of white sturgeon.

Se

Se

Hg


Input: In the current study, the combined use of kinetic analysis and that of the conventional approach of measuring tissue concentration changes provided a comprehensive understanding of the interactive effect of SeMet and MeHg on their respective metabolic processes in juvenile white sturgeon.

SeMet

MeHg


Input: Enhanced charge carrier mobility in two-dimensional high dielectric molybdenum oxide.

molybdenum oxide


Input: We demonstrate that the energy bandgap of layered, high-dielectric alpha-MoO (3) can be reduced to values viable for the fabrication of 2D electronic devices.

alpha-MoO (3)


Input: This is achieved through embedding Coulomb charges within the high dielectric media, advantageously limiting charge scattering.


Input: As a result, devices with alpha-MoO (3) of ~ 11 nm thickness and carrier mobilities larger than 1100 cm (2) V (-1) s (-1) are obtained.

alpha-MoO (3)


Input: Adsorption of multimeric T cell antigens on carbon nanotubes: effect on protein structure and antigen-specific T cell stimulation.

carbon


Input: Antigen-specific activation of cytotoxic T cells can be enhanced up to three-fold more than soluble controls when using functionalized bundled carbon nanotube substrates ((b) CNTs).

carbon


Input: To overcome the denaturing effects of direct adsorption on (b) CNTs, a simple but robust method is demonstrated to stabilize the T cell stimulus on carbon nanotube substrates through non-covalent attachment of the linker neutravidin.

carbon


Input: Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies.


Input: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients.


Input: The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury.


Input: Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy.

diclofenac

indomethacin

naproxen


Input: The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial beta-glucuronidase produces critical aglycones.


Input: The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates.


Input: The " first hit " is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death.


Input: The " second hit " is created by the significant subsequent inflammatory response that would follow such a first-hit injury.


Input: Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites.


Input: Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific beta-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy.


Input: Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits.


Input: Combination lopinavir and ritonavir alter exogenous and endogenous bile acid disposition in sandwich-cultured rat hepatocytes.

lopinavir

ritonavir

bile acid


Input: Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans.

bile salt

bile acids


Input: Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors.

lopinavir

LPV

ritonavir

RTV


Input: However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined.

LPV

RTV

LPV

bile acid

bile acid


Input: The effect of LPV, RTV, and LPV/r on cellular viability and the disposition of [(3) H] taurocholic acid (TCA) and [(14) C] chenodeoxycholic acid (CDCA) was determined in sandwich-cultured rat hepatocytes (SCRH) and suspended rat hepatocytes.

LPV

RTV

LPV

[(3) H] taurocholic acid

TCA

[(14) C] chenodeoxycholic acid

CDCA


Input: Lactate dehydrogenase and ATP assays revealed a concentration-dependent effect of LPV and RTV on cellular viability.

Lactate

ATP

LPV

RTV


Input: LPV (5 micro M), alone and combined with 5 micro M RTV, significantly decreased [(3) H] TCA accumulation in cells + bile of SCRHs compared with control.

LPV

RTV

[(3) H] TCA


Input: LPV/r significantly increased [(3) H] TCA cellular accumulation (7. 7 +/- 0. 1 pmol/mg of protein) compared with vehicle and 5 micro M LPV alone (5. 1 +/- 0. 7 and 5. 0 +/- 0. 5 pmol/mg of protein).

LPV

[(3) H] TCA

LPV


Input: The [(3) H] TCA biliary clearance was reduced significantly by LPV and RTV and further reduced by LPV/r.

[(3) H] TCA

LPV

RTV

LPV


Input: LPV and RTV did not affect the initial uptake rates of [(3) H] TCA or [(14) C] CDCA in suspended rat hepatocytes.

LPV

RTV

[(3) H] TCA

[(14) C] CDCA


Input: LPV (50 micro M), RTV (5 micro M), and LPV/r (5 and 50 micro M/5 micro M) significantly decreased the accumulation of total measured endogenous bile acids (TCA, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and alpha/beta-tauromuricholic acid) in SCRH.

LPV

RTV

LPV

bile acids

TCA

glycocholic acid

taurochenodeoxycholic acid

glycochenodeoxycholic acid

alpha/beta-tauromuricholic acid


Input: Quantification of endogenous bile acids in SCRH may reveal important adaptive responses associated with exposure to known BSEP inhibitors.

bile acids


Input: Bimodal surface ligand engineering: the key to tunable nanocomposites.


Input: Tuning the dispersion of inorganic nanoparticles within organic matrices is critical to optimizing polymer nanocomposite properties and is intrinsically difficult due to their strong enthalpic incompatibility.


Input: Conventional attempts to use polymer brushes to control nanoparticle dispersion are challenged by the need for high graft density to reduce particle core-core attractions and the need for low graft density to reduce the entropic penalty for matrix penetration into the brush.


Input: We validated a parametric phase diagram previously reported by Pryamtisyn et al.


Input: (Pryamtisyn, V.; Ganesan, V.; Panagiotopoulos, A. Z.; Liu, H.; Kumar, S. K. Modeling the Anisotropic Self-Assembly of Spherical Polymer-Grafted Nanoparticles. J. Chem. Phys. 2009, 131, 221102) for predicting dispersion of monomodal-polymer-brush-modified nanoparticles in polymer matrices.


Input: The theoretical calculation successfully predicted the experimental observation that the monomodal-poly (dimethyl siloxane) (PDMS)-brush-grafted TiO (2) nanoparticles can only be well dispersed within a small molecular weight silicone matrix.

poly (dimethyl siloxane)

PDMS

TiO (2)

silicone


Input: We further extended the parametric phase diagram to analyze the dispersion behavior of bimodal-PDMS-brush-grafted particles, which is also in good agreement with experimental results.

