Input: Bioassay-guided fractionation of the leaves of Eugenia rigida yielded three stilbenes, (Z)-3, 4, 3', 5'-tetramethoxystilbene (1), (E)-3, 4, 3', 5'-tetramethoxystilbene (2), and (E)-3, 5, 4'-trimethoxystilbene (3).

stilbenes

(Z)-3, 4, 3', 5'-tetramethoxystilbene

(E)-3, 4, 3', 5'-tetramethoxystilbene

(E)-3, 5, 4'-trimethoxystilbene


Input: Their structures were determined using 1D-and 2D-NMR spectroscopy and HRESIMS.


Input: The sterically hindered Z-stereoisomer 1, a new natural product, was prepared by time-dependent photoisomerization of the E-isomer (2) under UV irradiation at lambda 254 nm, while 2, 3, 5, 7-tetramethoxyphenanthrene (5) was identified at lambda 365 nm by UHPLC/APCI-MS and NMR spectroscopy.

2, 3, 5, 7-tetramethoxyphenanthrene


Input: Compounds 1-3 were tested against a panel of luciferase reporter gene assays that assess the activity of many cancer-related signaling pathways, and the Z-isomer (1) was found to be more potent than the E-isomer (2) in inhibiting the activation of Stat3, Smad3/4, myc, Ets, Notch, and Wnt signaling, with IC50 values between 40 and 80 mu M.


Input: However, both compounds showed similar inhibition against Ap-1 and NF-kappa B signaling.


Input: In addition, 1 demonstrated cytotoxic activity toward human leukemia cells, solid tumor cells of epidermal, breast, and cervical carcinomas, and skin melanoma, with IC50 values between 3. 6 and 4. 3 mu M, while 2 was weakly active against leukemia, cervical carcinoma, and skin melanoma cells.


Input: Interestingly, 2 showed antioxidant activity by inhibition of ROS generation to 50% at 33. 3 mu M in PMA-induced HL-60 cells, while 1 was inactive at 100 mu M (vs Trolox 1. 4 mu M).

PMA

Trolox


Input: Neoclerodanes as Atypical Opioid Receptor Ligands.

Neoclerodanes


Input: The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling and J a tiva (Lamiaceae).

neoclerodane diterpene salvinorin A


Input: Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects.

salvinorin A

morphine


Input: These effects are particularly remarkable because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist and (2) its effects are not mediated through the previously investigated targets of psychotomimetics.

salvinorin A


Input: This Perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence.


Input: The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other central nervous system disorders.


Input: Formation of a tyrosine adduct involved in lignin degradation by Trametopsis cervina lignin peroxidase: A novel peroxidase activation mechanism.

tyrosine


Input: Lignin peroxidase (LiP) from Trametopsis cervina has an exposed catalytic tyrosine (Tyr-181) instead of the conserved tryptophan of other lignin-degrading peroxidases.

tyrosine

Tyr

tryptophan


Input: Pristine LiP showed a lag period in veratryl alcohol (VA) oxidation.

veratryl alcohol


Input: However, LiP after turnover with H2O2/VA (VA-LiP) lacked this lag, and H2O2-pretreated LiP (H2O2-LiP) was inactive.


Input: MS analyses revealed that VA-LiP includes one VA molecule covalently bound to the side-chain of Tyr-181, whereas H2O2-LiP contains hydroxylated Tyr-181.

Tyr

Tyr


Input: No adduct is formed by the Y171N variant.


Input: Molecular docking showed that VA binding is favored by sandwich pi stacking with Tyr-181 and Phe-89.

Tyr

Phe


Input: EPR spectroscopy after peroxide activation of the pretreated LiPs showed other protein radicals than the tyrosine radical found in pristine LiP, which were assigned to a tyrosine/VA adduct radical in VA-LiP and a dihydroxyphenyalanine radical in H2O2-LiP.

peroxide

tyrosine

tyrosine

dihydroxyphenyalanine


Input: Both radicals are able to oxidize large low redox-potential substrates, but H2O2-LiP is unable to oxidize high redox-potential substrates.


Input: Transient-state kinetics showed that the tyrosine/VA adduct strongly promotes (> 100-fold) substrate oxidation by compound II, the rate-limiting step in catalysis.

tyrosine


Input: The novel activation mechanism is involved in ligninolysis, as demonstrated using lignin model substrates.


Input: This is the first report on autocatalytic modification, resulting in functional alteration, among class-II peroxidases.


Input: Nrf2-dependent neuroprotective activity of diterpenoids isolated from Sideritis spp.

diterpenoids


Input: ETHNOPHARMACOLOGICAL RELEVANCE: The species of the genus Sideritis are extensively used in the Mediterranean area in folk medicine for their digestive, antimicrobial, anti-inflammatory and antioxidant properties, among others.


Input: Moreover, Sideritis species as tea infusions are popularly known for improving memory function and cognitive ability.


Input: Diterpenoids are one of the most abundant and important pharmacological interest of the classes of natural products presented in these medicinal plants.

Diterpenoids


Input: AIM OF THE STUDY: To determine for the first time the neuroprotective effects, based on their antioxidant properties, of the three isolated major diterpenoids andalusol, conchitriol and lagascatriol in an oxidative stress model.

diterpenoids andalusol

conchitriol

lagascatriol


Input: MATERIALS AND METHODS: H2O2 was used as oxidant inductor and rat adrenal pheochromocytoma PC12 cells as cellular model.


Input: Cell viability was measured using MTT and LDH assays, lipid peroxidation was determined by HPLC, GSH and GSSG levels assessed by fluorometric techniques, enzymatic activity and protein expression were determined by spectrofometric techniques and Western blot, respectively.

MTT

GSH

GSSG


Input: RESULTS: Pretreatments with the three diterpenoids significantly attenuated H2O2-induced changes in mitochondrial integrity and activity (MTT assay), in cell membrane integrity (LDH assay) and in cell morphology.

diterpenoids

MTT


Input: Moreover, these diterpenoids inhibited intracellular ROS production H2O2-induced, reduced lipid peroxidation and counteracted GSH/GSSG changes.

diterpenoids

GSH

GSSG


Input: Furthermore, both activities and protein expression of the endogenous antioxidant enzymes (CAT, SOD, GR, GPx and HO-1) were increased.


Input: The Nrf2 pathway was involved, at least in part, in the protective effects of these diterpenoids.

diterpenoids


Input: CONCLUSION: These findings suggest that these natural compounds provide significant antioxidant effects in PC12 under for counteracting the oxidative damage H2O2-induced and their potential role as useful agents for the prevention of those oxidative stress-mediated dementia disorders.


Input: Andalusol was the most active compound among the studied diterpenoids.

Andalusol

diterpenoids


Input: The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro-and anti-inflammatory genes in the rat brain.


Input: The functional significance for activation of inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), nuclear factor (NF) kappa B or NF-interleukin (IL) 6 and their contribution to the induction of brain controlled sickness responses, such as fever, during infection and inflammation is unknown.


Input: Using AG490, previously shown to inhibit the STAT3-and NF-IL6-signaling pathway, we therefore investigated the central involvement of these two signaling pathways in mediating sickness behavior, fever and accompanying brain inflammation induced by peripheral lipopolysaccharide (LPS)-stimulation.


Input: Rats pre-treated i. c. v. with AG490 1 h before the i. p.


Input: LPS-challenge (100 mu g/kg) showed a modestly exaggerated fever, attenuated adipsia and almost unimpaired locomotor activity compared to LPS-controls receiving vehicle (i. c. v.).


Input: The LPS-induced anorexia was not altered and AG490 did not have any effect on rats receiving PBS (i. p.).


Input: We did observe effects of AG490 on STAT3-signaling at 4 h, while AG490-mediated changes in brain activity of inflammatory transcription factors at 8 h were not significant.


Input: Increased NF-IL6 and suppressor of cytokines 3 mRNA-expression in AG490/LPS-treated rats were indicative of a compensative activation at 24 h.


Input: Moreover, a significant decrease in hypothalamic anti-inflammatory IL-10-expression and an increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA-expression 8 h after LPS-injection was revealed in AG490 pre-treated animals compared to solvent-treated LPS-controls.

prostaglandin E


Input: In summary, we have shown a dissociation between the effects of central AG490 treatment on fever and components of sickness behavior, which appears to be related to reduced IL-10 and increased mPGES-expression in the brain.


Input: Thus, AG490 might have therapeutic potential to reduce sickness behavior.


Input: Distinct signaling cascades elicited by different formyl Peptide receptor 2 (FPR2) agonists.

formyl


Input: The formyl peptide receptor 2 (FPR2) is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR) family.

formyl


Input: FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion.


Input: In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro-or anti-inflammatory responses.

lipoxin A4


Input: Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (A beta)-42 and prion protein (Prp) 106-126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP)-27, and mitochondrial peptides.

resolvins

adenylate


Input: Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC), protein kinase C (PKC) isoforms, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, the mitogen-activated protein kinase (MAPK) pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants.

phosphoinositide

tyrosine

tyrosine

calcium


Input: FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases.


Input: Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2 agonists.

tyrosine


Input: Isolation and Structure Elucidation of Three New Dolastanes from the Brown Alga Dilophus spiralis.

Dolastanes


Input: Three new dolastane diterpenes (1-3) and five previously reported perhydroazulenes were isolated from the organic extracts of the brown alga Dilophus spiralis.

dolastane diterpenes

perhydroazulenes


Input: The structure elucidation and the assignment of the relative configurations of the isolated natural products were based on extensive analyses of their spectroscopic data, whereas the absolute configuration of metabolite 2 was determined through its chemical conversion to a previously isolated compound of known configuration.


Input: A Distal Enhancer Controls Cytokine-dependent Human cPLA2 alpha Gene Expression.


Input: Specific control of group IVA cytosolic phospholipase A2 (cPLA2 alpha or PLA2G4A) expression modulates arachidonic acid production, thus tightly regulating the downstream effects of pro-and anti-inflammatory eicosanoids.

arachidonic acid

eicosanoids


Input: The significance of this pathway in human disease is apparent in a range of pathologies from inflammation to tumorigenesis.


Input: While much of the regulation of cPLA2 alpha has focused on post-translational phosphorylation of the protein, studies on transcriptional regulation of this gene have focused only on proximal promoter regions.


Input: We have identified a DNase I hypersensitive site encompassing a 5' distal enhancer element containing a highly conserved consensus AP-1 site involved in transcriptional activation of cPLA2 alpha by IL-1 beta.


Input: ChIP, knockdown, knockout and overexpression analyses have shown that c-Jun acts both in a negative and positive regulatory role.


Input: Transcriptional activation of cPLA2 alpha occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBP beta with the distal novel enhancer.


Input: The association of C/EBP beta with the transcriptional activation complex does not require an obvious DNA binding site.


Input: These data provide new and important contributions to the understanding of cPLA2 alpha regulation at the transcriptional level with implications to eicosanoid metabolism, cellular signaling and disease pathogenesis.

eicosanoid


Input: Ultrahigh-efficiency photocatalysts based on mesoporous Pt-WO3 nanohybrids.

