Input: Crocin treatment improved cognitive performance and resulted in a significant reduction in MDA levels and elevation in total thiol content and GPx activity.

Crocin

MDA

thiol


Input: This study demonstrates that crocin may have beneficial effects in the treatment of neurodegenerative disorders such as Alzheimer' s disease.

crocin


Input: C16 peptide shown to prevent leukocyte infiltration and alleviate detrimental inflammation in acute allergic encephalomyelitis model.


Input: Integrins are important adhesion receptors for leukocytes binding to endothelial cellular adhesion molecules.


Input: Previous studies have suggested that blocking relevant integrins might prevent leukocyte infiltration and suppress clinical and pathological features of neuroinflammatory disease.


Input: Experimental autoimmune encephalomyelitis (EAE), a rodent model of Multiple sclerosis (MS), is characterized by chronic inflammatory disorder of the central nervous system in which circulating leukocytes enter the brain and spinal cord leading to inflammation, myelin damage and subsequent paralysis.


Input: To prove this hypothesis and explore a promising application for MS treatment, the effects of C16, an alpha nu beta 3 integrin-binding peptide, were tested in vitro and in vivo by transendothelial assay, electron microscopy observation, multiple histological and immunohistochemical staining.


Input: The results showed C16 inhibited transendothelial migration of the C8166-CD4 lymphoblast cells, and alleviated extensive spinal cord and brain infiltration of leukocytes and macrophages in the EAE model.


Input: Furthermore, a significant amelioration of astrogliosis and a dramatic decrease in demyelination and axonal loss were observed in C16 treated animals.


Input: The attenuating inflammatory progression may improve the regional environment and trigger further neuroprotective effects on myelin and axons, all this suggests that C16 peptide may be a promising therapeutic agent for multiple sclerosis.


Input: New imidazo [1, 2-a] pyridines carrying active pharmacophores: synthesis and anticonvulsant studies.

imidazo [1, 2-a] pyridines


Input: Five new series of imidazo [1, 2-a] pyridines carrying biologically active pyrazoline (4a-e), cyanopyridone (5a, b), cyanopyridine (6a-f), 2-aminopyrimidine (7a-f) and pyrimidine-2-thione (8a-d) systems were designed and synthesized as prominent anticonvulsant agents.

imidazo [1, 2-a] pyridines

pyrazoline

cyanopyridone

cyanopyridine


Input: The target compounds were screened for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentylene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg.

pentylene tetrazole


Input: Further, Rotarod toxicity method was used to study the toxicity profile of selected compounds.


Input: Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing 4-fluorophenyl substituent at 2nd position of imidazo [1, 2-a] pyridine ring displayed potent anticonvulsant activity without displaying any toxicity.

imidazo [1, 2-a] pyridine


Input: Enhanced activity profile was observed for new compounds in PTZ method over MES method.

PTZ


Input: Sensitizing capacity and allergenicity of enzymatically cross-linked sodium caseinate in comparison to sodium caseinate in a mouse model for cow' s milk allergy.

sodium

sodium


Input: A transglutaminase cross-linked caseinate was designed for use in dairy products to increase the viscosity of food matrices.


Input: The difference in structure of cross-linked caseinate might have implications for the risk of developing cow' s milk allergy.


Input: The sensitizing capacity and the allergenicity (the potency to induce an allergic effector response) of cross-linked sodium caseinate was investigated using a mouse model for cow' s milk allergy.

sodium


Input: Mice were orally sensitized with cross-linked caseinate or caseinate using cholera toxin as adjuvant.


Input: Anaphylactic shock reactions, change in body temperature, acute allergic skin response, caseinate-, cross-linked caseinate-IgE and mMCP-1 concentrations were determined after challenge with cross-linked caseinate or caseinate.


Input: Sensitization with cross-linked caseinate did not result in anaphylactic shock symptoms, drop in body temperature or release of serum mMCP-1.


Input: A tendency toward decreased casein-specific IgE levels was observed.


Input: The allergenicity did not differ between both products.


Input: These results indicate that in already caseinate-sensitized mice, cross-linked caseinate did not provoke more pronounced allergenic reactions compared to sodium caseinate.

sodium


Input: On top of that, reduced sensitization to cross-linked caseinate was observed.


