Input: In conclusion, astaxanthin could relieve the symptoms and halt the progression of pulmonary fibrosis, partly by preventing transdifferentiation, inhibiting proliferation, and promoting apoptosis of activated cells.

astaxanthin


Input: Interactions between the Fusarium toxin deoxynivalenol and lipopolysaccharides on the in vivo protein synthesis of acute phase proteins, cytokines and metabolic activity of peripheral blood mononuclear cells in pigs.

deoxynivalenol


Input: The in vivo effects of the Fusarium toxin deoxynivalenol (DON) on albumin and fibrinogen synthesis in pigs and metabolic activity of porcine peripheral blood mononuclear cells (PBMCs) were studied alone or in combination with lipopolysaccharides (LPSs) in order to examine proposed synergistic effects of both substances.

deoxynivalenol

DON


Input: A total of 36 male castrated pigs (initial weight of 26kg) were used.


Input: Uncontaminated (Control) and naturally DON-contaminated (chronic oral DON, 3. 1mg/kg diet) wheat was fed for 37days.

DON

DON


Input: On the day of protein synthesis measurement, pigs recruited from the Control group were treated once intravenously with (iv) DON (100 mu g/kg live weight (LW)/h), iv LPS (7. 5 mu g/kgLW/h) or a combination of both substances, and six pigs from the chronic oral group were treated once with iv LPS.

DON


Input: A treatment with DON alone exhibited no alterations of acute phase protein synthesis and metabolic activity of PBMC.

DON


Input: There was no evidence that the chosen dosing regimen of DON had influences on the induced sub-acute stage of sepsis, as the LPS challenge, irrespective of DON co-exposure, mediated an acute phase reaction with a typical decrease of albumin synthesis, as well as changes in cytokine concentration and a loss of metabolic activity in PBMC.

DON

DON


Input: Activation of ALDH2 with ethanol attenuates diabetes induced myocardial injury in rats.

ethanol


Input: This study assessed changes in myocardial ALDH2 expression in the diabetic rat, in particular the diabetic rat pretreated with ALDH2 activator ethanol (EtOH).

ethanol

EtOH


Input: The rats were divided into six groups: control, EtOH control, diabetic rat at 4th week (DM4W), 8th week (DM8W), 12th week (DM12W) and EtOH + DM8W groups.

EtOH

EtOH


Input: Compared with control group, fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were increased in DM groups.

glucose


Input: HbA1c level in DM12W group was higher than in DM4W group, HbA1c level in EtOH + DM8W group was lower than in DM8W group.

EtOH


Input: Compared with control group, there were no changes of LVDP, HR and +/- dp/dtmax in DM4W group, but there were decreased in DM8W and DM12W groups, and increased in the EtOH + DM8W group.

EtOH


Input: In DM groups, SOD activity, ALDH2 mRNA and protein levels were reduced, MDA content was increased compared with control group; which decreased further as diabetes progressed.

MDA


Input: Compared with DM8W group, SOD and ALDH2 in EtOH + DM8W group was increased, MDA was decreased.

EtOH

MDA


Input: Our results indicated with the development of diabetes, myocardial ALDH2 expression was further decreased accompanying decreased ventricular function.


Input: However, activation of ALDH2 can decrease diabetes induced myocardial injury.


Input: ALDH2 may be one key endogenous cardiac protective factor in diabetic individuals.


Input: Protective effects of a compound isolated from Alnus japonica on oxidative stress-induced death in transformed retinal ganglion cells.


Input: Here, we investigated whether hirsutenone, a compound isolated from Alnus japonica, was able to attenuate oxidative stress-induced death in transformed retinal ganglion (RGC-5) cells.

hirsutenone


Input: Hirsutenone effectively protected RGC-5 cells from oxidative insult induced by, l-buthionine-(S, R)-sulfoximine (BSO) plus glutamate in a concentration-dependent manner, as demonstrated by propidium iodide (PI)/Hoechst 33342 double staining, flow cytometry, and MTT assays.

l-buthionine-(S, R)-sulfoximine

BSO

glutamate

propidium iodide

MTT


Input: Moreover, hirsutenone inhibited the increase in apoptotic protein expression resulting from BSO plus glutamate.

hirsutenone

BSO


Input: Hirsutenone also effectively inhibited sodium nitroprusside (SNP)-induced lipid peroxidation in rat brain homogenates.

Hirsutenone

sodium nitroprusside

SNP


Input: To investigate the effects of hirsutenone in vivo, we used N-methyl-d-aspartate (NMDA) as a negative insult on the retinas of rats.

hirsutenone

N-methyl-d-aspartate

NMDA


Input: NMDA affects the thinning of the inner plexiform layer (IPL) and causes an increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive ganglion cells in the ganglion cell layer (GCL).

NMDA

dUTP


Input: Hirsutenone treatment led to a reduction in NMDA-induced IPL and TUNEL staining of the GCL.

Hirsutenone

NMDA


Input: In conclusion, hirsutenone isolated from A. japonica may act as neuroprotective agent for conditions such as glaucoma.

hirsutenone


Input: Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno [2, 3-d] pyrimidine derivatives.

2-pyridyl hexahyrocyclooctathieno [2, 3-d] pyrimidine


Input: A series of new 2-pyridyl hexahydrocycloocta [4, 5] thieno [2, 3-d] pyrimidines with different substituents as C-4 position was synthesized.

2-pyridyl hexahydrocycloocta [4, 5] thieno [2, 3-d] pyrimidines


Input: The anticancer activity of the newly synthesized compounds was tested in vitro using a two-stage process utilizing 60 different human tumor cell lines representing leukemia, melanoma and cancers of lung, colon, central nervous system, ovary, kidney, prostate as well as breast.


Input: Compounds 4a, 6a, 7a, 7d and 7g showed potent anticancer activity at low concentrations against most of the used human tumor cell lines comparable with doxorubicin as standard potent anticancer drug (average log10 GI50 over all cell lines =-6. 85).

doxorubicin


Input: Also, compound 4b was selective against SNB-75 (CNS cancer) log10 GI50 =-5. 57.


Input: Interestingly, compound 7e exhibited promising selectivity against 13 tumor cell lines showing growth inhibition percentages between 54. 05 and 89. 23.


Input: Synthesis and antibacterial evaluation of novel pleuromutilin derivatives.

pleuromutilin


Input: A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions.

pleuromutilin


Input: Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay.

methicillin

methicillin


Input: Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2-methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents.

14-O-[(4-methoxybenzamide-2-methylpropane-2-yl) thioacetate] mutilin

14-O-[(2-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin

14-O-[(4-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin


Input: Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients.

cyclosporine


Input: Aim: Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation.

Cyclosporine


Input: In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation. Methods: A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4 (*) 1G, CYP3A5 (*) 3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1-94 ins/del ATTG, and NR1I2 polymorphisms.

cyclosporine

cyclosporine


Input: Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay.

Cyclosporine


Input: Trough concentrations of cyclosporine were determined for days 7-18 following transplantation. Results: The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90. 4 +/- 24. 5 vs 67. 8 +/- 26. 8 (ng/mL)/(mg/kg), P = 0. 001].

cyclosporine

cyclosporine


Input: ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92. 0 +/- 24. 0 vs 68. 4 +/- 26. 5 (ng/mL)/(mg/kg), P = 0. 002].

cyclosporine


Input: Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97. 2 +/- 21. 8 vs 68. 7 +/- 26. 9 (ng/mL)/(mg/kg), P = 0. 001].


Input: Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1-94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the-94 ATTG del/del genotype [75. 9 +/- 32. 9 vs 55. 1 +/- 15. 1 (ng/mL)/(mg/kg), P = 0. 026]. Conclusion: These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.

cyclosporine

cyclosporine


Input: The exoribonuclease Dis3L2 defines a novel eukaryotic RNA degradation pathway.


Input: The final step of cytoplasmic mRNA degradation proceeds in either a 5'-3' direction catalysed by Xrn1 or in a 3'-5' direction catalysed by the exosome.


Input: Dis3/Rrp44, an RNase II family protein, is the catalytic subunit of the exosome.


Input: In humans, there are three paralogues of this enzyme: DIS3, DIS3L, and DIS3L2.


Input: In this work, we identified a novel Schizosaccharomyces pombe exonuclease belonging to the conserved family of human DIS3L2 and plant SOV.


Input: Dis3L2 does not interact with the exosome components and localizes in the cytoplasm and in cytoplasmic foci, which are docked to P-bodies.


Input: Deletion of dis3l2 (+) is synthetically lethal with xrn1 Delta, while deletion of dis3l2 (+) in an lsm1 Delta background results in the accumulation of transcripts and slower mRNA degradation rates.


Input: Accumulated transcripts show enhanced uridylation and in vitro Dis3L2 displays a preference for uridylated substrates.


Input: Altogether, our results suggest that in S. pombe, and possibly in most other eukaryotes, Dis3L2 is an important factor in mRNA degradation.


Input: Therefore, this novel 3'-5' RNA decay pathway represents an alternative to degradation by Xrn1 and the exosome.


Input: Composite dissolving microneedles for coordinated control of antigen and adjuvant delivery kinetics in transcutaneous vaccination.


Input: Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release.


Input: To this end, we demonstrate a microneedle materials platform for rapid implantation of controlled-release polymer depots into the cutaneous tissue.


Input: Arrays of microneedles comprised of drug-loaded poly (lactide-co-glycolide) (PLGA) microparticles or solid PLGA tips were prepared with a supporting and rapidly water-soluble poly (acrylic acid) (PAA) matrix.

poly (lactide-co-glycolide)

PLGA

PLGA

poly (acrylic acid)

PAA


Input: Upon application of microneedle patches to the skin of mice, the microneedles perforated the stratum corneum and epidermis.


Input: Penetration of the outer skin layers was followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which were retained following patch removal.

PAA


Input: These polymer depots remained in the skin for weeks following application and sustained the release of encapsulated cargos for systemic delivery.


Input: To show the utility of this approach we demonstrated the ability of these composite microneedle arrays to deliver a subunit vaccine formulation.


Input: In comparison to traditional needle-based vaccination, microneedle delivery gave improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery.


