Input: Single-walled carbon nanotube surface control of complement recognition and activation.

carbon


Input: Carbon nanotubes (CNTs) are receiving considerable attention in site-specific drug and nucleic acid delivery, photodynamic therapy, and photoacoustic molecular imaging.

Carbon


Input: Despite these advances, nanotubes may activate the complement system (an integral part of innate immunity), which can induce clinically significant anaphylaxis.


Input: We demonstrate that single-walled CNTs coated with human serum albumin activate the complement system through C1q-mediated classical and the alternative pathways.


Input: Surface coating with methoxypoly (ethylene glycol)-based amphiphiles, which confers solubility and prolongs circulation profiles of CNTs, activates the complement system differently, depending on the amphiphile structure.

methoxypoly (ethylene glycol)


Input: CNTs with linear poly (ethylene glycol) amphiphiles trigger the lectin pathway of the complement through both L-ficolin and mannan-binding lectin recognition.

poly (ethylene glycol)


Input: The lectin pathway activation, however, did not trigger the amplification loop of the alternative pathway.


Input: An amphiphile with branched poly (ethylene glycol) architecture also activated the lectin pathway but only through L-ficolin recognition.

poly (ethylene glycol)


Input: Importantly, this mode of activation neither generated anaphylatoxins nor induced triggering of the effector arm of the complement system.


Input: These observations provide a major step toward nanomaterial surface modification with polymers that have the properties to significantly improve innate immunocompatibility by limiting the formation of complement C3 and C5 convertases.


Input: Synthesis of novel phosphorylated guanidine derivatives from cyanamide and their anti-inflammatory activity.

phosphorylated guanidine

cyanamide


Input: A series of novel guanidine derivatives were synthesized in three steps and their anti-inflammatory activities in vitro and in vivo evaluated.

guanidine


Input: 2-Aminopyridin-3-ol (1) was reacted with thiophosphoryl chloride (2) to give a monochloride (3).

thiophosphoryl chloride

monochloride


Input: It was further reacted with cyanamide to afford the corresponding cyanamine (4), which was subsequently reacted with different heterocyclic amines to form the title compounds (5a-l).

cyanamide

cyanamine

heterocyclic amines


Input: The substituent in the guanidine function affected the potency of anti-inflammatory activity.

guanidine


Input: The compounds having benzothiazole, fluorophenyl, and piperazinyl moieties enhanced the anti-inflammatory activity.

benzothiazole

fluorophenyl

piperazinyl


Input: Discovering some novel 7-chloroquinolines carrying a biologically active benzenesulfonamide moiety as a new class of anticancer agents.

benzenesulfonamide


Input: Based on the reported anticancer activity of quinolines, a new series of 7-chloroquinoline derivatives bearing the biologically active benzenesulfonamide moiety 2-17 and 19-25 were synthesized starting with 4, 7-dichloroquinolne 1.

quinolines

benzenesulfonamide

4, 7-dichloroquinolne


Input: Compound 17 was the most active compound with IC (50) value 64. 41, 75. 05 and 30. 71 micro M compared with Doxorubicin as reference drug with IC (50) values 82. 53, 88. 32 and 73. 72 micro M on breast cancer cells, skin cancer cells and neuroblastoma, respectively.

Doxorubicin


Input: All the synthesized compounds were evaluated for their in vitro anticancer activity on breast cancer cells, skin cancer cells and neuroblastoma cells.


Input: Most of the synthesized compounds showed moderate activity.


Input: In order to suggest the mechanism of action for their cytotoxic activity, molecular docking for all synthesized compounds was done on the active site of phosphoinositide kinase (PI3K) and good results were obtained.

phosphoinositide


Input: Syntheses of 2-deoxy-2, 3-didehydro-N-acetylneuraminic acid analogues modified by alpha-acylaminoamido groups at the C-4 position using isocyanide-based four-component coupling and biological evaluation as inhibitors of human parainfluenza virus type 1.

2-deoxy-2, 3-didehydro-N-acetylneuraminic acid

alpha-acylaminoamido

isocyanide


Input: Novel sialidase inhibitors 11 having an alpha-acylaminoamido group at the C-4 position of Neu5Ac2en 1 against human parainfluenza virus type 1 (hPIV-1) were synthesized using one-pot isocyanide-based four-component condensation, and their inhibitory activities against hPIV-1 sialidase were studied.

alpha-acylaminoamido

isocyanide


Input: Compound 11b showed inhibitory activity (IC (50) = 5. 1 mM) against hPIV-1 sialidase.


Input: The degree of inhibition of 11b was much weaker than that of 1 (IC (50) = 0. 3 mM).


Input: Two new triterpenoid saponins from the root of Platycodon grandiflorum.

triterpenoid saponins


Input: Two new triterpenoid saponins, named platycodon A (3-O-beta-D-glucopyranosyl-16-O-beta-D-glucopyranosyl-2 beta, 3 beta, 16 beta, 21 beta-tetrahydroxyolean-12-en-28-oic acid) and platycodon B (3-O-beta-D-glucopyranosyl-16-O-beta-D-xylopyranosyl-2 beta, 3 beta, 16 beta, 21 beta-tetrahydroxyolean-12-en-28-oic acid) were isolated from the roots of Platycodon grandiflorum.

triterpenoid saponins

platycodon A

3-O-beta-D-glucopyranosyl-16-O-beta-D-glucopyranosyl-2 beta, 3 beta, 16 beta, 21 beta-tetrahydroxyolean-12-en-28-oic acid

platycodon B

3-O-beta-D-glucopyranosyl-16-O-beta-D-xylopyranosyl-2 beta, 3 beta, 16 beta, 21 beta-tetrahydroxyolean-12-en-28-oic acid


Input: The structures of these compounds were elucidated by means of various spectroscopic analyses.


Input: Compounds 1 and 2 were tested in HepG-2, A549 and DU145 human cancer cell lines and showed remarkable cytotoxic activities against HepG-2 and A549 cancer cell lines with IC (50) values ranging from 4. 9 to 9. 4 micro M, but they displayed weak cytotoxic activities against DU145 cancer cell line with IC (50) values greater than 10 micro M.


Input: Comparative toxicity of eight metals on freshwater fish.


Input: Two freshwater fish, Rasbora sumatrana (Cyprinidae) and Poecilia reticulata (guppy; Poeciliidae), were exposed to a range of eight heavy metals (copper (Cu), cadmium (Cd), zinc (Zn), lead (Pb), nickel (Ni), iron (Fe), aluminium (Al), and manganese (Mn)) at varied concentrations for 96 h in the laboratory.

copper

Cu

cadmium

Cd

zinc

Zn

Pb

nickel

Ni

iron

Fe

aluminium

Al

manganese

Mn


Input: Mortality was assessed and median lethal concentrations (LC (50)) were calculated.


Input: It was observed that the LC (50) values increased with a decrease in mean exposure times, for all metals and for both fish types.


Input: The 96-h LC (50) values for Cu, Cd, Zn, Pb, Ni, Fe, Al, and Mn were 0. 006, 0. 10, 0. 46, 0. 63, 0. 83, 1. 71, 1. 53, and 5. 71 mg/L for R. sumatrana and 0. 038, 0. 17, 1. 06, 1. 99, 15. 62, 1. 46, 6. 76, and 23. 91 mg/L for P. reticulata, respectively.

Cu

Cd

Zn

Pb

Ni

Fe

Al

Mn


Input: The metal toxicity trend for R. sumatrana and P. reticulata from most to least toxic was Cu > Cd > Zn > Pb > Ni > Al > Fe > Mn and Cu > Cd > Zn > Fe > Pb > Al > Ni > Mn, respectively.

Cu

Cd

Zn

Pb

Ni

Al

Fe

Mn

Cu

Cd

Zn

Fe

Pb

Al

Ni

Mn


Input: Results indicated that Cu was the most toxic metal on both fish, and R. sumatrana was more sensitive than P. reticulata to all the eight metals.

Cu


Input: Vertical flow immunoassay (VFA) biosensor for a rapid one-step immunoassay.


Input: A highly rapid, one-step immunoassay of high sensitivity C-reactive protein (hsCRP) using a biosensor with a vertical flow immunoassay (VFA) was developed.


Input: The VFA biosensor was primarily composed of a sample pad, conjugate pad, FTH film and nitrocellulose (NC) membrane, which were all vertically stacked upon one another.


Input: Anti-hsCRP and secondary antibodies were consecutively immobilized on the NC membrane at the position below the holes.


Input: Gold nanoparticles (AuNPs) conjugated with another anti-hsCRP antibody were encapsulated in the conjugation pad.


Input: Various assay conditions, including the size of the hole and the sample volume, were optimized.


Input: Under optimized conditions, hsCRP concentrations from 0. 01 to 10 mu g mL (-1) were detected within 2 min.


Input: In comparison with a lateral flow assay (LFA) system, the VFA sensor showed a gradual increase of signal in a concentration-dependent manner without a hook effect in the tested range.


Input: Synthesis and characterization of an MRI Gd-based probe designed to target the translocator protein.

Gd


Input: DPA-713 is the lead compound of a recently reported pyrazolo [1, 5-a] pyrimidineacetamide series, targeting the translocator protein (TSPO 18 kDa), and as such, this structure, as well as closely related derivatives, have been already successfully used as positron emission tomography radioligands.

pyrazolo [1, 5-a] pyrimidineacetamide


Input: On the basis of the pharmacological core of this ligands series, a new magnetic resonance imaging probe, coded DPA-C (6)-(Gd) DOTAMA was designed and successfully synthesized in six steps and 13% overall yield from DPA-713.

DPA-C (6)-(Gd) DOTAMA


Input: The Gd-DOTA monoamide cage (DOTA = 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid) represents the magnetic resonance imaging reporter, which is spaced from the phenylpyrazolo [1, 5-a] pyrimidineacetamide moiety (DPA-713 motif) by a six carbon-atom chain.

Gd-DOTA monoamide

DOTA

1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid

phenylpyrazolo [1, 5-a] pyrimidineacetamide

carbon


Input: DPA-C (6)-(Gd) DOTAMA relaxometric characterization showed the typical behavior of a small-sized molecule (relaxivity value: 6. 02 mM (-1) s (-1) at 20 MHz).

DPA-C (6)-(Gd) DOTAMA


Input: The good hydrophilicity of the metal chelate makes DPA-C (6)-(Gd) DOTAMA soluble in water, affecting thus its biodistribution with respect to the parent lipophilic DPA-713 molecule.

DPA-C (6)-(Gd) DOTAMA


Input: For this reason, it was deemed of interest to load the probe to a large carrier in order to increase its residence lifetime in blood.


Input: Whereas DPA-C (6)-(Gd) DOTAMA binds to serum albumin with a low affinity constant, it can be entrapped into liposomes (both in the membrane and in the inner aqueous cavity).

DPA-C (6)-(Gd) DOTAMA


Input: The stability of the supramolecular adduct formed by the Gd-complex and liposomes was assessed by a competition test with albumin.