PDMS


Input: Utilizing a bimodal grafted polymer brush design, with densely grafted short brushes to shield particle surfaces and sparsely grafted long brushes that favor the entanglement with matrix chains, we dispersed TiO (2) nanoparticles in high molecular weight commercial silicone matrices and successfully prepared thick (about 5 mm) transparent high-refractive-index TiO (2)/silicone nanocomposites.

TiO (2)

silicone

TiO (2)

silicone


Input: On the pH-Responsive, Charge-Selective, Polymer-Brush-Mediated Transport Probed by Traditional and Scanning Fluorescence Correlation Spectroscopy.


Input: The complete and reversible charge-selective sequestration of fluorophores by a weak polyelectrolyte brush, poly (2-(dimethylamino) ethylmethacrylate) (PDMAEMA) was demonstrated using fluorescence correlation spectroscopy (FCS).

poly (2-(dimethylamino) ethylmethacrylate)

PDMAEMA


Input: The chemistry and thickness of the weak polyelectrolyte PDMAEMA was tuned reversibly between neutral and cationic polymer forms.

PDMAEMA


Input: Thus, by switching the pH successively, the brush architecture was tuned to selectively trap and release anionic dye probes while continuously excluding cationic molecules.


Input: In addition, line-scan FCS was implemented and applied for the first time to a synthetic polymer system and used to identify a new, slower diffusion time on the order of seconds for the sequestered anionic probe under acidic conditions.


Input: These results, which quantify the selective sequestration properties of the PDMAEMA brush, are important because they enable a better understanding of transport in polymers and establish a spectroscopic means of evaluating materials with proposed applications in separations science, charge storage/release, and environmental remediation.

PDMAEMA


Input: An exploration of species boundaries in turret-building tarantulas of the Mojave Desert (Araneae, Mygalomorphae, Theraphosidae, Aphonopelma).


Input: Tarantulas in the North American genus Aphonopelma are poorly known due to their challenging patterns of morphological variation and questionable taxonomy; few specimens can be confidently identified using existing keys or comparisons to original descriptions.


Input: In an effort to identify new strategies for resolving what has been characterized as a " taxonomic and nomenclatural nightmare ", we employed five different approaches for delimiting species in a group of closely related tarantulas from the Mojave Desert in the southwestern United States.


Input: These methods included the application of single techniques (morphology, DNA barcoding, shared genealogical exclusivity among independent loci, and generalized mixed Yule coalescent) and an integrative approach that incorporates genealogical and ecological information.


Input: Results demonstrate that the taxonomy of these spiders as presently defined underestimates actual species-level diversity and the group is in need of revision.


Input: The number of species delimited by each approach, however, was variable and we argue that it is this discordance that emphasizes the importance of incorporating multiple lines of evidence into an integrative taxonomic framework that can be used for constructing robust taxonomic hypotheses for Aphonopelma species.


Input: mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells.


Input: Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively.

rapamycin


Input: Recent studies demonstrated the role of rictor in the development and function of beta-cells.


Input: mTORC1 has long been known to impact beta-cell function and development.


Input: However, most of the studies evaluating its role used either drug treatment (i. e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear.

rapamycin


Input: In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2.


Input: Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content.

glucose


Input: Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA.


Input: Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling.


Input: Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis.

glucose


Input: Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers.


Input: Ocular barriers and the poor water solubility of drug candidates present a number of problems for the development of ocular drug delivery systems.


Input: Recently, the emergence of lipid-based nanocarriers has provided a viable means of enhancing the bioavailability of ophthalmic formulations.


Input: A number of these formulations have been found to be clinically active and several others are currently undergoing clinical trials.


Input: In this review, the advantages of lipid-based nanocarriers as non-invasive topical ocular drug delivery systems are presented.


Input: Many systems, including emulsions, liposomes, cubosomes, niosomes and other lipid-based nanocarriers, are reviewed.


Input: Phosphoinositide-dependent kinase-1 and protein kinase C delta contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia.


Input: Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension.


Input: Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats.


Input: IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) delta-dependent manner in mesenteric arteries.


Input: Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKC delta activity, we hypothesized that PDK-1 contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH.


Input: Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O (2)/0% CO (2) and 5% O (2)/5% CO (2)) conditions for 7 h/day for 14 or 21 days.

O (2)

CO (2)

O (2)

CO (2)


Input: The contribution of PKC delta and PDK-1 to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors.


Input: Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats.


Input: Inhibition of PKC delta or PDK-1 blunted ET-1 constriction in arteries from IH but not sham group rats.


Input: Western analysis revealed similar levels of total and phosphorylated PDK-1 in arteries from sham and IH group rats but decreased protein-protein interaction between PKC delta and PDK-1 in arteries from IH-compared with sham-exposed rats.


Input: Blood pressure was increased in rats exposed to IH, and treatment with the PDK-1 inhibitor OSU-03012 [2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide] (33 mg/day) lowered blood pressure in IH but not sham group rats.

2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide


Input: Our results suggest that exposure to IH unmasks a role for PDK-1 in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions.


Input: These novel findings suggest that PDK-1 may be a uniquely effective antihypertensive therapy for OSA patients.


Input: Mouse liver protein sulfhydryl depletion after acetaminophen exposure.

sulfhydryl

acetaminophen


Input: Acetaminophen (APAP)-induced liver injury is the leading cause of acute liver failure in many countries.

Acetaminophen

APAP


Input: This study determined the extent of liver protein sulfhydryl depletion not only in whole liver homogenate but also in the zonal pattern of sulfhydryl depletion within the liver lobule.

sulfhydryl

sulfhydryl


Input: A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase levels, liver necrosis, and glutathione depletion in a dose-dependent manner.