Pt


Input: A reliable nanocasting method has been developed to synthesize mesoporous hybrids of platinum (Pt) nanoparticles decorating tungsten trioxide (WO3).

platinum

Pt

tungsten trioxide


Input: The process began with modification of the SBA-15 template with carbon polymers and Pt nanoparticles accompanied by adsorption of W (6 +), which was then converted into m-Pt-WO3 composites by heat treatment and subsequent template removal.

carbon

Pt

W (6 +)


Input: The synthetic strategy can be easily extended to prepare other mesoporous nanohybrids with metal oxide loaded precious metal composites.

metal oxide


Input: Comprehensive characterizations suggest that the as-developed m-Pt-WO3 nanohybrid exhibits unique properties with mesoporous structure, excellent crystalline structure, and high surface area.


Input: When the photocatalytic properties of m-Pt-WO3 nanohybrids were systematically investigated, it was revealed that the m-Pt-WO3 nanohybrids showed great promise for degrading the organic dye under visible light irradiation, which shows an excellent photocatalytic activity that far exceeded those of pure phase mesoporous WO3 and commercial TiO2 (P25), and was 10-fold more active than that of the bulk Pt-WO3 catalyst.

Pt


Input: The as-developed synthetic route opens up a new avenue for designing mesoporous hybrid materials for various applications benefiting from the unique porous structure, high surface area, and synergistic effects among constituents.


Input: An Active Role for Steroid-binding Globulins: An Update.

Steroid


Input: It has been 7 years (can it really be that long?) since we co-edited a volume (#38) of Hormone and Metabolic Research that focused on evidence that steroid-binding globulins play an active role in the actions of steroids.

steroid

steroids


Input: There has been considerable progress in identifying the location, the physiological actions, and of determining the role of binding globulins in the actions of steroids and identifying a membrane-associated receptor for a binding protein since then and this review will discuss this progress.

steroids


Input: Mechanisms of metal-catalyzed dehydrocoupling reactions.


Input: This review summarizes selected mechanistic insight garnered from reactions that form bonds between main group elements with liberation of hydrogen, dehydrocoupling or dehydropolymerization reactions.

hydrogen


Input: Focus has been made where mechanistic study has been done or provides unique insight as compared to previous work.


Input: Thus, a limited number of catalysts and substrates will be discussed, but a broad range of mechanistic features will be noted.


Input: A comparative approach considering dehydrocoupling reactions that appear to proceed by certain mechanistic steps is taken here, beginning with steps that are well established and general then moving to those that are newer, at least to this application.


Input: Dominant role of molybdenum in the electrochemical deposition of biological macromolecules on metallic surfaces.

molybdenum


Input: The corrosion of CoCrMo, an alloy frequently used in orthopedic implants, was studied with an electrochemical quartz crystal microbalance (QCM) in three physiologically relevant solutions.

CoCrMo

quartz


Input: Mass changes were measured during potentiodynamic tests, showing material deposition in protein solutions at potential levels that caused mass loss when the proteins were not present.


Input: X-ray photoelectron spectroscopy (XPS) data indicated that the deposited material was primarily organic and therefore was most likely derived from proteins in the electrolyte.


Input: Material deposition consistently occurred at a critical potential and was not dependent on the current density or total charge released into solution.


Input: Corrosion studies on pure Co, Cr, and Mo in protein solutions found material deposition only on Mo.

Corrosion

Cr

Mo

Mo


Input: We hypothesize that organic deposition results from the interaction of Mo (VI) with proteins in the surrounding solution.

Mo (VI)


Input: The organic layer is reminiscent of tribochemical reaction layers that form on the surface of CoCrMo hip bearings, suggesting that these types of layers can be formed by purely electrochemical means.

CoCrMo


Input: Spontaneous formation of hydrophobic domains in isolated peptides.


Input: Aromatic amino acids are known for their hydrophobicity and the active role they play in protein folding.

Aromatic amino acids


Input: Here, we investigate the intrinsic propensity of small peptides to form hydrophobic domains in the absence of solvent water molecules.


Input: The structures of three aromatic-rich isolated peptides, Ac-Phe-Phe-NH2 (FF), Ac-Trp-Tyr-NH2 (WY), and Ac-Phe-Phe-Phe-NH2 (FFF), all in the gas phase, have been studied by infrared-ultraviolet (IR/UV) double resonance laser spectroscopy, aided by dispersion-corrected density functional theory (DFT-D) calculations.


Input: Spontaneous formation of hydrophobic domains is systematically observed, whatever the secondary structure adopted by the backbone.


Input: Various types of aromatic-aromatic arrangements have been identified and associated to specific secondary structures, illustrating the interplay between the hydrophobic clusters and the backbone.


Input: Backbone NH amide groups surrounded by aromatic rings have also been evidenced and are found to contribute significantly to the stabilization of aromatic pairs.

NH amide


Input: These results suggest that the formation of aromatic clusters involving contiguous residues might be a very efficient process leading to the formation of hydrophobic domains in the early stages of protein folding, well before a hydrophobic collapse into the tertiary structure.


Input: Using genomic data to revisit an early example of reproductive character displacement in Haitian Anolis lizards.


Input: The pattern of reproductive character displacement (RCD)-in which traits associated with reproductive isolation are more different where two species occur together than where they occur in isolation-is frequently attributed to reinforcement, a process during which natural selection acting against maladaptive mating events leads to enhanced prezygotic isolation between species or incipient species.


Input: One of the first studies of RCD to include molecular genetic data was described 40 years ago in a complex of Haitian trunk anole lizards using a small number of allozyme loci.


Input: In this example, Anolis caudalis appears to experience divergence in the color and pattern of an extensible throat fan, or dewlap, in areas of contact with closely related species at the northern and southern limits of its range.


Input: However, this case study has been largely overlooked for decades; meanwhile, explanations for geographic variation in dewlap color and pattern have focused primarily on adaptation to local signalling environments.


Input: We reinvestigate this example using amplified fragment length polymorphism (AFLP) genome scans, mtDNA sequence data, information on dewlap phenotypes and GIS data on environmental variation to test the hypothesis of RCD generated by reinforcement in Haitian trunk anoles.


Input: Together, our phenotypic and genetic results are consistent with RCD at the southern and northern limits of the range of A. caudalis.


Input: We evaluate the evidence for reinforcement as the explanation for RCD in Haitian trunk anoles, consider alternative explanations and provide suggestions for future work on the relationship between dewlap variation and speciation in Haitian trunk anoles.


Input: Sensitive determination of lead, cadmium and nickel in soil, water, vegetable and fruit samples using STAT-FAAS after preconcentration with activated carbon.

cadmium

nickel

carbon


Input: In this study, lead (Pb), cadmium (Cd) and nickel (Ni) were determined in soil, water, vegetable and fruit samples taken from around oil refinery region in Batman, Turkey.

Pb

cadmium

Cd

nickel

Ni


Input: Digestion procedures for samples were optimized and all optimum parameters were used both in digestion and in determination steps.


Input: In order to determine Pb and Cd, slotted tube atom trap (STAT) was used to increase the sensitivity in atomic absorption spectrophotometry.

Pb

Cd


Input: Preconcentration procedure under the optimum conditions was applied to water, vegetable and fruit samples to determine Pb, Cd and Ni in trace levels.

Pb

Cd

Ni


Input: In soil samples, concentrations of analytes were found in the range of 4. 0 +/- 0. 2-12, 000 +/- 60 mg/kg for Pb, 0. 15 +/- 0. 01-3. 0 +/- 0. 1 mg/kg for Cd and 21 +/- 1-65 +/- 3. 4 mg/kg for Ni.

Pb

Cd

Ni


Input: In all water samples, concentration of Ni was expressed as nanogram per milliliter (ng/mL) and found to be higher than Pb and Cd levels.

Ni

Pb

Cd


Input: It was observed that Pb, Cd and Ni concentrations varied from both plant to plant and in same plants at different experimental sites.

Pb

Cd

Ni


Input: Pb concentrations in vegetable and fruit samples interested varied between 20 +/- 2 and 160 +/- 12 ng/g, and the highest level of Pb was found to be in green pepper taken from 1000 m away from refinery.

Pb

Pb


Input: UVA photoirradiation of benzo [a] pyrene metabolites: induction of cytotoxicity, reactive oxygen species, and lipid peroxidation.

benzo [a] pyrene

oxygen


Input: Benzo [a] pyrene (BaP) is a prototype for studying carcinogenesis of polycyclic aromatic hydrocarbons (PAHs).

Benzo [a] pyrene

BaP

polycyclic aromatic hydrocarbons

PAHs


Input: We have long been interested in studying the phototoxicity of PAHs.

PAHs


Input: In this study, we determined that metabolism of BaP by human skin HaCaT keratinocytes resulted in six identified phase I metabolites, for example, BaP trans-7, 8-dihydrodiol (BaP t-7, 8-diol), BaP t-4, 5-diol, BaP t-9, 10-diol, 3-hydroxybenzo [a] pyrene (3-OH-BaP), BaP (7, 10/8, 9) tetrol, and BaP (7/8, 9, 10) tetrol.

BaP

BaP trans-7, 8-dihydrodiol

BaP t-7, 8-diol

BaP t-4, 5-diol

BaP t-9, 10-diol

3-hydroxybenzo [a] pyrene

BaP (7, 10/8, 9) tetrol

BaP (7/8, 9, 10) tetrol


Input: The photocytotoxicity of BaP, 3-OH-BaP, BaP t-7, 8-diol, BaP trans-7, 8-diol-anti-9, 10-epoxide (BPDE), and BaP (7, 10/8, 9) tetrol in the HaCaT keratinocytes was examined.

BaP

BaP t-7, 8-diol

BaP trans-7, 8-diol-anti-9, 10-epoxide

BPDE

BaP (7, 10/8, 9) tetrol


Input: When irradiated with 1. 0 J/cm (2) UVA light, these compounds when tested at doses of 0. 1, 0. 2, and 0. 5 mu M, all induced photocytotoxicity in a dose-dependent manner.


Input: When photoirradiation was conducted in the presence of a lipid (methyl linoleate), BaP metabolites, BPDE, and three related PAHs, pyrene, 7, 8, 9, 10-tetrahydro-BaP trans-7, 8-diol, and 7, 8, 9, 10-tetrahydro-BaP trans-9, 10-diol, all induced lipid peroxidation.

methyl linoleate

BaP

BPDE

PAHs

pyrene

7, 8, 9, 10-tetrahydro-BaP trans-7, 8-diol

7, 8, 9, 10-tetrahydro-BaP trans-9, 10-diol


Input: The formation of lipid peroxides by BaP t-7, 8-diol was inhibited by NaN3 and enhanced by deuterated methanol, which suggests that singlet oxygen may be involved in the generation of lipid peroxides.