Gd


Input: 2-Carbaborane-3-phenyl-1H-indoles--synthesis via McMurry reaction and cyclooxygenase (COX) inhibition activity.


Input: Cyclooxygenase-2 (COX-2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed.


Input: As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX-2-selective 2, 3-disubstituted indoles.

carbaboranes

phenyl

carbaboranyl

2, 3-disubstituted indoles


Input: Despite the lability of carbaboranes under reducing conditions, 2-carbaborane-3-phenyl-1H-indoles could be synthesized by McMurry cyclization of the corresponding amides.

carbaboranes

amides


Input: Whereas the meta-carbaboranyl-substituted derivatives lacked COX inhibitory activity, an ortho-carbaboranyl analogue was active, but showed a selectivity shift toward COX-1.

meta-carbaboranyl

ortho-carbaboranyl


Input: Unwinding of primer-templates by archaeal family-B DNA polymerases in response to template-strand uracil.

uracil


Input: Archaeal family-B DNA polymerases bind tightly to deaminated bases and stall replication on encountering uracil in template strands, four bases ahead of the primer-template junction.

uracil


Input: Should the polymerase progress further towards the uracil, for example, to position uracil only two bases in front of the junction, 3'-5' proof-reading exonuclease activity becomes stimulated, trimming the primer and re-setting uracil to the + 4 position.

uracil

uracil

uracil


Input: Uracil sensing prevents copying of the deaminated base and permanent mutation in 50% of the progeny.

Uracil


Input: This publication uses both steady-state and time-resolved 2-aminopurine fluorescence to show pronounced unwinding of primer-templates with Pyrococcus furiosus (Pfu) polymerase-DNA complexes containing uracil at + 2; much less strand separation is seen with uracil at + 4.

uracil

uracil


Input: DNA unwinding has long been recognized as necessary for proof-reading exonuclease activity.


Input: The roles of M247 and Y261, amino acids suggested by structural studies to play a role in primer-template unwinding, have been probed.

amino acids


Input: M247 appears to be unimportant, but 2-aminopurine fluorescence measurements show that Y261 plays a role in primer-template strand separation.


Input: Y261 is also required for full exonuclease activity and contributes to the fidelity of the polymerase.


Input: An evolutionarily conserved signaling mechanism mediates far-red light responses in land plants.


Input: Phytochromes are plant photoreceptors important for development and adaptation to the environment.


Input: Phytochrome A (PHYA) is essential for the far-red (FR) high-irradiance responses (HIRs), which are of particular ecological relevance as they enable plants to establish under shade conditions.


Input: PHYA and HIRs have been considered unique to seed plants because the divergence of seed plants and cryptogams (e. g., ferns and mosses) preceded the evolution of PHYA.


Input: Seed plant phytochromes translocate into the nucleus and regulate gene expression.


Input: By contrast, there has been little evidence of a nuclear localization and function of cryptogam phytochromes.


Input: Here, we identified responses to FR light in cryptogams, which are highly reminiscent of PHYA signaling in seed plants.


Input: In the moss Physcomitrella patens and the fern Adiantum capillus-veneris, phytochromes accumulate in the nucleus in response to light.


Input: Although P. patens phytochromes evolved independently of PHYA, we have found that one clade of P. patens phytochromes exhibits the molecular properties of PHYA.


Input: We suggest that HIR-like responses had evolved in the last common ancestor of modern seed plants and cryptogams and that HIR signaling is more ancient than PHYA.


Input: Thus, other phytochromes in seed plants may have lost the capacity to mediate HIRs during evolution, rather than that PHYA acquired it.


Input: Current progresses of novel natural products and their derivatives/analogs as anti-Alzheimer candidates: an update.


Input: Alzheimer' s disease (AD) is one of the most threatening diseases affecting the aged with high incidence.


Input: Though AD has been defined for more than 100 years, it is still incurable.


Input: The drugs clinically used for the treatment of this disease, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist, can only provide a limited therapeutic effect.

N-methyl-D-aspartate

NMDA


Input: The need of effective drugs has stimulated the search for new compounds with potential clinical utility.


Input: Natural products are rich and unexplored sources for discovering novel leading compounds.


Input: Currently, a great number of natural products have been found possessing anti-AD property counteracting different etiological factors of AD.


Input: This review will give an update demonstration on the novel anti-AD natural products and their derivatives/analogues, which have been divided into five subgroups according to their different action mechanisms: AChEIs, antioxidants, neuroprotective agents, monoamine oxidase (MAO) inhibitors, and tau hyperphosphorylation inhibitors.

monoamine


Input: We put special emphasis on the findings in the past 5 years.


Input: Besides, the drug design strategy as well as the structure-activity relationship of the relevant compounds is also discussed when it is possible.


Input: Comparison of antiproliferative effects of metformine and progesterone on estrogen-induced endometrial hyperplasia in rats.

metformine

progesterone

estrogen


Input: Metformin has been shown to inhibit the growth of endometriotic implants, and reverse endometrial hyperplasia when combined with oral contraceptive in a case report.

Metformin


Input: The aim of this study is to compare the antiproliferative effects of medroxyprogesterone acetate (MPA), and metformin in oopherectomized rat endometrium.

medroxyprogesterone acetate

MPA

metformin


Input: Forty oopherectomized Wistar-Albino rats were used, and assigned to receive saline, 17 beta Estradiol hemihydrate (4 mg/kg), 17 beta Estradiol hemihydrate (4 mg/kg) and metformin (50 mg/kg), 17 beta Estradiol hemihydrate (4 mg/kg) and MPA (1 mg/day) for 14 days.

17 beta Estradiol hemihydrate

17 beta Estradiol hemihydrate

metformin

17 beta Estradiol hemihydrate

MPA


Input: Histological markers of uterotrophy, including endometrial height, luminal ephitelial cell height and density of endometrial glands on hysterectomy speciments were quantified for each specimen.


Input: Rats treated with estradiol had significantly increased in endometrial height, endomerial luminal epithelial height and endometrial gland densitiy than the other groups.

estradiol


Input: Metformin and MPA acetate significantly reduced all parameters indicating endometrial hyperplasia, and uterotrophy with respect to the control group.

Metformin

MPA acetate


Input: Antiproliferative effects of metformin, and MPA was found to be comparable for all three parameters.

metformin

MPA


Input: In conclusion, metformin attenuates estrogen-induced endometrial hyperplasia in ooferectomized rats to the same degree as progesterone.

metformin

estrogen

progesterone


Input: Photophysical and electrochemical investigations of the fluorescent probe, 4, 4'-bis (2-benzoxazolyl) stilbene.

4, 4'-bis (2-benzoxazolyl) stilbene


Input: In solution, 4, 4'-bis (2-benzoxazolyl) stilbene (BBS) was found to exhibit consistently high absolute fluorescence quantum yields (Phi (fl) >= 0. 88) and a monoexponential lifetime, both independent of BBS concentration.

4, 4'-bis (2-benzoxazolyl) stilbene

BBS

BBS


Input: The BBS steady-state and time-resolved photophysics were investigated by different techniques to understand the various deactivation pathways.

BBS


Input: Nonradiative deactivation of BBS singlet excited state by intersystem crossing was found to be negligible.

BBS


Input: Other than fluorescence, the excited state of BBS was found to be deactivated by trans-cis photoisomerization.

BBS


Input: At low concentrations (=~ 5 mu g/mL), UV spectroscopy and laser flash photolysis showed concordant results that the photoinduced cis isomer gradually replaced the original absorption spectrum of the pure trans isomer.


Input: However, at high concentrations (=~ 0. 2 mg/mL), (1) H NMR and DOSY measurements confirmed that irradiating BBS at 350 nm induced a conversion from the trans-BBS into its cis isomer by photoisomerization.

(1) H

BBS

trans-BBS


Input: It was further found that the stilbene moiety of both isomers was photocleaved.

stilbene


Input: The resulting photoproduct was an aldehyde that was oxidized under ambient conditions to its corresponding carboxylic acid, i. e., 4-(1, 3-benzoxazol-2-yl) benzoic acid.

aldehyde

carboxylic acid

4-(1, 3-benzoxazol-2-yl) benzoic acid


Input: The structure of the photoproduct was unequivocally confirmed by X-ray diffraction.


Input: Spectroscopic investigation of BBS showed a limited photoisomerization after irradiation at 350 nm of a trans solution.

BBS


Input: The BBS electrochemistry showed irreversible oxidation, resulting in an unstable and highly reactive radical cation.

BBS


Input: Similarly, the cathodic process was also found to be irreversible, giving rise to a radical anion and showing its n-doping character.


Input: Validating a faster method for reconstitution of Crotalidae Polyvalent Immune Fab (ovine).


Input: BACKGROUND: Reconstitution of CroFab ((R)) (Crotalidae Polyvalent Immune Fab [ovine]) lyophilized drug product was previously performed using 10 mL sterile water for injection followed by up to 36 min of gentle swirling of the vial.


Input: CroFab has been clinically demonstrated to be most effective when administered within 6 h of snake envenomation, and improved clinical outcomes are correlated with quicker timing of administration.


Input: An alternate reconstitution method was devised, using 18 mL 0. 9% saline with manual inversion, with the goal of shortening reconstitution time while maintaining a high quality, efficacious product.


Input: METHODS: An analytical study was designed to compare the physicochemical properties of 3 separate batches of CroFab when reconstituted using the standard procedure (10 mL WFI with gentle swirling) and a modified rapid procedure using 18 mL 0. 9% saline and manual inversion.


Input: The physical and chemical characteristics of the same 3 batches were assessed using various analytic methodologies associated with routine quality control release testing.


Input: In addition further analytical methodologies were applied in order to elucidate possible structural changes that may be induced by the changed reconstitution procedure.


Input: RESULTS: Batches A, B, and C required mean reconstitution times of 25 min 51 s using the label method and 3 min 07 s (a 88. 0% mean decrease) using the modified method.


Input: Physicochemical characteristics (color and clarity, pH, purity, protein content, potency) were found to be highly comparable.


Input: Characterization assays (dynamic light scattering, analytical ultracentrifugation, LC-MS, SDS-PAGE and circular dichroism spectroscopy were also all found to be comparable between methods.


Input: DISCUSSION: When comparing CroFab batches that were reconstituted using the labeled and modified methods, the physicochemical and biological (potency) characteristics of CroFab were not significantly changed when challenged by the various standard analytical methodologies applied in routine quality control analysis.


Input: Additionally, no changes in the CroFab molecule regarding degradation, aggregation, purity, structure, or mass were observed.


Input: CONCLUSION: The analyses performed validated the use of the more rapid reconstitution method using 18 mL 0. 9% saline in order to allow a significantly reduced time to administration of CroFab to patients in need.


Input: Neuroecology: a fly' s bug detector.


Input: Drosophila avoid food contaminated by pathogenic bacteria and fungi using an olfactory pathway that is exquisitely tuned to a single microbial odour.