Input: Cross-linked caseinate might therefore be an interesting new dietary concept for humans at risk for food allergy although more mechanistic studies and clinical trials are needed for validation.


Input: Poly (styrene oxide)-poly (ethylene oxide) block copolymers: From " classical " chemotherapeutic nanocarriers to active cell-response inducers.

Poly (styrene oxide)-poly (ethylene oxide)


Input: Two poly (styrene oxide)-poly (ethylene oxide) (PSO-PEO) triblock copolymers with different chain lengths were analyzed as potential chemotherapeutic nanocarriers, and their ability to inhibit the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line were measured in order to establish possible cell-responses induced by the presence of the copolymer molecules.

poly (styrene oxide)-poly (ethylene oxide)

PSO-PEO


Input: Thus, EO33SO14EO33 and EO38SO10EO38 polymeric micelles were tested regarding doxorubicin (DOXO) entrapment efficiency (solubilization test), physical stability (DLS), cytocompatibility (fibroblasts), release profiles at various pHs (in vitro tests), as well as P-gp inhibition and evasion and cytotoxicity of the DOXO-loaded micelles in an ovarian MDR NCI-ADR/RES cell line and in DOXO-sensitive MCF-7 cells.

doxorubicin

DOXO

DOXO

DOXO


Input: EO33SO14EO33 and EO38SO10EO38 formed spherical micelles (~ 13nm) at lower concentration than other copolymers under clinical evaluation (e. g. Pluronic (R)), exhibited 0. 2% to 1. 8% loading capacity, enhancing more than 60 times drug apparent solubility, and retained the cargo for long time.

Pluronic


Input: The copolymer unimers inhibited P-gp ATPase activity in a similar way as Pluronic P85, favoring DOXO accumulation in the resistant cell line, but not in the sensitive cell line.

Pluronic P85

DOXO


Input: DOXO loaded in the micelles accumulated more slowly inside the cells, but caused greater cytotoxicity than free drug solutions in the NCI-ADR-RES cell line, which overexpressed P-gp.

DOXO


Input: Hence, PSO-PEO block copolymers offer interesting features as new biological response modifiers to be used in the design of efficient nanocarriers for cancer chemotherapy.

PSO-PEO


Input: Encapsulation of Nod1 and Nod2 receptor ligands into poly (lactic acid) nanoparticles potentiates their immune properties.

poly (lactic acid)


Input: Most successful vaccines are able to induce persistent antibody responses that can last a lifetime.


Input: Emerging evidences indicate that activation of immune cells through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or Nod-like receptors (NLRs) may be critical mechanisms.


Input: Among PRRs, the use of TLR ligands as adjuvants is already largely described whereas the use of NLRs ligands remains largely unexplored.


Input: As activation of intracytoplasmic NLRs is able to induce proinflammatory molecules, the added value of encapsulation of Nod1 and Nod2 receptor ligands into Poly (Lactic Acid) (PLA) biodegradable nanocarriers to modulate their immune properties on human dendritic cells (DCs) maturation has been evaluated.

Poly (Lactic Acid)

PLA


Input: Their ability to induce systemic immune responses in mice was also measured and compared to free ligands and the Alum adjuvant.


Input: Nod ligands encapsulated into PLA NPs were efficiently taken up by DCs and subsequently induced a strong up-regulation of maturation markers and the enhancement of proinflammatory cytokine secretion by DCs.

PLA


Input: Furthermore, co-injection of encapsulated Nod-ligands with PLA particles carrying Gag p24 HIV-1 antigen allowed a 100 fold increase in antibody responses in comparison to Alum.

PLA


Input: These results suggest that encapsulation of Nod ligands into PLA-NPs could be an effective way to improve vaccine efficiency.

PLA


Input: PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells.


Input: Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC).


Input: However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC.


Input: To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases.


Input: Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells.


Input: Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC.


Input: After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers.

tryptanthrin


Input: With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization.


Input: When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated.


Input: Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a.


Input: Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells.


Input: Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors.


Input: In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone.