BaP t-7, 8-diol

deuterated methanol

oxygen


Input: The formation of lipid hydroperoxides was partially inhibited by superoxide dismutase (SOD).

hydroperoxides

superoxide


Input: Electron spin resonance spin trapping experiments indicated that both singlet oxygen and superoxide radical anion were generated from UVA photoirradiation of BPDE in a light dose responding manner.

oxygen

superoxide

BPDE


Input: Rapid self-healable poly (ethylene glycol) hydrogels formed by selective metal-phosphate interactions.

poly (ethylene glycol)

phosphate


Input: Rapid self-healable and biocompatible hydrogels were prepared using the selective formation of metal-ligand interactions between selected metal ions and phosphate end groups of poly (ethylene glycol) (PEG).

phosphate

poly (ethylene glycol)

PEG


Input: The phosphate-terminated branch of PEG was synthesized via a substitution reaction of the hydroxyl end groups using phosphoryl chloride.

phosphate

PEG

hydroxyl

phosphoryl chloride


Input: The gelation and gel properties including rheological properties can be tuned by the careful selection of metal ions, branch numbers, and temperature.


Input: Especially, the gels rapidly formed by trivalent metal ions such as Fe (3 +), V (3 +), Al (3 +), Ti (3 +), and Ga (3 +) have relatively small ionic radii.

Fe (3 +)

V (3 +)

Al (3 +)

Ti (3 +)

Ga (3 +)


Input: The ligand substitution rates also affected the repeatable autonomic healing ability.


Input: We have also demonstrated a gel-sol/sol-gel transition by switching the redox states of Fe (3 +)/Fe (2 +) ions.

Fe (3 +)

Fe (2 +)


Input: Learning from biological systems, the proposed phosphate-metal ion based self-healable hydrogels could become an attractive candidate for various biomedical and environmental applications.

phosphate


Input: Soluble Receptor for Advanced Glycation End-Product (sRAGE)/Pentosidine Ratio: A Potential Risk Factor Determinant for Type 2 Diabetic Retinopathy.

Pentosidine


Input: This study aims to investigate potential diabetic retinopathy (DR) risk factors by evaluating the circulating levels of pentosidine, soluble receptor for advanced glycation end-product (sRAGE), advanced oxidation protein product (AOPP) as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in DR patients.

pentosidine

glutathione

superoxide


Input: A total of 235 healthy controls, 171 type 2 diabetic without retinopathy (DNR) and 200 diabetic retinopathy (DR) patients were recruited.


Input: Plasma was extracted for the estimation of pentosidine, sRAGE, AOPP levels and GPx activity whereas peripheral blood mononuclear cells were disrupted for SOD activity measurement.

pentosidine


Input: DNR and DR patients showed significantly higher levels of plasma pentosidine, sRAGE and AOPP but lower GPx and SOD activities when compared to healthy controls.

pentosidine


Input: The sRAGE/pentosidine ratio in DR patients was significantly lower than the ratio detected in DNR patients.

pentosidine


Input: Proliferative DR patients had significantly higher levels of plasma pentosidine, sRAGE, AOPP and sRAGE/pentosidine ratio than non-proliferative DR patients.

pentosidine

pentosidine


Input: High HbA1c level, long duration of diabetes and low sRAGE/pentosidine ratio were determined as the risk factors for DR.

pentosidine


Input: This study suggests that sRAGE/pentosidine ratio could serve as a risk factor determinant for type 2 DR as it has a positive correlation with the severity of DR.

pentosidine


Input: Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines.

Dioscin


Input: Our previous study has revealed that dioscin, a compound with anti-inflammatory, lipid-lowering, anticancer and hepatoprotective effects, may induce autophagy in hepatoma cells.

dioscin


Input: Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis.


Input: In this study, the role of autophagy and related signaling pathways during dioscin-induced apoptosis in human lung cancer cells was investigated.

dioscin


Input: Results from 4'-6-diamidino-2-phenylindole and annexin-V/PI double-staining assay showed that caspase-3-and caspase-8-dependent, and dose-dependent apoptoses were detected after a 24-h dioscin treatment.

dioscin


Input: Meanwhile, autophagy was detected as early as 12 h after an exposure to low-dose dioscin, as indicated by an up-regulated expression of LC3-II and beclin-1 proteins.

dioscin


Input: Blockade of autophagy with bafilomycin A1 or 3-methyladenine sensitized the A549 and H1299 cells to apoptosis.

bafilomycin A1


Input: Treatment of A549 and H1299 cells with dioscin caused a dose-dependent increase in ERK1/2 and JNK1/2 activity, accompanied with a decreased PI3K expression and decreased phosphorylation of Akt and mTOR.

dioscin


Input: Taken together, this study demonstrated for the first time that autophagy occurred earlier than apoptosis during dioscin-induced human lung cancer cell line apoptosis.

dioscin


Input: Dioscin-induced autophagy via ERK1/2 and JNK1/2 pathways may provide a protective mechanism for cell survival against dioscin-induced apoptosis to act as a cytoprotective reaction.

Dioscin

dioscin


Input: Cytotoxic and Antibacterial Cembranoids from a South China Sea Soft Coral, Lobophytum sp.

Cembranoids


Input: Chemical examination of a South China Sea soft coral Lobophytum sp. led to the isolation of three new alpha-methylene-gamma-lactone-containing cembranoids, (1R *, 3R *, 4R *, 14R *, 7E, 11E)-3, 4-epoxycembra-7, 11, 15 (17)-trien-16, 14-olide (1), (1R *, 7S *, 14S *, 3E, 11E)-7-hydroperoxycembra-3, 8 (19), 11, 15 (17)-tetraen-16, 14-olide (2), and (1R *, 7S *, 14S *, 3E, 11E)-18-acetoxy-7-hydroperoxycembra-3, 8 (19), 11, 15 (17)-tetraen-16, 14-olide (3), along with eleven known analogues 4-14.

alpha-methylene-gamma-lactone

cembranoids

(1R *, 3R *, 4R *, 14R *, 7E, 11E)-3, 4-epoxycembra-7, 11, 15 (17)-trien-16, 14-olide

(1R *, 7S *, 14S *, 3E, 11E)-7-hydroperoxycembra-3, 8 (19), 11, 15 (17)-tetraen-16, 14-olide

(1R *, 7S *, 14S *, 3E, 11E)-18-acetoxy-7-hydroperoxycembra-3, 8 (19), 11, 15 (17)-tetraen-16, 14-olide


Input: The structures of the new compounds were elucidated through extensive spectroscopic analysis, including 1D and 2D NMR data.


Input: Compounds 1-3 exhibited moderate cytotoxic activity against the selected tumor cell lines.


Input: Moreover, 2 and 3 were found to be moderate inhibitors against the bacteria S. aureus and S. pneumoniae.


Input: Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders.


Input: RATIONALE: Autism and related pervasive developmental disorders (PDD) are characterized by impairments in social interaction and communication, restricted interests, and repetitive and stereotyped patterns of behavior.


Input: Individuals with PDD frequently display irritability and disruptive behaviors including tantrums, self-injurious behavior, and aggression.


Input: Atypical antipsychotics are currently the most efficacious pharmacological interventions available for treatment of irritability associated with PDD.


Input: OBJECTIVES: This article aims to review the body of literature pertaining to the use of atypical antipsychotics in the treatment of patients with PDD.


Input: METHODS: A PubMed literature search was conducted using the following key words: autism, pervasive developmental disorders, atypical antipsychotics, risperidone, aripiprazole, quetiapine, ziprasidone, olanzapine, clozapine, paliperidone, iloperidone, asenapine, and lurasidone.

risperidone

aripiprazole

quetiapine

ziprasidone

olanzapine

clozapine

paliperidone

iloperidone

asenapine

lurasidone


Input: Search terms were limited to English language, human subjects, and publication from 1999 to present.


Input: Relevant references from identified articles were also reviewed.


Input: RESULTS: The efficacy and tolerability of risperidone and aripiprazole for the treatment of irritability in autism have been established with multi-site, randomized, controlled trials.

risperidone

aripiprazole


Input: Studies supporting the use of other atypical antipsychotics are either limited in scope or less robust in their findings, though newer agents such as ziprasidone and paliperidone show promise.

ziprasidone

paliperidone


Input: CONCLUSIONS: Atypical antipsychotics are currently first-line pharmacological agents for the treatment of irritability and associated behaviors in children with PDD.


Input: Further placebo-controlled studies are warranted to characterize the efficacy and tolerability of the majority of these medications.


Input: There is also a need for the development of novel, targeted drugs with more favorable long-term side effect profiles.


Input: Development and Regulation of Biosimilars: Current Status and Future Challenges.


Input: Biologic medicinal products developed via rDNA technology as recombinant protein-based medicines that have been in clinical use since the early 1980s as original biopharmaceuticals have greatly contributed to the therapy of severe metabolic and degenerative diseases.


Input: The recent expiration of the data protection or patents for most of them created opportunities for the development of copy versions of original biopharmaceuticals with similar biologic activity (termed biosimilars).


Input: Production of these new products is expected to meet worldwide demand, promote market competition, maintain the incentives for innovation, and sustain the healthcare systems.


Input: The licencing of these products, however, relies on the experience gained with the original biopharmaceuticals.


Input: Critical issues related to this class of medicinal products include their terminology (to avoid confusion with generics and non-innovator copy versions that have not been tested according to the biosimilar guidelines), manufacturing, and regulation.


Input: The European Union (EU) has been the first to establish a regulatory framework for marketing authorization application (MAA) and has named these products biosimilars, a term also recently adopted by the US FDA.


Input: Unlike the conventional, more common small molecular weight human medicines and chemical generics, protein-based medicines exhibit higher molecular weight, complexity in structure and function that can be affected by changes in the manufacturing process.


Input: Therefore, biosimilars represent a relatively heterogeneous class of medicinal products that make their regulation quite challenging.


Input: According to the current understanding in the EU, a biosimilar is a copy version of an already authorized biopharmaceutical (or reference product) with similar biologic activity, physicochemical characteristics, efficacy, and safety, based on a full comparability exercise at quality, preclinical and clinical level to ensure similar efficacy and safety.


Input: Guidance has been provided through several Committee for Medicinal Products for Human Use (CHMP) guidelines as well as individual scientific advice requested from the European Medicines Agency (EMA) by various companies for the development and regulation of biosimilars.


Input: This review is mainly focused on the current status of regulation of biosimilars in the EU as well as on future challenges lying ahead for the improvement of the requirements needed for the marketing authorization of biosimilars.


Input: Emphasis is given on the quality requirements concerning these medicinal products (biologics).


Input: The evolving role of antifungal susceptibility testing.


Input: Although increasing numbers of hospital microbiology laboratories are performing antifungal susceptibility testing (AST), its routine use is uncommon.


Input: The utility of AST is founded on the belief that susceptibility (or resistance) of an agent allows some prediction of clinical outcome.


Input: This review provides an overview of the development of antifungal susceptibility testing methodology, including wild-type minimum inhibitory concentration (MIC) distributions, epidemiologic breakpoints, and Interpretive Clinical Breakpoints for antifungal agents.