Input: Synthesis and dual biological effects of hydroxycinnamoyl phenylalanyl/prolyl hydroxamic acid derivatives as tyrosinase inhibitor and antioxidant.

hydroxycinnamoyl phenylalanyl

prolyl hydroxamic acid


Input: We previously reported that caffeoyl-amino acidyl-hydroxamic acid (CA-Xaa-NHOH) acted as both a good antioxidant and tyrosinase inhibitor, in particular when caffeic acid was conjugated with proline or amino acids having aromatic ring like phenylalanine.

caffeoyl-amino acidyl-hydroxamic acid

CA-Xaa-NHOH

caffeic acid

proline

amino acids

phenylalanine


Input: Here, various hydroxycinnamic acid (HCA) derivatives were further conjugated with phenylalanyl hydroxamic acid and prolyl hydroxamic acid (HCA-Phe-NHOH and HCA-Pro-NHOH) to study the structure and activity relationship as both antioxidants and tyrosinase inhibitors.

hydroxycinnamic acid

HCA

phenylalanyl hydroxamic acid

prolyl hydroxamic acid

HCA-Phe-NHOH

HCA-Pro-NHOH


Input: When their biological activities were evaluated, all HCA-Phe-NHOH and HCA-Pro-NHOH exhibited enhanced antioxidant activity compared to HCA alone.

HCA-Phe-NHOH

HCA-Pro-NHOH

HCA


Input: Moreover, derivatives of caffeic acid, ferulic acid, and sinapic acid inhibited lipid peroxidation more efficiently than vitamin E analogue (Trolox).

caffeic acid

ferulic acid

sinapic acid

vitamin E

Trolox


Input: In addition, derivatives of caffeic acid and sinapic acid efficiently inhibited tyrosinase activity and reduced melanin content in melanocytes Mel-Ab cell.

caffeic acid

sinapic acid


Input: Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein.


Input: Due to the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication.


Input: The HIV-1 matrix (MA) protein is an essential viral component with established roles in the assembly of the virus.


Input: Using virtual and surface plasmon resonance (SPR)-based screening, we describe the identification of the first small molecule to bind to the HIV-1 MA protein and to possess broad range anti-HIV properties.


Input: Two distinct mechanisms of Topoisomerase 1-dependent mutagenesis in yeast.


Input: Topoisomerase 1 (Top1) resolves transcription-associated supercoils by generating transient single-strand breaks in DNA.


Input: Top1 activity in yeast is a major source of transcription-associated mutagenesis, generating a distinctive mutation signature characterized by deletions in short, tandem repeats.


Input: A similar signature is associated with the persistence of ribonucleoside monophosphates (rNMPs) in DNA, and it also depends on Top1 activity.

ribonucleoside monophosphates

rNMPs


Input: There is only partial overlap, however, between Top1-dependent deletion hotspots identified in highly transcribed DNA and those associated with rNMPs, suggesting the existence of both rNMP-dependent and rNMP-independent events.

rNMPs

rNMP

rNMP


Input: Here, we present genetic studies confirming that there are two distinct types of hotspots.


Input: Data suggest a novel model in which rNMP-dependent hotspots are generated by sequential Top1 reactions and are consistent with rNMP-independent hotspots reflecting processing of a trapped Top1 cleavage complex.

rNMP

rNMP


Input: The role of individual gastric emptying of pellets in the prediction of diclofenac in vivo dissolution.

diclofenac


Input: The objective of the present study was to check for the possibility to successfully predict individual in vivo dissolution/absorption profiles resulting from fasted administration of a diclofenac extended release pellet formulation.

diclofenac


Input: For this purpose dissolution profiles were generated with different dissolution setups using a set of media reflecting pH-conditions in the different segments of the gastrointestinal tract.


Input: Since gastric emptying of pellets seemed to be a critical factor for in vivo drug release, a set of different gastric residence times was screened in in vitro studies.


Input: Subsequently, in vitro release profiles were first directly compared with the individual in vivo absorption profiles and in a second step a mathematical model, which had been developed in a previous study, was applied to calculate predicted individual in vivo release profiles based on in vitro release profiles and individual gastric emptying.


Input: The comparison of predicted individual in vivo release profiles and individual in vivo absorption profiles showed a high degree of similarity, thus confirming the suitability of a set of different gastric residence times used in in vitro drug release testing.


Input: Additionally, obtained results indicated that a substantial part of variability of diclofenac absorption profiles can be explained by the variability of pellet gastric emptying kinetics.

diclofenac


Input: The colon carcinogen 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) is actively secreted in the distal colon of the rat: an integrated view on the role of PhIP transport and metabolism in PhIP-induced colon carcinogenesis.

2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine

PhIP

PhIP

PhIP


Input: Epidemiological studies show that a positive correlation exists between the consumption of strongly heated meat and fish and the development of colorectal tumours.


Input: In this context, it has been postulated that the uptake of toxic substances formed during meat and fish processing such as heterocyclic aromatic amines (HCAs) may be causally related to colon carcinogenesis.

heterocyclic aromatic amines

HCAs


Input: In a previous study, we have shown that 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP), the most abundantly formed HCA in the above-mentioned food items, is mainly absorbed in the small intestine (i. e. proximal jejunum) of the rat.

2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine

PhIP

HCA


Input: In the present study, we analysed whether PhIP can actively be secreted by enterocytes in the rat proximal jejunum and distal colon.

PhIP


Input: Unidirectional PhIP flux rates from the mucosal-to-the serosal compartment (J ms) and in the opposite direction (J sm) were examined in Ussing chambers with (14) C-PhIP as radiotracer and in the absence of electrochemical gradients.

PhIP

(14) C-PhIP


Input: Under these experimental conditions, significant negative net flux rates (J net = J ms-J sm) can only be explained by an active secretion of PhIP into the luminal compartment, and such an effect was observed in the rat distal colon, but not in the proximal jejunum.

PhIP


Input: Moreover, the data obtained suggest that the breast cancer resistance protein, the multidrug resistance protein 4 and P-glycoprotein are not involved in the active secretion of PhIP in the rat distal colon.

PhIP


Input: The potential role of PhIP transport in colon carcinogenesis is discussed.

PhIP


Input: Warfarin dose prediction in children using pharmacometric bridging-comparison with published pharmacogenetic dosing algorithms.

Warfarin


Input: PURPOSE: Numerous studies have investigated causes of warfarin dose variability in adults, whereas studies in children are limited both in numbers and size.

warfarin


Input: Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another.


Input: The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children.

warfarin

warfarin


Input: METHOD: An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for warfarin, with CYP2C9 and VKORC1 genotype, age and target international normalized ratio (INR) as dose predictors, was bridged to children using allometric scaling methods.

warfarin


Input: Its predictive properties were evaluated in an external data set of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children.


Input: RESULTS: Overall, the bridged model predicted INR response well in 64 warfarin-treated Swedish children (median age 4. 3 years), but with a tendency to overpredict INR in children <= 2 years old.

warfarin


Input: The bridged model predicted 20 of 49 children (41%) within +/- 20% of actual maintenance dose (median age 7. 2 years).


Input: In comparison, the published dosing algorithms predicted 33-41% of the children within +/- 20% of actual dose.


Input: Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within +/- 20% of actual dose to 70%.


Input: CONCLUSION: A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.

warfarin


Input: p300-mediated acetylation of TRF2 is required for maintaining functional telomeres.


Input: The human telomeric protein TRF2 is required to protect chromosome ends by facilitating their organization into the protective capping structure.


Input: Post-translational modifications of TRF2 such as phosphorylation, ubiquitination, SUMOylation, methylation and poly (ADP-ribosyl) ation have been shown to play important roles in telomere function.

ADP


Input: Here we show that TRF2 specifically interacts with the histone acetyltransferase p300, and that p300 acetylates the lysine residue at position 293 of TRF2.

lysine


Input: We also report that p300-mediated acetylation stabilizes the TRF2 protein by inhibiting its ubiquitin-dependent proteolysis and is required for efficient telomere binding of TRF2.


Input: Furthermore, overexpression of the acetylation-deficient mutant, K293R, induces DNA-damage response foci at telomeres, thereby leading to induction of impaired cell growth, cellular senescence and altered cell cycle distribution.


Input: A small but significant number of metaphase chromosomes show no telomeric signals at chromatid ends, suggesting an aberrant telomere structure.


Input: These findings demonstrate that acetylation of TRF2 by p300 plays a crucial role in the maintenance of functional telomeres as well as in the regulation of the telomere-associated DNA-damage response, thus providing a new route for modulating telomere protection function.


Input: Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3 protease.


Input: A series of new substrate analogue inhibitors of the WNV NS2B-NS3 protease containing decarboxylated arginine mimetics at the P1 position was developed.

decarboxylated arginine


Input: Among the various analogues, trans-(4-guanidino) cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue.

trans-(4-guanidino) cyclohexylmethylamide

GCMA


Input: In combination with dichloro-substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of < 0. 2 mu M were obtained.

dichloro-substituted phenylacetyl


Input: These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin-like serine proteases thrombin, factor Xa, and matriptase.

GCMA

agmatine

serine


Input: A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3, 4-dichlorophenylacetyl-Lys-Lys-GCMA (K (i) = 0. 13 mu M).

3, 4-dichlorophenylacetyl-Lys-Lys-GCMA


Input: The inhibitor adopts a horseshoe-like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom.

phenyl

cyclohexyl

hydrogen

guanidino

carbonyl oxygen


Input: These inhibitors are stable, readily accessible, and have a noncovalent binding mode.


Input: Therefore, they may serve as suitable lead structures for further development.


Input: Synthesis of a potent antimalarial agent through natural products conjugation.


Input: Au naturel!


Input: (+)-Usnic acid (green) is a weak antimalarial agent, however, in conjugation with known antimalarial scaffolds and drugs, such as dihydroartemisinin (blue), potent activity against the blood-stage parasite can be seen both in vitro and in vivo.

(+)-Usnic acid

dihydroartemisinin


Input: The compound shown exhibits an IC (50) value of 1. 4 nM against Plasmodium falciparum in vitro and proved nearly as efficacious as artesunate in a mouse model of infection.

artesunate


Input: Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice.


Input: Several lines of evidence, including the recent discovery of novel susceptibility genes, point out an important role for the mammalian target of rapamycin (mTOR) signaling pathway in the development of pheochromocytoma.

rapamycin


Input: Analyzing a set of pheochromocytomas from patients with different genetic backgrounds, we observed and confirmed a significant overexpression of key mTOR complex (mTORC) signaling mediators.


Input: Using selective ATP-competitive inhibitors targeting both mTORC1 and mTORC2, we significantly arrested the in vitro cell proliferation and blocked migration of pheochromocytoma cells as a result of the pharmacological suppression of the Akt/mTOR signaling pathway.

ATP


Input: Moreover, AZD8055, a selective ATP-competitive dual mTORC1/2 small molecular inhibitor, significantly reduced the tumor burden in a model of metastatic pheochromocytoma using female athymic nude mice.