Input: However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts.


Input: Impact of long-range van der Waals forces on chiral recognition in a Cinchona alkaloid chiral selector system.


Input: Singly-charged complexes of (8S, 9R)-tert-butylcarbamoylquinine (tBuCQN), N-3, 5-dinitrobenzoyl-(S, R)-leucine (DNB-S/R-leucine), and alkali metal counter ions (Li (+), Na (+), K (+)) were investigated by density-functional theory.

(8S, 9R)-tert-butylcarbamoylquinine

tBuCQN

N-3, 5-dinitrobenzoyl-(S, R)-leucine

DNB

S/R-leucine

Li (+)

Na (+)

K (+)


Input: It is shown that the cations prefer formation of an ionic pair with the carboxylate group of DNB-Leu over the formation of a cation-pi interaction.

carboxylate

DNB

Leu


Input: The [tBuCQN. DNB-S/R-Leu. Na] (+) complex is bound by a coulombic attraction, a hydrogen bond, a pi-pi interaction and van der Waals forces.

[tBuCQN. DNB-S/R-Leu. Na] (+)


Input: The tBuCQN chiral selector preferentially complexes with the DNB-S-Leu enantiomer, because the favourable stereochemistry allows the stabilization of the complex by at least one binding mode more compared to the complex containing the DNB-R-Leu molecule.

tBuCQN

DNB

S-Leu

DNB

R-Leu


Input: Weakening of the binding modes is observed using the lithium counter ion compared to the sodium one.

lithium

sodium


Input: The weakening is more pronounced in [tBuCQN. DNB-R-Leu. Li] (+) than in [tBuCQN. DNB-S-Leu. Li] (+).

[tBuCQN. DNB-R-Leu. Li] (+)

[tBuCQN. DNB-S-Leu. Li] (+)


Input: The exact opposite effect is observed using the potassium counter ion.

potassium


Input: Hence, the lithium counter ion enhances the enantioselectivity of tBuCQN while the potassium counter ion reduces the enantioselectivity of tBuCQN.

lithium

tBuCQN

potassium

tBuCQN


Input: Synthesis of new 1, 3, 4-benzotriazepin-5-one derivatives and their biological evaluation as antitumor agents.

1, 3, 4-benzotriazepin-5-one


Input: New derivatives of 1, 3, 4-benzotriazepin-5-one were designed and synthesized as structural analogues to the antitumor agents devazepide and asperlicin.

1, 3, 4-benzotriazepin-5-one

devazepide

asperlicin


Input: An efficient and novel approach to the synthesis of 2-amino-1, 3, 4-benzotriazepin-5-one 2 was developed and its structure was confirmed.

2-amino-1, 3, 4-benzotriazepin-5-one


Input: The newly synthesized derivatives were evaluated for their in vitro antitumor activity on 60 different cell lines.


Input: Compounds 8 and 9 displayed the most potent antitumor activity against several cell lines specifically ovarian cancer, renal cancer and prostate cancer, while compounds 5, 10 and 12 showed significant activities against UO-31 renal cancer cell line.


Input: Pharmacotherapy for the core symptoms in autistic disorder: current status of the research.


Input: The current review covers extant literature on pharmacotherapy for core symptoms of autism.


Input: The core symptoms of autism include impairments in social interaction and communication, as well as the presence of restricted and repetitive behaviors.


Input: There are no known efficacious treatments for the core social symptoms, although effects on repetitive behaviors are indicated with some data.


Input: While studies of fenfluramine, secretin, opiates, and mood stabilizers generally find no effect, mixed results suggest more research is needed on antidepressants and atypical antipsychotics.

fenfluramine


Input: Newer lines of research, including cholinergic and glutamatergic agents and oxytocin, will be of considerable interest in the future.

oxytocin


Input: However, research on the treatment of core symptoms is plagued by limitations in study design, statistical power, and other issues inherent to the study of treatments for autism (e. g., heterogeneity of the disorder) that continue to prevent the elucidation of efficacious treatments.


Input: Solar-Powered Nanomechanical Transduction from Crystalline Molecular Rotors.


Input: A photoinduced solid-state SO2 isomerism drives a larger mechanical change (benzene-ring rotation) in a neighbouring ion (i. e., the system acts as a solar-powered molecular transducer).

benzene


Input: The ring rotation and SO2 photoisomerisation are observed using in situ X-ray crystallography and are controllable, reproducible, and metastable at low temperatures.


Input: This discovery presents a new range of materials for solar-energy-based molecular transduction.


Input: Inhibitory Effect of Ketoconazole on the Pharmacokinetics of a Multireceptor Tyrosine Kinase Inhibitor BMS-690514 in Healthy Participants: Assessing the Mechanism of the Interaction With Physiologically-Based Pharmacokinetic Simulations.

Ketoconazole

Tyrosine


Input: BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development.


Input: The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism.


Input: It is also a substrate of P-glycoprotein (P-gp) in vitro.


Input: To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days).

ketoconazole

ketoconazole


Input: The AUC infinity of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone.

ketoconazole


Input: The dose-normalized Cmax and AUC infinity of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone.

ketoconazole


Input: Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed.

ketoconazole


Input: This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate.

ketoconazole

ketoconazole


Input: A Stochastic Simulator of Birth-Death Master Equations with Application to Phylodynamics.


Input: In this article, we present a versatile new software tool for the simulation and analysis of stochastic models of population phylodynamics and chemical kinetics.


Input: Models are specified via an expressive and human-readable XML format and can be used as the basis for generating either single population histories or large ensembles of such histories.


Input: Importantly, phylogenetic trees or networks can be generated alongside the histories they correspond to, enabling investigations into the interplay between genealogies and population dynamics.


Input: Summary statistics such as means and variances can be recorded in place of the full ensemble, allowing for a reduction in the amount of memory used-an important consideration for models including large numbers of individual subpopulations or demes.


Input: In the case of population size histories, the resulting simulation output is written to disk in the flexible JSON format, which is easily read into numerical analysis environments such as R for visualization or further processing.


Input: Simulated phylogenetic trees can be recorded using the standard Newick or NEXUS formats, with extensions to these formats used for non-tree-like inheritance relationships.


Input: A Comparative Study of Baby Immature and Adult Shoots of Aloe Vera on UVB-Induced Skin Photoaging in vitro.


Input: Ultraviolet (UV) irradiation induces photo-damage of the skin, which in turn causes depletion of the dermal extracellular matrix and chronic alterations in skin structure.


Input: Skin wrinkle formations are associated with collagen synthesis and matrix metalloproteinase (MMP) expression.


Input: The production of type I procollagen is regulated by transforming growth factor-beta 1 (TGF-beta 1) expression; the activation of MMP is also correlated with an increase of interleukin-6 (IL-6).


Input: Aloe barbadensis M.


Input: (Aloe vera) is widely used in cosmetic and pharmaceutical products.


Input: In this study, we examined whether baby aloe shoot extract (BAE, immature aloe extract), which is from the one-month-old shoots of Aloe vera, and adult aloe shoot extract (AE), which is from the four-month-old shoots of Aloe vera, have a protective effect on UVB-induced skin photoaging in normal human dermal fibroblasts (NHDFs).


Input: The effects of BAE and AE on UVB-induced photoaging were tested by measuring the levels of reactive oxygen species, MMP-1, MMP-3, IL-6, type I procollagen, and TGF-beta 1 after UVB irradiation.

oxygen


Input: We found that NHDF cells treated with BAE after UVB-irradiation suppressed MMP-1, MMP-3, and IL-6 levels compared to the AE-treated cells.


Input: Furthermore, BAE treatment elevated type I procollagen and TGF-beta 1 levels.


Input: Our results suggest that BAE may potentially protect the skin from UVB-induced damage more than AE.


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


Input: Diverse effects of macromolecular crowding on the sequential glycan-processing pathway involved in glycoprotein quality control.


Input: Compared with in vitro conditions, the intracellular environment is highly crowded with biomolecules; this has numerous effects on protein functions, including enzymatic activity.


Input: We examined the effects of macromolecular crowding on glycan processing of N-glycoprotein in the endoplasmic reticulum as a model sequential metabolic pathway.

N


Input: Experiments with synthetic substrates of physiological glycan structure clearly showed that the first half of the pathway (glucose trimming) was accelerated, whereas the second (mannose trimming) was decelerated under molecular crowding conditions.

glucose

mannose


Input: Furthermore, calreticulin, a lectin-like molecular chaperone, bound more strongly to a glycan-processing intermediate under these conditions.


Input: This study demonstrates the diverse effects of molecular crowding on sequential enzymatic processing, and the importance of the effects of macromolecular crowding on in vitro assays for understanding sequential metabolic pathways.


Input: A computational study of water and CO migration sites and channels inside myoglobin.

CO


Input: Pathways are computed for transport of H2O and CO in myoglobin (Mb), using the single sweep and zero-temperature string methods in a fully atomistic, explicitly solvated model system.

CO


Input: Our predictions of sites and barriers in the pathways for CO transport agree with previous studies.

CO


Input: For H2O, we predict a binding site in the distal pocket (DP), in agreement with crystallographic observations, and another one close to Leu 29 which explains the importance of this residue in controlling the pocket' s hydrophobicity, as well as disordered minima in the largely apolar xenon cavities.

Leu

xenon


Input: In particular, H2O can occupy and transition among the xenon cavities, Xe4, Xe2, and Xe3.

xenon


Input: Our results support the hypothesis that the thermodynamically most favorable entry/exit portal for H2O is the so-called histidine gate (HG), the same as for CO.

histidine

CO


Input: This result, along with the observation of water occupation of both DP and apolar Xe cavities, suggest that water and small gas molecules like CO compete for access to the protein interior, and therefore models of gas molecule transport within proteins should also explicitly consider water transport.

Xe

CO


Input: Detection of Nanosized Ordered Domains in DOPC/DPPC and DOPC/Ch Binary Lipid Mixture Systems of Large Unilamellar Vesicles Using a TEMPO Quenching Method.