Input: In addition, we examine the current clinical utility of AST and the clinical data support utilized in the development of clinical breakpoints (CBP) for common pathogens causing invasive fungal infections.


Input: In the treatment of fungal infections, identifying consistent correlations between MICs-or susceptibility category-and clinical outcomes is an ongoing challenge, and current data sets are insufficient for many drugs and pathogens to enable the development, revision, or confirmation of CBPs.


Input: Antifungal susceptibility testing is of current value, but further research in many areas is needed before MICs are independently used to guide treatment decisions.


Input: Role of Interleukin-1 Inhibitors in the Management of Gout.


Input: Interleukin-1 (IL-1) inhibitors potentially have a role as antiinflammatory agents in refractory gout or for patients who are unable to tolerate conventional therapy, such as nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, or glucocorticoids, for acute attacks.

colchicine


Input: Additionally, IL-1 inhibitors may also help patients with polyarticular and tophaceous gout by making them less vulnerable to breakthrough attacks during initiation of chronic urate-lowering treatment, the mainstay of gout therapy.


Input: Because evidence highlights the role of proinflammatory cytokine IL-1 in the inflammation process during an acute gouty attack, IL-1 inhibitors are used to modulate the pathogenesis of a variety of autoinflammatory diseases, providing support for its potential role in the inflammatory process of gout.


Input: After NSAIDs, colchicine, and steroids, IL-1 inhibitors are beneficial as fourth-line therapy for acute gout attacks due to their high cost and limited clinical experience.

colchicine

steroids


Input: The IL-1 inhibitors used in gout are anakinra, canakinumab, and rilonacept.


Input: Based on published evidence, anakinra has limited support in the form of anecdotal case reports to justify its use for treating gout.


Input: Canakinumab' s toxic profile in clinical trials precludes its use in treating patients for gout, and rilonacept shows promise with a few well-designed studies to support its use in gout patients initiating urate-lowering treatment.


Input: When combined with current traditional therapies, these newer agents present clinicians and patients with more potential treatment options in the difficult-to-treat gout population.


Input: Incidence and costs of adverse drug reactions in a tertiary care pediatric intensive care unit.


Input: Adverse drug reactions (ADRs) increase morbidity, mortality, and hospital costs in children treated in the Pediatric Intensive Care Unit (PICU).


Input: Few studies have reported the incidence and risk factors of ADRs in PICU.


Input: Our study aimed to evaluate incidence, risk factors, and economic burden of ADRs in PICU.


Input: An intensive ADR surveillance was conducted at the PICU of Children' s Hospital of Michigan between November 1, 2010 and May 31, 2011.


Input: A trigger list was used to screen for suspected ADR cases.


Input: Of the 697 consecutive PICU admissions reviewed, 13. 1% experienced at least one episode of ADR.


Input: The ADR incidence was 22% in patients with cardiovascular (CV) surgery and 11. 5% in other patients.


Input: The most frequently detected ADR was electrolyte imbalance associated with diuretic exposure.


Input: Mean age at admission was 4 years (interquartile range: 9 months-13 years).


Input: Risk factors for ADR included young age (< 1 year), Pediatric Risk of Mortality (PRISM) score upon admission >= 3, and administration of >= 16 medications.


Input: ADRs increased total ICU costs by 3. 5-fold and length of ICU stay by 3. 8-fold.


Input: Increased ADR surveillance of high risk patients in conjunction with early intervention may reduce drug related morbidity and costs in the PICU.


Input: A comparison of bone quality at the distal radius between Asian and Caucasian adolescents and young adults: An HR-pQCT study.


Input: Paradoxically, Asians have lower areal bone mineral density, but their rates of hip and wrist fractures are lower than Caucasians.


Input: Therefore, we used high-resolution pQCT (HR-pQCT) to determine whether differences in bone macro-and microstructure, BMD and bone strength at the distal radius are apparent in Asian (n = 91, 53 males, 38 females, 17. 3 +/- 1. 5 yrs) and Caucasian (n = 89, 46 males, 43 females, 18. 1 +/- 1. 8 yrs) adolescents and young adults.


Input: HR-pQCT outcomes included total BMD (Tt. BMD), trabecular bone volume fraction (BV/TV), trabecular number (Tb. N), thickness (Tb. Th) and separation (Tb. Sp).


Input: We used an automated segmentation algorithm to determine total bone area (Tt. Ar), cortical BMD (Ct. BMD), porosity (Ct. Po) and thickness (Ct. Th), and we applied finite element analysis to HR-pQCT scans to estimate bone strength.


Input: We fit sex-specific multivariable regression models to compare bone outcomes between Asians and Caucasians, adjusting for age, age at menarche (girls), lean mass, ulnar length, dietary calcium intake and physical activity.

calcium


Input: In males, after adjusting for covariates, Asians had 11% greater Tt. BMD, 8% greater Ct. BMD and 25% lower Ct. Po than Caucasians (p < 0. 05).


Input: Also, Asians had 9% smaller Tt. Ar and 27% greater Ct. Th (p < 0. 01).


Input: In females, Asians had smaller Tt. Ar than Caucasians (16%, p < 0. 001), but this difference was not significant after adjusting for covariates.


Input: Asian females had 5% greater Ct. BMD, 12% greater Ct. Th and 11% lower Tb. Sp than Caucasians after adjusting for covariates (p < 0. 05).


Input: Estimated bone strength did not differ between Asian and Caucasian males or females.


Input: Our study supports the notion of compensatory elements of bone structure that sustain bone strength; smaller bones as observed between those of Asian compared with Caucasian origin, have, on average, more dense, less porous and thicker cortices.


Input: Longitudinal studies are needed to determine whether ethnic differences in bone structure exist in childhood, persist into old age and whether they influence fracture risk.


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


Input: Impact of Phytolacca americana Extracts on Gene Expression of Colon Cancer Cells.


Input: Native Americans have used Phytolacca americana to treat breast ailments, gastrointestinal disorders, rashes, and inflammation.


Input: Some anti-cancer and anti-viral research has been reported on this perennial herb, but none has been published concerning the effects of its extracts on cancer cell genes.


Input: In this study, changes in gene expression at the transcription level were evaluated in HCT-116 colon cancer cells after exposure to P. americana ethanol extract and its water fraction using the Human Cancer Pathway Finder PCR Array.

ethanol


Input: Of the genes significantly affected in HCT-116 cells exposed to the ethanol extract at 3200 micro g/ml, changes in expression of MYC, PLAU, and TEK may benefit the treatment of colon cancer.

ethanol


Input: Exposing the cells to 1600 micro g/ml of the water fraction resulted in several gene changes that may also be beneficial in the treatment of colon cancer: NME4, TEK, and THBS1.


Input: A few genes on this array that are known to play a specific role in colon cancer had activities changed in a way that may be detrimental in the treatment of colon cancer.


Input: Further studies should be performed to understand how these changes would impact colon cancer treatment.


Input: Copyright (c) 2013 John Wiley & Sons, Ltd.


Input: Furanodiene Presents Synergistic Anti-proliferative Activity With Paclitaxel Via Altering Cell Cycle and Integrin Signaling in 95-D Lung Cancer Cells.

Furanodiene

Paclitaxel


Input: Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines.

Furanodiene

FUR

terpenoid


Input: Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells.

FUR

paclitaxel

TAX


Input: Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase.

FUR

TAX


Input: The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment.


Input: The dramatically down-regulated expression of integrin beta 4, focal adhesion kinase and paxillin might partially contribute to the synergic effect.


Input: Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group.

FUR

FUR


Input: Copyright (c) 2013 John Wiley & Sons, Ltd.


Input: A Mineral Extract from red Algae Ameliorates Chronic Spontaneous Colitis in IL-10 Deficient Mice in a Mouse Strain Dependent Manner.


Input: Inflammatory bowel disease is an urgent public health problem with a high incidence in developed countries.


Input: Alterations of lifestyle or dietary interventions may attenuate the disease progression and increase the efficacy of current therapies.


Input: Here we tested the effect of chronic supplementation with a mineral extract from red marine algae-rich in calcium (34%), magnesium, phosphorus, selenium and other trace minerals-in a clinically relevant model of spontaneous enterocolitis, interleukin (IL)-10 (-/-) mice.

calcium

magnesium

phosphorus

selenium


Input: The mineral extract was administered in the drinking water of Il10 (-/-) mice on C57BL/6 J and BALB/c strain backgrounds for 25 weeks commencing from 3 to 4 weeks of age.


Input: The mineral extract ameliorated the spontaneous development of colitis and severity of disease in Il10 (-/-) mice on a C57BL/6 J background.


Input: Mineral extract-treated Il10 (-/-) C57BL/6 J strain mice had significantly reduced mortality, circulating levels of serum Amyloid A and reduced colonic tissue damage.


Input: In contrast, comparable treatment of Il10 (-/-) mice on a BALB/c background with the mineral extract did not alter the course of colitis.


Input: These data demonstrate that chronic supplementation with a natural mineral extract selectively ameliorates spontaneous mild-moderate colitis in Il10 (-/-) mice on a C57BL/6 J, but does not attenuate more moderate-severe colitis in BALB/c strain animals.


Input: Copyright (c) 2013 John Wiley & Sons, Ltd.


Input: Expression, purification and proteomic analysis of recombinant histone H4 acetylated at lysine 16.

lysine


Input: Many histone covalent modifications have been identified and shown to play key regulatory roles in eukaryotic transcription, DNA damage repair, and replication.


Input: In vitro experiments designed to understand the mechanistic role of individual modifications require the availability of substantial quantities of pure histones, homogeneously modified at specific residues.


Input: We have applied the amber stop codon/suppressor tRNA strategy to the production of histone H4 acetylated at lysine 16, a particularly important isoform of this histone.

lysine


Input: Our success relies on adapting the H4 DNA sequence to the codon preference of E. coli and on preventing the premature decay of the H4 mRNA.


Input: These modifications to the original procedure render it easily applicable to the generation of any covalently modified histone H4 isoform.


Input: SiCN: SiCN Nanofibers with a Diameter Below 100 nm Synthesized via Concerted Block Copolymer Formation, Microphase Separation, and Crosslinking (Small 7/2013).

SiCN

SiCN


Input: SiCN fibers with a mean diameter of 50 nm and an aspect ratio of up to 100 are produced in a two-step process by R.

SiCN


Input: Kempe and co-workers.


Input: The key step to fabricate the longitudinal and crosssectional views of the mesofibers shown here is a concerted block-copolymer synthesis, microphase separation, and cross linking at 140 degrees C followed by pyrolysis at 1100 degrees C.


Input: Inexpensive components like a commercially available silazane and polyethylene are linked.

silazane

polyethylene


Input: The fibers may find application in electronic devices, as components of ceramic matrix composites, as fiber beds in hightemperature nano-filtering like diesel fine dust removal, or as thermally robust and chemically inert catalyst supports.


