Input: Expression of antagonists of WNT and BMP signaling after non-rigid fixation of osteotomies.


Input: Delayed fracture healing and non-unions represent rare but severe complications in orthopedic surgery.


Input: Further knowledge on the mechanisms of the bone repair process and of the development of a pseudoarthrosis is essential to predict and prevent impaired healing of fractures.


Input: The present study aimed at elucidating differences in gene expression during the repair of rigidly and non-rigidly fixed osteotomies.


Input: For this purpose, the MouseFix (TM) and the FlexiPlate (TM) systems (AO Development Institute, Davos, CH), allowing the creation of well defined osteotomies in mouse femora, were employed.


Input: A time course following the healing process of the osteotomy was performed and bones and periimplant tissues were analyzed by high-resolution X-ray, MicroCT and by histology.


Input: For the assessment of gene expression, Low Density Arrays (LDA) were done.


Input: In animals with rigid fixation, X-ray and MicroCT revealed healing of the osteotomy within 3 weeks.


Input: Using the FlexiPlate (TM) system, the osteotomy was still visible by X-ray after 3 weeks and a stabilizing cartilaginous callus was formed.


Input: After 4. 5 weeks, the callus was remodeled and the osteotomy was, on a histological level, healed.


Input: Gene expression studies revealed levels of transcripts encoding proteins associated with inflammatory processes not to be altered in tissues from bones with rigid and non-rigid fixation, respectively.


Input: Levels of transcripts encoding proteins of the extracellular matrix and essential for bone cell functions were not increased in the rigidly fixed group when compared to controls without osteotomy.


Input: In the FlexiPlate (TM) group, levels of transcripts encoding the same set of genes were significantly increased 3 weeks after surgery.


Input: Expression of transcripts encoding BMPs and BMP antagonists was increased after 3 weeks in repair tissues from bones fixed with FlexiPlate (TM), as were inhibitors of the WNT signaling pathways.


Input: Little changes only were detected in transcript levels of tissues from rigidly fixed bones.


Input: The data of the present study suggest that rigid fixation enables accelerated healing of an experimental osteotomy as compared to non-rigid fixation.


Input: The changes in the healing process after non-rigid fixation are accompanied by an increase in the levels of transcripts encoding inhibitors of osteogenic pathways and, probably as a consequence, by temporal changes in bone matrix synthesis.


Input: Microstructured, functional PVA hydrogels through bioconjugation with oligopeptides under physiological conditions.

PVA


Input: In this work, bioconjugation techniques are developed to achieve peptide functionalization of poly (vinyl alcohol), PVA, as both a polymer in solution and within microstructured physical hydrogels, in both cases under physiological conditions.

poly (vinyl alcohol)

PVA


Input: PVA is unique in that it is one of very few polymers with excellent biocompatibility and safety and has FDA approval for clinical uses in humans.

PVA


Input: However, decades of development have documented only scant opportunities in bioconjugation with PVA.

PVA


Input: As such, materials derived thereof fail to answer the call for functional biomaterials for advanced cell culture and tissue engineering applications.


Input: To address these limitations, PVA is synthesized with terminal thiol groups and conjugated with thiolated peptides using PVA in solution.

PVA

thiol

PVA


Input: Further, microstructured, surface-adhered PVA physical hydrogels are assembled, the available conjugation sites within the hydrogels are quantified, and quantitative kinetic data are collected on peptide conjugation to the hydrogels.

PVA


Input: The success of bioconjugation in the gel phase is quantified through the use of a cell-adhesive peptide and visualization of cell adhesion on PVA hydrogels as cell culture substrates.

PVA


Input: Taken together, the presented data establish a novel paradigm in bioconjugation and functionalization of PVA physical hydrogels.

PVA


Input: Coupled with an excellent safety profile of PVA, these results deliver a superior biomaterial for diverse biomedical applications.

PVA


Input: Novel Three-Dimensional Nanoporous Alumina as a Template for Hierarchical TiO2 Nanotube Arrays.

Alumina


Input: Hierarchical micro-/nano-structures made easy.


Input: By using extremely rough, chemically etched microstructured aluminium foils, anodization in phosphoric acid under very harsh conditions, e. g., 10 wt% phosphoric acid and room temperature, can be repeatedly accomplished without suffering from breakdown.

aluminium

phosphoric acid

phosphoric acid


Input: As a result, an alumina membrane with a three-dimensionally distributed nanopore structure is formed, which can be used as a general template to fabricate hierarchical micro-/nano-structures.

alumina


Input: Application of hybrid approach based on empirical and physiological concept for predicting pharmacokinetics in humans--usefulness of exponent on prospective evaluation of predictability.


Input: We developed a hybrid method for predicting plasma concentration-time curves in humans by integrating species differences in in vitro intrinsic clearance (CL (int)) into the Dedrick approach based on the allometry concept.


Input: With prediction of clearance (CL) by allometric scaling, taking in vitro CL (int) into consideration improved the accuracy and reduced the average fold error from 2. 72 to 1. 99.


Input: With the hybrid approach of applying the same concept to the Dedrick approach, the predictability of plasma concentration profiles was compared with the results of the conventional Dedrick approach and the physiologically based pharmacokinetic model using 15 compounds with widely ranging physicochemical and pharmacokinetic profiles.


Input: The hybrid approach showed the highest predictability among the examined methods.


Input: For CL and the apparent volume of distribution at the steady state (V (ss)), the relationship between the exponent of allometric equation and fold error was also evaluated with the hybrid approach.


Input: The relationship appeared to be a horseshoe curve.


Input: Six compounds with exponents ranging from 0. 7 to 1. 1 for both CL and V (ss) [antipyrine, caffeine, epiroprim, propafenone, theophylline, and verapamil] displayed higher predictability.

antipyrine

caffeine

epiroprim

propafenone

theophylline

verapamil


Input: Three compounds with an exponent ranging from 0. 7 to 1. 1 for CL showed better predictability for CL, and the other four compounds appeared to display similar relationship between the exponent and predictability for V (ss).


Input: These findings indicated that the exponent becomes a preliminary index to speculate on predictability.


Input: Combination of the hybrid approach and exponent allows us to prospectively draw human plasma concentration-time curves, with the implication of possible prediction accuracy prior to clinical studies.


Input: The potential of Sutherlandia frutescens for herb-drug interaction.


Input: In Africa, Sutherlandia frutescens is a popular medicinal herb widely consumed by people living with human immunodeficiency virus/AIDS.


Input: Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction (HDI).


Input: This study investigated the inhibitory effects of the crude extracts of S. frutescens on the major cytochrome P450 isozymes with the use of pooled human liver microsomes.


Input: Its effect on the metabolic clearance of midazolam using cryopreserved hepatocytes was also monitored.

midazolam


Input: The potential of S. frutescens to inhibit human ATP-binding cassette transporters (P-gp and BCRP) and the human organic anion transporting polypeptide (OATP1B1 and OATP1B3) activity was assessed using cell lines overexpressing the transporter proteins.

ATP


Input: S. frutescens showed inhibitory potency for CYP1A2 (IC (50) = 41. 0 micro g/ml), CYP2A6 (IC (50) = 160 micro g/ml), CYP2B6 (IC (50) = 20. 0 micro g/ml), CYP2C8 (IC (50) = 22. 4 micro g/ml), CYP2C9 (IC (50) = 23. 0 micro g/ml), CYP2C19 (IC (50) = 35. 9 micro g/ml), and CYP3A4/5 (IC (50) = 17. 5 micro g/ml [with midazolam1'-hydroxylation]; IC (50) = 28. 3 micro g/ml [with testosterone 6 beta-hydroxylation]).

testosterone


Input: Time-dependent (irreversible) inhibition by S. frutescens was observed for CYP3A4/5 (K (I) = 296 micro g/ml, k (inact) = 0. 063 min (-1)) under the conditions of this study.


Input: S. frutescens also delays the production of midazolam metabolites in the hepatocytes, decreasing its clearance by 40%.

midazolam


Input: Furthermore, S. frutescens inhibited P-gp (IC (50) = 324. 8 micro g/ml), OATP1B1 (IC (50) = 10. 4 micro g/ml), and OATP1B3 (IC (50) = 6. 6 micro g/ml).


Input: The result indicates the potential for HDI between S. frutescens and the substrates of the affected enzymes, if sufficient in vivo concentration of the extract is attained.


Input: Burial of the polymorphic residue 129 in amyloid fibrils of prion stop mutants.


Input: Misfolding of the natively alpha-helical prion protein into a beta-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Str a ussler-Scheinker syndrome.


Input: In humans, the disease phenotype is modified by a methionine/valine polymorphism at codon 129 of the prion protein gene.

methionine

valine


Input: Using a combination of hydrogen/deuterium exchange coupled to NMR spectroscopy, hydroxyl radical probing detected by mass spectrometry, and site-directed mutagenesis, we demonstrate that stop mutants of the human prion protein have a conserved amyloid core.

hydrogen

deuterium

hydroxyl


Input: The 129 residue is deeply buried in the amyloid core structure, and its mutation strongly impacts aggregation.


Input: Taken together the data support a critical role of the polymorphic residue 129 of the human prion protein in aggregation and disease.


Input: Bioresorbable surface-adhered enzymatic microreactors based on physical hydrogels of poly (vinyl alcohol).

poly (vinyl alcohol)


Input: Hydrogel biomaterials based on poly (vinyl alcohol), PVA, have an extensive history of biomedical applications, yet in their current form suffer from significant shortcomings, such as a lack of mechanism of biodegradation and poor opportunities in controlled drug release.

poly (vinyl alcohol)

PVA


Input: We investigate physical hydrogels of PVA as surface-adhered materials and present biodegradable matrices equipped with innovative tools in substrate-mediated drug release.

PVA


Input: Toward the final goal, PVA chains with narrow polydispersities (1. 1-1. 2) and molecular weights of 5, 10, and 28 kDa are synthesized via controlled radical polymerization (RAFT).

PVA


Input: These molecular weights are shown to be suitably high to afford robust hydrogel matrices and at the same time suitably low to allow gradual erosion of the hydrogels with kinetics of degradation controlled via polymer macromolecular characteristics.


Input: For opportunities in controlled drug release, hydrogels are equipped with enzymatic cargo to achieve an in situ conversion of externally added prodrug into a final product, thus giving rise to surface-adhered enzymatic microreactors.


Input: Hydrogel-mediated enzymatic activity was investigated as a function of polymer molecular weight and concentration of solution taken for assembly of hydrogels.


Input: Taken together, we present, to the best of our knowledge, the first example of bioresorbable physical hydrogel based on PVA with engineered opportunities in substrate-mediated enzymatic activity and envisioned utility in surface-mediated drug delivery and tissue engineering.

PVA


Input: Catechol-initiated polyethers: multifunctional hydrophilic ligands for PEGylation and functionalization of metal oxide nanoparticles.