Input: Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance.

tryptanthrin


Input: Differential regulation of drug transporter expression by all-trans retinoic acid in hepatoma HepaRG cells and human hepatocytes.

all-trans retinoic acid


Input: All-trans retinoic acid (atRA) is the active form of vitamin A, known to activate retinoid receptors, especially the heterodimer retinoid X receptor (RXR): retinoic acid receptor (RAR) that otherwise may play a role in regulation of some drug transporters.

All-trans retinoic acid

atRA

vitamin A

retinoic acid


Input: The present study was designed to characterize the nature of human hepatic transporters that may be targeted by atRA and the heterodimer RXR: RAR.

atRA


Input: Exposure of human hepatoma HepaRG cells and primary human hepatocytes to 5 mu M atRA down-regulated mRNA levels of various sinusoidal solute carrier (SLC) influx transporters, including organic anion transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1 and organic anion transporter (OAT) 2, and induced those of the canalicular breast cancer resistance protein (BCRP).

atRA


Input: The retinoid concomitantly reduced protein expression of OATP2B1 and OATP1B1 and activity of OATPs and OCT1 and induced BCRP protein expression in HepaRG cells.


Input: Some transporters such as OATP1B3 and the bile salt export pump (BSEP) were however down-regulated by atRA in primary human hepatocytes, but induced in HepaRG cells, thus pointing out discrepancies between these two liver cell models in terms of detoxifying protein regulation.

atRA


Input: atRA-mediated repressions of OATP2B1, OATP1B1, OAT2 and OCT1 mRNA expression were finally shown to be counteracted by knocking-down expression of RAR alpha and RXR alpha through siRNA transfection in HepaRG cells.

atRA


Input: atRA thus differentially regulated human hepatic drug transporters, mainly in a RXR: RAR-dependent manner, therefore establishing retinoids and retinoid receptors as modulators of liver drug transporter expression.

atRA


Input: 1, 2, 3, 4, 6 Penta-O-galloyl-beta-d-glucose, a bioactivity guided isolated compound from Mangifera indica inhibits 11 beta-HSD-1 and ameliorates high fat diet-induced diabetes in C57BL/6 mice.

1, 2, 3, 4, 6 Penta-O-galloyl-beta-d-glucose


Input: Methanolic leaf extract of Mangifera indica (MEMI) was subjected to bioactivity guided fractionation in order to identify the active antidiabetic constituent.


Input: 32 fractions were evaluated for possible 11 beta-HSD-1 inhibition activity under in vitro conditions.


Input: The EA-7/8-9/10-4 fraction was evolved as a most potent fraction among all the fractions and it was identified as well known gallotannin compound 1, 2, 3, 4, 6 penta-O-galloyl-beta-d-glucose (PGG) by spectral analysis.

gallotannin

1, 2, 3, 4, 6 penta-O-galloyl-beta-d-glucose

PGG


Input: Based on these results the PGG was further evaluated in ex vivo 11 beta-HSD-1 inhibition assay and high fat diet (HFD)-induced diabetes in male C57BL/6 mice.

PGG


Input: Single dose (10, 25, 50 and 100mg/kg) of PGG and carbenoxolone (CBX) have dose dependently inhibited the 11 beta-HSD-1 activity in liver and adipose tissue.

PGG

carbenoxolone

CBX


Input: Furthermore, HFD appraisal to male C57BL/6 mice caused severe hyperglycemia, hypertriglyceridemia, elevated levels of plasma corticosterone and insulin, increased liver and white adipose mass with increase in body weight was observed compare to normal control.

corticosterone


Input: Also, oral glucose tolerance was significantly impaired compare to normal control.

glucose


Input: Interestingly, post-treatment with PGG for 21 days had alleviated the HFD-induced biochemical alterations and improved oral glucose tolerance compare to HFD-control.

PGG

glucose


Input: In conclusion, the PGG isolated from MEMI inhibits 11 beta-HSD-1 activity and ameliorates HFD-induced diabetes in male C57BL/6 mice.

PGG


Input: History of scorpion antivenom: One Arizonan' s view.


Input: This paper was originally presented as the Elsevier Lecture in July, 2012 at the International Society on Toxinology/Venom Week combined meeting in Honolulu, Hawaii.