ATP


Input: This study suggests that targeting both mTORC1 and mTORC2 is a potentially rewarding strategy and supports the application of selective inhibitors in combinatorial drug regimens for metastatic pheochromocytoma.


Input: 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin-induced hypertension: The beneficial effects of melatonin.

2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin

melatonin


Input: Objective: The purpose of the present study was to evaluate the effects of melatonin on biochemical and cardiovascular changes resulting from exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a polychlorinated dibenzo-para-dioxin. Methods: A total of 24 Sprague-Dawley rats were divided equally into the following four groups: (1) control group was administered with 0. 5 mL corn oil by gavage and 0. 5 cc vehicle of melatonin (proportionally nine parts physiological serum + one part ethyl alcohol) intraperitoneally for 4 weeks, (2) the melatonin group was given 5 mg/kg/day melatonin intraperitoneally for 4 weeks, (3) the TCDD group was given 500 ng/kg/day TCDD by gavage for 4 weeks and (4) the TCDD + melatonin group was given TCDD (500 ng/kg/day) by gavage and melatonin (5 mg/kg/day) intraperitoneally simultaneously for 4 weeks.

melatonin

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin

TCDD

polychlorinated dibenzo-para-dioxin

melatonin

ethyl alcohol

melatonin

melatonin

TCDD

TCDD

TCDD

melatonin

TCDD

melatonin


Input: Systolic blood pressure was evaluated by the tail-cuff method.


Input: Vascular responses to phenylephrine and acetylcholine were evaluated in the isolated thoracic aortas. Results: TCDD not only augmented the systolic blood pressure but also increased the contractile responses to phenylephrine in aorta.

phenylephrine

acetylcholine

TCDD

phenylephrine


Input: Melatonin reversed the blood pressure augmented by TCDD and decreased the contractile responses to phenylephrine in aorta.

Melatonin

TCDD

phenylephrine


Input: TCDD induced an increase in the malondialdehyde levels in kidney tissue and melatonin did not change it.

TCDD

malondialdehyde

melatonin


Input: Therefore, TCDD caused a decrease in glutathione levels in kidney tissues and melatonin reversed it. Conclusion: Present data demonstrated that TCDD may lead to an increase in blood pressure via increased renal oxidative stress and vascular reactivity.

TCDD

glutathione

melatonin

TCDD


Input: However, melatonin might ameliorate the blood pressure disturbed by TCDD in part by decreasing the oxidant activity induced by TCDD.

melatonin

TCDD

TCDD


Input: Progress in the synthesis of canthine alkaloids and ring-truncated congeners.

canthine alkaloids


Input: The canthines represent a fairly large subclass of beta-carboline alkaloids, with the first members described 75 years ago.

canthines

beta-carboline alkaloids


Input: Over the last 60 years, many members of the parent compound, canthin-6-one (1), have been isolated from various plant sources, principally the Rutaceae and Simaroubaceae families, and recently from fungi.


Input: Structures isolated from these sources have been the subject of total synthesis, which continues to the present day.


Input: This review gives a broad overview of synthetic approaches to canthines over a 30-year period from 1982 to 2012 and summarizes recent reports on the synthesis of less well known ring-truncated congeners.

canthines


Input: These include C-ring-truncated (" ABD ", 2) and A-ring-truncated (" BCD ", 3) ring systems, which are providing new scaffolds for potentially useful therapeutic applications.


Input: Diels-Alder mediated controlled release from a poly (ethylene glycol) based hydrogel.

poly (ethylene glycol)


Input: A synthetic amino acid bearing a furan functionality was developed and incorporated into peptide sequences using solid phase synthesis.

amino acid

furan


Input: Peptides expressing the furan moiety were attached to poly (ethylene glycol) (PEG) hydrogels through a thermally reversible covalent bond formed by a Diels-Alder reaction.

furan

poly (ethylene glycol)

PEG


Input: Reactions of thiol and maleimide PEG macromers in an off-stoichiometric Michael addition were performed, such that the maleimide moiety was in excess, to create hydrogel networks with pendant Diels-Alder compatible tethering sites, that is, the maleimide.

thiol

maleimide PEG

maleimide

maleimide


Input: By making use of the Diels-Alder reaction, it was possible to control the release rate of reversibly bound moieties from the hydrogel by changing the temperature; higher temperatures favor a faster retro-Diels-Alder reaction and, therefore, a faster release from the polymer network.


Input: This concept was demonstrated by incorporating a fluorescently labeled furan-RGDS sequence into a hydrogel possessing excess maleimide functionalities and monitoring the subsequent liberation of RGDS at various temperatures, illustrating a Diels-Alder mediated release mechanism.

furan

maleimide


Input: The release profile was quantified at temperatures ranging from physiological (37 degrees C) to 80 degrees C.


Input: By changing the temperature, varying extents of release were attained over the time course of several days, ranging from 40% release for lower temperatures to complete release for the highest temperature considered.


Input: Further confirmation of a reaction-diffusion controlled release mechanism was obtained through comparison of experimental release data to a reaction-diffusion model of the release.


Input: In addition to thermal modulation, tuning of the release rate was accomplished by altering the number of possible Diels-Alder tethering sites present in the hydrogel.


Input: Increasing the amount of free maleimide and, therefore, the number of potential Diels-Alder reaction sites, effectively slowed the release of peptide from the polymer.

maleimide


Input: For instance, doubling the amount of maleimide sites present in the hydrogel system decreased the amount of peptide released from approximately 60% to about 40% in the same span of time.

maleimide


Input: Bottom-up approach to creating three-dimensional nanoring arrays composed of Au nanoparticles.

Au


Input: A bottom-up approach to creating 3D assemblies of Au nanorings by drying aqueous dispersions of PS colloidal particles and Au NPs is shown.

Au

Au


Input: The evaporation of water from the dispersion allowed for the formation of hexagonally assembled colloidal crystals and nanorings composed of Au nanoparticles among the PS colloidal particles.

Au


Input: The size of the nanorings could be controlled on a scale of tens to hundreds of nanometers.


Input: After sintering, the Au NPs formed Au nanorings.

Au

Au


Input: This simple approach supplies a potentially useful path to novel plasmonic materials and unique metamaterials for the visible light region.


Input: Covalent Layer-by-Layer Assembly of Redox-Active Polymer Multilayers.


Input: Poly (ferrocenyl (3-bromopropyl) methylsilane) and poly (ethylene imine) are employed in a layer-by-layer deposition process to form covalently connected, redox-active multilayer thin films by means of an amine alkylation reaction.

Poly (ferrocenyl (3-bromopropyl) methylsilane)

poly (ethylene imine)

amine


Input: The stepwise buildup of these multilayers on silicon, ITO, and quartz substrates was monitored by UV-vis absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), static contact angle measurements, surface plasmon resonance (SPR), atomic force microscopy, ellipsometry, and cyclic voltammetry, which provide evidence for a linear increase in multilayer thickness with the number of deposited bilayers.

silicon

ITO

quartz


Input: Upon oxidation and reduction, these covalently interconnected layers do not disassemble, in contrast to poly (ferrocenylsilane) (PFS) layers featuring similar backbone structures that are held together by electrostatic forces.

poly (ferrocenylsilane)

PFS


Input: The PFS/PEI multilayers are effective for the electrochemical sensing of ascorbic acid and hydrogen peroxide and show improved sensing performance at higher bilayer numbers.

PFS

PEI

ascorbic acid

hydrogen peroxide


Input: These covalently linked layers are readily derivatized further and can therefore be regarded as a versatile platform for creating robust, tailorable, redox-active interfaces with applications in sensing and biofuel cells.


Input: Tipping the energy balance toward longevity.


Input: AMPK is a cellular energy sensor conserved across eukaryotes that in C. elegans prolongs life span and mimics dietary restriction.


Input: Stenesen and colleagues (2012) activate AMPK both directly and indirectly by altering AMP biosynthesis to slow aging in Drosophila, highlighting AMPK as a conserved life span modulator that links energy sensing to longevity.

AMPK


Input: Quantitative photoacoustic imaging of nanoparticles in cells and tissues.


Input: Quantitative visualization of nanoparticles in cells and tissues, while preserving the spatial information, is very challenging.


Input: A photoacoustic imaging technique to depict the presence and quantity of nanoparticles is presented.


Input: This technique is based on the dependence of the photoacoustic signal on both the nanoparticle quantity and the laser fluence.


Input: Quantitative photoacoustic imaging is a robust technique that does not require knowledge of the local fluence, but a relative change in the fluence.


Input: This eliminates the need for sophisticated methods or models to determine the energy distribution of light in turbid media.


Input: Quantitative photoacoustic imaging was first applied to nanoparticle-loaded cells, and quantitation was validated by inductively coupled plasma mass spectrometry.


Input: Quantitative photoacoustic imaging was then extended to xenograft tumor tissue sections, and excellent agreement with traditional histopathological analysis was demonstrated.


Input: Our results suggest that quantitative photoacoustic imaging may be used in many applications including the determination of the efficiency and effectiveness of molecular targeting strategies for cell studies and animal models, the quantitative assessment of photoacoustic contrast agent biodistribution, and the validation of in vivo photoacoustic imaging.


Input: A comparative protease stability study of synthetic macrocyclic peptides that mimic two endocrine hormones.


Input: Peptide therapeutics have traditionally faced many challenges including low bioavailability, poor proteolytic stability and difficult cellular uptake.


Input: Conformationally constraining the backbone of a peptide into a macrocyclic ring often ameliorates these problems and allows for the development of a variety of new drugs.


Input: Such peptide-based pharmaceuticals can enhance the multi-faceted functionality of peptide side chains, permitting the peptides to bind cellular targets and receptors necessary to impart their role, while protecting them from degrading cellular influences.


Input: In the work described here, we developed three cyclic peptides, VP mimic1, VP mimic2 and OT mimic1, which mimic endocrine hormones vasopressin and oxytocin.

vasopressin

oxytocin


Input: Making notable changes to the overall structure and composition of the parent hormones, we synthesized the mimics and tested their durability against treatment with three proteases chosen for their specificity: pepsin, alpha-chymotrypsin, and pronase.


Input: Vasopressin and oxytocin contain a disulfide linkage leaving them particularly vulnerable to deactivation from the reducing environment inside the cell.

Vasopressin

oxytocin

disulfide


Input: Thus, we increased the complexity of our assays by adding reducing agent glutathione to each mixture.

glutathione


Input: Subsequently, we discovered each of our mimics withstood protease treatment with less degradation and/or a slower rate of degradation as compared to both parent hormones and a linear control peptide.


Input: Highly selective 2, 4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

2, 4-diaminopyrimidine-5-carboxamide


Input: We report the SAR around a series of 2, 4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

2, 4-diaminopyrimidine-5-carboxamide


Input: 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.


Input: Synthesis and antibacterial evaluation of a novel tricyclic oxaborole-fused fluoroquinolone.

tricyclic oxaborole

fluoroquinolone


Input: We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype.

fluoroquinolone


Input: The design concept involved the replacement of the 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group.