Input: Furthermore, the SiCN nanofibers introduced on page 984 are a promising alternative to ultrathin carbon fibers, due to their oxidation resistance.

SiCN

carbon


Input: Graphene in Light: Design, Synthesis and Applications of Photo-active Graphene and Graphene-Like Materials.

Graphene

Graphene

Graphene


Input: Graphene functionalized with photo-active units has become one of the most exciting topics of research in the last few years, which remarkably sustains and expands the graphene boom.

Graphene

graphene


Input: The rise of photo-active graphene in photonics and optoelectronics is evidenced by a spate of recent reports on topics ranging from photodetectors, photovoltaics, and optoelectronics to photocatalysis.

graphene


Input: For these applications, the fabrication of photo-active graphene through appropriate chemical functionalization strategies is essential as pristine graphene has zero bandgap and only weak absorption of photons.

graphene

graphene


Input: Written from the chemists' point of view, up-to-date chemical functionalization of graphene with various small organic molecules, conjugated polymers, rare-earth components, and inorganic semiconductors is reviewed.

graphene


Input: Particular attention is paid to the development of graphene functionalized with light-harvesting moieties, including materials synthesis, characterization, energy/charge-transfer processes, and applications in photovoltaics.

graphene


Input: Challenges currently faced by researchers and future perspectives in this field are also discussed.


Input: Potent Agonists of a Hematopoietic Stem Cell Cytokine Receptor, c-Mpl.


Input: Several growth factors feature prominently in the control of hematopoiesis.


Input: Thrombopoietin, a class I hematopoietic cytokine, plays critical roles in regulating hematopoietic stem cell numbers and also stimulates the production and differentiation of megakaryocytes, the bone marrow cells that ultimately produce platelets.


Input: Thrombopoietin interacts with the c-Mpl cell-surface receptor.


Input: Recently, several peptide and small-molecule agonists and antagonists of c-Mpl have been reported.


Input: We conducted a bioinformatics and molecular modeling study aimed at understanding the agonist activities of peptides that bind to c-Mpl, and developed new potent peptide agonists with low nanomolar activity.


Input: These agonists also show very high activity in human CD34 (+) primary cell cultures, and doubled the mean blood platelet counts when injected into mice.


Input: Amorphous Ni (OH) 2 Nanoboxes: Fast Fabrication and Enhanced Sensing for Glucose.

Ni (OH) 2

Glucose


Input: Inspired by Pearson' s hard and soft acid-base (HSAB) principle, uniform amorphous Ni (OH) 2 nanoboxes with intact shell structures and various sizes are quickly fabricated by deliberately selecting S2 O3 (2-) as the coordinating etchant toward Cu2 O templates and optimizing the reaction conditions.

Ni (OH) 2

S2 O3 (2-)

Cu2 O


Input: It is found that not only the solvent system but also the employing of a surfactant is vital for the fabrication of the nanoboxes.


Input: Ni (OH) 2 nanoboxes, as an example, demonstrate an improved electrochemical sensing ability for glucose, which might be due to their amorphous and hollow structural features.

Ni (OH) 2

glucose


Input: A Thyroxine Absorption Test Followed by Weekly Thyroxine Administration: A Method to Assess Non-Adherence to Treatment.

Thyroxine

Thyroxine


Input: OBJECTIVE: For patients, who remain hypothyroid despite the administration of what would seem adequate doses of levothyroxine, the underlying cause can be difficult to determine.

levothyroxine


Input: The possibility of a biological cause should first be explored; however, in the majority of cases poor adherence to medication is likely to be the main cause of treatment failure.


Input: When non-adherence is suspected but not volunteered, options to confirm the suspicion are limited.


Input: In this study we identified patients for whom known drug and pathological causes of levothyroxine malabsorption were excluded and despite often high doses of levothyroxine, the patients remained hypothyroid.

levothyroxine

levothyroxine


Input: DESIGN: Using a weight-determined oral levothyroxine bolus administration, absorption was initially assessed in twenty-three patients.

levothyroxine


Input: In nearly all patients this was shown to be maximal at 120mins post ingestion.


Input: This was then followed by the continued administration of a weekly thyroxine bolus for a four-week period after which TSH and free T4 levels were recorded.

thyroxine


Input: RESULTS: All patients showed a rise in free T4 at 120mins following the administration of the levothyroxine bolus, with a mean increase of 54 +/- 3% from baseline.

levothyroxine


Input: Following the treatment period, using an equivalent weekly levothyroxine dose which was significantly less than that of the daily dose taken by the patients before the test, the TSH reduced from baseline in ~ 75% of cases.

levothyroxine


Input: CONCLUSION: Using this combination of tests allows significant malabsorptive problems to be first identified, then potential non-adherence to be demonstrated.


Input: A management plan can then be implemented to increase adherence, aiming to improve treatment outcomes.


Input: Pressor and renal regional hemodynamic effects of urotensin II in neonatal pigs.

urotensin II


Input: Renal expression of the peptide hormone urotensin II (UII) and its receptor (UTR) are dependent on kidney maturation and anatomical regions.

urotensin II

UII


Input: However, renal regional hemodynamic effects of UII in neonates are unclear.

UII


Input: Here, we investigated regional hemodynamic responses to acute intrarenal arterial administration of UII in newborn pigs.

UII


Input: Western immunoblotting and immunofluorescence confirmed UTR expression and membrane localization in newborn pig renal afferent arterioles and afferent arteriolar smooth muscle cells respectively.


Input: Intrarenal arterial bolus injections of human UII (hUII; 1-100 ng/kg) resulted in a dose-dependent decrease in total renal blood flow (RBF) and an increase in mean arterial pressure (MAP) and renal vascular resistance (RVR) in newborn pigs.


Input: Moreover, hUII dose dependently reduced cortical blood flow (CBF) but increased medullary blood flow (MBF) in the piglets.


Input: hUII-induced MAP elevation and hemodynamic changes were inhibited by urantide, a UTR antagonist, but not losartan, a type 1 angiotensin II receptor antagonist.

urantide

losartan


Input: U-73122, a phospholipase C (PLC) inhibitor, and 2-aminoethoxydiphenyl borate, an inositol 1, 4, 5 trisphosphate (IP3) receptor antagonist, attenuated hUII-induced MAP and RVR elevations, RBF and CBF reductions, but not MBF increase.

2-aminoethoxydiphenyl borate

inositol 1, 4, 5 trisphosphate


Input: These findings indicate that intrarenal arterial administration of hUII elevates blood pressure and induces region-selective renal hemodynamic changes in newborn pigs.


Input: Our data also suggest that the PLC/IP3 signaling pathway contributes to hUII-induced alterations in MAP, RBF, RVR, and CBF but not MBF in newborn pigs.


Input: Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis.

glucosylceramide


Input: Hypothalamic neurons are main regulators of energy homeostasis.


Input: Neuronal function essentially depends on plasma membrane-located gangliosides.


Input: The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose: ceramide glucosyltransferase).

glucosylceramide

UDP

glucose

ceramide


Input: As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons.


Input: Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals.


Input: Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose: ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity.

UDP

glucose

ceramide


Input: Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis.


Input: Dose-dependent pharmacokinetics of bulleyaconitine A in rats.

bulleyaconitine A


Input: This study was conducted to determine the pharmacokinetic characteristics of bulleyaconitine A (BLA) after oral gavage and intravenous administration of BLA at a single dose of 0. 04, 0. 12, 0. 36 mg/kg (oral) or 0. 02 mg/kg (i. v.) in male Sprague-Dawley rats.

bulleyaconitine A

BLA

BLA


Input: Plasma concentration profiles were analysed using a non-compartmental pharmacokinetic method.


Input: Following i. v. 0. 02 mg/kg and oral administration 0. 04, 0. 12 or 0. 36 mg/kg, the geometric mean Cmax values were 19. 97, 2. 11, 5. 11 and 11. 47 ng/ml, respectively; the corresponding geometric mean AUC (0-t) values were 10. 50, 3. 19, 9. 59 and 18. 10 ng x h/ml, respectively.


Input: The median Tmax values were 0. 033, 0. 167, 0. 167 and 0. 167 h, respectively.


Input: The terminal elimination half-lives (t1/2) were 1. 23, 2. 48, 1. 93 and 2. 17h, respectively.


Input: The results showed that Cmax and AUC (0-t) increased with increasing doses of BLA.

BLA


Input: The increase in exposure with increasing dose was lower than expected under conditions of strict proportionality.


Input: Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo (His-Gly) and cyclo (His-Ala).

cyclic dipeptides

cyclo (His-Gly)

cyclo (His-Ala)


Input: Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities.

Cyclic dipeptides


Input: Cyclo (His-Gly) and cyclo (His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery.

Cyclo (His-Gly)

cyclo (His-Ala)


Input: Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation.

phosphatidylcholine

phosphatidylcholine

stearylamine

alpha-tocopherol

1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]

PEG-DSPE

folate-polyethylene glycol-cholesteryl hemisuccinate

F-PEG-CHEMS


Input: The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity.

cyclic dipeptides

folate


Input: However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0. 0962 mM for folate-targeted cyclo (His-Ala).

polyethylene glycol

folic acid

folic acid

folate

cyclo (His-Ala)


Input: Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes.

cyclic dipeptides


Input: Biological activities of selected basidiomycetes from Yemen.


Input: In a previous paper we demonstrated the results of biological screening of Yemeni basidiomycetes.


Input: The present study was aimed to investigate the antimicrobial and the antioxidant activity of further basidiomycetes collected in Yemen.


Input: Dichloromethane, methanol and aqueous extracts of the fruiting bodies of 25 species were screened in vitro for their antibacterial activities against three Gram-positive bacteria (Staphyloccocus aureus, Bacillus subtilis, Micrococcus flavus) and two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), against six human fungal pathogens (Candida albicans, Candida krusei, Aspergillus fumigatus, Mucor sp., Microsporum gypseum, Trichophyton mentagrophytes) and against one non human pathogenic fungus (Candida maltosa).

Dichloromethane

methanol


Input: The results indicated that 75 extracts exhibited activity against one or more of the bacteria.


Input: The methanol extracts of Agaricus cf. bernardii, Agrocybe pediades, Chlorophyllum molybdites, Coriolopsis polyzona, Ganoderma xylonoides, Pycnoporus sanguineus, Trametes lactinea and Trametes cingulata showed activity against all tested bacteria.

methanol


Input: The highest antibacterial activity was exhibited by methanol extracts from Chlorophyllum molybdites, Ganoderma xylonoides and Trametes cingulata and Agaricus cf. bernardii, Agrocybe pediades, Coriolopsis polyzona, Pycnoporus sanguineus and Trametes lactinea.

methanol


Input: The methanol extracts of Chlorophyllum molybdites, Ganoderma xylonoides and Pycnoporus sanguineus showed considerable antifungal activities against the tested fungal strains.

methanol


Input: Strong antioxidative effects employing the DPPH assay were exhibited by methanol extracts from Chlorophyllum molybdites, Ganoderma xylonoides, Hexagonia velutina, Pycnoporus sanguineus, Trametes lactinea and Trametes cingulata.