Input: In it, the author addresses the ancient history of venom and immunity, from the Silurian Era to the 1890s; the development of the first antivenoms; the impact of shifting political and economic pressures; the special case of Arizona; the relative stability of the 1960s through 1990s; the transition to regulatory compliance that took place at the time of the author' s own research; and concluding thoughts regarding the instability of apparent success.


Input: Labdane diterpenoids and lignans from Calocedrus macrolepis.

Labdane diterpenoids

lignans


Input: Three new labdane diterpenoids, calomacrins A-C (1-3), and a new diaryl butyrolactone-type lignan, calomacrol A (8), as well as four known labdane diterpenoids and six known lignans, were isolated from the twigs and leaves of Calocedrus macrolepis.

labdane diterpenoids

calomacrins A-C

diaryl butyrolactone

lignan

calomacrol A

labdane diterpenoids

lignans


Input: Structures of the new compounds were elucidated on the basis of their spectroscopic methods, including 1D and 2D NMR techniques.


Input: Compounds 3-14 were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines.


Input: Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53.

Tamoxifen

ceramide


Input: Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies.


Input: Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative.

Ceramide


Input: Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide).

Ceramide


Input: Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades.

ceramide

sphingolipids


Input: Human CRC cell lines were employed, HCT-15, HT-29, and LoVo.


Input: The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines.

tamoxifen

verapamil

cyclosporin A


Input: In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2.

tamoxifen


Input: At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis.


Input: Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill.

tamoxifen


Input: We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects.

tamoxifen


Input: The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease.

ceramide


Input: Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde.

adenosine dialdehyde


Input: Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins.

S-adenosylmethionine

SAM


Input: It is known that transmethylation plays critical roles in various cellular responses.


Input: In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor.

adenosylhomocysteine

SAH


Input: Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner.

adenosine dialdehyde

AdOx

adenosylhomocysteine

SAH

SAHH


Input: Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity.

AdOx


Input: Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses.

AdOx


Input: In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src.

SAH

DAZA


Input: Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity.

SAH


Input: Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1).

methyl rosmarinate


Input: A series of MMP-1 inhibitors have been identified based upon a methyl rosmarinate scaffold using structure-based drug design methods.

methyl rosmarinate


Input: The best compound in the series showed an IC50 value of 0. 4 mu M.


Input: A docking study was conducted for compound (S)-10n in order to investigate its binding interactions with MMP-1.


Input: The structure-activity relationships (SAR) were also briefly discussed.


Input: Useful SAR was established which provides important guidelines for the design of future generations of potent inhibitors against MMP-1.


Input: Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs.

isocombretastatin A-4


Input: A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis.

benzoxepins

N-tosylhydrazones

aryl iodides

palladium


Input: The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range.


Input: In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations.

benzoxepin


Input: Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on beta-tubulin.

benzoxepin


Input: Cytotoxicity of lapachol, beta-lapachone and related synthetic 1, 4-naphthoquinones against oesophageal cancer cells.

lapachol

beta-lapachone

1, 4-naphthoquinones


Input: Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells.

Naphthoquinones


Input: The secondary metabolites lapachol, alpha-and beta-lapachone and a series of 25 related synthetic 1, 4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1).

alpha-and beta-lapachone

1, 4-naphthoquinones


Input: Most of the compounds exhibited enhanced cytotoxicity (IC50 1. 6-11. 7 mu M) compared to the current drug of choice cisplatin (IC50 = 16. 5 mu M).

cisplatin


Input: This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3. 0 and 7. 3 mu M) and the previously reported compound 11a (IC50 = 3. 9 mu M), were non-toxic to NIH3T3 normal fibroblast cells.


Input: Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds.

naphthoquinone


Input: Synthesis of an MIF-1 analogue containing enantiopure (S)-alpha-trifluoromethyl-proline and biological evaluation on nociception.

(S)-alpha-trifluoromethyl-proline


Input: The synthesis and the effect of a novel MIF-1 analogue on nociception during acute pain in rat model are reported.


Input: The synthesis of this enantiopure trifluoromethyl group containing tripeptide was performed through a peptide coupling reaction between the HCl.

trifluoromethyl

tripeptide


Input: Leu-Gly-NH2 and the (S)-alpha-Tfm-proline.