3-carboxylic acid

ciprofloxacin

oxaborole


Input: The synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple functional groups.

boron


Input: The antibacterial activity of the newly synthesized compounds has been evaluated.


Input: Vinclozolin--no transgenerational inheritance of anti-androgenic effects after maternal exposure during organogenesis via the intraperitoneal route.

Vinclozolin


Input: The goal of this study was to examine the potential transgenerational inheritance of anti-androgenic effects induced by Vinclozolin administered intraperitoneally to pregnant Wistar rats (Crl: WI [Han]).

Vinclozolin


Input: Dams were dosed with Vinclozolin at 0, 4 or 100mg/kg bw/d on gestation days 6-15.

Vinclozolin


Input: Male offspring of F1-F3 generations were bred with untreated females to yield F2-F4 offspring.


Input: No evident anti-androgenic effects were observed at 4mg/kg bw/d, but a case of hypospadias as well as delayed sexual maturation in F1 male offspring was observed as a sign of anti-androgenicity at 100mg/kg bw/d.


Input: However, F1-F3 males developed normally to sexual maturity and were able to mate and to generate healthy progeny.


Input: Sperm count, morphology and motility were not affected in F1-F4 generation male offspring.


Input: In conclusion, transgenerational inheritance of Vinclozolin' s anti-androgenic effects was not evident in outbred Wistar rats.

Vinclozolin


Input: Enhancing nicotine vaccine immunogenicity with liposomes.

nicotine


Input: A major liability of existing nicotine vaccine candidates is the wide variation in anti-nicotine immune responses among clinical trial participants.

nicotine

nicotine


Input: In order to address this liability, significant emphasis has been directed at evaluating adjuvants and delivery systems that confer more robust potentiation of the anti-nicotine immune response.

nicotine


Input: Toward that end, we have initiated work that seeks to exploit the adjuvant effect of liposomes, with or without Toll-like receptor agonist (s).


Input: The results of the murine immunization study described herein support the hypothesis that a liposomal nicotine vaccine formulation may provide a means for addressing the immunogenicity challenge.

nicotine


Input: Triglyceride accumulation inhibitory effects of phenylpropanoid glycosides from Boschniakia rossica Fedtsch et Flerov.

Triglyceride

phenylpropanoid glycosides


Input: Bioassay-guided fractionation led to isolation of five new phenylpropanol glycosides, rossicasides G (1), H (2), I (3), J (4), and K (5), together with seven known compounds (6-12) from Boschniakia rossica.

phenylpropanol glycosides

rossicasides


Input: Their structures were elucidated by chemical and spectroscopic methods (UV, IR, HRESI-TOF-MS, 1D and 2D NMR).


Input: Activity screening results showed that some isolates had TG accumulation inhibitory effects in HepG2 cells.


Input: Furthermore, the structure-activity relationship was partly clarified.


Input: Computational identification and quantification of trabecular microarchitecture classes by 3-D texture analysis-based clustering.


Input: High resolution peripheral quantitative computed tomography (HR-pQCT) permits the non-invasive assessment of cortical and trabecular bone density, geometry, and microarchitecture.


Input: Although researchers have developed various post-processing algorithms to quantify HR-pQCT image properties, few of these techniques capture image features beyond global structure-based metrics.


Input: While 3D-texture analysis is a key approach in computer vision, it has been utilized only infrequently in HR-pQCT research.


Input: Motivated by high isotropic spatial resolution and the information density provided by HR-pQCT scans, we have developed and evaluated a post-processing algorithm that quantifies microarchitecture characteristics via texture features in HR-pQCT scans.


Input: During a training phase in which clustering was applied to texture features extracted from each voxel of trabecular bone, three distinct clusters, or trabecular microarchitecture classes (TMACs) were identified.


Input: These TMACs represent trabecular bone regions with common texture characteristics.


Input: The TMACs were then used to automatically segment the voxels of new data into three regions corresponding to the trained cluster features.


Input: Regional trabecular bone texture was described by the histogram of relative trabecular bone volume covered by each cluster.


Input: We evaluated the intra-scanner and inter-scanner reproducibility by assessing the precision errors (PE), intra class correlation coefficients (ICC) and Dice coefficients (DC) of the method on 14 ultradistal radius samples scanned on two HR-pQCT systems.


Input: DC showed good reproducibility in intra-scanner set-up with a mean of 0. 870 +/- 0. 027 (no unit).


Input: Even in the inter-scanner set-up the ICC showed high reproducibility, ranging from 0. 814 to 0. 964.


Input: In a preliminary clinical test application, the TMAC histograms appear to be a good indicator, when differentiating between postmenopausal women with (n = 18) and without (n = 18) prevalent fragility fractures.


Input: In conclusion, we could demonstrate that 3D-texture analysis and feature clustering seems to be a promising new HR-pQCT post-processing tool with good reproducibility, even between two different scanners.


Input: Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate.

hydroxytyrosol

hydroxytyrosyl laurate


Input: Hydroxytyrosol (HyT) is a polyphenol primarily released in olive mill wastewater and in olive oil.

Hydroxytyrosol

HyT

polyphenol


Input: In animal and cell model studies, HyT and its metabolites have strong antioxidant and antimicrobial activities, as well as beneficial effects on the cardiovascular system and in several human diseases.

HyT


Input: Differently, many researchers reported that HyT down-regulates tumor cell viability and cell cycle progression, and induces reactive oxygen species (ROS) production and apoptosis.

HyT

oxygen


Input: In this study we have investigated the effects of HyT and the corresponding ester hydroxytyrosyl laurate in U937 cells, a human monocytoid cell line, and in C2C12 myoblasts, a murine proliferating muscle cell model, after apoptotic death induction.

HyT

hydroxytyrosyl laurate


Input: Inverted, light and transmission electron microscopy have been utilized to characterize cell death patterns.


Input: H2O2, at the concentrations known to induce apoptosis, was utilized as cell death trigger.


Input: The results obtained show that laur-HyT has a protective antioxidant effect against H2O2 treatment, greater than HyT, so having a role in the prevention of apoptotic death in normal and tumor cells.

laur-HyT

HyT


Input: These data suggest these compounds as good candidate for novel therapeutic strategies.


Input: Zinc protection against aluminium induced altered lipid profile and membrane integrity.

Zinc

aluminium


Input: The aim of the present study was to investigate the effects of Zinc (Zn) supplementation on lipid profile and fluidity of cerebrum and cerebellum membranes of rats treated with aluminium (Al).

Zinc

Zn

aluminium

Al


Input: Sprague dawley male rats were divided into four different treatment groups viz: Control, aluminium treated, zinc treated and aluminium + zinc treated.

aluminium

zinc

aluminium

zinc


Input: Aluminium (AlCl3) was administered orally at a dose of 100mg/kgb. wt./day (dissolved in drinking water).

Aluminium


Input: Zinc as zinc sulphate was supplemented to rats at a dose of 227mg/l in drinking water.

Zinc

zinc sulphate


Input: A significant decrease in the levels of total lipids, glycolipids, phospholipids, cholesterol and gangliosides contents were observed in both the cerebrum and cerebellum following Al exposure, which were found to be significantly increased following Zn supplementation.

cholesterol

gangliosides

Al

Zn


Input: On the contrary, Al treatment caused a significant increase in the formation of conjugated dienes, which were observed to be reduced on Zn co-treatment.

Al

dienes

Zn


Input: Further, Al treatment significantly elevated the fluorescence polarization, anisotropy and order parameter, which however were normalized upon Zn co-administration.

Al

Zn


Input: Hence, the present study depicts the potential of Zn in moderating the changes caused by Al on membrane composition and fluidity in rat brain.

Zn

Al


Input: FXR-dependent and-independent interaction of glucocorticoids with the regulatory pathways involved in the control of bile acid handling by the liver.

bile acid


Input: Treatment with glucocorticoids (GCs) may cause adverse effects, including cholestasis.


Input: The ability of dexamethasone, prednisolone and budesonide to affect the liver handling of bile acids (BAs) has been investigated.

dexamethasone

prednisolone

budesonide

bile acids


Input: In rats treated with GCs for 4 days, altered serum and bile BA levels, changed conjugation pattern, and delayed and decreased ability to conjugate/secrete exogenously administered deoxycholate, were found using HPLC-MS/MS.

deoxycholate


Input: RT-QPCR analyses revealed that GC treatment also induced a down-regulation of liver nuclear receptors (Fxr, Gr and Shp), transporters (Ntcp, Mrp4 and Bcrp) and enzymes (Cyp7a1 and Baat), whereas Bsep, Mrp2 and Cyp27a1 were up-regulated.


Input: Human HepG2 and Alexander cell lines were used as in vitro models of liver cells with and without constitutive FXR expression, respectively.


Input: In HepG2 cells, GCs induced a decreased expression of FXR and SHP, and inhibited the regulatory effect of GW4064 on FXR-target genes.


Input: In Alexander cells, only when they were transfected with FXR + RXR, GW4064 caused up-regulation of SHP and OST beta, and a down-regulation of CYP27A1.


Input: GCs had the opposite effect on these genes, both in the absence and in the presence of FXR expression.


Input: Co-transfection of Alexander cells with IR-1-Luc and FXR + RXR revealed that GCs did not inhibit but moderately enhanced FXR activity.


Input: Moreover, GCs have a synergistic effect on GW4064-induced FXR activation, whereas chenodeoxycholate and GW4064 have an additive effect.

chenodeoxycholate


Input: In conclusion, GCs are able to directly or indirectly activate FXR but they also antagonize, through FXR-independent mechanisms, the expression of FXR and FXR target genes involved in the hepatic handling of BAs.


Input: Toxic effects of dietary exposure to T-2 toxin on intestinal and hepatic biotransformation enzymes and drug transporter systems in broiler chickens.

T-2 toxin


Input: The effects of the mycotoxin T-2 on hepatic and intestinal drug-metabolizing enzymes (cytochrome P450) and drug transporter systems (MDR1 and MRP2) in poultry were investigated during this study.

mycotoxin T-2


Input: Broiler chickens received either uncontaminated feed, feed contaminated with 68 mu g/kg or 752 mu g/kg T-2 toxin.

T-2 toxin


Input: After 3weeks, the animals were euthanized and MDR1, MRP2, CYP1A4, CYP1A5 and CYP3A37 mRNA expression were analyzed using qRT-PCR.


Input: Along the entire length of the small intestine no significant differences were observed.


Input: In the liver, genes coding for CYP1A4, CYP1A5 and CYP3A37 were significantly down-regulated in the group exposed to 752 mu g/kg T-2.


Input: For CYP1A4, even a contamination level of 68 mu g/kg T-2 caused a significant decrease in mRNA expression.


Input: Expression of MDR1 was not significantly decreased in the liver.


Input: In contrast, hepatic MRP2 expression was significantly down-regulated after exposure to 752 mu g/kg T-2.


Input: Hepatic and intestinal microsomes were prepared to test the enzymatic activity of CYP3A.