APAP

alanine

glutathione


Input: Free protein sulfhydryls were measured in liver protein homogenates by labeling with maleimide linked to a near infrared fluorescent dye followed by SDS-polyacrylamide gel electrophoresis.

sulfhydryls

maleimide

SDS

polyacrylamide


Input: Global protein sulfhydryl levels were decreased significantly (48. 4%) starting at 1 hour after the APAP dose and maintained at this reduced level through 24 hours.

sulfhydryl

APAP


Input: To visualize the specific hepatocytes that had reduced protein sulfhydryl levels, frozen liver sections were labeled with maleimide linked to horseradish peroxidase.

sulfhydryl

maleimide


Input: The centrilobular areas exhibited dramatic decreases in free protein sulfhydryls while the periportal regions were essentially spared.

sulfhydryls


Input: These protein sulfhydryl-depleted regions correlated with areas exhibiting histopathologic injury and APAP binding to protein.

sulfhydryl

APAP


Input: The majority of protein sulfhydryl depletion was due to reversible oxidation since the global-and lobule-specific effects were essentially reversed when the samples were reduced with tris (2-carboxyethy) phosphine before maleimide labeling.

sulfhydryl

tris (2-carboxyethy) phosphine

maleimide


Input: These temporal and zonal pattern changes in protein sulfhydryl oxidation shed new light on the importance that changes in protein redox status might play in the pathogenesis of APAP hepatotoxicity.

sulfhydryl

APAP


Input: Distinct sensitivity of slo1 channel proteins to ethanol.

ethanol


Input: Ethanol levels reached in circulation during moderate-to-heavy alcohol intoxication (50-100 mM) modify Ca (2 +)-and voltage-gated K (+) (BK) channel steady-state activity, eventually altering both physiology and behavior.

Ethanol

alcohol

Ca (2 +)

K (+)


Input: Ethanol action on BK steady-state activity solely requires the channel-forming subunit slo1 within a bare lipid environment.

Ethanol


Input: To identify the protein regions that confer ethanol sensitivity to slo1, we tested the ethanol sensitivity of heterologously expressed slo1 and structurally related channels.

ethanol

ethanol


Input: Ethanol (50 mM) increased the steady-state activities of mslo1 and Ca (2 +)-gated MthK, the latter after channel reconstitution into phospholipid bilayers.

Ethanol

Ca (2 +)


Input: In contrast, 50-100 mM ethanol failed to alter the steady-state activities of Na (+)/Cl (-)-gated rslo2, H (+)-gated mslo3, and an mslo1/3 chimera engineered by joining the mslo1 region encompassing the N terminus to S6 with the mslo3 cytosolic tail domain (CTD).

ethanol

Na (+)

Cl (-)

H (+)

N


Input: Collectively, data indicate that the slo family canonical design, which combines a transmembrane 6 (TM6) voltage-gated K (+) channel (K (V)) core with CTDs that empower the channel with ion-sensing, does not necessarily render ethanol sensitivity.

K (+)

K

ethanol


Input: In addition, the region encompassing the N terminus to the S0-S1 cytosolic loop (missing in MthK) is not necessary for ethanol action.

N

ethanol


Input: Moreover, incorporation of both this region and an ion-sensing CTD to TM6 K (V) cores (a design common to mslo1, mslo3, and the mslo1/mslo3 chimera) is not sufficient for ethanol sensitivity.

K

ethanol


Input: Rather, a CTD containing Ca (2 +)-sensing regulator of conductance for K (+) domains seems to be critical to bestow K (V) structures, whether of TM2 (MthK) or TM6 (slo1), with sensitivity to intoxicating ethanol levels.

Ca (2 +)

K (+)

K

ethanol


Input: Identification of determinants required for agonistic and inverse agonistic ligand properties at the ADP receptor P2Y12.

ADP


Input: The ADP receptor P2Y (12) belongs to the superfamily of G protein-coupled receptors (GPCRs), and its activation triggers platelet aggregation.

ADP


Input: Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events.

clopidogrel


Input: P2Y (12) displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists.


Input: Only a few inverse agonists of P2Y (12) have been described.


Input: To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y (12) and 28 constitutively active mutants.

purine


Input: Results showed that ATP and ATP derivatives are agonists at P2Y (12).

ATP

ATP


Input: The potency at P2Y (12) was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP.

ADP

ATP


Input: Determinants required for agonistic ligand activity were identified.


Input: Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y (12,) with Y (105), E (188), R (256), Y (259), and K (280) playing a particularly important role in ligand interaction.

ATP


Input: N-Methyl-anthraniloyl modification at the 3'-OH of the 2'-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity.

N-Methyl-anthraniloyl

ATP

ADP


Input: Inverse agonist activity of mant-dATP was found at the WT human P2Y (12) and half of the constitutive active P2Y (12) mutants.


Input: This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y (12) but also agonists.

ADP

ATP

ATP


Input: Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands.

ATP

ATP


Input: Restricted distribution and limited gene flow in the model ciliate Tetrahymena thermophila.


Input: The biogeography of microbial eukaryotes has long been debated, but few phylogeographic data have been available to assess whether protists tend to have ubiquitous or endemic distributions.


Input: We addressed this issue in the ciliate Tetrahymena thermophila, a highly successful model system in cell and molecular biology.


Input: We found that this species has a distribution that is restricted to the Eastern United States, with high diversity in the northeast and low diversity across the rest of its distribution.


Input: We find high levels of population subdivision, low rates of migration and significant isolation by distance, supporting the moderate endemicity model of protist biogeography.