DOPC

DPPC

DOPC


Input: Nanosized ordered domains formed in 1, 2-dioleoyl-sn-glycero-3-phosphocholine/1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DOPC/DPPC) and DOPC/cholesterol (Ch) liposomes were characterized using a newly developed (2, 2, 6, 6-tetramethylpiperidin-1-yl) oxyl (TEMPO) quenching method.

1, 2-dioleoyl-sn-glycero-3-phosphocholine

1, 2-dipalmitoyl-sn-glycero-3-phosphocholine

DOPC

DPPC

DOPC

cholesterol

(2, 2, 6, 6-tetramethylpiperidin-1-yl) oxyl

TEMPO


Input: The membrane fluidity of the DOPC/DPPC liposomes, evaluated by the use of 1, 6-diphenyl-1, 3, 5-hexatriene (DPH), increased significantly above their phase-transition temperature.

DOPC

DPPC

1, 6-diphenyl-1, 3, 5-hexatriene

DPH


Input: The fluorescence spectra of 6-lauroyl-2-dimethylamino naphthalene (Laurdan) indicated the formation of an immiscible ordered phase in the DOPC/DPPC (50/50) liposomal membrane at 30 degrees C.

6-lauroyl-2-dimethylamino naphthalene

Laurdan

DOPC

DPPC


Input: The analysis of the membrane polarity indicated that the surface of the liquid-disordered phase was hydrated whereas that of the ordered phase was dehydrated.


Input: DOPC/DPPC and DOPC/Ch (70/30) liposomes exhibited heterogeneous membranes, indicating that nanosized ordered domains formed on the surface of the DOPC/DPPC liposomes.

DOPC

DPPC

DOPC

DOPC

DPPC


Input: The size of these nanosized ordered domains was estimated using the TEMPO quenching method.

TEMPO


Input: Because TEMPO can quench DPH distributed in the disordered phases, the remaining fluorescence from DPH is proportional to the size of the ordered domain.

TEMPO

DPH

DPH


Input: The domain sizes calculated for DOPC/DPPC (50/50), DOPC/DPPC (25/75), DOPC/Ch (70/30), and DOPC/DPPC/Ch (40/40/20) were 13. 9, 36. 2, 13. 2, and 35. 5 A, respectively.

DOPC

DPPC

DOPC

DPPC

DOPC

DOPC

DPPC


Input: Novel regulatory system nemRA-gloA for electrophile reduction in Escherichia coli K-12.


Input: Electrophilic compounds such as glyoxals, which are toxic due to their reactive carbonyl group, are generated in vivo through various pathways.

glyoxals

carbonyl


Input: In this study, we obtained evidence indicating that the nemRA operon, previously reported to encode a repressor and the N-ethylmaleimide reductase, respectively, is co-transcribed with the 3'-proximal gloA gene encoding glyoxalase I.

N-ethylmaleimide


Input: The operon is not only involved in cytosolic detoxification but is also regulated by electrophiles such as quinones and glyoxals.

quinones

glyoxals


Input: A gel mobility shift assay revealed that purified NemR repressor bound to DNA was dissociated upon interaction with quinones and glyoxals, while their reduced forms were ineffective.

quinones

glyoxals


Input: The cysteines of NemR at 21 and 116 were essential in sensing electrophiles in vivo and in vitro.


Input: Reversible intermolecular disulphide bonds were observed with a reducing agent as well as with electrophiles.

disulphide


Input: DNA binding affinity reduced by glyoxal was also increased with a reducing agent.

glyoxal


Input: The NemA reductase, an FMN-containing enzyme, exhibited catalytic activity toward various electrophiles including quinones, while GloA played a major role in glyoxal detoxification.

FMN

quinones

glyoxal


Input: Therefore, we propose that cells have a cytosolic system consisting of the nemRA-gloA operon for the reduction of electrophiles, especially quinones and glyoxals, to maintain an appropriate intracellular redox balance.

quinones

glyoxals


Input: Interfacial rheology of asphaltenes at oil-water interfaces and interpretation of the equation of state.


Input: In an earlier study, (1) oil-water interfacial tension was measured by the pendant drop technique for a range of oil-phase asphaltene concentrations and viscosities.


Input: The interfacial tension was found to be related to the relative surface coverage during droplet expansion.


Input: The relationship was independent of aging time and bulk asphaltenes concentration, suggesting that cross-linking did not occur at the interface and that only asphaltene monomers were adsorbed.


Input: The present study extends this work to measurements of interfacial rheology with the same fluids.


Input: Dilatation moduli have been measured using the pulsating droplet technique at different frequencies, different concentrations (below and above CNAC), and different aging times.


Input: Care was taken to apply the technique in conditions where viscous and inertial effects are small.


Input: The elastic modulus increases with frequency and then plateaus to an asymptotic value.


Input: The asymptotic or instantaneous elasticity has been plotted against the interfacial tension, indicating the existence of a unique relationship, between them, independent of adsorption conditions.


Input: The relationship between interfacial tension and surface coverage is analyzed with a Langmuir equation of state.


Input: The equation of state also enabled the prediction of the observed relationship between the instantaneous elasticity and interfacial tension.


Input: The fit by a simple Langmuir equation of state (EOS) suggests minimal effects of aging and of nanoaggregates or gel formation at the interface.


Input: Only one parameter is involved in the fit, which is the surface excess coverage Gamma infinity = 3. 2 molecules/nm (2) (31. 25 A (2)/molecule).


Input: This value appears to agree with flat-on adsorption (2) of monomeric asphaltene structures consisting of aromatic cores composed of an average of six fused rings and supports the hypothesis that nanoaggregates do not adsorb on the interface.


Input: The observed interfacial effects of the adsorbed asphaltenes, correlated by the Langmuir EOS, are consistent with the asphaltene aggregation behavior in the bulk fluid expected from the Yen-Mullins model.


Input: (3, 4).


Input: The heart in sepsis: from basic mechanisms to clinical management.


Input: Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production.


Input: In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated.


Input: As a result, cells and organs may survive in a non-functioning hibernation-like condition.


Input: Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown.


Input: Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors.


Input: Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins.

calcium

calcium


Input: All these changes are mediated by cytokines.


Input: Treatment includes preload optimization with sufficient fluids.


Input: However, excessive volume loading is harmful.


Input: The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines.

norepinephrine

catecholamines


Input: During early sepsis, cardiac output can be increased by dobutamine.

dobutamine


Input: While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful.

catecholamines


Input: Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article.


Input: Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands.

levosimendan

istaroxime

omecamtiv mecarbil

oxygen


Input: Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling.

ivabradine

oxygen


Input: Beta-blockers additionally reduce local and systemic inflammation.


Input: Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions.

pyruvate

succinate


Input: All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.


Input: BACE2 as a new diabetes target: a patent review (2010-2012).


Input: Introduction: When two novel aspartyl proteases were published in 1999 and 2000, beta-site APP-cleaving enzyme 1 (BACE1) was confirmed as the long sought after beta-secretase and Alzheimer' s disease drug target.


Input: However, the role of its paralogue, BACE2, proved elusive until a 2011 publication implicated it as a Collectrin (TMEM27) secretase controlling pancreatic beta-cell proliferation and a new therapeutic intervention for diabetes.


Input: Areas covered: This review, using SureChemOpen, encompasses early validation compounds and small-molecule BACE2 inhibitors for diabetes.


Input: Since 2010, one assay patent and several chemical series have been published by Roche but these were followed by filings from Novartis and Schering in 2012.


Input: The patents from these three companies include BACE2-only filings but also some specifying both BACE1 and BACE2 inhibitors.


Input: Expert opinion: Roche' s early collaborative target validation has given them a lead in BACE2 medicinal chemistry.


Input: However, the extensive data output for BACE1 in patents and papers over the last decade, plus liganded crystal structures for both proteases, should expedite the design of BACE2 inhibitors by other organisations.


Input: This may also shorten the development time for clinical candidates that, unlike those now entering Phase I trials for BACE1, would not need to be brain-penetrant.


Input: A novel benzo [d] imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome.

benzo [d] imidazole

sodium


Input: NLRP3 inflammasome has been reported to be associated with various kinds of immunological diseases including colitis.


Input: However, there are few drug candidates targeting inflammasomes for the treatment of colitis.


Input: In the present study, we aimed at examining the effect of 1-ethyl-5-methyl-2-phenyl-1H-benzo [d] imidazole, a synthetic small molecular compound also named Fc11a-2, for the treatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice via targeting NLRP3 inflammasome.

1-ethyl-5-methyl-2-phenyl-1H-benzo [d] imidazole

sulfate sodium


Input: Treatment with Fc11a-2 dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS.


Input: In addition, the disease activity index, histopathologic scores and myeloperoxidase activity were also significantly reduced by Fc11a-2 treatment.


Input: Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF-alpha, IL-1 beta, IL-18, IL-17A and IFN-gamma, were markedly suppressed by Fc11a-2.


Input: Furthermore, a decreased CD11c (+) macrophage infiltration in colons and inactivation of caspase-1 in peritoneal macrophages were detected in Fc11a-2-treated mice.


Input: The mechanism of action of Fc11a-2 was related to the inhibition of the cleavage of pro-caspase-1, pro-IL-1 beta and pro-IL-18 which in turn suppressed the activation of NLRP3 inflammasome.


Input: Taken together, our results demonstrate the ability of Fc11a-2 to inhibit NLRP3 inflammasome activation and its potential use in the treatment of inflammatory bowel diseases.


Input: Intact inhibitory control processes in abstinent drug abusers (II): A high-density electrical mapping study in former cocaine and heroin addicts.

cocaine

heroin


Input: Response inhibition deficits are well-documented in drug users, and are related to the impulsive tendencies characteristic of the addictive phenotype.


Input: Addicts also show significant motivational issues that may accentuate these inhibitory deficits.


Input: We investigated the extent to which these inhibitory deficits are present in abstinence.


Input: Salience of the task stimuli was also manipulated on the premise that emotionally-valenced inputs might impact inhibitory efficacy by overcoming the blunted responses to everyday environmental inputs characteristic of this population.


Input: Participants performed response inhibition tasks consisting of both neutral and emotionally valenced stimuli while high-density event-related potentials (ERPs) were recorded.