Input: In the ileum and liver CYP3A activity was significantly increased in the group receiving 752 mu g/kg T-2 compared to the control group.


Input: The results of this study show that drug metabolizing enzymes and drug transporter mechanisms can be influenced due to prolonged exposure to relevant doses of T-2.


Input: Enhanced chemopreventive activity of hydroxytyrosol on HL60 and HL60R cells by chemical conversion into thio derivatives.

hydroxytyrosol

thio


Input: Thio derivatives of hydroxytyrosol containing thiol, thioacetate and disulfide functionalities were synthesized from natural hydroxytyrosol (3, 4-DHPEA) via 3, 4-dihydroxyphenethyl halides.

hydroxytyrosol

thiol

thioacetate

disulfide

hydroxytyrosol

3, 4-DHPEA

3, 4-dihydroxyphenethyl halides


Input: These compounds, containing the combination of catechol moiety and divalent sulfur functions, were tested for the pro-apoptotic and anti-proliferative activities on both parental HL60 and multi-drug resistant HL60R cells.

catechol

sulfur


Input: It was found that all synthesized compounds were more effective than 3, 4-DHPEA in inducing apoptosis on HL60R cells, and that the hydroxytyrosol disulfide was the most active pro-apoptotic and anti-proliferative compound on both HL60 and HL60R cells.

3, 4-DHPEA

hydroxytyrosol disulfide


Input: Different from 3, 4-DHPEA, all thio derivatives of hydroxytyrosol induced apoptosis by a mechanism not involving the release of H (2) O (2) in the culture medium.

3, 4-DHPEA

hydroxytyrosol

H (2) O (2)


Input: The data on HL60R cells suggest that these compounds could be able to reverse the resistance toward the most common drugs in cancer therapy.


Input: In-line monitoring of the drug content of powder mixtures and tablets by near-infrared spectroscopy during the continuous direct compression tableting process.


Input: Continuous manufacturing methods offer economic and quality advantages when compared with batch manufacturing methods.


Input: In continuous manufacturing, one requires real time assurance of quality of product via the implementation of PAT tools.


Input: This study focuses on an in-line near-infrared (NIR) spectroscopic method for determining the drug content of powder mixtures and tablets during a continuous tableting process.


Input: Tablets consisting of acetaminophen (20-30%), lactose (69. 07-78. 93%) and magnesium stearate (0. 93-1. 07%) were prepared in a continuous direct compression line that consisted of two loss-in-weight feeders, one for acetaminophen and one for premixed lactose and magnesium stearate, and a continuous mixer followed by a rotary tablet press.

acetaminophen

lactose

magnesium stearate

acetaminophen

lactose

magnesium stearate


Input: NIR spectroscopy was applied to the continuous mixer and tablet press to perform a 100% product check at full tableting speed.


Input: The UV-spectrophotometric method was used as an off-line reference method to determine the acetaminophen content in the samples.

acetaminophen


Input: The powder mixture and tablet samples were taken during the process for the calibration of continuous mixer and tablet press, respectively.


Input: For the continuous mixer, model creation with the PLS method yielded R-Square and RMSEC (root mean square error of calibration) values of 0. 975% and 0. 56%, respectively.


Input: For the tablet press, the corresponding R-Square and RMSEC values were 0. 943% and 0. 75%, respectively.


Input: A test run demonstrated good predictability in the estimation of the API content in the powder mixtures and tablets during the continuous tableting process.


Input: For the continuous mixer and tablet press, the RMSEP (root mean square error of prediction) values were 0. 96% and 1. 37%, respectively.


Input: This study demonstrates that an NIR instrument capable of fast spectra acquisition can be a valuable tool for the in-line monitoring of the continuous mixing and tableting processes.


Input: OAT1 and OAT3: targets of drug-drug interaction between entecavir and JBP485.

entecavir


Input: Entecavir and JBP485 (a dipeptide) exhibit the antihepatitis activities and it is possible for the two drugs to be coadministered in the treatment of hepatitis.

Entecavir

dipeptide


Input: We aimed to elucidate whether entecavir was a substrate of OAT1, OAT3, OCT, and PEPT1 and to investigate the targets of drug-drug interactions between entecavir and JBP485.

entecavir

entecavir


Input: Plasma and urine concentrations of entecavir following intravenous and oral administration in vivo, uptake of entecavir in kidney slices and transfected cells in vitro, were determined by LC-MS/MS.

entecavir

entecavir


Input: Following intravenous co-administration of entecavir and JBP485 in rats, entecavir AUC increased 1. 93-fold, t1/2 beta was prolonged 2. 08-fold, CLP decreased 49%, CLR decreased 73%, and accumulated urinary excretion decreased 54%.

entecavir

entecavir


Input: However, following oral co-administration, the entecavir Tmax and Cmax were not affected; the degree of change in other pharmacokinetic parameters (AUC, t1/2 beta, CLP, and accumulated urinary excretion) was similar to that of intravenous administration.

entecavir


Input: The uptake of entecavir was nearly identical in hPEPT1-as in vector-HELA cells.

entecavir


Input: In rat kidney slices, uptake of entecavir was markedly inhibited by p-aminohippurate, benzylpenicillin, JBP485, and tetraethyl ammonium.

entecavir

p-aminohippurate

benzylpenicillin

tetraethyl ammonium


Input: In hOAT1-and hOAT3-HEK293 cells, uptake of entecavir was significantly higher compared to vector-HEK293 cells and was markedly inhibited by p-aminohippurate, benzylpenicillin, and JBP485.

entecavir

p-aminohippurate

benzylpenicillin


Input: Km and Vmax values of entecavir were 250 mu M and 0. 83 nmol/mg protein/30s (OAT1) and 23 mu M and 1. 1 nmol/mg protein/30 s (OAT3), respectively.

entecavir


Input: Entecavir is the substrate of OAT1, OAT3, and OCT.

Entecavir


Input: Moreover, OAT1 and OAT3 are the targets of DDI between entecavir and JBP485.

entecavir


Input: Bioactive barrigenol type triterpenoids from the leaves of Xanthoceras sorbifolia Bunge.

barrigenol

triterpenoids


Input: In order to find out new natural barrigenol type triterpenenoids as antitumor agent and reveal the difference on material basis of different parts of Xanthoceras sorbifolia Bunge, the bioassay-directed separation of the saponin fraction from leaves of X. sorbifolia Bunge was carried out to afford 5 new barrigenol type triterpenoids (1-5), together with 2 known ones.

barrigenol

triterpenenoids

saponin

barrigenol

triterpenoids


Input: The antitumor activities were evaluated and compounds 2 and 7 showed significant cytotoxic activity.


Input: Furthermore, the SAR was discussed briefly.


Input: On the basis of our research work and related literature, the difference of chemical constituents from different parts of X. sorbifolia was analyzed and concluded.


Input: The result can be a useful reference for phytochemistry taxology and safe and rational drug use of X. sorbifolia.


Input: Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer' s disease.

quinoline


Input: Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain.

cGMP


Input: Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory.

nitric oxide

cGMP

cAMP


Input: Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer' s disease (AD), a neurodegenerative disorder characterized by memory loss.


Input: To explore this possibility, a series of quinoline derivatives were synthesized and evaluated.

quinoline


Input: We found that compound 7a selectively inhibits PDE5 with an IC (50) of 0. 27 nM and readily crosses the blood brain barrier.


Input: In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects.


Input: Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.

Quinoline


Input: Benzo [alpha] pyrene repressed DNA mismatch repair in human breast cancer cells.

Benzo [alpha] pyrene


Input: DNA mismatch repair (MMR) has been recently implicated to play a significant role in breast cancer progression, however, few studies have examined how various carcinogens affect MMR system in breast cancer cells.


Input: The present study employs an in vivo MMR assay developed in our laboratory to assess how prevalent environmental carcinogens such as polycyclic aromatic hydrocarbons (PAHs) affect MMR activity in human breast carcinoma cells.

polycyclic aromatic hydrocarbons

PAHs


Input: Specifically, we quantitatively measured MMR activity in ZR75-1 cells after they were exposed to benzo [alpha] pyrene (BaP), a prototypical PAH, at various concentrations.

benzo [alpha] pyrene

BaP

PAH


Input: Our findings revealed that BaP exposure at high concentrations of 1 and 5 mu M induced significant inhibition of MMR activity in ZR75-1 cells.

BaP


Input: Further, we also identified that MMR repression induced by 5 mu M BaP was mediated through one of the MMR key proteins MSH6 as significant reduction in protein level was detected by western blot.

BaP


Input: More importantly, ectopic expression of hMSH6 restored MMR activity in the BaP treated cells to the same level as in the control cells.

BaP


Input: Impaired MMR plays an important role in carcinogenesis.


Input: Our findings suggest that BaP induced repression of MMR activity may also contribute to the progression of mutagenesis event.

BaP


Input: Meanwhile, the present study also for the first demonstrated that our in vivo DNA MMR assay can be applied in the field of environmental toxicology.


Input: Detoxification of aldehydes by histidine-containing dipeptides: from chemistry to clinical implications.

aldehydes

histidine


Input: Aldehydes are generated by oxidized lipids and carbohydrates at increased levels under conditions of metabolic imbalance and oxidative stress during atherosclerosis, myocardial and cerebral ischemia, diabetes, neurodegenerative diseases and trauma.

Aldehydes

carbohydrates


Input: In most tissues, aldehydes are detoxified by oxidoreductases that catalyze the oxidation or the reduction of aldehydes or enzymatic and nonenzymatic conjugation with low molecular weight thiols and amines, such as glutathione and histidine dipeptides.

aldehydes

aldehydes

thiols

amines

glutathione

histidine


Input: Histidine dipeptides are present in micromolar to millimolar range in the tissues of vertebrates, where they are involved in a variety of physiological functions such as pH buffering, metal chelation, oxidant and aldehyde scavenging.

Histidine

aldehyde


Input: Histidine dipeptides such as carnosine form Michael adducts with lipid-derived unsaturated aldehydes, and react with carbohydrate-derived oxo-and hydroxy-aldehydes forming products of unknown structure.

Histidine

carnosine

unsaturated aldehydes

carbohydrate

oxo-and hydroxy-aldehydes


Input: Although these peptides react with electrophilic molecules at lower rate than glutathione, they can protect glutathione from modification by oxidant and they may be important for aldehyde quenching in glutathione-depleted cells or extracellular space where glutathione is scarce.

glutathione

glutathione

aldehyde

glutathione

glutathione


Input: Consistent with in vitro findings, treatment with carnosine has been shown to diminish ischemic injury, improve glucose control, ameliorate the development of complications in animal models of diabetes and obesity, promote wound healing and decrease atherosclerosis.

carnosine

glucose


Input: The protective effects of carnosine have been linked to its anti-oxidant properties, its ability to promote glycolysis, detoxify reactive aldehydes and enhance histamine levels.

carnosine

aldehydes

histamine


Input: Thus, treatment with carnosine and related histidine dipeptides may be a promising strategy for the prevention and treatment of diseases associated with high carbonyl load.

carnosine

histidine

carbonyl


Input: The effect of manganese on dopamine toxicity and dopamine transporter (DAT) in control and DAT transfected HEK cells.

manganese

dopamine

dopamine


Input: Chronic exposure to Mn results in the development of a neurological disorder known as manganism characterized by neurological deficits resembling that seen in Parkinsonism.