DPPH

methanol


Input: Our previous and presented studies about 48 basidiomycetes collected in Yemen provide evidence that basidiomycetes from the Arabic region so far should attract more attention as potential source for new biologically active agents.


Input: Rovibrational Energies of the Hydrocarboxyl Radical from a RCCSD (T) Study.

Hydrocarboxyl


Input: A RCCSD (T)/cc-pVQZ potential energy surface is constructed for the HOCO radical in the ground electronic state and used to compute rotation-vibration levels of HOCO and DOCO.

HOCO

HOCO

DOCO


Input: Two numerical strategies are employed to study in detail the wave function properties.


Input: The importance of stretch-bend coupling, such as nu 4/nu 5 and nu 3/nu 4, for the internal dynamics is demonstrated.


Input: The rotational constants computed for the vibrational ground state of trans and cis conformers are in good agreement with experimental values.


Input: Institutional Profile: Jayne Haines Center for Pharmacogenomics and Drug Safety: educating future generations of healthcare professionals.


Input: The Jayne Haines Center for Pharmacogenomics and Drug Safety operates in the Temple University School of Pharmacy and serves as an educational and research facility for professional pharmacy students, graduate students, residents, postdoctoral fellows and faculties.


Input: The Center is involved in educational and investigational projects in a setting that includes an inner city research/teaching hospital and the Temple University Schools of Pharmacy, Medicine, Dentistry and Health Professions.


Input: The mission of the Haines Center is to facilitate the basic science approach to the problems of pharmacotherapy, and to provide education for future healthcare professionals in the genetics of drug response.


Input: With the expanding role of genetic analysis in preventing adverse effects of pharmacotherapy, we are working towards truly personalized pharmacotherapy that fully exploits the advances of modern biomedical science.


Input: Antioxidant activity of Tunisian Geranium robertianum L.


Input: (Geraniaceae).


Input: The present investigation focuses on the methanolic extract obtained from Geranium robertianum L.


Input: (Geraniaceae) (Herb Robert), a herbal plant used in traditional medicine for the treatment of human and animal diseases.


Input: The antioxidant capacities of the extract were evaluated using 1, 1-diphenyl-2-picrylhydrazyl radical, beta-carotene/linoleic acid and reducing power and metal chelating activity assays.

1, 1-diphenyl-2-picrylhydrazyl

beta-carotene

linoleic acid


Input: The amount of total phenolic content, flavonoids and condensed tannins was very high, and the correlation between the antioxidant activity potential and total phenolic level of the extract was pointed out.

flavonoids

tannins


Input: Galactose-Based Amphiphilic Block Copolymers: Synthesis, Micellization, and Bioapplication.

Galactose


Input: Redox-responsive amphiphilic diblock copolymers, poly (6-O-methacryloyl-d-galactopyranose-co-2-(N, N-dimethylaminoethyl) methacrylate)-b-poly (pyridyl disulfide ethyl methylacrylate) (P (MAGP-co-DMAEMA)-b-PPDSMA) were obtained by deprotection of poly ((6-O-methacryloyl-1, 2: 3, 4-di-O-isopropylidene-d-galactopyranose)-co-DMAEMA)-b-PPDSMA [P (MAlpGP-co-DMAEMA)-b-PPDSMA], which were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization of PDSMA using P (MAlpGP-co-DMAEMA) as macro-RAFT agent.

poly (6-O-methacryloyl-d-galactopyranose-co-2-(N, N-dimethylaminoethyl) methacrylate)-b-poly (pyridyl disulfide ethyl methylacrylate)

P (MAGP-co-DMAEMA)-b-PPDSMA

poly ((6-O-methacryloyl-1, 2: 3, 4-di-O-isopropylidene-d-galactopyranose)-co-DMAEMA)-b-PPDSMA

P (MAlpGP-co-DMAEMA)-b-PPDSMA

PDSMA

P (MAlpGP-co-DMAEMA)


Input: Dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies showed that diblock copolymers P (MAGP-co-DMAEMA)-b-PPDSMA can self-assemble into micelles.

P (MAGP-co-DMAEMA)-b-PPDSMA


Input: Doxorubicin (DOX) could be encapsulated by P (MAGP-co-DMAEMA)-b-PPDSMA upon micellization and released upon adding glutathione (GSH) into the micelle solution.

Doxorubicin

DOX

P (MAGP-co-DMAEMA)-b-PPDSMA

glutathione

GSH


Input: The galactose functional groups in the PMAGP block had specific interaction with HepG2 cells, and P (MAGP-co-DMAEMA)-b-PPDSMA can act as gene delivery vehicle.

galactose

PMAGP

P (MAGP-co-DMAEMA)-b-PPDSMA


Input: So, this kind of polymer has potential applications in hepatoma-targeting drug and gene delivery and biodetection.


Input: Effects of prediabetes and diabetes on left ventricular and coronary microvascular functions.


Input: BACKGROUND: Coronary flow reserve (CFR) provides independent prognostic information in diabetic patients with known or suspected coronary artery disease.


Input: However, there have been no substantial data to evaluate CFR in prediabetics.


Input: Accordingly, we aimed to evaluate CFR in subjects with prediabetes using second harmonic transthoracic Doppler echocardiography.


Input: METHODS AND RESULTS: We measured CFR of 65 subjects with prediabetes, 45 patients with overt type 2 diabetes, and 43 sex and age matched normoglycemic healthy subjects with normal glucose tolerance.

glucose


Input: Ages, gender, existence of hypertension or hypercholesterolemia, smoking status were similar among the groups.


Input: CFR was significantly lower in diabetics (2. 15 +/- 0. 39) than in prediabetics (2. 39 +/- 0. 45) and controls (2. 75 +/- 0. 35); in addition, it was significantly lower in prediabetics than controls.


Input: Only 2 (5%) of control subjects had abnormal CFR (< 2) but 11 (17%) prediabetic subjects and 19 (42%) diabetic patients had abnormal CFR.


Input: We found that only age (beta =-0. 31, P < 0. 01) and presence of the diabetes (beta =-0. 57, P < 0. 01) were significant predictors of lower CFR in a multivariable model that adjusted for other variables.


Input: CFR was significantly and inversely correlated with age (r =-0. 15, P = 0. 04), fasting glucose level (r =-0. 27, P = 0. 001), postprandial glucose level (r = 0. 43, P < 0. 001), hemoglobin A1C level (r =-0. 34, P < 0. 001), LDL cholesterol level (r = 0. 22, P = 0. 009), mitral A velocity (r =-0. 27, P = 0. 001) and Tei index (r =-0. 19, P = 0. 02), whereas mitral E/A ratio, mitral Em (r = 0. 18, P = 0. 02), mitral Em/Am ratio (r = 0. 23, P = 0. 004) were significantly and positively correlated with CFR.

glucose

glucose

cholesterol


Input: CONCLUSION: CFR is impaired in subjects with prediabetics, but this impairment is not as severe as that in diabetics.


Input: Does 4-tert-octylphenol affect estrogen signaling pathways in bank vole Leydig cells and tumor mouse Leydig cells in vitro?

estrogen


Input: Primary Leydig cells obtained from bank vole testes and the established tumor Leydig cell line (MA-10) have been used to explore the effects of 4-tert-octylphenol (OP).


Input: Leydig cells were treated with two concentrations of OP (10 (-4) M, 10 (-8) M) alone or concomitantly with anti-estrogen ICI 182, 780 (1 mu M).

estrogen ICI 182, 780


Input: In OP-treated bank vole Leydig cells, inhomogeneous staining of estrogen receptor alpha (ER alpha) within cell nuclei was found, whereas it was of various intensity among MA-10 Leydig cells.

estrogen


Input: The expression of ER alpha mRNA and protein decreased in both primary and immortalized Leydig cells independently of OP dose.


Input: ICI partially reversed these effects at mRNA level while at protein level abrogation was found only in vole cells.


Input: Dissimilar action of OP on cAMP and androgen production was also observed.

cAMP

androgen


Input: This study provides further evidence that OP shows estrogenic properties acting on Leydig cells.


Input: However, its effect is diverse depending on the cellular origin.


Input: mTOR Regulates Nox4-Mediated Podocyte Depletion in Diabetic Renal Injury.


Input: Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis.


Input: Pharmacological doses of the mTOR inhibitor rapamycin reduce albuminura in diabetes.

rapamycin


Input: We explored the hypothesis that mTOR mediates podocyte injury in diabetes.


Input: High glucose (HG) induces apoptosis of podocytes, inhibits AMPK activation, inactivates tuberin and activates mTOR.

glucose


Input: HG also increases the levels of Nox4 and Nox1 and NADPH oxidase activity.

NADPH


Input: Inhibition of mTOR by low dose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase activity and podocyte apoptosis.

rapamycin

NADPH


Input: Inhibition of mTOR had no effect on AMPK or tuberin phosphorylation indicating that mTOR is downstream of these signaling molecules.


Input: In isolated glomeruli of OVE26 mice, there is similar decrease in the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 and NADPH oxidase activity.

NADPH


Input: Inhibition of mTOR by small dose of rapamycin reduces podocyte apoptosis, attenuates glomerular injury and albuminuria.

rapamycin


Input: Our data provide evidence for a novel function of mTOR in Nox4-derived ROS generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes.


Input: Thus mTOR and or NADPH oxidase inhibition may represent a therapeutic modality of diabetic kidney disease.

NADPH


Input: Application of Target-Mediated Drug Disposition Model to Small Molecule Heat Shock Protein 90 Inhibitors.


Input: Replacement of hydrogen with fluorine within three pairs of structurally similar small molecule inhibitors of heat shock protein 90 (HSP90) resulted in differences in inhibition constants (Ki) in vitro as well as marked differences in rat intravenous pharmacokinetic profiles.

hydrogen

fluorine


Input: The difference in pharmacokinetic profiles between lower and higher affinity inhibitors (LAIs and HAIs, respectively) was characterized by remarkably different estimates for steady-state volumes of distribution (Vss: 1. 8 to 2. 0 versus 10 to 13 L/kg) with comparable clearance estimates (3. 2 to 3. 5 L/h/kg).


Input: When the observed Vss estimates were compared to the values predicted with the tissue-composition-based model, the observed Vss estimates for HAIs were 4 to 8-fold larger than the predicted values whereas the Vss values for LAIs were comparable each other.


Input: Accordingly, a negative relationship between in vitro HSP90 Ki versus in vivo Vss estimates was observed among these inhibitors.


Input: We therefore hypothesized that pharmacokinetic profiles of these inhibitors could be characterized by target-mediated drug disposition (TMDD) model.


Input: In vivo equilibrium dissociation constant (KD) estimates for HAIs due to target binding by TMDD model with rapid binding approximation were 1 to 6 nM (equivalent to 0. 3 to 2 nM free drug), which appeared comparable to the in vitro Ki estimates (2 to 3 nM).