Catechol

polyethers

metal oxide


Input: Bifunctional CA-PEG (catechol-poly (ethylene glycol)) and multifunctional CA-PEG-PGA/PEVGE (poly (glycidyl amine)/poly (ethylene glycol vinyl glycidyl ether)) ligands for the functionalization and solubilization of nanoparticles are introduced.

PEG

catechol

poly (ethylene glycol)

PEG

PGA

PEVGE

poly (glycidyl amine)

poly (ethylene glycol vinyl glycidyl ether)


Input: Tunable polymers with polydispersities < 1. 25 and molecular weights in the range 500-7700 g mol (-1) containing a catechol moiety for conjugation to metal oxide nanoparticles were prepared.

catechol

metal oxide


Input: The functional PEG ligands were synthesized starting from the acetonide-protected catechol initiator 2, 2-dimethyl-1, 3-benzodioxole-5-propanol (CA-OH) for oxyanionic polymerization.

PEG

acetonide

catechol

2, 2-dimethyl-1, 3-benzodioxole-5-propanol

OH


Input: CA-OH was used both for homopolymerization of ethylene oxide (EO) as well as copolymerization with functional epoxides N, N-diallyl glycidyl amine (DAGA), releasing primary amino groups and ethylene glycol vinyl glycidyl ether (EVGE), exhibiting a double bond for click-type reactions, to generate CA-PEG and CA-PEG-PGA/PEVGE.

OH

ethylene oxide

epoxides N, N-diallyl glycidyl amine

DAGA

primary amino

ethylene glycol vinyl glycidyl ether

EVGE

PEG

PEG

PGA

PEVGE


Input: We demonstrate the potential of the functional ligands by binding to MnO nanoparticles, rendering the PEGylated nanoparticles highly stable in aqueous environment.

MnO


Input: Furthermore, addressability of the functional groups has been proven, for example, by coupling with fluoresceine isothiocyanate (FITC), to allow for optical monitoring of the nanoparticle fate in biological systems.

fluoresceine isothiocyanate

FITC


Input: New chemotherapeutic strategies against malaria, leishmaniasis and trypanosomiases.


Input: Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites.


Input: However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance.


Input: In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return.


Input: The establishment of adequately funded public-private partnerships is currently reversing the trend.


Input: This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development.


Input: The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.


Input: New molecular and cellular targets for chemoprevention and treatment of skin tumors by plant polyphenols: a critical review.

polyphenols


Input: As the incidence of skin tumors has been steadily growing, there is an urgent need for the preventive measures as well as the improved therapeutic approaches.


Input: In the last two decades, natural plant derived polyphenols (PPs, resveratrol, silibinin, green tea polyphenols, flavonoids, anthocyanins, etc.) have been drawing particular interest as emerging active substances in dermatological/cosmeceutical compositions for the prevention, slowing, or reversion of skin tumorigenesis (chemoprevention).

polyphenols

resveratrol

silibinin

polyphenols

flavonoids

anthocyanins


Input: When chronically applied to the skin, they supposedly would not damage normal skin cells or negatively affect their functions while they would suppress tumorigenic cell transformation, inhibit tumor cell proliferation, and activate tumor cell apoptosis.


Input: PPs are also reported to synergize with conventional anti-cancer therapies.


Input: The major aim of this critical review is to provide recent updates on the molecular and cellular targets for the prevention and therapy of skin tumors with a special focus on the crossroad between inflammation and carcinogenesis as the most promising approach to chemoprevention.


Input: Novel therapeutic targets as different as epidermal stem cells, cellular senescence, epigenetic enzymes involved in carcinogenesis, epidermal growth factor and aryl hydrocarbon receptors, and metabolic CYP1 subfamily enzymes are highlighted.

aryl hydrocarbon


Input: The mechanisms of PPs interaction with these molecular and cellular targets are reviewed.


Input: The feasibility of PPs to prevent/cure specific cutaneous toxicity connected to anti-EGFR therapy and to reduce multidrug resistance of skin tumors is also discussed.


Input: Colchicine semisynthetics: chemotherapeutics for cancer?

Colchicine


Input: Nitrogen-containing bioactive alkaloids of plant origin play a significant role in human health and medicine.

Nitrogen


Input: Several semisynthetic antimitotic alkaloids are successful in anticancer drug development.


Input: Gloriosa superba biosynthesizes substantial quantities of colchicine, a bioactive molecule for gout treatment.

colchicine


Input: Colchicine also has antimitotic activity, preventing growth of cancer cells by interacting with microtubules, which could lead to the design of better cancer therapeutics.

Colchicine


Input: Further, several colchicine semisynthetics are less toxic than colchicine.

colchicine

colchicine


Input: Research is being conducted on effective, less toxic colchicine semisynthetic formulations with potential drug delivery strategies directly targeting multiple solid cancers.

colchicine


Input: This article reviews the dynamic state of anticancer drug development from colchicine semisynthetics and natural colchicine production and briefly discusses colchicine biosynthesis.

colchicine

colchicine

colchicine


Input: Antimicrobial plant metabolites: structural diversity and mechanism of action.


Input: Microbial infectious diseases continue to be one of the leading causes of morbidity and mortality.


Input: It has been estimated that microbial species comprise about 60% of the Earth' s biomass.


Input: This, together with the fact that their genetic, metabolic and physiological diversity is extraordinary, makes them a major threat to the health and development of populations across the world.


Input: Widespread antibiotic resistance, the emergence of new pathogens in addition to the resurgence of old ones, and the lack of effective new therapeutics exacerbate the problems.


Input: Thus, the need to discover and develop new antimicrobial agents is critical to improve mankind' s future health.


Input: Plant secondary metabolites (PSMs) offer particular promise in this sense.


Input: Plant Kingdom could be considered a rich source of the most diverse structures (e. g. there are more than 12, 000 known alkaloids, more than 8, 000 phenolic compounds and over 25, 000 different terpenoids), many of which were proven to possess strong antimicrobial properties (e. g. thymol, eurabienol, etc.).

phenolic

terpenoids

thymol

eurabienol


Input: In many instances, PSMs can be easily isolated from the plant matrix, either in pure state or in the form of mixtures of chemically related compounds.


Input: What is also important is that the development of bacterial resistance toward natural plant products (that are generally regarded as eco-friendly) has been thus far documented in a very limited number of cases (e. g. for reserpine).

reserpine


Input: Having all of the mentioned advantages of PSMs as potential antimicrobials in mind, a major question arises: why is it that there are still no commercially available or commonly used antibiotics of plant origin?


Input: This review tries to give a critical answer to this question by considering potential mechanisms of antimicrobial action of PSMs (inhibition of cell wall or protein synthesis, inducing leakage from the cells by tampering with the function of the membranes, interfering with intermediary metabolisms or DNA/RNA synthesis/function), as well as their physical and chemical properties (e. g. hydrophilicity/lipophilicity, chemical stability).


Input: To address the possible synergistic/antagonistic effects between PSMs and with standard antibiotics, special attention has been given to the antimicrobial activity of PSM-mixtures (e. g. essential oils, plant extracts).


Input: Moreover, possible ways of overcoming some of PSMs molecular limitations in respect to their usage as potential antibiotics were also discussed (e. g. derivatization that would enable fine tuning of certain molecular characteristics).


Input: From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer' s disease: acetylcholinesterase inhibitors.


Input: The leading Alzheimer' s disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation.


Input: In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants.


Input: Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example.

Galanthamine


Input: The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory.


Input: Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD.

Galanthamine


Input: Preclinical profile of bacopasides from Bacopa monnieri (BM) as an emerging class of therapeutics for management of chronic pains.

bacopasides


Input: Chronic pains management costs billions of dollars in medical exchequer to the world population.


Input: Additionally, 77% of people with chronic pains also have a degree of medically treatable depression.


Input: Opioids have a narrower safety index due to their side effects associated with its tolerance, hyperalgesia and subsequent dependence.


Input: Likewise, non steroidal anti-inflammatory drugs and anticonvulsants, also have limited safety and tolerability profile in the management of chronic pains.

steroidal


Input: Bacopa monnieri, a renowned ayurvedic medicine has a strong antidepressant effect and significant antinociceptive effect, which is comparable to the effect of morphine via adenosinergic, opioidergic, and adrenergic mechanisms.

morphine


Input: BM has been also reported to be effective in neuropathic pains.


Input: Additionally, it has a strong anti-inflammatory effect mediated via COX-2 inhibitory mechanism.


Input: Apart from its effect of augmenting morphine analgesia, BM also inhibits opioid-withdrawal induced hyperalgesia, and acquisition and expression of morphine tolerance.

morphine

morphine


Input: BM is reported to have a strong protective effect against toxic effects of opiates on major organs like brain, kidneys and heart.


Input: BM is well documented to be safe and well tolerated herbal therapy in multiple clinical trials including various age groups.


Input: This minireview evaluated the preclinical data that highlights potential of BM as a future candidate for clinical management of chronic pains.


Input: Cantharidin as an antitumor agent: a retrospective review.

Cantharidin


Input: This review summarizes the progress that has been made recently in the medicinal chemistry of cantharidin, a potent antitumor agent from traditional Chinese medicine.

cantharidin


Input: Thousands of analogs have been synthesized on the basis of cantharidin, a part of which shows excellent properties, in particular, norcantharidin and norcantharimide.

cantharidin

norcantharidin

norcantharimide


Input: Despite the enormous efforts made, the intriguing bioactivities, mechanism, indications, and their interplay are still ill-defined.


Input: This review provides our up-to-date understanding in connection with the therapeutic use, mechanism, structure-activity relationship (SAR) and interesting properties of cantharidin analogs.

cantharidin


Input: Considerable development in the design of cantharidin analogs, in combination with mechanistic studies, has laid a foundation for transforming novel antitumor drugs into the clinic.

cantharidin


Input: Metabolomics analysis for biomarker discovery: advances and challenges.


Input: Over the last decades there has been a change in biomedical research with the search for single genes, transcripts, proteins, or metabolites being substituted by the coverage of the entire genome, transcriptome, proteome, and metabolome with the " omics " approaches.


Input: The emergence of metabolomics, defined as the comprehensive analysis of all metabolites in a system, is still recent compared to other " omics " fields, but its particular features and the improvement of both analytical techniques and pattern recognition methods has contributed greatly to its increasingly use.


Input: The feasibility of metabolomics for biomarker discovery is supported by the assumption that metabolites are important players in biological systems and that diseases cause disruption of biochemical pathways, which are not new concepts.


Input: In fact, metabolomics, meaning the parallel assessment of multiple metabolites, has been shown to have benefits in various clinical areas.


Input: Compared to classical diagnostic approaches and conventional clinical biomarkers, metabolomics offers potential advantages in sensitivity and specificity.