Input: This restricted gene flow may be a result of small population size, which would reduce the probability of migration events, or the inability to establish after migration.


Input: This work lays the foundation for T. thermophila to become a valuable model system for studying population biology.


Input: Differential effects of antipsychotic agents on obsessive-compulsive symptoms in schizophrenia: a longitudinal study.


Input: Indirect evidence supports the assumption that antiserotonergic second-generation antipsychotics (SGA) induce and aggravate obsessive-compulsive symptoms (OCS) in schizophrenia.


Input: However, multimodal studies assessing the long-term interaction of pharmacotherapy and psychopathology are missing.


Input: Over 12 months, we followed-up 75 schizophrenia patients who were classified into two groups according to antipsychotic treatment: clozapine or olanzapine (group I) versus aripiprazole or amisulpride (group II).

clozapine

olanzapine

aripiprazole

amisulpride


Input: We applied the Yale Brown Obsessive Compulsive Scale (YBOCS) and investigated between-group changes over time as the primary endpoint.


Input: Group I showed markedly higher YBOCS scores at both time points.


Input: Repeated measure analyses of variance (ANOVAs) revealed significant interaction effects of group and time (per protocol sample (PP): p = 0. 006).


Input: This was due to persistently high OCS severity within group I, and decreasing YBOCS scores within group II.


Input: OCS severity correlated significantly with the negative and general psychopathology subscales of the Positive and Negative Syndrome Scale (PANSS), as well as with depressive symptoms.


Input: The progressive differences in OCS severity between our groups support the assumption of differential pharmacodynamic effects on comorbid OCS in schizophrenia.


Input: Further studies should address the pathogenetic mechanism, define patients at risk and facilitate early detection as well as therapeutic interventions.


Input: Intercellular adhesion molecule-2 is involved in apical ectoplasmic specialization dynamics during spermatogenesis in the rat.


Input: In this study, we investigated the role of intercellular adhesion molecule-2 (ICAM2) in the testis.


Input: ICAM2 is a cell adhesion protein having important roles in cell migration, especially during inflammation when leukocytes cross the endothelium.


Input: Herein, we showed ICAM2 to be expressed by germ and Sertoli cells in the rat testis.


Input: When a monospecific antibody was used for immunolocalization experiments, ICAM2 was found to surround the heads of elongating/elongated spermatids in all stages of the seminiferous epithelial cycle.


Input: To determine whether ICAM2 is a constituent of apical ectoplasmic specialization (ES), co-immunoprecipitation and dual immunofluorescence staining were performed.


Input: Interestingly, ICAM2 was found to associate with beta 1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and actin.

tyrosine


Input: Following CdCl 2 treatment, ICAM2 was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for ICAM2 by 6-16 h.

CdCl 2


Input: Interestingly, there was a loss in the binding of ICAM2 to actin during CdCl 2-induced germ cell loss, suggesting that a loss of ICAM2-actin interactions might have facilitated junction restructuring.

CdCl 2


Input: Taken collectively, these results illustrate that ICAM2 plays an important role in apical ES dynamics during spermatogenesis.


Input: A single-device universal logic gate based on a magnetically enhanced memristor.


Input: Memristors are one of the most promising candidates for future information and communications technology (ICT) architectures.


Input: Two experimental proofs of concept are presented based on the intermixing of spintronic and memristive effects into a single device, a magnetically enhanced memristor (MEM).


Input: By exploiting the interaction between the memristance and the giant magnetoresistance (GMR), a universal implication (IMP) logic gate based on a single MEM device is realized.


Input: Novel screening assay for the selective detection of G-protein-coupled receptor heteromer signaling.


Input: Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines.


Input: The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets.


Input: However, current in vitro assays are ill equipped to detect heteromer-selective compounds.


Input: We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable.


Input: Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition.


Input: Using this assay, we reveal that the delta-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against delta-opioid receptor homomers than delta/mu-opioid receptor heteromers (pEC (50) = 6. 7 +/- 0. 1 versus 5. 8 +/- 0. 2).


Input: The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents.


Input: Two new anthraquinone dimers from the fruit bodies of Bulgaria inquinans.

anthraquinone


Input: Two new dimeric anthraquinone derivatives, bulgareone A (1) and bulgareone B (2), were isolated from the fruit bodies of Bulgaria inquinans.

anthraquinone

bulgareone A

bulgareone B


Input: Their structures were elucidated on the basis of extensive spectroscopic analysis.


Input: The in vitro cytotoxic activity of compounds 1 and 2 was assayed.


Input: They displayed inhibitive activities against human cancer cell lines HL60 and K562.


Input: Sex differences in effects of low level domoic acid exposure.

domoic acid


Input: Consumption of seafood containing the phytoplankton-derived toxin domoic acid (DOM) causes neurotoxicity in humans and in animals.

domoic acid

DOM


Input: It has been reported that DOM-induced symptoms may be more severe in men than women, but to date the effect of sex on DOM-induced effects in adults is not known.

DOM

DOM


Input: We investigated sex differences in DOM-induced effects in adult rats.

DOM


Input: Since low level exposure is of greatest relevance to human health (due to DOM regulatory limit), we examined the effects of low level exposure.

DOM


Input: Adult male and female Sprague Dawley rats were administered a single intraperitoneal injection of DOM (0, 1. 0, 1. 8 mg/kg).

DOM


Input: Behaviour was monitored for 3h and immunohistochemistry in the dorsal hippocampus and olfactory bulb was also examined.


Input: DOM increased locomotor and grooming activity, compared to vehicle group.

DOM


Input: DOM exposure also significantly increased stereotypic behaviours and decreased phosphorylated cAMP response element-binding protein immunoreactivity (pCREB-IR).