Input: Electrophysiological responses (N2/P3 components) to successful inhibitions in abstinent abusers (N = 20) and non-using participants (N = 21) were compared.


Input: In contrast to previous work in current users, our abstinent cohort showed no detectable behavioral or electrophysiological differences in their inhibitory responses, and no differences on self-reports of impulsivity, despite their long histories of chronic use (mean = 10. 3 years).


Input: The current findings are consistent with a recovery of inhibitory control processes as a function of abstinence.


Input: Abstinent former users, however, did show a reduced modulation, relative to controls, of their ERPs to valenced input while performing successful inhibitions, although contrary to our hypothesis, the use of valenced inputs had no impact on inhibitory performance.


Input: Reduced ERP modulation to emotionally valenced inputs may have implications for relapse in emotional contexts outside the treatment center.


Input: Minireview: Nuclear Insulin and Insulin-like Growth Factor-1 Receptors: A Novel Paradigm in Signal Transduction.


Input: The specificity of the insulin receptor (InsR) and insulin-like growth factor-1 receptor (IGF1R) signaling pathways has been the focus of significant debate over the past few years.


Input: Recent evidence showing nuclear import and a direct transcriptional role for both InsR and IGF1R adds a new layer of complexity to this dialog.


Input: Hence, in addition to the classical roles associated with cell-surface receptors (eg, ligand binding, autophosphorylation of the tyrosine kinase domain, activation of insulin receptor substrate 1 (IRS-1) and additional substrates, protein-protein interactions with membrane and cytoplasm components), new data are consistent with nuclear (genomic) role (s) for both InsR and IGF1R.

tyrosine


Input: The present review provides a brief overview of the physical and functional similarities and differences between InsR and IGF1R and describes data from a number of laboratories providing evidence for a new layer of signaling regulation (ie, the ability of InsR and IGF1R to translocate to the cell nucleus and to elicit genomic activities usually associated with transcription factors).


Input: The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction.


Input: Although research on the role of nuclear InsR/IGF1R is still in its infancy, we believe that this rapidly developing area may have a major basic and translational impact on the fields of metabolism, diabetes, and cancer.


Input: Loss of an ig kappa gene enhancer in mature B cells results in rapid gene silencing and partial reversible dedifferentiation.


Input: We address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state.


Input: We have previously shown that the mouse Ig kappa gene' s downstream enhancers, E3' and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development.


Input: To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3' in mature B cells that possessed Ed (-/-) alleles.


Input: Upon E3' deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and-2 along with certain other pro-B cell makers, and then redifferentiated after triggering Ig lambda gene rearrangements.


Input: We conclude that the Ig kappa gene' s downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus.


Input: Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation.


Input: This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery.


Input: Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels.

glucose


Input: AIMS/HYPOTHESIS: We previously identified the G6PC2 locus as a strong determinant of fasting plasma glucose (FPG) and showed that a common G6PC2 intronic single nucleotide polymorphism (SNP) (rs560887) and two common G6PC2 promoter SNPs (rs573225 and rs13431652) are highly associated with FPG.

glucose


Input: However, these promoter SNPs have complex effects on G6PC2 fusion gene expression, and our data suggested that only rs13431652 is a potentially causative SNP.


Input: Here we examine the effect of rs560887 on G6PC2 pre-mRNA splicing and the contribution of an additional common G6PC2 promoter SNP, rs2232316, to the association signal.


Input: METHODS: Minigene analyses were used to characterise the effect of rs560887 on G6PC2 pre-mRNA splicing.


Input: Fusion gene and gel retardation analyses characterised the effect of rs2232316 on G6PC2 promoter activity and transcription factor binding.


Input: The genetic association of rs2232316 with FPG variation was assessed using regression adjusted for age, sex and BMI in 4, 220 Europeans with normal FPG.


Input: RESULTS: The rs560887-G allele was shown to enhance G6PC2 pre-mRNA splicing, whereas the rs2232316-A allele enhanced G6PC2 transcription by promoting Foxa2 binding.


Input: Genetic analyses provide evidence for association of the rs2232316-A allele with increased FPG (beta = 0. 04 mmol/l; p = 4. 3 x 10 (-3)) as part of the same signal as rs560887, rs573225 and rs13431652.


Input: CONCLUSIONS/INTERPRETATION: As with rs13431652, the in situ functional data with rs560887 and rs2232316 are in accord with the putative function of G6PC2 in pancreatic islets, and suggest that all three are potentially causative SNPs that contribute to the association between G6PC2 and FPG.


Input: DNA Methylation and Cancer Development: Molecular Mechanism.


Input: DNA methylation is a significant regulator of gene expression, and its role in carcinogenesis recently has been a subject of remarkable interest.


Input: The aim of this review is to analyze the mechanism and cell regulatory effects of both hypo-and hyper-DNA methylation on cancer.


Input: In this review, we report new developments and their implications regarding the effects of DNA methylation on cancer development.


Input: Indeed, alteration of the pattern of DNA methylation has been a constant finding in cancer cells of the same type and differences in the pattern of DNA methylation not only occur in a variety of tumor types, but also in developmental processes Furthermore, the pattern of histone modification appears to be a predicator of the risk of recurrence of human cancers.


Input: It is well known that hypermethylation represses transcription of the promoter sections of tumor-suppressor genes leading to gene silencing.


Input: However, hypomethylation also has been identified as a cause of oncogenesis.


Input: Furthermore, experiments concerning the mechanism of methylation and its control have led to the discovery of many regulatory enzymes and proteins.


Input: This review reports on methods developed for the detection of 5-hydroxymethylcytosine methylation at the 5-methylcytosine of protein domains in the CpG context compared to non-methylated DNA, histone modification, and microRNA change.


Input: Agonist-induced Down-regulation of Endogenous Protein Kinase C alpha through an Endolysosomal Mechanism.


Input: Protein kinase C (PKC) isozymes undergo down-regulation upon sustained stimulation.


Input: Previous studies have pointed to the existence of both proteasome-dependent and-independent pathways of PKC alpha processing.


Input: Here we demonstrate that these down-regulation pathways are engaged in different subcellular compartments; proteasomal degradation occurs mainly at the plasma membrane, whereas non-proteasomal processing occurs in the perinuclear region.


Input: Using cholesterol depletion, pharmacological inhibitors, RNA interference, and dominant-negative mutants, we define the mechanisms involved in perinuclear accumulation of PKC alpha and identify the non-proteasomal mechanism mediating its degradation.

cholesterol


Input: We show that intracellular accumulation of PKC alpha involves at least two clathrin-independent, cholesterol/lipid raft-mediated pathways that do not require ubiquitination of the protein; one is dynamin-dependent and likely involves caveolae, whereas the other is dynamin-and small GTPase-independent.

cholesterol


Input: Internalized PKC alpha traffics through endosomes and is delivered to the lysosome for degradation.


Input: Supportive evidence includes (a) detection of the enzyme in EEA1-positive early endosomes, Rab7-positive late endosomes/multivesicular bodies, and LAMP1-positive lysosomes and (b) inhibition of its down-regulation by lysosome-disrupting agents and leupeptin.

leupeptin


Input: Only limited dephosphorylation of PKC alpha occurs during trafficking, with fully mature enzyme being the main target for lysosomal degradation.


Input: These studies define a novel and widespread mechanism of desensitization of PKC alpha signaling that involves endocytic trafficking and lysosome-mediated degradation of the mature, fully phosphorylated protein.


Input: 2-aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease.


Input: Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ~ 40%, and high exposure in the brains of mice.

aminothiazole

(4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine


Input: Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrP (Sc).


Input: Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties.


Input: Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl) thiazol-2-yl] amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl) amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1.

(6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl) thiazol-2-yl] amine

cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl) amide


Input: Enhanced Catalytic Four-Electron Dioxygen (O2) and Two-Electron Hydrogen Peroxide (H2O2) Reduction with a Copper (II) Complex Possessing a Pendant Ligand Pivalamido Group.

Dioxygen

Hydrogen Peroxide

Copper (II)


Input: A copper complex, [(PV-tmpa) Cu (II)] (ClO4) 2 (1) [PV-tmpa = bis (pyrid-2-ylmethyl) {[6-(pivalamido) pyrid-2-yl] methyl} amine], acts as a more efficient catalyst for the four-electron reduction of O2 by decamethylferrocene (Fc *) in the presence of trifluoroacetic acid (CF3COOH) in acetone as compared with the corresponding copper complex without a pivalamido group, [(tmpa) Cu (II)] (ClO4) 2 (2) (tmpa = tris (2-pyridylmethyl) amine).

copper

[(PV-tmpa) Cu (II)] (ClO4) 2

PV-tmpa

bis (pyrid-2-ylmethyl) {[6-(pivalamido) pyrid-2-yl] methyl} amine

decamethylferrocene

trifluoroacetic acid

acetone

copper

pivalamido

[(tmpa) Cu (II)] (ClO4) 2

tmpa

tris (2-pyridylmethyl) amine


Input: The rate constant (kobs) of formation of decamethylferrocenium ion (Fc * (+)) in the catalytic four-electron reduction of O2 by Fc * in the presence of a large excess CF3COOH and O2 obeyed first-order kinetics.

decamethylferrocenium


Input: The kobs value was proportional to the concentration of catalyst 1 or 2, whereas the kobs value remained constant irrespective of the concentration of CF3COOH or O2.


Input: This indicates that electron transfer from Fc * to 1 or 2 is the rate-determining step in the catalytic cycle of the four-electron reduction of O2 by Fc * in the presence of CF3COOH.


Input: The second-order catalytic rate constant (kcat) for 1 is 4 times larger than the corresponding value determined for 2.


Input: With the pivalamido group in 1 compared to 2, the Cu (II)/Cu (I) potentials are-0. 23 and-0. 05 V vs SCE, respectively.

pivalamido

Cu (II)

Cu (I)


Input: However, during catalytic turnover, the CF3COO (-) anion present readily binds to 2 shifting the resulting complex' s redox potential to-0. 35 V.

CF3COO (-)


Input: The pivalamido group in 1 is found to inhibit anion binding.

pivalamido


Input: The overall effect is to make 1 easier to reduce (relative to 2) during catalysis, accounting for the relative kcat values observed.