Input: Despite its potential, metabolomics still retains several intrinsic limitations which have a great impact on its widespread implementation-these limitations in biological and experimental measurements.


Input: This review will provide an insight to the characteristics, strengths, limitations, and recent advances in metabolomics, always keeping in mind its potential application in clinical/health areas as a biomarker discovery tool.


Input: Confined synthesis and integration of functional materials in sub-nanoliter volumes.


Input: We present a novel microchip-based approach to combine the synthesis, characterization, and utilization of different functional materials on a single platform.


Input: A two-layer microfluidic device comprising 10 parallel actuated reaction chambers with volumes of a few hundred picoliters is used to localize and confine the synthesis, while the surfaces of the reaction chambers comprise an electrode array for direct integration and further characterization of the created crystalline assemblies without the need for further manipulation or positioning devices.


Input: First we visualized and evaluated the dynamics of our method by monitoring the formation of a fluorescent metal-organic complex (Zn (bix)).

Zn (bix)


Input: Next, we induced the site-specific growth of two types of organic conductive crystals, AuTTF and AgTCNQ, directly onto the electrode arrays in one-and two-step reactions, respectively.

AuTTF

AgTCNQ


Input: The performance of the created AgTCNQ crystals as memory elements was thoroughly examined.

AgTCNQ


Input: Moreover, we proved for first time that AuTTF composites can be used as label-free sensing elements.

AuTTF


Input: Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects.

1-nitrosocyclohexyl acetate

nitroxyl


Input: Nitroxyl (HNO) donors have potential benefit in the treatment of heart failure and other cardiovascular diseases.

Nitroxyl

HNO


Input: 1-Nitrosocyclohexyl acetate (NCA), a new HNO donor, in contrast to the classic HNO donors Angeli' s salt and isopropylamine NONOate, predominantly releases HNO and has a longer half-life.

1-Nitrosocyclohexyl acetate

NCA

HNO

HNO

Angeli' s salt

isopropylamine NONOate

HNO


Input: This study investigated the vasodilatative properties of NCA in isolated aortic rings and human platelets and its mechanism of action.

NCA


Input: NCA was applied on aortic rings isolated from wild-type mice and apolipoprotein E-deficient mice and in endothelial-denuded aortae.

NCA


Input: The mechanism of action of HNO was examined by applying NCA in the absence and presence of the HNO scavenger glutathione (GSH) and inhibitors of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC), calcitonin gene-related peptide receptor (CGRP), and K (+) channels.

HNO

NCA

HNO

glutathione

GSH

guanylyl

adenylyl

K (+)


Input: NCA induced a concentration-dependent relaxation (EC (50), 4. 4 micro M).

NCA


Input: This response did not differ between all groups, indicating an endothelium-independent relaxation effect.


Input: The concentration-response was markedly decreased in the presence of excess GSH; the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide had no effect.

GSH

nitric oxide

2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide


Input: Inhibitors of sGC, CGRP, and voltage-dependent K (+) channels each significantly impaired the vasodilator response to NCA.

K (+)

NCA


Input: In contrast, inhibitors of AC, ATP-sensitive K (+) channels, or high-conductance Ca (2 +)-activated K (+) channels did not change the effects of NCA.

ATP

K (+)

Ca (2 +)

K (+)

NCA


Input: NCA significantly reduced contractile response and platelet aggregation mediated by the thromboxane A (2) mimetic 9, 11-dideoxy-11 alpha, 9 alpha-epoxymethanoprostaglandin F (2) (alpha) in a cGMP-dependent manner.

NCA

thromboxane A (2)

9, 11-dideoxy-11 alpha, 9 alpha-epoxymethanoprostaglandin F (2) (alpha)

cGMP


Input: In summary, NCA shows vasoprotective effects and may have a promising profile as a therapeutic agent in vascular dysfunction, warranting further evaluation.

NCA


Input: Liver X Receptors and female reproduction: when cholesterol meets fertility!

cholesterol


Input: The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown.

cholesterol


Input: Cholesterol is the precursor of ovarian steroid biosynthesis and is also essential for fertility.

Cholesterol

steroid


Input: In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects.

cholesterol

cholesterol


Input: Liver X Receptor (LXR) alpha and LXR beta are nuclear receptors activated by oxysterols, oxidized derivatives of cholesterol.

oxysterols

cholesterol


Input: Since their discovery, the role of LXR in the control of cholesterol homeostasis has been widely described.

cholesterol


Input: Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes.

cholesterol


Input: In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility.


Input: Their contribution to female reproductive cancers will also be discussed.


Input: This review will try to enlighten on the LXR as a molecular link between dietary cholesterol and reproductive diseases in women.

cholesterol


Input: In the future, a better comprehension of the various physiological processes regulated by the LXR will help to develop new ligands to prevent or to cure these pathologies in women.


Input: Studies on the bioactivity of aqueous extract of pu-erh tea and its fractions: in vitro antioxidant activity and alpha-glycosidase inhibitory property, and their effect on postprandial hyperglycemia in diabetic mice.


Input: Despite abundant research that has been carried out on the potential health benefits of pu-erh tea, no consensus till now, has been reached on which constituent is mainly responsible for its bioactivity.


Input: In this work, the aqueous extract (AE) and its fraction enriched with active constituents were prepared from pu-erh tea, and their bioactivities were investigated.


Input: It was found that tea polyphenols (TP), tea polysaccharides (TPS), caffeine (Caf), protein (Pro), amino acids (AA) were accumulated in several fractions after solvent extraction despite not being separated completely.

polyphenols

caffeine

Caf

amino acids


Input: Meanwhile, 95% ethanol precipitate (EP) and ethyl acetate fraction (EF) possessed remarkable antioxidant activity and potent inhibitory effects against alpha-glycosidase in vitro.

ethanol

ethyl acetate


Input: Furthermore, all the extracts (50 mg/kg BW) showed a significant (p < 0. 05) effect on postprandial hyperglycemia in diabetic mice as compared with a model group, and the suppression of EP was not significantly (p > 0. 05) different from that of acarbose at the same dosage (50 mg/kg BW), which indicate that these fractions could be developed as potential anti-diabetic agents.

acarbose


Input: beta-catenin regulates GnRH-induced FSH beta gene expression.

GnRH


Input: The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction.

GnRH


Input: The known signaling mechanisms involved in gonadotropin synthesis have been expanding.


Input: For example, involvement of beta-catenin in LH beta induction by GnRH has been discovered.

GnRH


Input: We examined the role of beta-catenin in FSH beta gene expression in L beta T2 gonadotrope cells.


Input: GnRH caused a sustained increase in nuclear beta-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition.

GnRH

N


Input: Small interfering RNA-mediated knockdown of beta-catenin mRNA demonstrated that induction of FSH beta mRNA by GnRH depended on beta-catenin and that regulation of FSH beta by beta-catenin occurred independently of the JNK-c-jun pathway.

GnRH


Input: beta-Catenin depletion had no impact on FSH beta mRNA stability.


Input: In L beta T2 cells transfected with FSH beta promoter luciferase fusion constructs, GnRH responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by beta-catenin knockdown.

GnRH


Input: However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by GnRH.

GnRH


Input: Chromatin immunoprecipitation further corroborated the absence of direct interaction between beta-catenin and the 1. 8-kb FSH beta promoter.


Input: To elucidate the mechanism for the beta-catenin effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing beta-catenin knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study.


Input: Subsequent experiments confirmed that Brms1L mRNA expression was decreased by beta-catenin knockdown as well as by JNK inhibition.


Input: Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSH beta expression.

GnRH


Input: Thus, our findings indicate that the expression of Brms1L depends on beta-catenin activity and contributes to FSH beta induction by GnRH.

GnRH


Input: GATA2-induced silencing and LIM-homeodomain protein-induced activation are mediated by a bi-functional response element in the rat GnRH receptor gene.

GnRH


Input: GATA2 transcription factor and LIM homeodomain proteins Islet1 (ISL1) and LIM homeobox 3 (LHX3) are suspected to be involved in gonadotrope cell fate and maintenance.


Input: The GnRH receptor gene (Gnrhr), crucial for gonadotrope function, is expressed in the pituitary gland from embryonic day 13. 5 onward, well before LH and FSH beta-subunits.

GnRH


Input: This expression pattern together with the presence of WGATAR and TAAT motifs in Gnrhr promoter sequences suggests the involvement of early transcription factors in promoter activation.


Input: In this study, using a well-characterized transgenic mouse model, GATA2 was found colocalized with Gnrhr promoter activity in the pituitary.


Input: Transient transfection of Gnrhr promoter luciferase fusion constructs together with either GATA2 expression vectors or small interfering RNA in gonadotrope cell lines indicated that GATA2, which typically acts as a trans-activator, unexpectedly repressed Gnrhr promoter activity.


Input: Using DNA chromatography affinity and EMSA, we demonstrated that GATA2 operates via a response element containing a peculiar palindromic GATA motif that overlaps a critical TAAT motif involved in LHX3/ISL1 trans-activation.


Input: Indeed, despite the inhibitory action of GATA2, this element displayed a clear-cut enhancer activity in gonadotrope cells.


Input: Chromatin immunoprecipitation assays indicated that GATA2, LHX3, and ISL1 interact with a Gnrhr promoter fragment encompassing this element.


Input: The trans-repressive action of GATA2 on Gnrhr promoter activity is likely balanced or even hindered by trans-activating effects of LIM homeodomain proteins via this novel bifunctional LIM/GATA response element.


Input: Such a hierarchical interplay may contribute to finely adjust Gnrhr gene expression in gonadotrope cell lineage during pituitary development as well as in the adult animal.


Input: Halting metastasis through CXCR4 inhibition.


Input: Metastasis occurs when cancer cells leave the primary tumor site and migrate to distant parts of the body.


Input: The CXCR4-SDF-1 pathway facilitates this migration, and its expression has become the hallmark of several metastatic cancers.


Input: Targeted approaches are currently being developed to inhibit this pathway, and several candidates are now in clinical trials.


Input: Continued exploration of CXCR4 inhibitors will generate compounds that have improved activity over current candidates.


Input: l-DOPA modifies the antidepressant-like effects of reboxetine and fluoxetine in rats.

l-DOPA

reboxetine

fluoxetine


Input: Nowadays the most widely used antidepressants are selective serotonin reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors (NRI), however, these take four to eight weeks to exert their effects and each drug is efficacious only in 60-70% of patients.

serotonin

noradrenaline


Input: In an attempt to improve the efficacy of antidepressants, new drugs that also modify dopamine levels are being developed.

dopamine


Input: The aim of this study was to investigate the impact of l-DOPA administration on the effect elicited by antidepressants on serotonergic and noradrenergic neurotransmission.

l-DOPA


Input: To this end, single-unit extracellular recordings of the noradrenergic nucleus, locus coeruleus (LC), and the serotonergic nucleus, dorsal raphe (DRN) combined with behavioural approaches were performed.