Mn


Input: Although dopaminergic neurons within the nigrostriatal pathway appear intact, Mn-induced irregularities in DA transmission have been observed including decreased amphetamine-induced DA release and loss of the dopamine transporter (DAT).

Mn

amphetamine

dopamine


Input: Results of studies to evaluate the effect of Mn and DA on cell viability in control and DAT-transfected HEK cells reveal that Mn is equally toxic to both cell lines whereas DA was only toxic to cells containing DAT.

Mn

Mn


Input: DA toxicity was saturable suggesting that transport may be rate limiting.


Input: When Mn and DA were added simultaneously to the media, cell toxicity was similar to that produced by Mn alone suggesting that Mn may suppress DA uptake in the DAT containing cells.

Mn

Mn

Mn


Input: Preincubation of DA prior to the addition of Mn resulted in cell death which was essentially additive with that produced independently by the two agents.

Mn


Input: Mn was also shown to decrease DA uptake and amphetamine-induced DA efflux in DAT containing cells.

Mn

amphetamine


Input: Time-lapsed confocal microscopy indicates that Mn can promote trafficking of cell surface DAT into intracellular compartments which may account for the decrease in DA uptake and DA efflux in these cells.

Mn


Input: Mn-induced internalization of DAT may provide an explanation for disruption in DA transmission previously reported in the striatum.

Mn


Input: Flavonoids profiles, antioxidant, acetylcholinesterase inhibition activities of extract from Dryoathyrium boryanum (Willd.) Ching.

Flavonoids


Input: The profiles and bioactivities of flavonoids extracted from Dryoathyrium boryanum (Willd.) Ching were investigated.

flavonoids


Input: The total flavonoids content in extract from D. boryanum is about 145. 8mg/g.

flavonoids


Input: By means of HPLC-DAD-ESI-MS, the main flavonoids in D. boryanum were tentatively identified as 3-hydroxyphloretin 6'-O-hexoside, quercetin-7-hexoside, apigenin7-O-glucoside, luteolin 7-O-glucoside, apigenin 7-O-galactoside, acacetin 7-O-(alpha-D-apio-furanosyl) (1 --> 6)-beta-d-glucoside, 3-hydroxy phloretin 6-O-hexoside, luteolin-6-C-glucoside.

flavonoids

3-hydroxyphloretin 6'-O-hexoside

luteolin 7-O-glucoside

apigenin 7-O-galactoside

acacetin 7-O-(alpha-D-apio-furanosyl) (1 --> 6)-beta-d-glucoside

3-hydroxy phloretin 6-O-hexoside


Input: 0. 21mg/ml flavonoids extract from D. boryanum showed very strong superoxide anion radical scavenging potential, which is higher than that of rutin (0. 25mg/ml).

flavonoids

superoxide

rutin


Input: The extract (0. 21mg/ml of flavonoids) from D. boryanum exhibited similar DPPH scavenging potential with that of rutin (0. 25mg/ml).

flavonoids

DPPH

rutin


Input: However, rutin (0. 25mg/ml) showed a significantly higher reducing power and ABTS scavenging potential than that of 0. 21mg/ml flavonoids extract from D. boryanum.

rutin

ABTS

flavonoids


Input: It had no effect on acetylcholinesterase.


Input: D. boryanum can be considered as a medicinal plant and the flavonoids from D. boryanum are excellent antioxidants.

flavonoids


Input: Profiling of neuraminidase inhibitory polyphenols from the seeds of Paeonia lactiflora.

polyphenols


Input: Bacterial neuraminidase (NA) is a lynch pin enzyme in the formation of biofilms.


Input: Thus NA continues to be one of the key enzymes targeted by bacterial infection.


Input: The purpose of this manuscript is to communicate four new naturally derived inhibitors of neuraminidase (IC50s 3. 7-24. 4 mu M).


Input: All these active species (1-4) contained a resveratrol chemotype, however resveratrol itself was inactive (IC50 > 100 mu M).

resveratrol

resveratrol


Input: 1-4 were isolated from the 60% aqueous ethanol extract of seeds of Paeonia lactiflora, which exhibited potent neuraminidase inhibition.

ethanol


Input: Purification of the extracts yielded four chiral polyphenols, suffruticosol A (1), suffruticosol B (2), trans-epsilon-viniferin (3), and trans-gnetin H (4).

polyphenols

suffruticosol A

suffruticosol B

trans-epsilon-viniferin

trans-gnetin H


Input: Mechanistic analysis of 1-4' s inhibition showed that they were all reversible, noncompetitive inhibitors.


Input: Trans-epsilon-viniferin (3) underwent trans-cis isomerization, which led to a reduction in inhibition potency.

Trans-epsilon-viniferin


Input: This correlates with the fact that the cis-isomer is a weaker inhibitor of neuraminidase than the trans-isomer.


Input: Importantly, significantly different optical rotations ([alpha] D) compared to previous reports were found for suffruticosols A (+ 95 vs-34) and B (+ 136 vs + 13).

suffruticosols A (+ 95 vs-34) and B


Input: These two species are the most important standard metabolites in the whole paeoniaceae family and therefore correction of this error is important.


Input: Identification of novel antimycobacterial chemical agents through the in silico multi-conformational structure-based drug screening of a large-scale chemical library.


Input: The increasing prevalence of drug-resistant tuberculosis, which is resistant to effective multiple antibiotic, presents a major global health threat.


Input: The thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (M. tuberculosis), which is an essential enzyme for the maintenance of the thymidine triphosphate pools, is considered an attractive target for the development of effective antibiotics against tuberculosis.

thymidine monophosphate

thymidine triphosphate


Input: In this study, we attempted to identify novel chemical compounds that specifically target the M. tuberculosis TMPK (mtTMPK).


Input: We performed in silico structure-based drug screening using the crystal structure data of mtTMPK and a large-scale virtual compound library, which is composed of 6, 192, 930 chemicals.


Input: Through a three-step screening method using the DOCK and GOLD, we identified ten chemical compounds that were predicted to have high binding affinity to the active site cleft of the mtTMPK.


Input: We then evaluated the antibiotic effects of these chemical compounds on model mycobacteria strains.


Input: As a result, we found that a chemical compound, K10, completely inhibited the growth of Mycobacterium vanbaalenii (M. vanbaalenii) and Mycobacterium smegmatis (M. smegmatis).


Input: Moreover, K10 does not exhibit any toxic effects on the growth of enterobacteria and mammalian cells.


Input: The structural and experimental information regarding this novel chemical compound, K10, is likely to be useful for the hit-to-lead optimization of new antibiotics for the treatment of tuberculosis.


Input: Monocyclic beta-lactams as antibacterial agents: facing antioxidant activity of N-methylthio-azetidinones.

Monocyclic beta-lactams

N-methylthio-azetidinones


Input: A series of N-methylthio-beta-lactams with antibacterial activity were thoroughly evaluated as antioxidants.

N-methylthio-beta-lactams


Input: We found that only the presence of a polyphenolic moiety anchored to the beta-lactam ring ensured an adequate antioxidant potency.

polyphenolic

beta-lactam


Input: New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place.


Input: Antimicrobial activity of various 4-and 5-substituted 1-phenylnaphthalenes.

4-and 5-substituted 1-phenylnaphthalenes


Input: Bacterial cell division occurs in conjunction with the formation of a cytokinetic Z-ring structure comprised of FtsZ subunits.


Input: Agents that can disrupt Z-ring formation have the potential, through this unique mechanism, to be effective against several of the newly emerging multi-drug resistant strains of infectious bacteria.


Input: 1-and 12-Aryl substituted benzo [c] phenanthridines have been identified as antibacterial agents that could exert their activity by disruption of Z-ring formation.

1-and 12-Aryl substituted benzo [c] phenanthridines


Input: Substituted 4-and 5-amino-1-phenylnaphthalenes represent substructures within the pharmacophore of these benzo [c] phenanthridines.

4-and 5-amino-1-phenylnaphthalenes

benzo [c] phenanthridines


Input: Several 4-and 5-substituted 1-phenylnaphthalenes were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis.

4-and 5-substituted 1-phenylnaphthalenes


Input: The impact of select compounds on the polymerization dynamics of S. aureus FtsZ was also assessed.


Input: Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors.

N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide


Input: We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1, 2-b] pyrrole-9-carbonitrile (S1).

3-thiomorpholin-8-oxo-8H-acenaphtho [1, 2-b] pyrrole-9-carbonitrile


Input: S1 plays its function by binding to the BH3 groove of Mcl-1.


Input: Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach.


Input: By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment.


Input: In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments.


Input: A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC (50) value of 54 nM was obtained.

N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide


Input: Compound 12c demonstrated a better aqueous solubility than S1.


Input: Cellular and molecular mechanisms of accelerated fracture healing by COX2 gene therapy: studies in a mouse model of multiple fractures.


Input: This study sought to determine the cellular and molecular mechanisms of cyclooxygenase-2 (COX2) gene therapy to accelerate fracture repair in a mouse multiple tibial fractures model.


Input: The lenti-COX2 (or lenti-gfp control vector) was injected into fractures on day 1 post-fracture.


Input: At days 3-7, the COX2 treatment increased Sdf1-, Cxcr4-, Nes-, and Podxl-expressing mesenchymal stem cells (MSCs) within fracture calluses, suggesting an enhanced MSC recruitment or expansion.


Input: The COX2-treated mice formed smaller cartilaginous calluses that had less cartilage tissues than control mice.


Input: The expression of Sox9 mRNA was 7-fold less in COX2-treated than in control calluses at day 14, implying that COX2 reduces chondrocytic differentiation of MSCs.


Input: The therapy also enhanced angiogenesis as reflected by increased immunostaining of CD31, vWF, and alpha-SMA over controls in the cartilaginous callus at day 14-21.


Input: At which time, the COX2 gene therapy promoted bony remodeling of the cartilaginous callus to bridge the fracture gap that was accompanied by 2-fold increase in osteoclasts along the surface of the woven bone and an onset of osteogenesis.


Input: Blocking angiogenesis with daily injection of endostatin from day 4 to day 10 into fracture sites blocked the COX2-mediated reduction of callus size that was associated with an increase in hypertrophic chondrocytes and concomitant reduction in osteoclasts.


Input: In conclusion, COX2 accelerates fracture healing in part through three biological actions: 1) increased recruitment/expansion of MSCs; 2) decreased cartilaginous callus formation; and 3) increased angiogenesis-dependent cartilage remodeling.


Input: These effects were associated with an earlier onset of bony bridging of the fracture gap.


Input: Singular phase nano-optics in plasmonic metamaterials for label-free single-molecule detection.