DOM

phosphorylated cAMP


Input: There was no effect of sex on the magnitude of the behavioural responses, but the onset of DOM-induced locomotor activity and ear scratches was quicker in females than in males.

DOM


Input: Mixed effect modelling revealed the predicted peak in locomotor activity in response to DOM was also quicker in females than in males.

DOM


Input: Severe toxicity was evident in 2/7 male rats and 0/8 female rats dosed with 1. 8 mg/kg DOM.

DOM


Input: These data suggest that males exposed to low level DOM may be more susceptible to severe neurotoxicity, whereas females are affected more quickly.

DOM


Input: Understanding sex differences in DOM-induced neurotoxicity may contribute to future protective strategies and treatments.

DOM


Input: Toxicokinetic study and absolute oral bioavailability of deoxynivalenol, T-2 toxin and zearalenone in broiler chickens.

deoxynivalenol

T-2 toxin

zearalenone


Input: Mycotoxins lead to economic losses in animal production.


Input: A way to counteract mycotoxicosis is the use of detoxifiers.


Input: The European Food Safety Authority stated that the efficacy of detoxifiers should be investigated based on toxicokinetic studies.


Input: Little information is available on the absolute oral bioavailability and the toxicokinetic parameters of deoxynivalenol, T-2 and zearalenone in broilers.

deoxynivalenol

zearalenone


Input: Toxins were administered intravenously and orally in a two-way cross-over design.


Input: For deoxynivalenol a bolus of 0. 75mg/kg BW was administered, for T-2 toxin 0. 02mg/kg BW and for zearalenone 0. 3mg/kg BW.

deoxynivalenol

T-2 toxin

zearalenone


Input: Blood was collected at several time points.


Input: Plasma levels of the mycotoxins and their metabolite (s) were quantified using LC-MS/MS methods and toxicokinetic parameters were analyzed.


Input: Deoxynivalenol has a low absolute oral bioavailability (19. 3%).

Deoxynivalenol


Input: For zearalenone and T-2 no plasma levels above the limit of quantification were observed after an oral bolus.

zearalenone


Input: Volumes of distribution were recorded, i. e. 4. 99, 0. 14 and 22. 26L/kg for deoxynivalenol, T-2 toxin and zearalenone, respectively.

deoxynivalenol

T-2 toxin

zearalenone


Input: Total body clearance was 0. 12, 0. 03 and 0. 48L/minkg for deoxynivalenol, T-2 toxin and zearalenone, respectively.

deoxynivalenol

T-2 toxin

zearalenone


Input: After IV administration, T-2 toxin had the shortest elimination half-life (3. 9min), followed by deoxynivalenol (27. 9min) and zearalenone (31. 8min).

T-2 toxin

deoxynivalenol

zearalenone


Input: Citrus peel polymethoxylated flavones extract modulates liver and heart function parameters in diet induced hypercholesterolemic rats.

polymethoxylated flavones


Input: The primary aim of this study was to investigate the effects of Ortanique peel polymethoxylated flavones extract (PMF (ort)) on organ function parameters in the serum of hypercholesterolemic and normal rats.

polymethoxylated flavones

PMF


Input: Thirty Sprague-Dawley rats were fed high cholesterol diets supplemented with 1. 5% PMF (ort) and niacin respectively for 49days.

cholesterol

PMF


Input: Hypercholesterolemic rats fed PMF (ort) had significant reductions in the activities of aspartate aminotransferase and alkaline phosphatase (69. 12 +/- 3. 34 and 87. 22 +/- 8. 42U/L respectively) compared to the untreated hypercholesterolemic group (118. 61 +/- 4. 85 and 132. 62 +/- 10. 62U/L respectively, p < 0. 05).

PMF

aspartate


Input: Supplementation of the diet with niacin or PMF (ort) resulted in no significant differences in the serum levels of creatinine or urea in any of the groups.

niacin

PMF

creatinine

urea


Input: Total bilirubin was highest in the untreated hypercholesterolemic group.

bilirubin


Input: Supplementation of the diets of hypercholesterolemic rats with PMF (ort) resulted in significant reductions in the activities of serum creatine kinase and lactate dehydrogenase (119. 3 +/- 25. 3; 222. 5 +/- 50. 3U/L, p < 0. 05) respectively relative to the untreated hypercholesterolemic group (257. 2 +/- 48. 3; 648. 8 +/- 103U/L, p < 0. 05).

PMF

creatine

lactate


Input: The results would suggest that PMF (ort) modulates hypercholesterolemia-associated organ injury in rats.

PMF


Input: PMF (ort) could therefore be a suitable candidate for prophylactic and therapeutic treatment of hypercholesterolemia-associated organ injury.

PMF


Input: Assessment of immunotoxicity and genotoxicity in workers exposed to low concentrations of formaldehyde.

formaldehyde


Input: Formaldehyde (FA), which is an important chemical with a wide commercial use, has been classified as carcinogenic to humans by International Research on Cancer (IARC).

Formaldehyde


Input: The genotoxic and carcinogenic potential of FA has been documented in mammalian cells and in rodents.


Input: A recent evaluation by the E. U.


Input: Scientific Committee for Occupational Exposure Limits (SCOEL) anticipated that an 8-h time-weighted average exposure to 0. 2 ppm FA would not be irritating and not genotoxic in humans.


Input: In order to verify this prediction, a field study was performed that aimed at evaluating immune alterations and genetic damage in peripheral lymphocytes of workers in medium density fiberboard plants exposed to a level of FA equivalent to the OEL recommended by SCOEL (0. 2 ppm).