Input: l-DOPA did not modify the basal neuronal activity in either the LC or the DRN or induce any change in the modified forced swimming test.

l-DOPA


Input: However, l-DOPA enhanced the neuronal response to reboxetine in the LC and increased its antidepressant-like effects but counteracted the effect of fluoxetine on neurons in the LC and decreased its antidepressant-like effect.

l-DOPA

reboxetine

fluoxetine


Input: The sensitivity of neurons in the DRN to reboxetine and fluoxetine was not altered by the administration of l-DOPA.

reboxetine

fluoxetine

l-DOPA


Input: Taken together, these results indicate that l-DOPA modifies the effect of SSRI and NRI antidepressants in opposing ways.

l-DOPA


Input: Prospects for treatment of latent HIV.


Input: Recent advances in antiretroviral therapy (ART) have drastically improved the quality of life for people with HIV infection.


Input: However, owing to the persistence of latent HIV in the presence of therapy, patients must remain on therapy indefinitely.


Input: Currently, the solution to the HIV pandemic rests on the prevention of new infections and many decades of ART for the steadily expanding number of people infected worldwide.


Input: ART is costly, requires ongoing medical care, and can have side effects, thereby preventing its universal availability.


Input: Therefore, to escape the ironic burdens of therapy, efforts have begun to develop treatments for latent HIV infection.


Input: Current approaches propose either complete eradication of infection or induction of a state of stringent control over viral replication without ART.


Input: This review will discuss these strategies in detail and their potential for clinical development.


Input: Emerging target-based paradigms to prevent and treat migraine.


Input: Migraine is a primary brain disorder resulting from altered modulation of normal sensory stimuli and trigeminal nerve dysfunction.


Input: The second edition of the International Classification of Headache Disorders (ICHD-2) defines seven subtypes of migraine.


Input: Migraine treatment can be acute or preventive.


Input: New targeted therapies include 5-HT (1F) receptor agonists, calcitonin gene-related peptide (CGRP) antagonists, nitric oxide synthetase inhibitors, and ion channel antagonists.

nitric oxide


Input: A recent development is the creation of antibodies to CGRP and its receptor for migraine prevention.


Input: Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance.


Input: The immunoregulatory properties of hematopoietic stem cells (HSCs) have been recognized for more than 60 years, beginning in 1945, when Owen reported that genetically disparate freemartin cattle sharing a common placenta were red blood cell chimeras.


Input: In 1953, Billingham, Brent, and Medawar demonstrated that murine neonatal chimeras prepared by infusion of donor-derived hematopoietic cells exhibited donor-specific tolerance to skin allografts.


Input: Various approaches using HSCs in organ transplantation have gradually brought closer to reality the dream of inducing donor-specific tolerance in organ transplant recipients.


Input: Several hurdles needed to be overcome, especially the risk of graft-versus-host disease (GVHD), the toxicity of ablative conditioning, and the need for close donor-recipient matching.


Input: For wide acceptance, HSC therapy must be safe and reproducible in mismatched donor-recipient combinations.


Input: Discoveries in other disciplines have often unexpectedly and synergistically contributed to progress in this area.


Input: This review presents a historic perspective of the quest for tolerance in organ transplantation, highlighting current clinical approaches.


Input: Impairment of novel object recognition in adulthood after neonatal exposure to diazinon.

diazinon


Input: Diazinon is an organophosphate pesticide that is still heavily used in agriculture, home gardening, and indoor pest control in Japan.

Diazinon

organophosphate


Input: The present study investigated the effect of neonatal exposure to diazinon on hippocampus-dependent novel object recognition test performance and the expression of the N-methyl-D-aspartate (NMDA) receptor and its signal transduction pathway-related genes in the hippocampi of young adult and adult mice.

diazinon

N-methyl-D-aspartate

NMDA


Input: Male offspring of C3H/HeN mice were subcutaneously treated with 0, 0. 5, or 5 mg/kg of diazinon for 4 consecutive days beginning on postnatal day (PND) 8.

diazinon


Input: Beginning on PND 46 or PND 81, a novel object recognition test was performed on 4 consecutive days.


Input: The hippocampi were collected on PND 50 or PND 85 after the completion of the novel object recognition test, and the expression levels of neurotrophins and the NMDA receptor and its signal transduction pathway-related genes were examined using real-time RT-PCR.

NMDA


Input: Diazinon-injected mice exhibited a poor ability to discriminate between novel and familiar objects during both the PND 49 and the PND 84 tests.

Diazinon


Input: The NMDA receptor subunits NR1 and NR2B and the related protein kinase calcium/calmodulin-dependent protein kinase (CaMK)-IV and the transcription factor cyclic AMP responsive element binding protein (CREB)-1 mRNA levels were reduced in the PND 50 mice.

NMDA

calcium

cyclic AMP


Input: However, no significant changes in the expressions of the NMDA subunits and their signal transduction molecules were observed in the hippocampi of the PND 85 mice.

NMDA


Input: The expression level of nerve growth factor mRNA was significantly reduced in the PND 50 or 85 mice.


Input: These results indicate that neonatal diazinon exposure impaired the hippocampus-dependent novel object recognition ability, accompanied by a modulation in the expressions of the NMDA receptor and neurotrophin in young adult and adult mice.

diazinon

NMDA


Input: The role of native salinity regime on grass shrimp (Palaemonetes pugio) sensitivity to cadmium.

cadmium


Input: In euryhaline crustaceans, sensitivity to toxic trace metals may be linked to osmoregulation and salinity conditions.


Input: This study investigated if grass shrimp (Palaemonetes pugio) populations from different salinity regimes differed in sensitivity to cadmium (Cd).

cadmium

Cd


Input: Grass shrimp were collected in May 2011 from two marsh sites with average salinities of ~ 3. 0 ppt and 24. 0 ppt.


Input: Groups were acclimated for 3-32 weeks in either their respective native salinity (3. 0 ppt --> 3. 0 ppt and 24. 0 ppt --> 24. 0 ppt), or the average of the salinities of the two collection sites (3. 0 ppt --> 13. 5 ppt and 24. 0 ppt --> 13. 5 ppt).


Input: After acclimation, groups were exposed to equivalent free-ion Cd concentration (4. 8 +/- 0. 3 mg/L, Cd (2 +)) in their respective acclimated salinity to compare survival among salinity treatments.

Cd

Cd (2 +)


Input: Results of Kaplan-Meier survival analysis indicated that 3. 0 ppt --> 3. 0 ppt shrimp were more sensitive to Cd (2 +) than any other group (p < 0. 0001).

Cd (2 +)


Input: Additionally, 3. 0 ppt --> 13. 5 ppt shrimp were less sensitive to Cd (2 +) than were 24. 0 ppt --> 13. 5 ppt shrimp (p = 0. 0013).

Cd (2 +)


Input: These results suggest that sensitivity of grass shrimp to Cd is dependent upon the salinity during exposure, and the salinity regime from which the tested population originated.

Cd


Input: The implication is that toxicity studies and risk assessments using euryhaline crustaceans should consider the salinity of test population collection sites when interpreting and comparing results.


Input: Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia.

25-hydroxyvitamin D3


Input: Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency.

vitamin D


Input: Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response.

vitamin D


Input: In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3) were evaluated after exposure to P450-inducing drugs.

25-hydroxyvitamin D3


Input: With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA.

phenobarbital

hyperforin

carbamazepine

rifampin


Input: In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3, 4 beta, 25 (OH) 2 D3.

rifampin

4 beta, 25 (OH) 2 D3


Input: This inductive effect was blocked by the addition of 6', 7'-dihydroxybergamottin, a selective CYP3A4 inhibitor.

6', 7'-dihydroxybergamottin


Input: With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression.


Input: 24R, 25 (OH) 2 D3 was the predominant monohydroxy metabolite produced from 25OHD3, but its formation was unaffected by the inducers.

24R, 25 (OH) 2 D3

monohydroxy


Input: With healthy volunteers, the mean plasma concentration of 4 beta, 25 (OH) 2 D3 was increased 60% (p < 0. 01) after short-term rifampin administration.

4 beta, 25 (OH) 2 D3

rifampin


Input: This was accompanied by a statistically significant reduction in plasma 1 alpha, 25 (OH) 2 D3 (-10%; p = 0. 03), and a nonsignificant change in 24R, 25 (OH) 2 D3 (-8%; p = 0. 09) levels.

1 alpha, 25 (OH) 2 D3

24R, 25 (OH) 2 D3


Input: Further analysis revealed a negative correlation between the increase in 4 beta, 25 (OH) 2 D3 and decrease in 1 alpha, 25 (OH) 2 D3 levels.

4 beta, 25 (OH) 2 D3

1 alpha, 25 (OH) 2 D3


Input: Examination of the plasma monohydroxy metabolite/25OHD3 ratios indicated selective induction of the CYP3A4-dependent 4 beta-hydroxylation pathway of 25OHD3 elimination.

monohydroxy


Input: These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia.


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


Input: Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations.


Input: Large-scale analysis of balanced chromosomal translocation breakpoints has shown nonhomologous end joining and microhomology-mediated repair to be the main drivers of interchromosomal structural aberrations.


Input: Breakpoint sequences of de novo unbalanced translocations have not yet been investigated systematically.


Input: We analyzed 12 de novo unbalanced translocations and mapped the breakpoints in nine.


Input: Surprisingly, in contrast to balanced translocations, we identify nonallelic homologous recombination (NAHR) between (retro) transposable elements and especially long interspersed elements (LINEs) as the main mutational mechanism.


Input: This finding shows yet another involvement of (retro) transposons in genomic rearrangements and exposes a profoundly different mutational mechanism compared with balanced chromosomal translocations.


Input: Furthermore, we show the existence of compound maternal/paternal derivative chromosomes, reinforcing the hypothesis that human cleavage stage embryogenesis is a cradle of chromosomal rearrangements.


Input: Bioengineered chimeric spider silk-uranium binding proteins.

uranium


Input: Heavy metals constitute a source of environmental pollution.


Input: Here, novel functional hybrid biomaterials for specific interactions with heavy metals are designed by bioengineering consensus sequence repeats from spider silk of Nephila clavipes with repeats of a uranium peptide recognition motif from a mutated 33-residue of calmodulin protein from Paramecium tetraurelia.

uranium


Input: The self-assembly features of the silk to control nanoscale organic/inorganic material interfaces provides new biomaterials for uranium recovery.

uranium


Input: With subsequent enzymatic digestion of the silk to concentrate the sequestered metals, options can be envisaged to use these new chimeric protein systems in environmental engineering, including to remediate environments contaminated by uranium.

uranium


Input: Interparticle dispersion, membrane curvature, and penetration induced by single-walled carbon nanotubes wrapped with lipids and PEGylated lipids.

carbon


Input: Single-walled carbon nanotubes (SWNTs) wrapped with different types of lipids and polyethylene glycol (PEG)-grafted lipids were simulated with lipid bilayers.

carbon

polyethylene glycol

PEG


Input: Simulations were carried out with the previously parametrized coarse-grained (CG) SWNT and PEG force fields that had captured the experimentally observed conformations of self-assembled SWNT-lipid complexes and phase behavior of PEG-grafted lipids.