Input: 1 is also an excellent catalyst for the two-electron two-proton reduction of H2O2 to water and is also more efficient than is 2.


Input: For both complexes, reaction rates are greater than for the overall four-electron O2-reduction to water, an important asset in the design of catalysts for the latter.


Input: Structure-Based Design of beta-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer' s Disease.


Input: The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-beta (A beta) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer' s disease and dementia.


Input: The A beta hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer' s and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia.


Input: This review summarizes two distinct categories of inhibitors designed based on conformational states of " closed " and " open " forms of the enzyme.


Input: In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM).

aspartyl


Input: This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data.


Input: Mechanism of One-Way Traffic of Hexameric Phi29 DNA Packaging Motor with Four Electropositive Relaying Layers Facilitating Antiparallel Revolution.


Input: The importance of nanomotors in nanotechnology is akin to that of mechanical engines to daily life.


Input: The AAA + superfamily is a class of nanomotors performing various functions.


Input: Their hexagonal arrangement facilitates bottom-up assembly for stable structures.


Input: The bacteriophage phi29 DNA translocation motor contains three coaxial rings: a dodecamer channel, a hexameric ATPase ring, and a hexameric pRNA ring.


Input: The viral DNA packaging motor has been believed to be a rotational machine.


Input: However, we discovered a revolution mechanism without rotation.


Input: By analogy, the earth revolves around the sun while rotating on its own axis.


Input: One-way traffic of dsDNA translocation is facilitated by five factors: (1) ATPase changes its conformation to revolve dsDNA within a hexameric channel in one direction; (2) the 30 degrees tilt of the channel subunits causes an antiparallel arrangement between two helices of dsDNA and channel wall to advance one-way translocation; (3) unidirectional flow property of the internal channel loops serves as a ratchet valve to prevent reversal; (4) 5'-3' single-direction movement of one DNA strand along the channel wall ensures single direction; and (5) four electropositive layers interact with one strand of the electronegative dsDNA phosphate backbone, resulting in four relaying transitional pauses during translocation.

phosphate


Input: The discovery of a riding system along one strand provides a motion nanosystem for cargo transportation and a tool for studying force generation without coiling, friction, and torque.


Input: The revolution of dsDNA among 12 subunits offers a series of recognition sites on the DNA backbone to provide additional spatial variables for nucleotide discrimination for sensing applications.

nucleotide


Input: Mechanical Regulation of Cellular Adhesion onto Honeycomb-Patterned Porous Scaffolds by Altering the Elasticity of Material Surfaces.


Input: In this report, we show the preparation of honeycomb scaffolds for cell culturing by using " breath figure " method, and we found that their mechanical and topographical properties strongly affect the adhesion of fibroblasts.


Input: By photo-cross-linking of the poly (1, 2-butadiene), the hardness of the honeycomb scaffold can be successfully controlled without any surface chemical changes, and detail modulus values of scaffolds were measured by atomic force microscopy.

poly (1, 2-butadiene)


Input: We found that only small numbers of the cells adhered on the softer honeycomb scaffolds, which has even higher modulus value than conventional gels, comparing with flat films and a hard honeycomb scaffold.


Input: These results indicate that the elastomeric honeycomb substrates are useful for evaluating the effect of the mechanical signal-derived geometry on the transduction system of cells.


Input: Synthesis of a DOTA (Gd (3 +))-conjugate of proton-pump inhibitor pantoprazole for gastric wall imaging studies.

DOTA

Gd (3 +)

pantoprazole


Input: Magnetic resonance imaging (MRI) is used to evaluate gastrointestinal (GI) structure and functions in humans.


Input: Despite filling the viscus lumen with a contrast agent, visualization of the viscus wall is limited.


Input: To overcome this limitation, we de novo synthesized a conjugate that covalently combines a Gd-based MRI contrast agent, encaged with a chelating agent (DOTA), with pantoprazole, which is a widely used proton pump inhibitor that binds to proton pumps in the stomach and colon.

Gd

DOTA

pantoprazole


Input: The DOTA linkage was installed at a mechanism-based strategic location in the pantoprazole molecule to minimize a possible negative effect of the structural modification on the drug.

DOTA

pantoprazole


Input: It is anticipated that by defining the wall of the stomach and colon, this compound will facilitate functional MRI of the GI tract in humans.


Input: Evaluation of anti-HCV activity and SAR study of (+)-lycoricidine through targeting of host heat-stress cognate 70 (Hsc70).

(+)-lycoricidine


Input: The anti hepatitis C virus (HCV) activity of (+)-lycoricidine (1) was evaluated for the first time in this letter, yielding an EC50 value of 0. 55nmol/mL and an selection index (SI) value of 12. 72.

(+)-lycoricidine


Input: Further studies indicated that 1 induced this effect by down-regulating host heat-stress cognate 70 (Hsc70) expression.


Input: In addition, 20 derivatives were designed and synthesised to investigate the basic structure-activity relationship (SAR) of the title compound.


Input: Several of these derivatives exhibit a good inhibition of HCV, such as compound 3 (EC50 = 0. 68nmol/mL, SI = 33. 86), compound 2d (EC50 = 15nmol/mL, SI = 12) and compound 5 (EC50 = 33nmol/mL, SI > 10. 91).


Input: Meanwhile, the experimental data suggest that the modification of certain groups of (+)-lycoricidine can reduce the cytotoxicity of the compounds.

(+)-lycoricidine


Input: Photosensitized protein damage by dimethoxyphosphorus (V) tetraphenylporphyrin.

dimethoxyphosphorus (V) tetraphenylporphyrin


Input: For the purpose of the basic study of photodynamic therapy, the activity of the water-soluble P (V) porphyrin, dimethoxyP (V) tetraphenylporphyrin chloride (DMP (V) TPP), on photosensitized protein damage was examined.

P (V) porphyrin

dimethoxyP (V) tetraphenylporphyrin chloride

DMP (V) TPP


Input: The quantum yield of singlet oxygen generation by DMP (V) TPP (0. 64) was comparable with that of typical porphyrin photosensitizers.

oxygen

DMP (V) TPP

porphyrin


Input: Absorption spectrum measurement demonstrated the binding interaction between DMP (V) TPP and human serum albumin, a water-soluble protein.

DMP (V) TPP


Input: Photo-irradiated DMP (V) TPP damaged the amino acid residue of human serum albumin, resulting in the decrease of the fluorescence intensity from the tryptophan residue of human serum albumin.

DMP (V) TPP

amino acid

tryptophan


Input: A singlet oxygen quencher, sodium azide, could not completely inhibit the damage of human serum albumin, suggesting that the electron transfer mechanism contributes to protein damage as does singlet oxygen generation.

oxygen

sodium azide

oxygen


Input: The decrease of the fluorescence lifetime of DMP (V) TPP by human serum albumin supported the electron transfer mechanism.

DMP (V) TPP


Input: The estimated contribution of the electron transfer mechanism is 0. 64.


Input: These results suggest that the activity of DMP (V) TPP can be preserved under lower oxygen concentration condition such as tumor.

DMP (V) TPP

oxygen


Input: Evaluation of an alternative in vitro test battery for detecting reproductive toxicants.


Input: The application of alternative methods in developmental and reproductive toxicology is challenging in view of the complexity of mechanisms involved.


Input: A battery of complementary test systems may provide a better prediction of developmental and reproductive toxicity than single assays.


Input: We tested twelve compounds with varying mechanisms of toxic action in an assay battery including 24 CALUX transcriptional activation assays, mouse cardiac embryonic stem cell test, ReProGlo assay, zebrafish embryotoxicity assay, and two CYP17 and two CYP19 activity assays.


Input: The battery correctly detected 11/12 compounds tested, with one false negative occurring, which could be explained by the absence of the specific mechanism of action of this compound in the battery.


Input: Toxicokinetic modeling revealed that toxic concentrations were in the range expected from in vivo reproductive toxicity data.


Input: This study illustrates added value of combining assays that contain complementary biological processes and mechanisms, increasing predictive value of the battery over individual assays.


Input: Derivatives of Dictyostelium discoideum differentiation-inducing factor-3 suppress the activities of Trypanosoma cruzi in vitro and in vivo.


Input: Chagas disease (human American trypanosomiasis), which is caused by the protozoan parasite Trypanosoma cruzi, is responsible for numerous deaths each year; however, established treatments for the disease are limited.


Input: Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities.

alkylphenones


Input: Here, we investigated the effects of DIF-3 derivatives on the infection rate and growth of T. cruzi by using an in vitro assay system utilizing host human fibrosarcoma HT1080 cells.


Input: Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells.

butoxy


Input: For example, the IC50 of DIF-3 and Bu-DIF-3 versus the growth of T. cruzi in HT1080 cells were 3. 95 and 0. 72 mu M, respectively, and the LD50 of the two compounds versus HT1080 cells were both greater than 100 mu M.


Input: We also examined the effects of DIF-3 and Bu-DIF-3 on T. cruzi activity in C57BL/6 mice.


Input: Intraperitoneally administered Bu-DIF-3 (50mg/kg) significantly suppressed the number of trypomastigotes in blood with no apparent adverse effects.


Input: These results strongly suggest that DIF-3 derivatives could be new lead compounds in the development of anti-trypanosomiasis drugs.


Input: Acetylcholinesterase inhibition reveals endogenous nicotinic modulation of glutamate inputs to CA1 stratum radiatum interneurons in hippocampal slices.

glutamate


Input: The involvement of brain nicotinic acetylcholine receptors (nAChRs) in the neurotoxicological effects of soman, a potent acetylcholinesterase (AChE) inhibitor and a chemical warfare agent, is not clear.

acetylcholine


Input: This is partly due to a poor understanding of the role of AChE in brain nAChR-mediated functions.


Input: To test the hypothesis that AChE inhibition builds sufficient acetylcholine (ACh) in the brain and facilitates nAChR-dependent glutamate transmission, we used whole-cell patch-clamp technique to record spontaneous glutamate excitatory postsynaptic currents (EPSCs) from CA1 stratum radiatum interneurons (SRI) in hippocampal slices.

acetylcholine

glutamate

glutamate


Input: First, the frequency, amplitude and kinetics of EPSCs recorded from slices of control guinea pigs were compared to those recorded from slices of guinea pigs after a single injection of the irreversible AChE inhibitor soman (25. 2 mu g/kg, s. c.).