Input: Subsets of peripheral lymphocytes, immunoglobulins (IgG, IgA, IgM), complement proteins, and tumor necrosis factor-alpha (TNF-alpha) levels were evaluated.


Input: DNA damage of the workers was assessed by the Comet assay.


Input: The absolute numbers and the percentages of T lymphocytes and of natural killer cells, and the levels of TNF-alpha were higher than the controls, whereas IgG and IgM levels were found to be lower in workers.


Input: Other examined immunological parameters were not different from those of the controls.


Input: There was no increased DNA damage in the workers compared to controls.


Input: Mitochondrial fusion: a mechanism of cisplatin-induced resistance in neuroblastoma cells?

cisplatin


Input: Cisplatin induces apoptosis through different pathways.

Cisplatin


Input: The intrinsic apoptotic pathway is mediated by mitochondria, which, as a result of cisplatin treatment, undergo morphological alterations.

cisplatin


Input: The aim of this study was to investigate cisplatin-induced mitochondrial functional and morphological long-term effects in neuroblastoma B50 rat cells.

cisplatin


Input: To this purpose, we followed evaluated different several apoptotic markers by means of flow cytometry, confocal and electron microscopy and western blotting techniques.


Input: We applied different treatment protocols based on the incubation of the neuroblastoma B50 rat cells with 40 mu M cisplatin: (i) for 48 h and harvesting of the cells at the end of the treatment; (ii) further recovery in drug-free medium for 7 days post-treatment; (iii) conditions as in (ii) followed by re-seeding in normal medium and growth for a further 4 days.

cisplatin


Input: We observed apoptosis induction after the first treatment and after the recovery from cell death after long-term culture in drug-free medium.


Input: Interestingly, the latter phenomenon was characterized by mitochondrial elongation and mitochondrial protein rearrangement.


Input: In recovered and re-seeded cells, mitochondrial equilibrium moved toward fusion, possibly protecting cells from apoptosis.


Input: The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: findings from a pQCT case-control study.


Input: High bone mass (HBM), detected in 0. 2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations.


Input: We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.


Input: pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.


Input: HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm (3)), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0. 001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use).

steroid

estrogen


Input: Similar results were obtained at the distal radius.


Input: Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0. 001).


Input: Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0. 05 versus family controls), suggesting greater periosteal apposition.


Input: Cortical thickness was increased at the mid tibia and radius (adjusted p < 0. 001), implying reduced endosteal expansion.


Input: Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0. 001).


Input: We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted beta-0. 01 [-0. 02, 0. 01], p = 0. 41), but declined in family controls (-0. 05 [-0. 03,-0. 07], p < 0. 001) interaction p = 0. 002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent.


Input: In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.


Input: HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength.


Input: In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.


Input: Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique.


Input: The purpose of this study was to evaluate the use of human intestinal tissue in Ussing chamber to predict oral and colonic drug absorption and intestinal metabolism.


Input: Data on viability, correlation between apparent permeability coefficients (P (app)) and fraction absorbed (f (a)) after oral and colonic administration, regional permeability, active uptake and efflux of drugs as well as intestinal metabolism were compiled from experiments using 159 human donors.


Input: Permeability coefficients for up to 28 drugs were determined using one or several of four intestinal regions: duodenum, jejunum, ileum and colon and 10 drugs were studied bidirectionally.


Input: Viability was monitored simultaneously with transport experiments by recording potential difference (PD), short-circuit current (SCC) and the resistance (TER).


Input: Intestinal metabolism was studied using testosterone and midazolam as probe substrates.

testosterone

midazolam


Input: There was a steep sigmoidal correlation between P (app) in the Ussing chamber, using jejunal segments, and oral f (a) in humans, for a set of 25 drugs (R (2): 0. 85, p < 0. 01).


Input: A clear sigmoidal relationship was also obtained between P (app) in colonic segments and f (a) after colonic administration in humans for a set of 10 drugs (R (2): 0. 93, p < 0. 05).


Input: Regional permeability data showed a tendency for highly permeable compounds to have higher or similar P (app) in colon as in the small intestinal segments, while the colonic regions showed a lower P (app) for more polar compounds as well as for d-glucose and l-leucine.

d-glucose

l-leucine


Input: Bidirectional transport (mucosa to serosa and serosa to mucosa direction) in jejunum showed well functioning efflux-and uptake asymmetry.


Input: Intestinal metabolic extraction during transport across jejunum segments was found for both testosterone and midazolam.

testosterone

midazolam


Input: In conclusion, viable excised human intestine mounted in the Ussing chamber, is a powerful technique for predicting regional fraction absorbed (f (a)), transporter-mediated uptake or efflux as well as intestinal metabolism of drug candidates in man.


Input: Furthermore, a sigmoidal relationship of P (app) vs. f (a) was obtained when permeability data from the present study were merged with data from 2 other independent laboratories (R (2): 0. 83, p < 0. 01).


Input: The correlation curve reported can be used by any laboratory for predictions of human permeability and f (a) (.) In addition, for the first time a correlation curve between colonic P (app) and human colonic f (a) is reported, which demonstrates the usefulness of this methodology in early assessment of the colonic absorption potential of extended release formulation candidates.


Input: Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells?

nilotinib


Input: The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukaemia cells.

nilotinib


Input: We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P-gp expression.

Dox


Input: These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene.

Dox


Input: Functional analysis of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression.


Input: We observed that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp.

Dox

nilotinib


Input: This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib.

Dox

nilotinib


Input: Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR).

nilotinib

daunorubicin

DNR


Input: Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR.

nilotinib

DNR


Input: Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level.

nilotinib


Input: Reversal of the deleterious effects of chronic dietary HFCS-55 intake by PPAR-delta agonism correlates with impaired NLRP3 inflammasome activation.