Input: The non-trivial behaviour of phase is crucial for many important physical phenomena, such as, for example, the Aharonov-Bohm effect and the Berry phase.


Input: By manipulating the phase of light one can create' twisted' photons, vortex knots and dislocations which has led to the emergence of the field of singular optics relying on abrupt phase changes.


Input: Here we demonstrate the feasibility of singular visible-light nano-optics which exploits the benefits of both plasmonic field enhancement and the peculiarities of the phase of light.


Input: We show that properly designed plasmonic metamaterials exhibit topologically protected zero reflection yielding to sharp phase changes nearby, which can be employed to radically improve the sensitivity of detectors based on plasmon resonances.


Input: By using reversible hydrogenation of graphene and binding of streptavidin-biotin, we demonstrate an areal mass sensitivity at a level of fg mm (-2) and detection of individual biomolecules, respectively.

graphene

biotin


Input: Our proof-of-concept results offer a route towards simple and scalable single-molecule label-free biosensing technologies.


Input: A physiologically based pharmacokinetic model for the oxime TMB-4: simulation of rodent and human data.

oxime TMB-4


Input: Multiple oximes have been synthesized and evaluated for use as countermeasures against chemical warfare nerve agents.

oximes


Input: The current U. S. military and civilian oxime countermeasure, 2-[(hydroxyimino) methyl]-1-methylpyridin-1-ium chloride (2-PAM), is under consideration for replacement with a more effective acetylcholinesterase reactivator, 1, 1'-methylenebis {4-hydroxyiminomethyl} pyridinium dimethanesulfonate (MMB-4).

oxime

2-[(hydroxyimino) methyl]-1-methylpyridin-1-ium chloride

1, 1'-methylenebis {4-hydroxyiminomethyl} pyridinium dimethanesulfonate


Input: Kinetic data in the scientific literature for MMB-4 are limited; therefore, a physiologically based pharmacokinetic (PBPK) model was developed for a structurally related oxime, 1, 1'-trimethylenebis {4-hydroximinomethyl} pyridinium dibromide.

oxime

1, 1'-trimethylenebis {4-hydroximinomethyl} pyridinium dibromide


Input: Based on a previous model structure for the organophosphate diisopropylfluorophosphate, the model includes key sites of acetylcholinesterase inhibition (brain and diaphragm), as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues.

organophosphate diisopropylfluorophosphate


Input: All tissue compartments are diffusion limited.


Input: Model parameters were collected from the literature, predicted using quantitative structure-property relationships or, when necessary, fit to available pharmacokinetic data from the literature.


Input: The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as well as human blood and urine data from intravenous and intramuscular administration; sensitivity analyses were performed.


Input: The PBPK model successfully simulates rat and human data sets and has been evaluated by predicting intravenous mouse and intramuscular human data not used in the development of the model.


Input: Monte Carlo analyses were performed to quantify human population kinetic variability in the human evaluation data set.


Input: The model identifies potential pharmacokinetic differences between rodents and humans, indicated by differences in model parameters between species.


Input: The PBPK model can be used to optimize the dosing regimen to improve oxime therapeutic efficacy in a human population.

oxime


Input: Improving the dispersity of detonation nanodiamond: differential scanning calorimetry as a new method of controlling the aggregation state of nanodiamond powders.


Input: Detonation nanodiamond (ND) is a suitable source material to produce unique samples consisting of almost uniform diamond nanocrystals (d = 3-5 nm).


Input: Such samples exist in the form of long stable aqueous dispersions with narrow size distribution of diamond particles.

diamond


Input: The material is finding ever increasing application in biomedicine.


Input: The major problem in producing monodispersed diamond colloids lies in the necessity of deagglomeration of detonation soot and/or removing of clusters formed by already isolated core particles in dry powders.

diamond


Input: To do this one must have an effective method to monitor the aggregation state or dispersity of powders and gels prior to the preparation of aqueous dispersions.


Input: In the absence of dispersity control at various stages of preparation the reproducibility of properties of existing ND materials is poor.


Input: In this paper we introduce differential scanning calorimetry (DSC) as a new tool capable to distinguish the state of aggregation in dry and wetted ND materials and to follow changes in this state under different types of treatment.


Input: Samples with identical X-ray diffraction patterns (XRD) and high resolution transmission electron microscopy (HRTEM) images gave visibly different DSC traces.


Input: Strong correlation was found between dynamic light scattering (DLS) data for colloids and DSC parameters for gels and powders of the same material.


Input: Based on DSC data we improved dispersity of existing ND materials and isolated samples with the best possible DSC parameters.


Input: These were true monodispersed easily dispersible fractions of ND particles with diameters of ca.


Input: 3 nm.


Input: The sequence of the enterococcal cytolysin imparts unusual lanthionine stereochemistry.

lanthionine


Input: The enterococcal cytolysin is a two-component lantibiotic of unknown structure with hemolytic activity that is important for virulence.


Input: We prepared cytolysin by coexpression of each precursor peptide with the synthetase CylM in Escherichia coli and characterized its structure.


Input: Unexpectedly, cytolysin is to our knowledge the first example of a lantibiotic containing lanthionine and methyllanthionine structures with different stereochemistries in the same peptide.

lanthionine

methyllanthionine


Input: The stereochemistry is determined by the sequence of the substrate peptide.


Input: Fibronectin in the palatine tonsil as a susceptibility marker in Egyptian rheumatic families: Histological and immunohistochemical studies.


Input: Rheumatic fever (RF) and rheumatic heart disease (RHD) are the multisystem autoimmune sequel of group A streptococci (GAS) infection of the upper respiratory passages, mainly tonsillopharyngitis.


Input: The major receptor on the surface of human palatine tonsil for GAS is fibronectin (FN; adhesin receptor).


Input: Early detection of RF susceptibility is considered as an important aim of this study.


Input: Therefore, the present study aimed to use FN immunoreactivity (FN-ir) as a marker for early detection of rheumatic susceptible children with palatine tonsil crypts surface epithelium.


Input: A total of 30 palatine tonsillar specimens were obtained from children aged from 3 to 15 years.


Input: Histological studies showed moderate vascular changes and more than four apparent epithelial disruptions in the crypt epithelium.


Input: FN-ir showed a significant increase in FN in the basal layers of surface epithelium, subepithelial connective tissue and interfollicular areas.


Input: Tonsils of children in rheumatic families showed significant increase in FN in subepithelial connective tissue areas with more than one apparent crypt epithelial disruption compared to normal children.


Input: We can conclude that FN plays a central role in the RF and differentially distributed in the functional compartments of the palatine tonsil in children with RHD, so FN-ir can be used as a marker for rheumatic susceptibility.


Input: Relationship between oxidative stress and chronic daily headache in children.


Input: The aim of this study was to investigate the relationship between oxidative stress and chronic daily headache (CDH) in children.


Input: Although there are reports that oxidative injury may play a role in the pathophysiology of some neurologic disorders, such as migraine and epilepsy, by disrupting or destroying cell membranes through the formation of free radical and reactive oxygen species, the pathophysiology of headache is not clearly established.

oxygen


Input: A total of 38 children (16 boys and 22 girls) with CDH, aged between 7 and 15 years, were enrolled in the study.


Input: The control group consisted of 39 healthy children (17 boys and 22 girls), aged between 7 and 14 years.


Input: The mean age was 10. 9 +/- 2. 2 years for both the groups.


Input: Activities of erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as well as malondialdehyde (MDA) levels in all the children of both the groups were measured.

superoxide

glutathione

malondialdehyde

MDA


Input: Mean activities of erythrocyte SOD, CAT, and GPx as well as MDA levels were significantly higher in the study group than in the control group (p < 0. 001).

MDA


Input: The findings of this study suggest that oxidative stress may play a causal or consequential role in children with CDH.


Input: Study of intracellular delivery of doxorubicin from poly (lactide-co-glycolide) nanoparticles by means of fluorescence lifetime imaging and confocal Raman microscopy.

doxorubicin

poly (lactide-co-glycolide)


Input: The intracellular delivery of Doxorubicin (Dox) from poly (lactide-co-glycolide) (PLGA) nanoparticles stabilised with bovine serum albumin, in HepG2 cells, is studied via flow cytometry, fluorescence lifetime imaging microscopy (FLIM), confocal Raman microscopy (CRM) and cell viability studies.

Doxorubicin

Dox

poly (lactide-co-glycolide)

PLGA


Input: Flow cytometry shows that the initial uptake of PLGA and Dox follow the same kinetics.

PLGA

Dox


Input: However, following 8 h of incubation, the fluorescence intensity and cellular uptake of Dox decreases, while in the case of PLGA both parameters remain constant.

Dox

PLGA


Input: FLIM shows the presence of a single-lifetime species, with a lifetime of 1. 15 ns when measured inside the cells.


Input: Cell viability decreases by approximately 20% when incubated for 24 h with PLGA loaded with Dox, with a particle concentration of 100 micro g. mL (-1).

PLGA

Dox


Input: At the single-cell level, CRM shows changes in the bands from DNA and proteins in the cell nucleus when incubated with PLGA loaded with Dox.

PLGA

Dox


Input: Modern subunit vaccines: development, components, and research opportunities.


Input: Traditional vaccines, based on the administration of killed or attenuated microorganisms, have proven to be among the most effective methods for disease prevention.


Input: Safety issues related to administering these complex mixtures, however, prevent their universal application.


Input: Through identification of the microbial components responsible for protective immunity, vaccine formulations can be simplified, enabling molecular-level vaccine characterization, improved safety profiles, prospects to develop new high-priority vaccines (e. g. for HIV, tuberculosis, and malaria), and the opportunity for extensive vaccine component optimization.


Input: This subunit approach, however, comes at the expense of decreased immunity, requiring the addition of immunostimulatory agents (adjuvants).


Input: As few adjuvants are currently used in licensed vaccines, adjuvant development represents an exciting area for medicinal chemists to play a role in the future of vaccine development.


Input: In addition, immune responses can be further customized though optimization of delivery systems, tuning the size of particulate vaccines, targeting specific cells of the immune system (e. g. dendritic cells), and adding components to aid vaccine efficacy in whole immunized populations (e. g. promiscuous T-helper epitopes).


Input: Herein we review the current state of the art and future direction in subunit vaccine development, with a focus on the described components and their potential to steer the immune response toward a desired response.


Input: Directed motion of colloidal particles in a galvanic microreactor.


Input: The mechanisms leading to the deposition of colloidal particles in a copper-gold galvanic microreactor are investigated.

copper


Input: Using in situ current density measurements and particle velocimetry, we establish correlations between the spatial arrangement and the geometry of the electrodes, current density distribution, and particle aggregation behavior.


Input: Ionic transport phenomena are responsible for the occurrence of strongly localized high current density at the edges and corners of the copper electrodes at large electrode separation, leading to a preferential aggregation of colloidal particles at the electrode edges.

copper


Input: Preferential aggregation appears to be the result of a combination of electrophoretic effects and changes in bulk electrolyte flow patterns.