Input: In vivo KD values of LAIs were not accurately determined by the TMDD model, likely due to non-specific binding dependent-tissue distribution obscuring TMDD profiles.


Input: Overall, these results suggest that the observed large Vss estimates for potent HSP90 inhibitors are likely due to pharmacological target binding.


Input: 1, 3, 4-Oxadiazol-2-ones as fatty-acid amide hydrolase and monoacylglycerol lipase inhibitors: Synthesis, in vitro evaluation and insight into potency and selectivity determinants by molecular modelling.

1, 3, 4-Oxadiazol-2-ones

fatty-acid amide

monoacylglycerol


Input: Inhibition of the key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been proposed as potential mode of action for various therapeutic applications.

fatty acid amide

monoacylglycerol


Input: Continuing our previous work, we take the first steps of structure-activity relationship exploration and show that 1, 3, 4-oxadiazol-2-ones can serve as scaffold for both selective FAAH and MAGL inhibitors, and also function as a dual FAAH/MAGL inhibitor at sub-micromolar IC50 values.

1, 3, 4-oxadiazol-2-ones


Input: Moreover, 10-fold selectivity against MAGL over FAAH was achieved with compound 3d (FAAH and MAGL IC50; 2. 0 and 0. 22 mu M).


Input: Lastly, enzyme and ligand features contributing to the potency and selectivity differences are analysed by molecular docking.


Input: Development of solid lipid nanoparticles based controlled release system for topical delivery of terbinafine hydrochloride.

terbinafine hydrochloride


Input: The study describes the development and evaluation of solid lipid nanoparticles (SLNs) of terbinafine hydrochloride (TH) for sustained release and skin targeting.

terbinafine hydrochloride


Input: TH-loaded SLNs were prepared by solvent-injection technique and optimized using 3 (3) full-factorial design.


Input: Effect of drug: lipid ratio, surfactant concentration and volume of organic solvent were studied on% entrapment efficiency (% EE) and particle size (PS).


Input: The optimum formulation based on desirability (0. 945) exhibited% EE of 73. 74% and PS of 300nm.


Input: Optimized SLNs were incorporated into Carbopol gel and evaluated for drug content, pH, in vitro release, ex vivo retention, in vivo pharmacodynamic and stability studies.

Carbopol


Input: Drug release from SLNs dispersion followed Korsmeyer-Peppas model, indicating Fickian drug release, while that from the gel followed Higuchi model.


Input: The ex vivo studies through rat abdominal skin indicated skin retention ability of SLNs as compared to commercial product.


Input: In vivo pharmacodynamic studies showed that the SLNs based gel reduced fungal burden of Candida albicans in rats as compared to commercial product in shorter duration of time.


Input: The SLNs dispersion and gel exhibited physicochemical stability under refrigeration upto 3months.


Input: It was concluded that SLNs incorporated Carbopol gel had skin targeting ability and may serve as a promising carrier in treatment of fungal skin infections.

Carbopol


Input: Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells.


Input: 5-Fluorouracil (5-FU) is the most used chemotherapeutic agent in colorectal cancer.


Input: However, resistance to this drug is relatively frequent, and new strategies to overcome it are urgently needed.


Input: The aim of this work was to determine the antitumor properties of a supercritical fluid rosemary extract (SFRE), alone and in combination with 5-FU, as a potential adjuvant therapy useful for colon cancer patients.


Input: This extract has been recognized as a healthy component by the European Food Safety Authority (EFSA).


Input: The effects of SFRE both alone and in combination with 5-FU were evaluated in different human colon cancer cells in terms of cell viability, cytotoxicity, and cell transformation.


Input: Additionally, colon cancer cells resistant to 5-FU were used to assay the effects of SFRE on drug resistance.


Input: Finally, qRT-PCR was performed to ascertain the mechanism by which SFRE potentiates the effect of 5-FU.


Input: Our results show that SFRE displays dose-dependent antitumor activities and exerts a synergistic effect in combination with 5-FU on colon cancer cells.


Input: Furthermore, SFRE sensitizes 5-FU-resistant cells to the therapeutic activity of this drug, constituting a beneficial agent against both 5-FU sensitive and resistant tumor cells.


Input: Gene expression analysis indicates that the enhancement of the effect of 5-FU by SFRE might be explained by the downregulation of TYMS and TK1, enzymes related to 5-FU resistance.


Input: A new method for stranded whole transcriptome RNA-seq.


Input: This report describes an improved protocol to generate stranded, barcoded RNA-seq libraries to capture the whole transcriptome.


Input: By optimizing the use of duplex specific nuclease (DSN) to remove ribosomal RNA reads from stranded barcoded libraries, we demonstrate improved efficiency of multiplexed next generation sequencing (NGS).


Input: This approach detects expression profiles of all RNA types, including miRNA (microRNA), piRNA (Piwi-interacting RNA), snoRNA (small nucleolar RNA), lincRNA (long non-coding RNA), mtRNA (mitochondrial RNA) and mRNA (messenger RNA) without the use of gel electrophoresis.


Input: The improved protocol generates high quality data that can be used to identify differential expression in known and novel coding and non-coding transcripts, splice variants, mitochondrial genes and SNPs (single nucleotide polymorphisms).

nucleotide


Input: A diarylheptanoid phytoestrogen from Curcuma comosa, 1, 7-diphenyl-4, 6-heptadien-3-ol, accelerates human osteoblast proliferation and differentiation.

diarylheptanoid

1, 7-diphenyl-4, 6-heptadien-3-ol


Input: Curcuma comosa Roxb.


Input: is ginger-family plant used to relieve menopausal symptoms.


Input: Previous work showed that C. comosa extracts protect mice from ovariectomy-induced osteopenia with minimal effects on reproductive organs, and identified the diarylheptanoid (3R)-1, 7-diphenyl-(4E, 6E)-4, 6-heptadien-3-ol (DPHD) as the major active component of C. comosa rhizomes.

diarylheptanoid (3R)-1, 7-diphenyl-(4E, 6E)-4, 6-heptadien-3-ol

DPHD


Input: At 1-10 mu M, DPHD increased differentiation in transformed mouse osteoblasts, but the effect of DPHD on normal bone cells was unknown.

DPHD

DPHD


Input: We examined the concentration dependency and mechanism of action of DPHD relative to 17 beta-estradiol in nontransformed human osteoblasts (h-OB).

DPHD

17 beta-estradiol


Input: The h-OB were 10-100 fold more sensitive to DPHD than transformed osteoblasts: DPHD increased h-OB proliferation at 10nM and, at 100nM, activated MAP kinase signaling within 30min.

DPHD

DPHD


Input: In long-term differentiation assays, responses of h-OB to DPHD were significant at 10nM, and optimal response in most cases was at 100nM.

DPHD


Input: At 7-21 days, DPHD accelerated osteoblast differentiation, indicated by alkaline phosphatase activity and osteoblast-specific mRNA production.

DPHD


Input: Effects of DPHD were eliminated by the estrogen receptor antagonist ICI182780.

DPHD

estrogen


Input: During differentiation, DPHD promoted early expression of osteoblast transcription factors, RUNX2 and osterix.

DPHD


Input: Subsequently, DPHD accelerated production of bone structural genes, including COL1A1 and osteocalcin comparably to 17 beta-estradiol.

DPHD

17 beta-estradiol


Input: In h-OB, DPHD increased the osteoprotegerin to RANKL ratio and supported mineralization more efficiently than 10nM 17 beta-estradiol.

DPHD

17 beta-estradiol


Input: We conclude that DPHD promotes human osteoblast function in vitro effectively at nanomolar concentrations, making it a promising compound to protect bone in menopausal women.

DPHD


Input: Cyclohexanone derivatives with cytotoxicity from the fungus Penicillium commune.

Cyclohexanone


Input: Four new cyclohexanone derivatives (2-5) and one known analog, (-)-Palitantin (1) were isolated from the EtOAc extract of Penicillium commune, a fungal strain of low-temperature habitats.

cyclohexanone

(-)-Palitantin

EtOAc


Input: The structures of 2-5 were determined on the basis of extensive spectroscopic analysis.


Input: Furthermore, the absolute configuration of 2 was assigned by electronic circular dichroism (ECD) calculations, whereas that 3-5 were deduced via the CD data.


Input: Cytotoxicities of 2-5 against five human carcinoma cell lines (Hela, A549, MCF7, HCT116, T24) were evaluated.


Input: Biological Therapies for Rheumatoid Arthritis: Progress to Date.


Input: Biologic drugs for the management of rheumatoid arthritis (RA) have revolutionized the therapeutic armamentarium with the development of several novel monoclonal antibodies, which include murine, chimeric, humanized, fully human antibodies and fusion proteins.


Input: These biologics bind to their targets with high affinity and specificity.


Input: Since 1998, nine different biologics have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA, and several others are in different stages of clinical trials.


Input: This field is in continuous evolution and new biologics are tested every year.


Input: Therefore a precise analysis is required in order to have a detailed and updated state of the art of this field.


Input: In this review, our main aim is to analyse all available biological therapies that are FDA and EMA approved for the treatment of RA and also those that are in clinical trials for the management of RA patients.


Input: Lixisenatide: first global approval.


Input: The selective once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide (Lyxumia ((R))) is under development with Sanofi for the treatment of type 2 diabetes mellitus.


Input: Lixisenatide belongs to a class of GLP-1 compounds designed to mimic the endogenous hormone GLP-1.


Input: Native GLP-1 stimulates insulin secretion in a glucose-dependent manner, as well as suppressing glucagon production and slowing gastric emptying.

glucose


Input: A once-daily subcutaneous formulation of lixisenatide has been approved in the EU, Iceland, Liechtenstein, Norway and Mexico for the treatment of type 2 diabetes, and is under regulatory review in the USA, Switzerland, Brazil, Canada, Ukraine, South Africa, Japan and Australia.


Input: This article summarizes the milestones in the development of lixisenatide, leading to this first approval for use in adults with type 2 diabetes.


Input: Annexin A2 regulates beta 1 integrin internalization and intestinal epithelial cell migration.


Input: The gastrointestinal epithelium functions as an important barrier that separates luminal contents from the underlying tissue compartment and is vital in maintaining mucosal homeostasis.

luminal


Input: Mucosal wounds in inflammatory disorders compromise the critical epithelial barrier.


Input: In response to injury, intestinal epithelial cells (IECs) rapidly migrate to reseal wounds.


Input: We have previously observed that a membrane associated, Actin binding protein, Annexin A2 (AnxA2), is up-regulated in migrating IECs and plays an important role in promoting wound closure.


Input: To identify the mechanisms by which AnxA2 promotes IEC movement and wound closure we used a loss of function approach.


Input: AnxA2 specific shRNA was utilized to generate IECs with stable down-regulation of AnxA2.


Input: Loss of AnxA2 inhibited IEC migration while promoting enhanced cell-matrix adhesion.