Input: Although high-fructose corn syrup (HFCS-55) is the major sweetener in foods and soft-drinks, its potential role in the pathophysiology of diabetes and obesity (" diabesity ") remains unclear.

high-fructose corn syrup


Input: Peroxisome-proliferator activated receptor (PPAR)-delta agonists have never been tested in models of sugar-induced metabolic abnormalities.

sugar


Input: This study was designed to evaluate (i) the metabolic and renal consequences of HFCS-55 administration (15% wt/vol in drinking water) for 30 weeks on male C57Bl6/J mice and (ii) the effects of the selective PPAR-delta agonist GW0742 (1 mg/kg/day for 16 weeks) in this condition.


Input: HFCS-55 caused (i) hyperlipidemia, (ii) insulin resistance, and (iii) renal injury/inflammation.


Input: In the liver, HFCS-55 enhanced the expression of fructokinase resulting in hyperuricemia and caused abnormalities in known insulin-driven signaling events.


Input: In the kidney, HFCS-55 enhanced the expression of the NLRP3 (nucleotide-binding domain and leucine-rich-repeat-protein 3) inflammasome complex, resulting in caspase-1 activation and interleukin-1 beta production.

nucleotide

leucine


Input: All of the above effects of HFCS-55 were attenuated by the specific PPAR-delta agonist GW0742.


Input: Thus, we demonstrate for the first time that the specific PPAR-delta agonist GW0742 attenuates the metabolic abnormalities and the renal dysfunction/inflammation caused by chronic HFCS-55 exposure by preventing upregulation of fructokinase (liver) and activation of the NLRP3 inflammasome (kidney).


Input: Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras.

hydrogen sulfide

hydrogen sulfide


Input: Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance.

Hydrogen sulfide


Input: However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology.

nitric oxide

NO

carbon monoxide

CO


Input: In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds.


Input: The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin.

sulforaphane

erucin

iberin


Input: The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine.

cysteine

S-propyl cysteine

S-allyl cysteine

S-propargyl cysteine

N-acetyl cysteine


Input: Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail.

Dithiolethione

L-DOPA

sildenafil

aspirin

diclofenac

naproxen

ibuprofen

indomethacin

mesalamine


Input: The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed.

NOSH-aspirin

NO


Input: The diversity of microbial aldo/keto reductases from Escherichia coli K12.


Input: The genome of Escherichia coli K12 contains 9 open reading frames encoding aldo/keto reductases (AKRs) that are differentially regulated and sequence diverse.


Input: A significant amount of data is available for the E. coli AKRs through the availability of gene knockouts and gene expression studies, which adds to the biochemical and kinetic data.


Input: This together with the availability of crystal structures for nearly half of the E. coli AKRs and homologues of several others provides an opportunity to look at the diversity of these representative bacterial AKRs.


Input: Based around the common AKR fold of (beta/alpha) 8 barrel with two additional alpha-helices, the E. coli AKRs have a loop structure that is more diverse than their mammalian counterparts, creating a variety of active site architectures.


Input: Nearly half of the AKRs are expected to be monomeric, but there are examples of dimeric, trimeric and octameric enzymes, as well as diversity in specificity for NAD as well as NADP as a cofactor.

NAD

NADP


Input: However in functional assignments and characterisation of enzyme activities there is a paucity of data when compared to the mammalian AKR enzymes.


Input: Dietary exposure to inorganic arsenic of the Hong Kong population: results of the first Hong Kong total diet study.

arsenic


Input: Inorganic arsenic, a human carcinogen, can be found in the environment and food.

arsenic


Input: In the first Hong Kong Total Diet Study, the dietary exposure of the Hong Kong people, including various age-gender subgroups, to inorganic arsenic was estimated for assessing the associated health risk.

arsenic


Input: Food samples, which represented the Hong Kong people' s diet, were collected and prepared " as consumed " for analysis.


Input: Concentrations of inorganic arsenic, as sum of arsenite (As (III)) and arsenate (As (V)) were determined in 600 composite samples by using inductively coupled plasma mass spectrometry.

arsenic

arsenite

As (III)

arsenate

As (V)


Input: The dietary exposures were estimated by combining the analytical results with the local food consumption data of the adult population.


Input: The mean and 95th percentile of inorganic arsenic exposures of the Hong Kong people were 0. 22 and 0. 38 mu g/kg body weight (bw)/day, respectively.

arsenic


Input: Among the 12 age-gender subgroups, the respective exposures ranged from 0. 19 to 0. 26 mu g/kg bw/day and from 0. 33 to 0. 46 mu g/kg bw/day.


Input: The main food category that contributed inorganic arsenic was " cereals and their products " (53. 5% of the total exposure), particularly rice.

arsenic


Input: Having considered the carcinogenic risk of inorganic arsenic to humans, it is suggested that efforts should be made to reduce the inorganic arsenic exposure of the Hong Kong population.

arsenic

arsenic


Input: Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse.


Input: The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory.


Input: Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia.


Input: HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition.


Input: The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM.


Input: We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology.


Input: In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory.


Input: Reelin supplementation also increases pre-pulse inhibition.


Input: These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults.


Input: Identification of two-component system AfsQ1/Q2 regulon and its cross-regulation with GlnR in Streptomyces coelicolor.


Input: The two-component system AfsQ1/Q2 of Streptomyces coelicolor was identified in our previous work as a pleiotropic regulator for antibiotic biosynthesis and morphological differentiation under the condition of a minimal medium supplemented with 75 mM glutamate.

glutamate


Input: In this work, we report the dissection of the mechanism underlying the function of AfsQ1/Q2 on antibiotic production and also the identification of the AfsQ1/Q2 regulon.