PEG

PEG


Input: Simulations of multiple copies of the SWNT in water show that all pure SWNTs aggregate, lipid-wrapped SWNTs partially aggregate, but those wrapped with lipids grafted to PEG (M (w) = 550) completely disperse, indicating the effect of short PEG chains on interparticle aggregation, in agreement with experiment.

PEG

PEG


Input: Starting with initial SWNT orientation parallel to the bilayer surface, SWNTs wrapped with lysophospholipids and PEG (M (w) = 550)-grafted lipids insert into the hydrophobic region of the bilayer, while SWNTs wrapped with phospholipids and longer PEG (M (w) = 2000)-grafted lipids do not.

PEG

PEG


Input: These indicate that SWNTs insert because of the hydrophobic interaction with the bilayer tails, but the tight wrapping of charged lipid headgroups and long hydrophilic PEG chains can weaken the hydrophobic interaction and inhibit SWNT insertion.

PEG


Input: The inserted SWNTs contact the entire tails of neighboring lipids in one leaflet of the bilayer, which disorders the lipid bilayer and induces positive curvature.


Input: Our findings indicate that interparticle aggregation, SWNT penetration, and membrane curvature can be modulated by the SWNT-lipid structure and the PEG length.

PEG


Input: Radiosynthesis and evaluation of [(1) (1) C-carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography.

(1) (1) C-carbonyl

carbamates

fatty acid amide


Input: Fatty acid amide hydrolase (FAAH) plays a key role in regulating the tone of the endocannabinoid system.

Fatty acid amide


Input: Radiotracers are required to image and quantify FAAH activity in vivo.


Input: We have synthesized a series of potent FAAH inhibitors encompassing two classes of N-alkyl-O-arylcarbamates and radiolabeled eight of them with carbon-11.

N-alkyl-O-arylcarbamates


Input: The [(1) (1) C-carbonyl]-radiotracers were evaluated in vitro and ex vivo in rats as potential FAAH imaging agents for positron emission tomography (PET).

(1) (1) C-carbonyl


Input: Both sets of [(1) (1) C] O-arylcarbamates showed good to excellent brain penetration and an appropriate regional distribution.

[(1) (1) C] O-arylcarbamates


Input: Pretreatments with a FAAH inhibitor demonstrated that 80-95% of brain uptake of radioactivity constituted binding of the radiotracers to FAAH.


Input: Brain extraction measurements showed that binding to FAAH was irreversible and kinetically different for the two classes of carbamates.

carbamates


Input: These promising results are discussed in terms of the requirements of a suitable radiotracer for the in vivo imaging of FAAH using PET.


Input: Foams stabilized by multilamellar polyglycerol ester self-assemblies.

polyglycerol ester


Input: The importance of surfactant self-assemblies in foam stabilization is well-known.


Input: The aim of the current study was to investigate the self-assemblies of the nonionic surfactant polyglycerol ester (PGE) in bulk solutions, at the interface and within foams, using a combined approach of small-angle neutron scattering, neutron reflectivity, and electron microscopy.

polyglycerol ester

PGE


Input: PGE bulk solutions contain vesicles as well as open lamellar structures.

PGE


Input: Upon heating of the solutions the lamellar spacing increases, with significant differences in the presence of NaCl or CaCl (2) as compared to the standard solution.

NaCl

CaCl (2)


Input: The adsorption of the multilamellar structures present in the bulk solutions lead to a multilayered film at the air-water interface.


Input: The ordering within this film was increased as a result of a 20% area compression mimicking a coalescence event.


Input: Finally, PGE foams were shown to be stabilized not only by strong interfacial films but also by agglomerated self-assemblies within the interstitial areas of the foams.

PGE


Input: Analysis of 15N-1H NMR relaxation in proteins by a combined experimental and molecular dynamics simulation approach: picosecond-nanosecond dynamics of the Rho GTPase binding domain of plexin-B1 in the dimeric state indicates allosteric pathways.


Input: We investigate picosecond-nanosecond dynamics of the Rho-GTPase Binding Domain (RBD) of plexin-B1, which plays a key role in plexin-mediated cell signaling.


Input: Backbone 15N relaxation data of the dimeric RBD are analyzed with the model-free (MF) method, and with the slowly relaxing local structure/molecular dynamics (SRLS-MD) approach.


Input: Independent analysis of the MD trajectories, based on the MF paradigm, is also carried out.


Input: MF is a widely popular and simple method, SRLS is a general approach, and SRLS-MD is an integrated approach we developed recently.


Input: Corresponding parameters from the RBD dimer, a previously studied RBD monomer mutant, and the previously studied complex of the latter with the GTPase Rac1, are compared.


Input: The L2, L3, and L4 loops of the plexin-B1 RBD are involved in interactions with other plexin domains, GTPase binding, and RBD dimerization, respectively.


Input: Peptide groups in the loops of both the monomeric and dimeric RBD are found to experience weak and moderately asymmetric local ordering centered approximately at the C (i-1) (alpha)-C (i) (alpha) axes, and nanosecond backbone motion.


Input: Peptide groups in the alpha-helices and the beta-strands of the dimer (the beta-strands of the monomer) experience strong and highly asymmetric local ordering centered approximately at the C (i-1) (alpha)-C (i) (alpha) axes (N-H bonds).

N-H


Input: N-H fluctuations occur on the picosecond time scale.

N-H


Input: An allosteric pathway for GTPase binding, providing new insights into plexin function, is delineated.


Input: Surface-scribed transparency-based microplates.


Input: Transparency sheets, which are normally associated with use on overhead projectors, offer lowered costs and high amenability for optical diagnostics in microplate instrumentation.


Input: An alternative microplate design in which circles are scribed on the surface of the transparency to create the boundaries to hold the drop in place is investigated here.


Input: The 3D profile of the scribed regions obtained optically showed strong likelihood of affecting three-phase contact line interactions.


Input: During dispensation, the contact angle (=~ 95 degrees) was larger than the drop advancing state (=~ 80 degrees) due to a period of nonadhesion, where the contact angle later reduced to the drop advancing state followed by increase in the liquid area coverage on the substrate.


Input: It was established that 50 mu L was needed to fill the well fully, and the maximum volume retainable before breaching was 190 mu L.


Input: While the tilt angle needed for displacement reduced significantly from 50 to 95 mu L, this was markedly better than nonscribed surfaces, where tilt angles always had to be kept to within 30 degrees.


Input: It was found that there was greater ability to fill the well with smaller volumes with dispensation at the center.


Input: This was attributed to the growing contact line not meeting the scribed edge in parallel if liquid was dispensed closer to it, wherein pinning reduction in some directions permitted liquid travel along the scribed edge to undergo contact angle hysteresis.


Input: Fluorescence measurements conducted showed no performance compromise when using scribed transparency microplates over standard microplates.


Input: Amplified fluorescent sensing of DNA using graphene oxide and a conjugated cationic polymer.

graphene oxide


Input: We explore the interactions between a fluorescein (FAM)-labeled single-stranded DNA (P), graphene oxide (GO), and a cationic conjugated polymer, poly [(9, 9-bis (6'-N, N, N-trimethylammonium) hexyl)-fluorenylene phenylene dibromide] (PFP).

fluorescein

FAM

graphene oxide

poly [(9, 9-bis (6'-N, N, N-trimethylammonium) hexyl)-fluorenylene phenylene dibromide]

PFP


Input: It is found that the fluorescence change of P-GO-PFP system is dependent on the addition order of P and PFP.

PFP

PFP


Input: When adding PFP into P/GO complex, the fluorescence resonance energy transfer (FRET) from PFP to P is inefficient.

PFP

PFP


Input: If P is added to PFP/GO complex, efficient FRET is obtained.

PFP


Input: This may be attributed to the equal binding ability for P and PFP to GO.

PFP


Input: The results of time-resolved fluorescence and fluorescence anisotropy support the different fluorescent response under different addition order of P and PFP to GO.

PFP


Input: Based on the above phenomenon, we demonstrate a method to reduce the high background signal of a traditional PFP-based DNA sensor by introducing GO.

PFP


Input: In comparison to the use of single PFP, the combination of PFP with GO-based method shows enhanced sensitivity with a detection limit as low as 40 pM for target DNA detection.

PFP

PFP


Input: Alpha-heteroatom derivatized analogues of 3-(acetylhydroxyamino) propyl phosphonic acid (FR900098) as antimalarials.

3-(acetylhydroxyamino) propyl phosphonic acid


Input: To explore the hitherto successful derivatization of the alpha-carbon of fosmidomycin, a series of new alpha-substituted analogues was prepared.

alpha-carbon

fosmidomycin


Input: This was done by introduction of a heteroatom (N or O) in alpha-position to the phosphonate and using the resultant OH and NH 2 groups as a handle for appending a variety of substituents by means of several functional groups such as ether, amide, urea, and 1, 4-triazole.

N

O

phosphonate

OH

NH 2

ether

amide

urea

1, 4-triazole


Input: The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory potency.


Input: Both the alpha-azido-analogue and the alpha-hydroxylated analogue proved most promising, and docking experiments were performed.

alpha-azido


Input: Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not be found.


Input: Super-resolution mapping of reactive sites on titania-based nanoparticles with water-soluble fluorogenic probes.

titania


Input: Interfacial charge transfer at the heterogeneous surface of semiconductor nanoparticles is a fundamental process that is relevant to many important applications, such as photocatalysis, solar cells, and sensors.


Input: In this study, we developed new water-soluble fluorogenic probes for interfacial electron transfer reactions on semiconductor nanoparticles.


Input: The synthesized boron-dipyrromethene-based fluorescence dyes have one or two sulfonate groups, which confer solubility in aqueous media, and a dinitrophenyl group as a redox reaction site.

boron-dipyrromethene

sulfonate

dinitrophenyl


Input: These probes produce the corresponding fluorescent products via multiple interfacial electron transfer processes, allowing us to investigate the photoinduced redox reactions over individual pristine and Au-nanoparticle-deposited TiO (2) nanoparticles at the single-particle, single-molecule levels.

Au

TiO (2)


Input: The minimum probe concentration to detect single-product molecules on a single TiO (2) nanoparticle was found to be in the nanomolar range (< 10 nM) in acidic solution.