Input: These functional effects were associated with increased levels of beta 1 integrin protein, which is reported to play an important role in mediating the cell-matrix adhesive properties of epithelial cells.


Input: Since cell migration requires dynamic turnover of integrin based adhesions, we tested if AnxA2 modulates internalization of cell surface beta 1 integrin required for forward cell movement.


Input: Indeed, pulse-chase biotinylation experiments in IECs lacking AnxA2 demonstrated a significant increase in cell surface beta 1 integrin that was accompanied by decreased beta 1 integrin internalization and degradation.


Input: These findings support an important role of AnxA2 in controlling dynamics of beta 1 integrin at the cell surface that in turn is required for the active turnover of cell-matrix associations, cell migration and wound closure.


Input: Human polymerase kappa uses a template-slippage deletion mechanism, but can realign the slipped strands to favour base substitution mutations over deletions.


Input: Polymerases belonging to the DinB class of the Y-family translesion synthesis DNA polymerases have a preference for accurately and efficiently bypassing damaged guanosines.

guanosines


Input: These DinB polymerases also generate single-base (-1) deletions at high frequencies with most occurring on repetitive' deletion hotspot' sequences.


Input: Human DNA polymerase kappa (hPol kappa), the eukaryotic DinB homologue, displays an unusual efficiency for to extend from mispaired primer termini, either by extending directly from the mispair or by primer-template misalignment.


Input: This latter property explains how hPol kappa creates single-base deletions in non-repetitive sequences, but does not address how deletions occur in repetitive deletion hotspots.


Input: Here, we show that hPol kappa uses a classical Streisinger template-slippage mechanism to generate-1 deletions in repetitive sequences, as do the bacterial and archaeal homologues.


Input: After the first nucleotide is added by template slippage, however, hPol kappa can efficiently realign the primer-template duplex before continuing DNA synthesis.

nucleotide


Input: Strand realignment results in a base-substitution mutation, minimizing generation of more deleterious frameshift mutations.


Input: On non-repetitive sequences, we find that nucleotide misincorporation is slower if the incoming nucleotide can correctly basepair with the nucleotide immediately 5' to the templating base, thereby competing against the mispairing with the templating base.

nucleotide

nucleotide

nucleotide


Input: Exploring the zebrafish embryo as an alternative model for the evaluation of liver toxicity by histopathology and expression profiling.


Input: The whole zebrafish embryo model (ZFE) has proven its applicability in developmental toxicity testing.


Input: Since functional hepatocytes are already present from 36 h post fertilization onwards, whole ZFE have been proposed as an attractive alternative to mammalian in vivo models in hepatotoxicity testing.


Input: The goal of the present study is to further underpin the applicability of whole ZFE for hepatotoxicity testing by combining histopathology and next-generation sequencing-based gene expression profiling.


Input: To this aim, whole ZFE and adult zebrafish were exposed to a set of hepatotoxic reference compounds.


Input: Histopathology revealed compound and life-stage-specific effects indicative of toxic injury in livers of whole ZFE and adult zebrafish.


Input: Next-generation sequencing (NGS) was used to compare transcript profiles in pooled individual RNA samples of whole ZFE and livers of adult zebrafish.


Input: This revealed that hepatotoxicity-associated expression can be detected beyond the overall transcription noise in the whole embryo.


Input: In situ hybridization verified liver specificity of selected highly expressed markers in whole ZFE.


Input: Finally, cyclosporine A (CsA) was used as an illustrative case to support applicability of ZFE in hepatotoxicity testing by comparing CsA-induced gene expression between ZFE, in vivo mouse liver and HepaRG cells on the levels of single genes, pathways and transcription factors.

cyclosporine A

CsA

CsA


Input: While there was no clear overlap on single gene level between the whole ZFE and in vivo mouse liver, strong similarities were observed between whole ZFE and in vivo mouse liver in regulated pathways related to hepatotoxicity, as well as in relevant overrepresented transcription factors.


Input: In conclusion, both the use of NGS of pooled RNA extracts analysis combined with histopathology and traditional microarray in single case showed the potential to detect liver-related genes and processes within the transcriptome of a whole zebrafish embryo.


Input: This supports the applicability of the whole ZFE model for compound-induced hepatotoxicity screening.


Input: Synthesis and Cytostatic and Antiviral Activities of 2'-Deoxy-2', 2'-difluororibo-and 2'-Deoxy-2'-fluororibonucleosides Derived from 7-(Het) aryl-7-deazaadenines.

2'-Deoxy-2', 2'-difluororibo-and 2'-Deoxy-2'-fluororibonucleosides

7-(Het) aryl-7-deazaadenines


Input: A series of sugar-modified derivatives of cytostatic 7-heteroaryl-7-deazaadenosines (2'-deoxy-2'-fluororibo-and 2'-deoxy-2', 2'-difluororibonucleosides) bearing an aryl or heteroaryl group at position 7 was prepared and screened for biological activity.

sugar

2'-deoxy-2'-fluororibo-and 2'-deoxy-2', 2'-difluororibonucleosides

aryl

heteroaryl


Input: The difluororibonucleosides were prepared by non-stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2, 2-difluoro-D-erythro-pentofuranosyl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het) arylboronic acids.

difluororibonucleosides

benzoyl-protected 2-deoxy-2, 2-difluoro-D-erythro-pentofuranosyl-1-mesylate

(het) arylboronic acids


Input: The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the corresponding 7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside 20 with (het) arylboronic acids.

fluororibo

palladium

7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside

(het) arylboronic acids


Input: The key intermediate 20 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3'-and 5'-hydroxy groups with acid-labile groups, followed by stereoselective SN 2 fluorination and deprotection.

arabinonucleoside

3'-and 5'-hydroxy


Input: Some of the title nucleosides and 7-iodo-7-deazaadenine intermediates showed micromolar cytostatic or anti-HCV activity.

nucleosides


Input: The most active were 7-iodo and 7-ethynyl derivatives.


Input: The corresponding 2'-deoxy-2', 2'-difluororibonucleoside 5'-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase alpha.

2'-deoxy-2', 2'-difluororibonucleoside 5'-O-triphosphates


Input: Tissue Factor Activity and ECM-Related Gene Expression in Human Aortic Endothelial Cells Grown on Electrospun Biohybrid Scaffolds.


Input: All blood vessels are lined with a quiescent endothelium, which aids in regulating regular blood flow and avoiding thrombus formation.


Input: Current attempts at replacing diseased blood vessels frequently fail due to the intrinsic thrombogenicity of the materials used as vascular grafts.


Input: In extending our previous work where we introduced a new candidate scaffolds for vascular grafts electrospun from a blend solution of PLGA, gelatin, and elastin (PGE), this study aimed to evaluate the potential of PGE scaffolds to support nonthrombogenic monolayers of primary isolates of human aortic endothelial cells (HAECs), as assessed by a combination of biochemical, molecular, and bioinformatics-based analyses.


Input: After 24 h of culture on 3-D fibrous PGE scaffolds, HAECs formed a confluent, nonthrombogenic, and physiologically competent monolayer, as assessed by tissue factor (TF) gene expression and protein activity assays.


Input: The levels of TF mRNA/protein activity in HAECs grown on PGE scaffolds were similar to those on gelatin or collagen IV-coated 2-D surfaces.


Input: In addition, bioinformatics-based analysis of a focused microarray containing 84 ECM-related cDNA probes demonstrated that HAECs essentially expressed a histotypic ECM-related " transcriptome " on PGE scaffolds, where cells were more quiescent than cells cultured on 2-D coverslips coated with gelatin (a well-known " inert " substrate for conventional EC culture), but less so than on 2-D PGE films.


Input: These data suggest an important role for nanorough substrates (PGE films) in passivating endothelial cells and confirm the crucial effect of substrate composition in this process.


Input: Principal component analysis of microarray data on the above substrates (including collagen IV) implied that substrate composition plays a greater role than surface topography in affecting the endothelial ECM-related " transcriptome ".


Input: Taken together, our findings suggest that electrospun PGE scaffolds are potentially suitable for application in small diameter vascular tissue engineering.


Input: Pressure modulation of ras-membrane interactions and intervesicle transfer.


Input: Proteins attached to the plasma membrane frequently encounter mechanical stresses, including high hydrostatic pressure (HHP) stress.


Input: Signaling pathways involving membrane-associated small GTPases (e. g., Ras) have been identified as critical loci for pressure perturbation.


Input: However, the impact of mechanical stimuli on biological outputs is still largely terra incognita.


Input: The present study explores the effect of HHP on the membrane association, dissociation, and intervesicle transfer process of N-Ras by using a FRET-based assay to obtain the kinetic parameters and volumetric properties along the reaction path of these processes.


Input: Notably, membrane association is fostered upon pressurization.


Input: Conversely, depending on the nature and lateral organization of the lipid membrane, acceleration or retardation is observed for the dissociation step.


Input: In addition, HHP can be inferred as a positive regulator of N-Ras clustering, in particular in heterogeneous membranes.


Input: The susceptibility of membrane interaction to pressure raises the idea of a role of lipidated signaling molecules as mechanosensors, transducing mechanical stimuli to chemical signals by regulating their membrane binding and dissociation.


Input: Finally, our results provide first insights into the influence of pressure on membrane-associated Ras-controlled signaling events in organisms living under extreme environmental conditions such as those that are encountered in the deep sea and sub-seafloor environments, where pressures reach the kilobar (100 MPa) range.


Input: Modeling the Conformational Preference of the Carbon-Bonded Covalent Adduct Formed upon Exposure of 2'-Deoxyguanosine to Ochratoxin A.

Carbon

Ochratoxin A


Input: The conformational flexibility of the C8-linked guanine adduct formed from attachment of ochratoxin A (OTA) was analyzed using a systematic computational approach and models ranging from the nucleobase to the adducted DNA helix.

guanine

ochratoxin A

OTA

nucleobase


Input: A focus was placed on the influence of the C8-modification of 2'-deoxyguanosine (dG) on the preferred relative arrangement of the nucleobase and the C8-substituent and, more importantly, the anti/syn conformational preference with respect to the glycosidic bond.

nucleobase


Input: Although OTA is twisted with respect to the base in the nucleobase model, addition of the deoxyribose sugar induces a further twist and restricts rotation about the C-C linkage due to close contacts between OTA and the sugar.

OTA

nucleobase

deoxyribose sugar

C-C

OTA


Input: The nucleoside model preferentially adpots a syn orientation (by 10-20 kJ mol (-1) depending on the OTA conformation) due to the presence of an O5'-H... N3 interaction.

nucleoside

OTA

H


Input: However, when this hydrogen bond is eliminated, which better mimics the DNA environment, a small (< 5 kJ mol (-1)) anti/syn energy difference is predicted.

hydrogen


Input: Inclusion of the 5'-monophosphate group leads to an up to 20 kJ mol (-1) preference for the syn (nucleotide) conformation due to stabilizing base-phosphate interactions involving the amino group of guanine.

syn (nucleotide)

phosphate

amino

guanine