Input: The results showed that AfsQ1/Q2 stimulated antibiotic ACT, RED and CDA production directly through the pathway-specific activator genes actII-ORF4, redZ and cdaR respectively.


Input: In addition, expression of sigQ that encodes a sigma factor and is divergently transcribed from afsQ1 was also subject to direct regulation by AfsQ1/Q2.


Input: The precise AfsQ1 binding sites in the upstream regions of these target genes were determined by DNase I footprinting assays coupled with site-directed DNA mutagenesis.


Input: By computational prediction and functional analysis, at least 17 new AfsQ1 targets were identified, including pstS gene encoding a high-affinity phosphate-binding protein and two developmental genes whiD, bldM.

phosphate


Input: For the AfsQ1/Q2 regulon, an AfsQ1 binding motif comprising the sequence GTnAC-n (6)-GTnAC has been defined.


Input: Interestingly, we found from electrophoretic mobility shift assays and transcriptional analysis that AfsQ1/Q2 can also function as a repressor for nitrogen assimilation, and AfsQ1 can compete with GlnR for the promoter regions of glnA and nirB, suggesting the cross-regulation between AfsQ1/Q2 and GlnR in nitrogen metabolism.

nitrogen

nitrogen


Input: These findings suggested that AfsQ1/Q2 is important not only for antibiotic biosynthesis but also in maintaining the metabolic homeostasis of nutrient utilization under the stress of high concentration of glutamate in S. coelicolor.

glutamate


Input: Cryopreservation of precision-cut tissue slices.


Input: 1. Cryopreservation of precision-cut tissue slices (PCTS) would have many advantages for drug development and would encourage more extensive use of the PCTS preparation.


Input: 2. Three methods have been studied to date: slow freezing, fast freezing, and vitrification.


Input: 3. Slow freezing can be very effective for some PCTS but is devastating to rat liver PCTS.


Input: Fast freezing can be successful for rat liver PCTS but is devastating to renal PCTS and has given inconsistent results even for rat liver PCTS.


Input: Vitrification has been effective for some slice systems but less effective for rat liver PCTS.


Input: Rat liver PCTS appear to be particularly difficult to cryopreserve well.


Input: 4. The general cryobiological principles of slow freezing, rapid freezing, and vitrification are reviewed.


Input: The empirical literature on the cryopreservation of PCTS has not taken sufficient account of these principles, and may, for example, include the effects of easily preventable osmotic injury.


Input: 5. More attention is needed to the effects of cryopreservation on specific cell types within PCTS and to the general integrity and viability of cryopreserved PCTS.


Input: Drug metabolism as a sole endpoint of study can be highly misleading.


Input: 6. Better application of cryobiological principles may enable improved results in the future.


Input: Evaluation of the intestinal toxicity and transport of xenobiotics utilizing precision-cut slices.


Input: 1. The precision-cut intestinal slice (PCIS) technology is a relatively new addition to the battery of in vitro assays for evaluation of xenobiotic toxicity, metabolism, and transport.


Input: 2. The intestine is an important target for drug-induced toxicity due to its high exposure after oral administration.


Input: Therefore, the prediction of drug-induced intestinal side effects remains a significant safety issue in pharmaceutical development.


Input: Although animal experiments have been proven useful, species differences and the requirement for reduction of animal use warrant the development of in vitro methods which can apply human tissue.


Input: 3. The enterocytes lining the villi express high activities of enzymes and transporters involved in drug disposition.


Input: They vary highly in activities: along the length of the intestine and along the villi, gradients of expression levels of the enzymes and proteins exist, which necessitates an in vitro model that can reflect the different regions of the intestine.


Input: 4. In this chapter, the application of PCIS in studies on transport and toxicity of xenobiotics is reviewed.


Input: PCIS can be prepared from each region of the intestine and from various species in a similar manner, and the results published so far indicate that they represent a promising model to evaluate intestinal toxicity and transport.


Input: Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity.

doxorubicin


Input: This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of doxorubicin (DXR) in vitro as well as in a tumour-bearing mouse model of acute doxorubicin-induced cardiotoxicity.

doxorubicin

DXR

doxorubicin


Input: We examined the effect of an increase or inhibition of autophagy in combination with DXR on apoptosis, reactive oxygen species (ROS) production and mitochondrial function.

DXR

oxygen


Input: H9C2 rat cardiac myoblasts were pre-treated with bafilomycin A1 (autophagy inhibitor, 10 nM) or rapamycin (autophagy inducer, 50 mu M) followed by DXR treatment (3 mu M).

bafilomycin A1

rapamycin

DXR


Input: The augmentation of autophagy with rapamycin in the presence of DXR substantially ameliorated the detrimental effects induced by DXR.

rapamycin

DXR

DXR


Input: This combination treatment demonstrated improved cell viability, decreased apoptosis and ROS production and enhanced mitochondrial function.


Input: To corroborate these findings, GFP-LC3 mice were inoculated with a mouse breast cancer cell line (EO771).


Input: Following the appearance of tumours, animals were either treated with one injection of rapamycin (4 mg/kg) followed by two injections of DXR (10 mg/kg).

rapamycin

DXR


Input: Mice were then sacrificed and their hearts rapidly excised and utilized for biochemical and histological analyses.


Input: The combination treatment, rather than the combinants alone, conferred a cardioprotective effect.


Input: These hearts expressed down-regulation of the pro-apoptotic protein caspase-3 and cardiomyocyte cross-sectional area was preserved.


Input: These results strongly indicate that the co-treatment strategy with rapamycin can attenuate the cardiotoxic effects of DXR in a tumour-bearing mouse model.

rapamycin

DXR