TiO (2)


Input: Furthermore, super-resolution mapping of the reaction sites revealed that visible-light-induced reduction reactions preferentially occurred on the TiO (2) surface within a distance of a few tens of nanometers around the deposited Au nanoparticles.

TiO (2)

Au


Input: This result was qualitatively interpreted on the basis of plasmon-induced electron and/or energy transfer mechanisms.


Input: Overall, this study provides a great deal of valuable information related to solar-energy-conversion processes that is impossible or difficult to obtain from ensemble-averaged experiments.


Input: Self-assembled pH-sensitive cholesteryl pullulan nanogel as a protein delivery vehicle.

cholesteryl


Input: A self-assembled nanogel, derived from an acid-labile cholesteryl-modified pullulan (acL-CHP), was prepared by grafting vinyl ether-cholesterol substituents onto a 100 kD pullulan main chain polymer backbone.

cholesteryl

vinyl ether

cholesterol


Input: Stable nanogels are formed by acL-CHP self-assemblies at neutral pH.


Input: The hydrodynamic radius of the nanogels, observed to be 26. 5 +/- 5. 1 nm at pH 7. 0, increased by ~ 135% upon acidification of the solution to pH 4. 0.


Input: SEC analysis of the acL-CHP nanogel at pH 4. 0 showed that the grafts were nearly 80% degraded after 24 h, whereas little or no degradation was observed over the same time period for a pH stable analog (acS-CHP) at pH 4. 0 or the acL-CHP at pH 7. 0.


Input: Complexation of BSA with the acL-CHP nanogel was observed at pH 7. 0 with subsequent release of the protein upon acidification.


Input: These findings suggest that stimuli-responsive, self-assembled nanogels can release protein cargo in a manner that is controlled by the degradation rate of the cholesterol-pullulan grafting moiety.

cholesterol


Input: An ultrastrong nanofibrillar biomaterial: the strength of single cellulose nanofibrils revealed via sonication-induced fragmentation.


Input: We report the mechanical strength of native cellulose nanofibrils.


Input: Native cellulose nanofibrils, purified from wood and sea tunicate, were fully dispersed in water via a topochemical modification of cellulose nanofibrils using 2, 2, 6, 6-tetramethylpiperidinyl-1-oxyl (TEMPO) as a catalyst.

2, 2, 6, 6-tetramethylpiperidinyl-1-oxyl

TEMPO


Input: The strength of individual nanofibrils was estimated based on a model for the sonication-induced fragmentation of filamentous nanostructures.


Input: The resulting strength parameters were then analyzed based on fracture statistics.


Input: The mean strength of the wood cellulose nanofibrils ranged from 1. 6 to 3 GPa, depending on the method used to measure the nanofibril width.


Input: The highly crystalline, thick tunicate cellulose nanofibrils exhibited higher mean strength of 3-6 GPa.


Input: The strength values estimated for the cellulose nanofibrils in the present study are comparable with those of commercially available multiwalled carbon nanotubes.

carbon


Input: Synergistic activity and mechanism of action of ceftazidime and apigenin combination against ceftazidime-resistant Enterobacter cloacae.

ceftazidime

apigenin

ceftazidime


Input: The purpose of this investigation was to examine the antibacterial and synergistic effect of naturally occurring flavonoids, apigenin, quercetin, naringenin and ceftazidime when use singly and in combination against ceftazidime-resistant Enterobacter cloacae strains by minimum inhibitory concentration (MIC), checkerboard and viable count methods.

flavonoids

apigenin

quercetin

naringenin

ceftazidime

ceftazidime


Input: The mode of actions were also studied by electronmicoscopy, enzyme assay, outer and inner membrane permeabilisation.


Input: The results showed that these strains were positive in the ESBL-ampC genes combination by multiplex PCR.


Input: These findings were confirmed by MICs that these strains were resistant to ceftazidime, cefepime and flomoxef at > 1024, 16-24, > 256 mu g/ml respectively, while susceptible to imipenem at 1-2 mu g/ml.

ceftazidime

cefepime

flomoxef

imipenem


Input: The synergistic activity was observed at ceftazidime plus either apigenin or naringenin combinations with FIC indixes between < 0. 01 and < 0. 27 against these strains, whereas ceftazidime plus clavulanic acid or quercetin did not exhibit synergy.

ceftazidime

apigenin

naringenin

ceftazidime

clavulanic acid

quercetin


Input: The modulation of ceftazidime-resistance by apigenin or narigenin significantly enhanced the activities of ceftazidime.

ceftazidime

apigenin

narigenin

ceftazidime


Input: The 5, 7-OH group of A ring and one 4'-OH group of the B ring in apigenin and naringenin are important for synergistic activity.

5, 7-OH

apigenin

naringenin


Input: Viable counts showed that the killing of ceftazidime-resistant E. cloacae DMST 21394 (CREC) cells by 3 mu g/ml ceftazidime was potentiated by 3 mu g/ml apigenin to low levels (10 (3) cfu/ml) over 6h.

ceftazidime

ceftazidime

apigenin


Input: Electronmicroscopy clearly showed that ceftazidime 3 mu g/ml in combination with 3 mu g/ml of apigenin also caused marked morphological damage of cell wall, cell shape and plasma membrane of this strain.

ceftazidime

apigenin


Input: Enzymes assays indicated that apigenin showed marked inhibitory activity against penicillinase type IV from E. cloacae.

apigenin


Input: The results for outer membrane (OM) permeabilization in both nitrocefin (NCF) assay and crystal violet uptake showed that the combination of ceftazidime plus apigenin significantly altered OM permeabilisation of CREC compared to control or single treatment of these agents.

nitrocefin

NCF

crystal violet

ceftazidime

apigenin


Input: Both o-nitrophenyl-beta-D-galactoside (ONPG) uptake and release of UV-absorbing material concentrations results exhibited that ceftazidime and apigenin combination damaged CREC cytoplasmic membrane (CM) and caused subsequent leakage of intracellular constituents.

o-nitrophenyl-beta-D-galactoside

ONPG

ceftazidime

apigenin


Input: From the results, it can be concluded that apigenin and naringenin have the synergistic effect with ceftazidime to reverse bacterial resistance to this cephalosporin against CREC.

apigenin

naringenin

ceftazidime

cephalosporin


Input: This activity may be involved three mechanisms of action by apigenin.

apigenin


Input: The first is on the peptidoglycan synthesis inhibition.


Input: The second mechanism is inhibition the activity of certain beta-lactamase enzymes.


Input: The third mode of action is alteration of OM and CM permeabilization.


Input: Apigenin and naringenin have a sufficient margin of safety for therapeutic use.

Apigenin

naringenin


Input: For this reason, apigenin and naringenin offer for the development of a valuable adjunct to ceftazidime against CREC, which currently almost cephalosporins resistance.

apigenin

naringenin

ceftazidime

cephalosporins


Input: Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: identification of sulfonamido-1, 2, 3-triazole-4, 5-dicarboxylic acid.

sulfonamido-1, 2, 3-triazole-4, 5-dicarboxylic acid


Input: Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH (2) to PGE (2) and represents a novel target for therapeutic treatment of inflammatory disorders.

prostaglandin E

prostaglandin E

prostaglandin PGH (2)

PGE (2)


Input: It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs.


Input: Herein we report the discovery of sulfonamido-1, 2, 3-triazole-4, 5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds.

sulfonamido-1, 2, 3-triazole-4, 5-dicarboxylic


Input: 1-[2-(N-Phenylbenzenesulfonamido) ethyl]-1H-1, 2, 3-triazole-4, 5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC (50) of 1. 1 mu M) with high selectivity (ca. 1000-fold) over both COX-1 and COX-2 in a cell-free assay.

1-[2-(N-Phenylbenzenesulfonamido) ethyl]-1H-1, 2, 3-triazole-4, 5-dicarboxylic acid


Input: In addition, the activity of compound 6f was again tested at 10 mu M concentration in presence of 0. 1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent.

Triton X-100


Input: Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors.


Input: The discovery of potent and selective 4-aminothienopyridines as B-Raf kinase inhibitors.


Input: A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design.


Input: Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC (50) = 5. 1, 16. 6 nM) and cellular assay (IC (50) = 0. 2, 0. 2 mu M), but also had an outstanding selectivity profile against other kinases.


Input: Mutational consequences of dNTP pool imbalances in E. coli.


Input: The accuracy of DNA synthesis depends on the accuracy of the polymerase as well as the quality and concentration (s) of the available 5'-deoxynucleoside-triphosphate DNA precursors (dNTPs).

dNTPs


Input: The relationships between dNTPs and error rates have been studied in vitro, but only limited insights exist into these correlations during in vivo replication.

dNTPs


Input: We have investigated this issue in the bacterium Escherichia coli by analyzing the mutational properties of dcd and ndk strains.


Input: These strains, defective in dCTP deaminase and nucleoside diphosphate kinase, respectively, are characterized by both disturbances of dNTP pools and a mutator phenotype. ndk strains have been studied before, but were included in this study, as controversies exist regarding the source of its mutator phenotype.

dCTP

nucleoside diphosphate

dNTP


Input: We show that dcd strains suffer from increased intracellular levels of dCTP (4-fold) and reduced levels of dGTP (2-fold), while displaying, as measured using a set of lacZ reversion markers in a mismatch-repair defective (mutL) background, a strong mutator effect for G. C --> T. A and A. T --> T. A transversions (27-and 42-fold enhancement, respectively).

dCTP

dGTP


Input: In contrast, ndk strains possess a lowered dATP level (4-fold) and modestly enhanced dCTP level (2-fold), while its mutator effect is specific for just the A. T --> T. A transversions.

dATP

dCTP


Input: The two strains also display differential mutability for rifampicin-resistant mutants.

rifampicin


Input: Overall, our analysis reveals for both strains a satisfactory correlation between dNTP pool alterations and the replication error rates, and also suggests that a minimal explanation for the ndk mutator does not require assumptions beyond the predicted effect of the dNTP pools.

dNTP

dNTP


Input: Parametrisation of the free energy of ATP binding to wild-type and mutant Kir6. 2 potassium channels.

ATP

potassium


Input: ATP-sensitive K (+) (K (ATP)) channels, comprised of pore-forming Kir6. x and regulatory SURx subunits, play important roles in many cellular functions; because of their sensitivity to inhibition by intracellular ATP, K (ATP) channels provide a link between cell metabolism and membrane electrical activity.

ATP

K (+)

K

ATP

ATP

K

ATP


Input: We constructed structural homology models of Kir6. 2 and a series of Kir6. 2 channels carrying mutations within the putative ATP-binding site.

ATP


Input: Computational docking was carried out to determine the conformation of ATP in its binding site.

ATP


Input: The Linear Interaction Energy (LIE) method was used to estimate the free-energy of ATP binding to wild-type and mutant Kir6. 2 channels.