Input: Second, EPSCs were recorded from rat hippocampal slices before and after their superfusion with the reversible AChE inhibitor donepezil (100nM).

donepezil


Input: The frequency of EPSCs was significantly higher in slices taken from guinea pigs 24h but not 7 days after the soman injection than in slices from control animals.


Input: In 52% of the rat hippocampal slices tested, bath application of donepezil increased the frequency of EPSCs.

donepezil


Input: Further, exposure to donepezil increased both burst-like and large-amplitude EPSCs, and increased the proportion of short (20-100ms) inter-event intervals.

donepezil


Input: Donepezil' s effects were suppressed significantly in presence of 10 mu M mecamylamine or 10nM methyllycaconitine.

Donepezil

mecamylamine

methyllycaconitine


Input: These results support the concept that AChE inhibition is able to recruit nAChR-dependent glutamate transmission in the hippocampus and such a mechanism can contribute to the acute neurotoxicological actions of soman.

glutamate


Input: SEVERE HYPOGLYCEMIC EPISODES: A PERSISTENT THREAT FOR CHILDREN WITH TYPE 1 DIABETES MELLITUS AND THEIR FAMILIES.


Input: Background: As lowering HbA1c levels is still the main goal of insulin treatment, severe hypoglycaemia (SH) remains a common experience in children with type 1 diabetes mellitus (T1DM) and their families.


Input: Aim: This study aims to evaluate the incidence and the clinical features of SH episodes in our Centre in the last 20 years.


Input: Subjects and Methods: We analysed SH incidence in 269 patients diagnosed from 1990 to 2010 (total follow-up 2212. 9 patient-years).


Input: Inclusion criteria: at least 3 visits/year and 1 year of follow-up.


Input: SH episode was defined as any condition of low blood glucose requiring third-party assistance.

glucose


Input: Results: 50. 2% of patients experienced at least 1 SH episode for a total of 345 episodes.


Input: Whole incidence was 15. 6/100 pts/yr, slightly different between first and second decade (12. 6 vs 16. 5, p = 0. 047).


Input: HbA1c at the time of SH was lower in the non-BB group (7. 4 +/- 1. 3 vs 8. 2 +/- 1. 4; p = 0. 0001) and worsened 3 months later (p = 0. 0001).


Input: Impaired awareness was the main or only symptom in 43. 5%.


Input: SH occurred at night in 32% of patients and they were significantly younger than those with SH at other times.


Input: 5 SH episodes or more occurred in 8. 1% of patients who presented a lower HbA1c, a younger age and shorter disease duration than the other patients.


Input: HbA1c at first SH was negatively correlated with number of SH (r =-0. 20; p = 0. 05).


Input: Conclusions: Despite the advent of new insulin regimens, we confirm that SH still represents a relevant risk and a current threat for patients with T1DM and their families.


Input: Effectiveness of in-patient rehabilitation in obesity-related orthopedic conditions.


Input: Background: The aim of the present paper is to provide initial evidence that in-patient multidisciplinary rehabilitation is effective in minimizing the obesity-related disability and enhancing functional capacities in obese patients with motor disability.


Input: Subjects: 464 obese patients with orthopedic conditions admitted to our Rehabilitation Unit for multidisciplinary rehabilitation were enrolled in this study.


Input: Methods: At admission and discharge (after 4 weeks), the following outcome measures were computed: body weight (BW; Kg), body mass index (BMI; Kg/m2), Functional Independence Measure (FIM) motor and cognitive, Obesity-related disability test (TSD-OC), Visual Analogue Score (VAS) for functioning, Timed-Up-Go (TUG).


Input: Intensive rehabilitation addressed to obese patients with orthopedic conditions and motor difficulties consisted of a 4-week and 3-hour daily multidisciplinary program covering nutritional, motor and psychological aspects.


Input: Results: All of the outcomes measured, except the FIM cognitive score, improved significantly after in-patient rehabilitation.


Input: The obesity-specific disability scale appears sensitive to changes among groups with different grades of disability and the percentage of change does not differ among groups.


Input: Younger obese individuals generally showed to benefit more from rehabilitation interventions than the older ones.


Input: Conclusions: In-patient rehabilitation interventions appear effective in reducing both mild and severe disabilities related to obesity with orthopedic co-morbidities.


Input: This paper provides initial evidence that in-patient multidisciplinary intensive rehabilitation is effective in minimizing the obesity-related disability and initial support to the indications of the Italian Ministry of Health for such rehabilitation pathway.


Input: The disability grading could help the decision making of allocating patients to appropriate rehabilitation settings.


Input: Patterning of controllable surface wettability for printing techniques.


Input: Patterning of controllable surface wettability has attracted wide scientific attention due to its importance in both fundamental research and practical applications.


Input: In particular, it is crucial to form clear image areas and non-image areas in printing techniques based on wetting and dewetting.


Input: This review summarizes the recent research on and applications of patterning of controllable surface wettability for printing techniques, with a focus on the design and fabrication of the precise surface wettability patterning by enhancing the contrast of hydrophilicity and hydrophobicity, such as superhydrophilicity and superhydrophobicity.


Input: The selected topics mainly include patterned surface wettability for lithographic printing with different plate-making techniques, patterned surface wettability for microcontact printing with a patterned wetting stamp and special wettability mediated patterning microtransfer printing, patterned surface wettability for inkjet printing with controllable surface wettability of the substrate and printing head to ink, and patterned surface wettability by a combination of different printing techniques.


Input: A personal perspective on the future development and remaining challenges of this research is also briefly discussed.


Input: A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions.

Midazolam


Input: The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam.

midazolam


Input: We administered four escalating single doses of oral midazolam (0. 0001-3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity.

midazolam


Input: We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q. d.) after nanogram and regular doses of midazolam.

ketoconazole

midazolam


Input: Area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses.


Input: Ketoconazole reduced midazolam oral clearance by 92. 8%.

Ketoconazole

midazolam


Input: AUC and Cmax increased by 1, 540 and 363%, respectively.


Input: CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole.

midazolam

ketoconazole


Input: This is the first study showing that midazolam pharmacokinetics is linear in a 30, 000-fold concentration range, and therefore that nano-and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors. Clinical Pharmacology & Therapeutics (2013); advance online publication 20 March 2013. doi: 10. 1038/clpt. 2013. 27.

midazolam

midazolam

midazolam


Input: PEG as a spacer arm markedly increases the immunogenicity of meningococcal group Y polysaccharide conjugate vaccine.

PEG


Input: Neisseria meningitidis is a life-threatening pathogen that causes meningitis and other clinical manifestations.


Input: As a key virulence determinant, meningococcal capsular polysaccharide (PS) can be used to prevent meningococcal diseases.


Input: Conjugation of PS to carrier protein can significantly improve the immunogenicity of PS and induce memory response in infants and young children.


Input: However, the conjugate vaccine may suffer from steric shielding of antigenic PS epitopes by carrier protein.


Input: Here, a heterobifunctional polyethylene glycol (PEG) was used as a spacer arm to conjugate meningococcal group Y capsular PS with tetanus toxoid (TT).

polyethylene glycol

PEG


Input: PEG can avoid self-crosslink of PS and increase the PS/TT ratio of the vaccine.

PEG


Input: Significant structural change in TT and PS was not observed upon conjugation.


Input: As compared to the vaccine without PEG, immunization with the vaccine using PEG as the spacer arm led to 3. 0-fold increase in the PS-specific IgG titers and a prolonged immune persistence.

PEG

PEG


Input: Paradoxically, PEG, a non-immunogenic hydrophilic polymer has been widely used to couple therapeutic protein for increasing its circulatory time and decreasing its immunogenicity.

PEG


Input: Presumably, PEG can fully decrease the steric shielding effect of TT on antigenic epitopes of PS and suppress the immunogenicity of TT.

PEG


Input: In addition, PEG can prolong the immune persistence of the conjugate vaccine and improve its ability to elicit cellular immunity.

PEG


Input: Thus, PEG can be used as a spacer arm to develop more effective PS conjugate vaccine for prevention of bacterial infection.

PEG


Input: It is important research, but why is it necessary?


Input: The findings regarding cardiovascular actions of dietary supplements labeled as " ephedra free " reported by Foster et al. in the March issue reaffirm decades of research that began in the 1920s with K. K.


Input: Chen' s study of naturally occurring adrenergic chemicals.


Input: Although the study by Foster et al. provides scientifically sound data needed by the US Food and Drug Administration (FDA) as it evaluates the safety of these products, we should ask, " Why was it necessary that these chemicals be studied again for their cardiovascular actions in humans? "


Input: Model-based drug development in oncology: what' s next?


Input: Model-based estimates of tumor growth inhibition (TGI) metrics have the potential to enhance learning in early (phase II) clinical studies.


Input: They can be used as end points and biomarkers to predict treatment effect on clinical outcome measures-e. g., overall survival (OS)-and support phase II study design, end-of-phase II decisions, and phase III planning and execution.


Input: Efforts should be made to assess models in simulating independent studies with treatments of varying mechanisms of action.


Input: The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing.


Input: Despite progress in mechanistic understanding of the RNA interference (RNAi) pathways, the subcellular sites of RNA silencing remain under debate.


Input: Here we show that loading of lipid-transfected siRNAs and endogenous microRNAs (miRNA) into RISC (RNA-induced silencing complexes), encounter of the target mRNA, and Ago2-mediated mRNA slicing in mammalian cells are nucleated at the rough endoplasmic reticulum (rER).


Input: Although the major RNAi pathway proteins are found in most subcellular compartments, the miRNA-and siRNA-loaded Ago2 populations co-sediment almost exclusively with the rER membranes, together with the RISC loading complex (RLC) factors Dicer, TAR RNA binding protein (TRBP) and protein activator of the interferon-induced protein kinase (PACT).