ATP


Input: Comparisons of the theoretical binding free energies for ATP with those determined from mutational experiments enabled the identification of the most probable conformation of ATP bound to the Kir6. 2 channel.

ATP

ATP


Input: A set of LIE parameters was defined that may enable prediction of the effects of additional Kir6. 2 mutations within the ATP binding site on the affinity for ATP.

ATP

ATP


Input: Achyrofuran is an antibacterial agent capable of killing methicillin-resistant vancomycin-intermediate Staphylococcus aureus in the nanomolar range.

Achyrofuran

methicillin

vancomycin


Input: Currently, there is a pressing need for novel antibacterial agents against drug-resistant bacteria, especially those which have been common in our communities and hospitals, such as methicillin-resistant Staphylococcus aureus (MRSA).

methicillin


Input: The South American plant Achyrocline satureioides (" Marcela ") has been widely used in traditional medicine for a number of diseases, including infections.


Input: Several crude extracts from this plant have shown good antimicrobial activities in vitro.


Input: In the search for the active principle (s) that confers these antimicrobial activities, we have processed the dichloromethane extract from the aerial parts of the plant.

dichloromethane


Input: One of the isolated compounds showed extraordinary antibacterial activities against a set of clinically relevant Gram-positive strains that widely differ in their antibiogram profiles.


Input: This compound was identified as achyrofuran on the basis of its spectroscopic and physical data.

achyrofuran


Input: We determined the MIC to be around 0. 1 mu M (0. 07 mu g/ml) for the reference methicillin-resistant and vancomycin-intermediate S. aureus strain NRS402.

methicillin

vancomycin


Input: Moreover, nanomolar concentrations of achyrofuran killed 10 (6) bacteria within 12 h.

achyrofuran


Input: Based on the presence of the 2, 2'-biphenol core, we further studied whether achyrofuran killed bacteria through a mechanism of action similar to that reported for the naturally occurring antibiotic MC21-A.

2, 2'-biphenol

achyrofuran


Input: Indeed, we found that achyrofuran was not bacteriolytic by itself although it greatly compromised membrane impermeability as determined by increased SYTOX Green uptake.

achyrofuran

SYTOX Green


Input: Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis.

wogonin


Input: Tumor growth and metastasis are associated with angiogenesis and lymphangiogenesis through the production of vascular endothelial growth factor (VEGF) or VEGF-C in tumors, and the phosphorylation of VEGF receptor (VEGFR)-2 or VEGFR-3 in vascular endothelial cells or lymphatic endothelial cells (LECs).


Input: Tumor-associated macrophages (TAMs) play an important role in tumor lymphangiogenesis, and consequently stimulate metastasis through the lymphatic system to lymph nodes.


Input: We examined the effects of wogonin isolated from Scutellaria baicalensis roots on tumor growth and metastasis using a highly metastatic model in osteosarcoma LM8-bearing mice.

wogonin


Input: Wogonin (25 and 50 mg/kg, twice daily) reduced tumor growth and metastasis to the lung, liver and kidney, angiogenesis (CD31-positive cells), lymphangiogenesis (LYVE-1-positive cells), and TAM (F4/80-positive cell) numbers in the tumors of LM8-bearing mice.

Wogonin


Input: Wogonin (10-100 mu M) also inhibited increases in IL-1 beta production and cyclooxygenase (COX)-2 expression induced by lipopolysaccharide in THP-1 macrophages.

Wogonin


Input: Wogonin had no effect on VEGF-C production in LM8 cells, or VEGFR-3 expression in human lymphatic endothelial cells (HLECs), however, it inhibited VEGF-C-induced VEGFR-3 phosphorylation in HLECs.

Wogonin


Input: The anti-tumor and anti-metastatic actions of wogonin may be associated with the inhibition of VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation by the inhibition of COX-2 expression and IL-1 beta production in TAMs.

wogonin


Input: Ginkgo biloba leaves extract (EGb 761) attenuates lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and NF-kappa B-dependent matrix metalloproteinase-9 pathway.


Input: Acute lung injury (ALI) presents high mortality and morbidity clinically and by far no effective preventive strategy has been established.


Input: Extract of Ginkgo biloba leaves, EGb 761, is a complex mixture that possesses several clinical beneficial effects such as anti-oxidation, anti-inflammation, anti-tumor, and cardioprotective property.


Input: With EGb 761 pretreatment, both lipopolysaccharide (LPS)-induced protein leakage and neutrophil infiltration, and LPS-induced inflammatory responses including increased myeloperoxidase (MPO) activity, lipid peroxidation, and metalloproteinase (MMP)-9 activity, were inhibited; LPS-suppressed activation of antioxidative enzymes (AOE) were reversed; and not only the phosphorylation of NF-kappa B but also the degradation of its inhibitor, I kappa B, were suppressed.


Input: These results suggested that the protection mechanism of EGb 761 is by inhibition of NF kappa B activation, possibly via the up-regulation of antioxidative enzymes.


Input: More studies are needed to further evaluate whether EGb 761 is a suitable candidate as an effective dietary strategy to reduce the incidence of endotoxin-induced ALI.


Input: The discovery, engineering and characterisation of a highly potent anti-human IL-13 fab fragment designed for administration by inhalation.


Input: We describe the discovery, engineering and characterisation of a highly potent anti-human interleukin (IL)-13 Fab fragment designed for administration by inhalation.


Input: The lead candidate molecule was generated via a novel antibody discovery process, and the selected IgG variable region genes were successfully humanised and reformatted as a human IgG gamma 1 Fab fragment.


Input: Evaluation of the biophysical properties of a selection of humanised Fab fragments in a number of assays allowed us to select the molecule with the optimal stability profile.


Input: The resulting lead candidate, CA652. g2 Fab, was shown to have comparable activity to the parental IgG molecule in a range of in vitro assays and was highly stable.


Input: Following nebulisation using a mesh nebuliser, CA652. g2 Fab retained full binding affinity, functional neutralisation potency and structural integrity.


Input: Epitope mapping using solution nuclear magnetic resonance confirmed that the antibody bound to the region of human IL-13 implicated in the interaction with IL-13R alpha 1 and IL-13R alpha 2.


Input: The work described here resulted in the discovery and design of CA652. g2 human gamma 1 Fab, a highly stable and potent anti-IL-13 molecule suitable for delivery via inhalation.


Input: beta-phenylethyl isothiocyanate reverses platinum resistance by a GSH-dependent mechanism in cancer cells with epithelial-mesenchymal transition phenotype.

beta-phenylethyl isothiocyanate

platinum

GSH


Input: Platinum (Pt)-based chemotherapy is an important regimen in the clinical treatment of cancer, but development of drug resistance presents a major challenge.

Platinum

Pt


Input: One key mechanism involved in resistance to Pt drugs is the decrease of intracellular Pt due to the drug efflux through the glutathione (GSH)-mediated export, and this is particularly significant in cancer cells with stem-cell like properties.

Pt

Pt

glutathione

GSH


Input: In the present study, we showed that two Pt-resistant human cancer cell lines exhibited stem-cell like EMT properties, had high cellular GSH and accumulated significantly less cellular Pt compared to their parental cells, and failed to undergo apoptosis when exposed to Pt at the drug concentrations toxic to the parental cells.

Pt

GSH

Pt

Pt


Input: Importantly, we found that the natural compound beta-phenylethyl isothiocyanate (PEITC) was able to effectively abolish this drug resistant mechanism by effective depletion of cellular GSH, leading to a significant increase in cellular Pt as well as DNA-bound Pt.

beta-phenylethyl isothiocyanate

PEITC

GSH

Pt

Pt


Input: A combination of PEITC and Pt showed a striking synergistic anticancer activity both in vitro and in vivo, as evidenced by an increase in drug-induced apoptosis, a loss of colony formation capacity, and significant suppression of tumor growth in mice.

PEITC

Pt


Input: Taken together, our study shows a promising therapeutic strategy to overcome drug resistance to platinum-based chemotherapy and may potentially have broad implications in clinical treatment of cancer.

platinum


Input: Analysis by substituted cysteine scanning mutagenesis of the fourth transmembrane domain of the CXCR4 receptor in its inactive and active state.

cysteine


Input: The chemokine SDF-1 (CXCL12) selectively binds to CXCR4, a member of the G protein-coupled receptor (GPCR) superfamily.


Input: In this study, we used the substituted-cysteine accessibility method (SCAM) to identify specific residues of the fourth transmembrane domain (TM4) that contribute to the formation of the binding pocket of CXCR4 in its inactive and active state.

cysteine


Input: We successively substituted each residue from E179 ((4. 68)) to K154 ((4. 43)) with cysteine and expressed the mutants in COS-7 cells.

cysteine


Input: Mutant receptors were then alkylated with methanethiosulfonate-ethylammonium (MTSEA), and binding inhibition was monitored using the CXCR4 antagonist FC131 [cyclo (-D-Tyr (1)-Arg (2)-Arg (3)-Nal (4)-Gly (5)-)], which displays anti-HIV activity.

methanethiosulfonate-ethylammonium

MTSEA

cyclo (-D-Tyr (1)-Arg (2)-Arg (3)-Nal (4)-Gly (5)-)


Input: MTSEA treatment resulted in a significant reduction of FC131 binding to D171C ((4. 60)) and P170C ((4. 59)).

MTSEA


Input: To assess TM4 accessibility in an active state of CXCR4, TM4 cysteine mutants were transposed within the constitutively active mutant N119S ((3. 35)).

cysteine


Input: MTSEA treatment of TM4 mutants N119S-S178C ((4. 67)), N119S-V177C ((4. 66)) and N119S-I173C ((4. 62)) resulted in a significant reduction in FC131 binding.

MTSEA


Input: Protection assays using FC131 prior to MTSEA treatment significantly reduced the alkylation of all MTSEA-sensitive mutants.

MTSEA

MTSEA


Input: The accessibility of the D171C ((4. 60)) and P170C ((4. 59)) residues suggests that they are oriented towards a water-accessible area of the binding pocket of CXCR4.


Input: S178C ((4. 67)), V177C ((4. 66)) and I173C ((4. 62)) showed binding inhibition only in an N119S ((3. 35)) background.


Input: Taken together our results suggest that TM4 and ECL2 undergo conformational changes during CXCR4 activation and also demonstrate how TM4 is an important feature for the binding of anti-HIV compounds.


Input: Discovery of alkenylboronic acids as neuroprotective agents affecting multiple biological targets involved in Alzheimer' s disease.

alkenylboronic acids


Input: Alkenylboronic acids have shown important biological activities that contribute to neuroprotection.

Alkenylboronic acids


Input: We have determined their influence on the beta-amyloid (beta A) aggregation process, beta-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment.

hydrogen peroxide


Input: We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD.

2-arylvinylboronic acids

esters


Input: These properties are not paralleled by the related 2-arylboronic acids.

2-arylboronic acids


Input: Studies on percutaneous penetration of chemicals-Impact of storage conditions for excised human skin.


Input: According to international guidelines skin penetration experiments can be carried out using freshly excised or frozen stored skin.


Input: However, this recommendation refers to data obtained in experiments with human cadaver skin.


Input: In our study, the percutaneous penetration of the occupationally relevant chemicals anisole, cyclohexanone and 1, 4-dioxane was investigated for freshly excised as well as for 4 and 30 days at-20 degrees C stored human skin using the diffusion cell technique.

anisole

cyclohexanone

1, 4-dioxane


Input: As indicator for the impairment of skin barrier by freezing cholesterol dissolution was determined in the solvents in exposure chambers of diffusion cells.

cholesterol


Input: Considering the percutaneously penetrated amounts, the following ranking was determined: 1, 4-dioxane > anisole > cyclohexanone (decline to a factor of 5. 9).

1, 4-dioxane

anisole

cyclohexanone


Input: The differences of fluxes between freshly excised and frozen stored skin (4 and 30 days) were not significant (p > 0. 05).


Input: Cholesterol dissolved from the skin indicates no significant differences between freshly excised and frozen stored skin.

Cholesterol


Input: This study shows that freezing of human skin for up to 30 days does not alter the skin barrier function and the permeability of chemicals.


Input: Off-target effects of thrombolytic drugs: apolipoprotein A-I proteolysis by alteplase and tenecteplase.


Input: The administration of thrombolytic drugs is of proven benefit in a variety of clinical conditions requiring acute revascularization, including acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism, and venous thrombosis.


Input: Generated plasmin can degrade non-target proteins, including apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoproteins (HDL).


Input: Aim of the present study was to compare the extent of apoA-I proteolytic degradation in AMI patients treated with two thrombolytic drugs, alteplase and the genetically engineered t-PA variant tenecteplase.


Input: ApoA-I degradation was evaluated in sera from 38 AMI patients treated with alteplase or tenecteplase.


Input: In vitro, apoA-I degradation was tested by incubating control sera or purified HDL with alteplase or tenecteplase at different concentrations (5-100 mu g/ml).


Input: Treatment with alteplase and tenecteplase results in apoA-I proteolysis; the extent of apoA-I degradation was more pronounced in alteplase-treated patients than in tenecteplase-treated patients.


Input: In vitro, the extent of apoA-I proteolysis was higher in alteplase-treated sera than in tenecteplase-treated sera, in the whole drug concentration range.


Input: No direct effect of the two thrombolytic agents on apoA-I degradation was observed.


Input: In addition to apoA-I, apoA-IV was also degraded by the two thrombolytic agents and again proteolytic degradation was higher with alteplase than tenecteplase.


Input: In conclusion, this study indicates that both alteplase and tenecteplase cause plasmin-mediated proteolysis of apoA-I, with alteplase resulting in a greater apoA-I degradation than tenecteplase, potentially causing a transient impairment of HDL atheroprotective functions.


Input: Structural determinants of substrate specificity in aldehyde dehydrogenases.

aldehyde


Input: Within the aldehyde dehydrogenase (ALDH) superfamily, proteins belonging to the ALDH9, ALDH10, ALDH25, ALDH26 and ALDH27 families display activity as omega-aminoaldehyde dehydrogenases (AMADHs).

aldehyde

omega-aminoaldehyde


Input: These enzymes participate in polyamine, choline and arginine catabolism, as well as in synthesis of several osmoprotectants and carnitine.

polyamine

choline

arginine

carnitine


Input: Active site aromatic and acidic residues are involved in binding the omega-aminoaldehydes in plant ALDH10 enzymes.

omega-aminoaldehydes


Input: In order to ascertain the degree of conservation of these residues among AMADHs and to evaluate their possible relevance in determining the aminoaldehyde specificity, we compared the known amino acid sequences of every ALDH family that have at least one member with known crystal structure, as well as the electrostatic potential surface of the aldehyde binding sites of these structures.

aminoaldehyde

amino acid

aldehyde


Input: Our analyses showed that four or three aromatic residues form a similar " aromatic box " in the active site of the AMADH enzymes, being the equivalents to Phe170 and Trp177 (human ALDH2 numbering) strictly conserved in all of them, which supports their relevance in binding the aminoaldehyde by cation-pi interactions.

aminoaldehyde


Input: In addition, all AMADHs exhibit a negative electrostatic potential surface in the aldehyde-entrance tunnel, due to side-chain carboxyl and hydroxyl groups or main-chain carbonyl groups.

aldehyde

carboxyl

hydroxyl

carbonyl


Input: In contrast, ALDHs that have non-polar or negatively charged substrates exhibit neutral or positive electrostatic potential surfaces, respectively.


Input: Finally, our comparative sequence analyses revealed that the residues equivalent to Asp121 and Phe170 are highly conserved in many ALDH families irrespective of their substrate specificity-suggesting that they perform a role in catalysis additional or different to binding of the substrate-and that the positions Met124, Cys301, and Cys303 are hot spots changed during evolution to confer aldehyde specificity to several ALDH families.

aldehyde


Input: Micelles of zinc protoporphyrin conjugated to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer for imaging and light-induced antitumor effects in vivo.

zinc protoporphyrin

N-(2-hydroxypropyl) methacrylamide

HPMA


Input: We synthesized N-(2-hydroxypropyl) methacrylamide polymer conjugated with zinc protoporphyrin (HPMA-ZnPP) and evaluated its application for tumor detection by imaging and treatment by light exposure using in mouse sarcoma model.

N-(2-hydroxypropyl) methacrylamide

zinc protoporphyrin

HPMA

ZnPP


Input: To characterize HPMA-ZnPP micelle, we measured its micellar size, surface charge, stability, photochemical, biochemical properties and tissue distribution.

HPMA

ZnPP


Input: In vivo anti-tumor effect and fluorescence imaging were carried out to validate the tumor selective accumulation and therapeutic effect by inducing singlet oxygen by light exposure.

oxygen


Input: HPMA-ZnPP was highly water soluble and formed micelles spontaneously having hydrophobic clustered head group of ZnPP, in aqueous solution, with a hydrodynamic diameter of 82. 8 +/- 41. 8 nm and zeta-potential of + 1. 12 mV.

HPMA

ZnPP

ZnPP


Input: HPMA-ZnPP had a long plasma half-life and effectively and selectively accumulated in tumors.

HPMA

ZnPP


Input: Although HPMA-ZnPP alone had no toxicity in S-180 tumor-bearing mice, light-irradiation significantly suppressed tumor growth in vivo, similar to the cytotoxicity to HeLa cells in vitro upon endoscopic light-irradiation.

HPMA

ZnPP


Input: HPMA-ZnPP can visualize tumors by fluorescence after i. v. injection, which suggests that this micelle may be useful for both tumor imaging and therapy.

HPMA

ZnPP


Input: Here we describe preparation of a new fluorescence nanoprobe that is useful for simultaneous tumor imaging and treatment, and application to fluorescence endoscopy is now at visible distance.


Input: In vivo biocompatibility, sustained-release and stability of triptorelin formulations based on a liquid, degradable polymer.

triptorelin


Input: Hexylsubstituted poly (lactic acid) (hexPLA) is a viscous polymer, which degrades in the presence of water similar to the structure related poly (lactic acid).

Hexylsubstituted poly (lactic acid)

hexPLA

poly (lactic acid)


Input: With hydrophilic active compounds, like Triptorelin acetate, the lipophilic polymer was formulated in form of parenterally injectable suspensions.

Triptorelin acetate


Input: This first in vivo study toward the biocompatibility of hexPLA implants in rats over 3 months in comparison to in situ forming poly (lactic-co-glycolic acid) (PLGA) formulations is presented here.

hexPLA

poly (lactic-co-glycolic acid)

PLGA


Input: The hexPLA implants showed only a mild acute inflammation at the injection site after application, which continuously regressed.

hexPLA


Input: In contrast to the PLGA formulations, hexPLA did not provoke an encapsulation of the implant with extracellular matrix.

PLGA

hexPLA


Input: Prior to the formulation application, the stability of Triptorelin inside the hexPLA matrix was assessed under different storage conditions and in the presence of buffer to simulate a peptide degrading environment.

Triptorelin

hexPLA


Input: At 5 degrees C Triptorelin showed a stability of 98% inside the polymer for at least 6 months.

Triptorelin


Input: The stability was still 78% at an elevated temperature of 40 degrees C.


Input: HexPLA protected the incorporated peptide from the surrounding aqueous environment, which resulted in 20% less degradation inside the polymer compared to the solution.

HexPLA


Input: This protection effect supports the use of Triptorelin-hexPLA formulations for parenteral sustained-release formulations.

Triptorelin

hexPLA


Input: In a second in vivo evaluation in Wistar Hannover rats, formulations containing 5% and 10% Triptorelin in the polymeric matrix released the active compound continuously for 6 months.

Triptorelin


Input: The formulations showed a higher release during the initial 7 days, which is necessary for the clinical use to down-regulate all GnRH-receptors.


Input: Afterwards, a zero order drug release was observed over the first 3 months.


Input: After 3 months, the plasma levels decreased slowly but remained at effective concentrations for the total of 6 months.


Input: Furthermore, a qualitative in vitro-in vivo correlation was observed, possibly facilitating future optimization of the Triptorelin-hexPLA sustained-release formulations.

Triptorelin

hexPLA


Input: Nanogel vaccines targeting dendritic cells: contributions of the surface decoration and vaccine cargo on cell targeting and activation.


Input: Dendritic cells (DCs) play crucial roles in initiating and promoting immune defences, providing a pivotal target for vaccines.


Input: Although nanoparticle/nanogel-based delivery vehicles are showing potential for delivering vaccines to the immune system, there is little information on their characteristics of interaction with DCs.


Input: While particle uptake by DCs has been shown, the mechanism of cell targeting has not been studied.


Input: Moreover, it is still unclear how particle surface decoration influences the handling of such vaccines by DCs.


Input: Accordingly, chitosan nanogels carrying a model antigen, ovalbumin (ova), were analysed for interaction with and processing by DCs.


Input: Nanogel surfaces decorated with alginate (alg) or mannosylated alginate (alg-man), were used for targeting particular DC receptors.

mannosylated


Input: DC uptake of particles was observed, being dependent on endosomal-based processes.


Input: Inhibiting PI3-kinase or lipid raft activities impaired the uptake, which was only reduced, indicating the involvement of more than one endocytic pathway; notably, this was observed with both nanogel-delivered or free ova.


Input: Importantly, surface decoration of particles was less influential on particle uptake, contrasting with the ova cargo which played the major role.


Input: Such influence of the vaccine cargo has to date been largely ignored.


Input: When receptors interacting directly with ova were blocked, this altered the uptake of alg-nanogels and alg-man-nanogels carrying ova.

man