Input: Fractionation and membrane co-immune precipitations further confirm that siRNA-loaded Ago2 physically associates with the cytosolic side of the rER membrane.


Input: Additionally, RLC-associated double-stranded siRNA, diagnostic of RISC loading, and RISC-mediated mRNA cleavage products exclusively co-sediment with rER.


Input: Finally, we identify TRBP and PACT as key factors anchoring RISC to ER membranes in an RNA-independent manner.


Input: Together, our findings demonstrate that the outer rER membrane is a central nucleation site of siRNA-mediated RNA silencing.


Input: Extending the range of FRET-the Monte Carlo study of the antenna effect.


Input: The problem of extending the utilizable range of F o rster resonance energy transfer (FRET) is of great current interest, due to the demand of conformation studies of larger biological structures at distances exceeding typical limiting distance of 100 A.


Input: One of the ways to address this issue is the use of so-called antenna effect.


Input: In the present work, the influence of the antenna effect on the FRET efficiency is investigated by the Monte Carlo analysis.


Input: The previously published results Bojarski et al.


Input: (J Phys Chem B 115: 10120-10125, 2011) indicate that using a simple model of donor linked with a protein labeled with multiple acceptors, significantly increases the transfer efficiency in comparison with donor-single acceptor system.


Input: The effect is stronger if the transition moments of acceptors are mutually parallel.


Input: In this work, to extend the scope of possible biological systems to be analyzed, different distributions of donor-acceptors distance are analyzed, as well as the size and shape of the attached molecule.


Input: Self-Assembled PAA-Based Nanoparticles as Potential Gene and Protein Delivery Systems.

PAA


Input: A series of nanoparticles is prepared via layer-by-layer assembly of oppositely charged, synthetic biocompatible polyamidoamine polymers as potential carriers.

polyamidoamine


Input: Particle size, surface charge and internal chain mobility are quantified as a function of the polymer type and number of layers.


Input: The effect of addition of surfactant is examined to simulate the effects of nanoparticle dissolution.


Input: The cyctotoxicity of these particles (in epithelia and murine cell lines) are orders of magnitude lower than polyethyleneimine controls.

polyethyleneimine


Input: Stable nanoparticles may be prepared from mixtures of strongly, oppositely charged polymers, but less successfully from weakly charged polymers, and, given their acceptable toxicity characteristics, such modularly designed constructs show promise for drug and gene delivery.


Input: Impact of DNA Sequence and Oligonucleotide Length on a Polythiophene-Based Fluorescent DNA Biosensor.

Polythiophene


Input: DNA hybridization is a universal and specific mechanism for the recognition of biological targets.


Input: Some cationic polythiophene transducers sensitive to DNA structure have been previously utilized to detect such biomolecules.

polythiophene


Input: Further characterization of these systems indicates that both DNA sequence composition and length modulate the biosensor performance.


Input: It appears that different repeated sequence patterns cause different conformational changes of the polythiophene, from a more relaxed form to an extremely rigid one.

polythiophene


Input: A length difference between the DNA oligonucleotide probe and target has a detrimental effect on the fluorescent signal, but it can be attenuated by changing the sequence composition of the protruding target sequence.


Input: This demonstrates that the nature of DNA can be critical for hybridization-based detection systems.


Input: Pesticide tolerant and phosphorus solubilizing Pseudomonas sp. strain SGRAJ09 isolated from pesticides treated Achillea clavennae rhizosphere soil.

phosphorus


Input: In this study, an attempt was made to identify an effective phosphate solubilizing bacteria from pesticide polluted field soil.

phosphate


Input: Based on the formation of solubilization halo on Pikovskaya' s agar, six isolates were selected and screened for pesticide tolerance and phosphate (P) solubilization ability through liquid assay.

phosphate


Input: The results showed that only one strain (SGRAJ09) obtained from Achillea clavennae was found to tolerate maximum level of the pesticides tested and it was phylogenetically identified as Pseudomonas sp.


Input: It possessed a wide range of pesticide tolerance, ranging from 117 mu g mL (-1) for alphamethrin to 2, 600 mu g mL (-1) for endosulfan.

alphamethrin

endosulfan


Input: The available P concentrations increased with the maximum and double the maximum dose of monocrotophos and imidacloprid, respectively.

monocrotophos

imidacloprid


Input: On subjected to FT-IR and HPLC analysis, the presence of organic acids functional group in the culture broth and the production of gluconic acid as dominant acid aiding the P solubilization were identified.

gluconic acid


Input: On comparison with control broth, monocrotophos and imidacloprid added culture broth showed quantitatively high organic acids production.

monocrotophos

imidacloprid


Input: In addition to gluconic acid production, citric and acetic acids were also observed in the pesticide amended broth.

gluconic acid

citric and acetic acids


Input: Furthermore, the Pseudomonas sp. strain SGRAJ09 possessed all the plant growth promoting traits tested.


Input: In presence of monocrotophos and imidacloprid, its plant growth promoting activities were lower than that of the pesticides unamended treatment.

monocrotophos

imidacloprid


Input: Effect of the Potent Antiviral 1-Cinnamoyl-3, 11-Dihydroxymeliacarpin on Cytokine Production by Murine Macrophages Stimulated with HSV-2.

1-Cinnamoyl-3, 11-Dihydroxymeliacarpin


Input: The limonoid 1-cinnamoyl-3, 11-dihydroxymeliacarpin (CDM) isolated from leaf extracts of Melia azedarach L, has potent antiherpetic effect in epithelial cells.

1-cinnamoyl-3, 11-dihydroxymeliacarpin

CDM


Input: Since Meliacine, the partially purified extract source of CDM, has therapeutic effect on murine genital herpes, the potential use of CDM as microbicide against herpetic infections was studied here.

CDM

CDM


Input: To determine the cytotoxic effect of CDM, the MTT assay and acridine orange staining of living cells were performed.

CDM

MTT


Input: The antiherpetic action of CDM was measured by plaque reduction assay, and the immunomodulatory effect was determined by measuring the cytokine production using a bioassay and ELISA method.

CDM


Input: The results presented here showed that CDM inhibited Herpes Simplex Virus type 2 (HSV-2) multiplication in Vero cells but did not affect its replication in macrophages which were not permissive to HSV infection.

CDM


Input: In macrophages, levels of TNF-alpha, IFN-gamma, NO, IL-6 and IL-10 were increased by CDM used alone or in combination with HSV-2.

CDM


Input: Besides, CDM not only synergized TNF-alpha production combined with IFN-gamma, but also prolonged its expression in time.

CDM


Input: Results indicate that CDM inhibits HSV-2 multiplication in epithelial cells and also increases cytokine production in macrophages, both important actions to the clearance of infecting virus in the mouse vagina.

CDM


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


Input: Recruiting the Host' s Immune System to Target Helicobacter pylori' s Surface Glycans.


Input: Due to the increased prevalence of bacterial strains that are resistant to existing antibiotics, there is an urgent need for new antibacterial strategies.


Input: Bacterial glycans are an attractive target for new treatments, as they are frequently linked to pathogenesis and contain distinctive structures that are absent in humans.


Input: We set out to develop a novel targeting strategy based on surface glycans present on the gastric pathogen Helicobacter pylori (Hp).


Input: In this study, metabolic labeling of bacterial glycans with an azide-containing sugar allowed selective delivery of immune stimulants to azide-covered Hp.

azide

azide


Input: We established that Hp' s surface glycans are labeled by treatment with the metabolic substrate peracetylated N-azidoacetylglucosamine (Ac4 GlcNAz).

peracetylated N-azidoacetylglucosamine

Ac4 GlcNAz


Input: By contrast, mammalian cells treated with Ac4 GlcNAz exhibited no incorporation of the chemical label within extracellular glycans.

Ac4 GlcNAz


Input: We further demonstrated that the Staudinger ligation between azides and phosphines proceeds under acidic conditions with only a small loss of efficiency.

azides

phosphines


Input: We then targeted azide-covered Hp with phosphines conjugated to the immune stimulant 2, 4-dinitrophenyl (DNP), a compound capable of directing a host immune response against these cells.

azide

phosphines

2, 4-dinitrophenyl

DNP


Input: Finally, we report that immune effector cells catalyze selective damage in vitro to DNP-covered Hp in the presence of anti-DNP antibodies.

DNP

DNP


Input: The technology reported herein represents a novel strategy to target Hp based on its glycans.


Input: Fluorescent Polymeric Micelles with Aggregation-Induced Emission Properties for Monitoring the Encapsulation of Doxorubicin.

Doxorubicin


Input: A new type of fluorescent polymeric micelles is developed by self-assembly from a series of amphiphilic block copolymers, poly (ethylene glycol)-b-poly [styrene-co-(2-(1, 2, 3, 4, 5-pentaphenyl-1H-silol-1-yloxy) ethyl methacrylate)] [PEG-b-P (S-co-PPSEMA)].

poly (ethylene glycol)-b-poly [styrene-co-(2-(1, 2, 3, 4, 5-pentaphenyl-1H-silol-1-yloxy) ethyl methacrylate)]

PEG-b-P (S-co-PPSEMA)


Input: Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles.

doxorubicin

DOX


Input: F o rster resonance energy transfer from PPSEMA to DOX is observed in DOX-loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles.

PPSEMA

DOX

DOX

DOX


Input: The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX-loaded micelles.

DOX


Input: Nonviral Gene Delivery to Neural Stem Cells with Minicircles by Microporation.


Input: The main purpose of this work was to evaluate the transfection of novel DNA vectors, minicircles (mC), on embryonic stem cell-derived neural stem cells (NSC).


Input: We demonstrated that by combining microporation with mC, 75% of NSC expressing a transgene is achieved without compromising cell survival, morphology, and differentiation potential.


Input: When comparing mC with their plasmid DNA (pDNA) counterparts, both gave rise to similar transfection levels but cells harboring mC showed 10% higher cell viability, maintaining 90% of survival at least for 10 days.


Input: Long-term analysis showed that NSC harbor a higher number of mC copies and consequently exhibit higher transgene expression when compared to their pDNA counterpart.


Input: Taken together, our results offer the first insights on the use of mC as a novel and safe strategy to genetically engineer NSC envisaging their use as biopharmaceuticals in clinical settings for the treatment of neurodegenerative or neurological diseases.


Input: The role of platelet/lymphocyte serotonin transporter in depression and beyond.

serotonin


Input: A large amount of the data gathered in the last 50 years support the hypothesis that alterations of the serotonin (5-HT) neurotransmission play a crucial role in the pathophysiology of not only major depression (MD), but also of different neuropsychiatric disorders.

serotonin


Input: Research in this field has been substantially promoted by the evidence that the reuptake protein (SERT), present in presynaptic neurons, is a key element in terminating the activity of the neurotransmitter in the synaptic cleft.


Input: For this reason, it was specifically targeted for the development of second-generation antidepressants, in particular of selective 5-HT reuptake inhibitors (SSRIs), with the aim of increasing the intrasynaptic 5-HT concentrations.


Input: Moreover, since a lot of studies showed that circulating platelets and, more recently, lymphocytes possess functional SERT proteins, they have been widely used as peripheral mirrors of the same structures located in the central nervous system.


Input: The presence of functional SERT in blood cells suggests strict relationships between the nervous and the immune system that need to be better clarified in MD, as well as the possibility of reciprocal modulation of the two systems by different drugs.


Input: This paper aims to review briefly the literature on the 5-HT hypothesis of depression with a major focus on the possible role of SERT in this disorder, while highlighting how recent data are more oriented on dimensional rather than nosological involvement of this structure in different conditions spanning from normality to pathology.


Input: GC-Targeted C8-Linked Pyrrolobenzodiazepine-Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models.

Pyrrolobenzodiazepine

Biaryl


Input: DNA binding 4-(1-methyl-1H-pyrrol-3-yl) benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA.

4-(1-methyl-1H-pyrrol-3-yl) benzenamine

MPB


Input: They have been conjugated to a pyrrolo [2, 1-c] [1, 4] benzodiazepine (PBD) molecule to produce C8-linked PBD-MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA.

pyrrolo [2, 1-c] [1, 4] benzodiazepine

PBD

PBD-MPB


Input: Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines.


Input: One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses.


Input: Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.


Input: Hyaluronic Acid nanoparticles titrate the viscoelastic properties of viscosupplements.


Input: Hyaluronic acid (HA) is a glycosaminoglycan with diverse biomedical applications including viscosupplementation of synovial fluid for the treatment osteoarthritis.


Input: Current HA viscosupplements such as Synvisc, Orthovisc, and Hyalgan have shown positive effects of reducing pain and improving joint function.


Input: The therapeutic efficacy, however, is highly transient, and these viscous fluids suffer from poor injectability.


Input: HA nanoparticles were found to modify the rheological properties of a model of the HA viscosupplement Orthovisc.


Input: Nanoparticles were successfully synthesized from 17 and 1500 kDa HA.


Input: Nanoparticle suspensions of HA were studied at different concentrations and in blends with the model viscosupplement.


Input: Nanoparticles made from 1500 kDa HA reduced the viscosupplement viscosity and elasticity to a much greater degree than nanoparticles made from 17 kDa HA.


Input: The difference in the nanoparticle effect on viscoelasticity suggested that nanoparticles made from 17 kDa HA may have dangling surface polymers that facilitated interactions with HA in solution.


Input: This hypothesis was supported by the greater compressibility of 17 kDa nanoparticles as determined by ultrasonic vibrational spectroscopy.


Input: Rheological investigations showed that the viscoelasticity of viscosupplements could be discretely titrated by modulating the concentration and type of HA nanoparticle additive (hard sphere or hairy).


Input: Thus, the injectability of viscosupplements may be enhanced while maintaining high elasticity.


Input: Functional Diversity of HDL Cargo.


Input: For decades high-density lipoproteins (HDL) and HDL-cholesterol (HDL-C) levels were viewed as synonymous and modulation of HDL-C levels by drug therapy held great promise for the prevention and treatment of cardiovascular disease.

cholesterol


Input: Nevertheless, recent failures of drugs that raise HDL-C to reduce cardiovascular risk and the now greater understanding of the complexity of HDL composition and biology have prompted researchers in the field to redefine HDL.


Input: As such, the focus of HDL has now started to shift away from a cholesterol centric view towards HDL particle number, subclasses, and other alternative metrics of HDL.

cholesterol


Input: Many of the recently discovered functions of HDL are, in fact, not strictly conferred by its ability to promote cholesterol flux, but by the other molecules it transports, including a diverse set of proteins, small RNAs, hormones, carotenoids, vitamins, and bioactive lipids.

cholesterol


Input: Based on the ability of HDL to interact with almost all cells and transport and deliver fat-soluble cargo, HDL has the remarkable capacity to affect a wide-variety of endocrine-like systems.


Input: Here in this review, we characterize the unique cargo on HDL and address the functional relevance and consequences of HDL transport and delivery of non-cholesterol molecules to recipient cells and tissues.

cholesterol


Input: Evaluation of estrogenic effects of polychlorinated biphenyls and organochlorinated pesticides using immature rat uterotrophic assay.

polychlorinated biphenyls

organochlorinated


Input: In this study, we investigated the effects of polychlorinated biphenyls (PCBs) and organochlorinated pesticides on the serum levels of luteinising hormone (LH), follicle stimulating hormone (FSH) and weights and histomorphometry of uterine tissue in immature female rats using uterotrophic assay.

polychlorinated biphenyls

PCBs

organochlorinated


Input: A total of 36 rats were randomly divided into six groups (n = 6 per group) as control, oestradiol (E2, 100 mu g/kg), PCB 180, Aroclor 1221, endosulfan and mirex at 10 mg/kg dosage.

oestradiol

PCB 180

Aroclor 1221

endosulfan

mirex


Input: After 3 days of injections (subcutaneous), animals were decapitated and blood samples were collected.


Input: Uteri were dissected, weighed out and then fixed in 10% formaldehyde.

formaldehyde


Input: They were processed for histomorphometry.


Input: The serum levels of LH and FSH were determined by enzyme immunoassay. Uterine weight was significantly increased by E2 and reduced by mirex (p < 0. 001 and p < 0. 05, respectively).

mirex


Input: Total volume of uterus was significantly raised by E2, Aroclor 1221 and endosulfan compared with that of the control group (p < 0. 01).

Aroclor 1221

endosulfan


Input: The ratio of epithelium was significantly increased by E2, PCBs and pesticides (p < 0. 01).

PCBs


Input: The uterine cavity ratio was decreased by aroclor (p < 0. 01), PCB 180 and mirex (p < 0. 05).

PCB 180

mirex


Input: The serum levels of LH did not significantly differ among the groups but the levels of FSH were decreased by PCB 180 and endosulfan (p < 0. 05 and p < 0. 01, respectively).

PCB 180

endosulfan


Input: These findings suggest that PCB 180, Aroclor 1221 and endosulfan may be estrogenic in immature uterotrophic assay.

PCB 180

Aroclor 1221

endosulfan


Input: Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation.

escitalopram


Input: RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water (" flower pot ") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus.


Input: MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS.


Input: OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons.

serotonin

escitalopram


Input: METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats.

Escitalopram


Input: During the 3-h-long " rebound sleep ", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry.


Input: RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease.


Input: All these effects of REMS deprivation were significantly attenuated by escitalopram treatment.

escitalopram


Input: Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound.

escitalopram


Input: CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel.

escitalopram


Input: Escitalopram caused a shift from REMS to slow wave sleep during the rebound.

Escitalopram


Input: Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders.


Input: Mechanisms involved in the antinociceptive effects of orally administered oleanolic acid in the mouse.

oleanolic acid


Input: The antinociceptive effects of oleanolic acid were examined in ICR mice.

oleanolic acid


Input: Oleanolic acid administered orally (1, 5 and 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test.

Oleanolic acid

acetic acid


Input: In the time-course study, duration of antinociceptive action of oleanolic acid maintained at least for 60 min.

oleanolic acid


Input: In addition, the cumulative nociceptive response time for intraplantar formalin injection (2nd phase), intrathecal injection of substance P (0. 7 mu g) or glutamate (20 mu g) was diminished by oleanolic acid.

glutamate

oleanolic acid


Input: Intraperitoneal (i. p.) pretreatment with naloxone (opioid receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) attenuated antinociceptive effect induced by oleanolic acid in the writhing test.

naloxone

methysergide

oleanolic acid


Input: However, yohimbine (adrenergic receptor antagonist) did not affect antinociception induced by oleanolic acid.

yohimbine

oleanolic acid


Input: The results indicate that oleanolic acid shows an antinociceptive property in various pain models such as writhing, formalin, substance P and glutamate pain tests.

oleanolic acid

formalin

glutamate


Input: Furthermore, this antinociceptive effect of oleanolic acid may be mediated by opioidergic and serotonergic receptors, but not adrenergic receptors.

oleanolic acid


Input: Multifocal motor neuropathy: current therapies and novel strategies.


Input: Multifocal motor neuropathy (MMN) is a purely motor mononeuritis multiplex characterized by the presence of conduction block on motor but not on sensory nerves and by the presence of high titers of anti-GM1 antibodies.


Input: Several data point to a pathogenetic role of the immune system in this neuropathy, although this has not yet been proved.


Input: Several uncontrolled studies and randomized controlled trials have demonstrated the efficacy of therapy with high-dose intravenous immunoglobulin (IVIg) in MMN.


Input: However, this therapy has a short-lasting effect that needs to be maintained with periodic infusions.


Input: This can be partly overcome by the use of subcutaneous immunoglobulin (SCIg) at the same dose.


Input: The high cost and need for repeated infusions have led to the search for other immune therapies, the efficacy of which have not yet been confirmed in randomized trials.


Input: In addition, some therapies, including corticosteroids and plasma exchange, are not only ineffective but have been associated with clinical worsening.


Input: More recently, a number of novel therapies have been investigated in MMN, including interferon-beta 1a, the anti-CD20 monoclonal antibody rituximab and the complement inhibitor eculizumab.


Input: Preliminary data from open-label uncontrolled studies show that some patients improve after these therapies; however, randomized controlled trials are needed to confirm efficacy.