(S)-alpha-Tfm-proline


Input: The analgesic effect of the CF3-(MIF-1) 2 has been evaluated in vivo on rat model by paw pressure (PP) and hot plate (HP) tests and compared to the native peptide MIF-1.


Input: Highest analgesic effect was observed with CF3-(MIF-1) 2 only in PP test.


Input: In order to study the mechanisms of nociception induced by the studied peptides, the involvement of the opioid and the nitric oxideergic systems was investigated.

nitric


Input: The results are in favor of a participation of both system since pretreatment, 20 min before injection of the CF3-(MIF-1) 2, with the non-competitive antagonist of opiate receptors naloxone, the nitric oxide synthase (NOS) inhibitor l-N (G)-nitroarginine ester (l-NAME) or the nitric oxide (NO) donor l-arginine (l-Arg) significantly decreased the pain perception in PP and HP tests.

naloxone

nitric oxide

l-N (G)-nitroarginine ester

l-NAME

nitric oxide

NO

l-arginine

l-Arg


Input: Synthesis, characterization, cytotoxicity and antimicrobial studies on bis (N-furfuryl-N-(2-phenylethyl) dithiocarbamato-S, S') zinc (II) and its nitrogen donor adducts.

bis (N-furfuryl-N-(2-phenylethyl) dithiocarbamato-S, S') zinc (II)

nitrogen


Input: [Zn (fpedtc) 2] (1), [Zn (fpedtc) 2 (py)] (2), [Zn (fpedtc) 2 (1, 10-phen)] (3) and [Zn (fpedtc) 2 (2, 2'-bipy)] (4) (where fpedtc = N-furfuryl-N-(2-phenylethyl) dithiocarbamate, py = pyridine, 1, 10-phen = 1, 10-phenanthroline and 2, 2'-bipy = 2, 2'-bipyridine) were synthesized.

Zn (fpedtc) 2

Zn (fpedtc) 2 (py)

Zn (fpedtc) 2 (1, 10-phen)

Zn (fpedtc) 2 (2, 2'-bipy)

fpedtc

N-furfuryl-N-(2-phenylethyl) dithiocarbamate

pyridine

1, 10-phen

1, 10-phenanthroline

2, 2'-bipy

2, 2'-bipyridine


Input: Characterization of the complexes were achieved by IR and NMR ((1) H and (13) C) spectra and in addition, for 2 and 3, by X-ray crystallography.

(1) H

(13) C


Input: Single crystal X-ray structural analysis of 2 and 3 showed that complex 2 is almost half way between trigonal bipyramidal and square pyramidal and complex 3 has a distorted octahedral geometry.


Input: Zn-N distances in 2 is shorter than that found in a six coordinate complex 3 due to the change in coordination number.

Zn

N


Input: These complexes were also screened for in vitro antibacterial and antifungal activities and significant activities have been found.


Input: In vitro cytotoxic activity of all the synthesized complexes was evaluated on HeLa cell line.


Input: Complex 1 exhibits maximum inhibitory effect at a concentration of 40 mu g mL (-1) on HeLa cell line.


Input: Novel agmatine dipeptide inhibitors against the West Nile virus NS2B/NS3 protease: A P3 and N-cap optimization study.

agmatine dipeptide


Input: This communication describes the synthesis and inhibitory activities of thirty-seven novel C-terminal agmatine dipeptides used as screening compounds to study the structure-activity relationship between active-site peptidomimetics and the West Nile virus (WNV) NS2B/NS3 serine protease.

C

agmatine dipeptides

serine


Input: Our efforts lead to the discovery of a novel agmatine dipeptide inhibitor (compound 33, IC50 2. 6 +/- 0. 3 mu M) with improved inhibitory activity in comparison to the most potent inhibitor described in our recent report [IC50 4. 7 +/- 1. 2 mu M; Lim et al., Eur. J. Med. Chem. 46 (2011) 3130-3134].

agmatine dipeptide


Input: In addition, our study cleared the contention surrounding the previous X-ray co-crystallization study and an enzyme inhibition report on the binding conformation adopted by active-site peptide aldehydes.

aldehydes


Input: Our data should provide valuable insights into the design of future peptidomimetic antivirals against WNV infections.


Input: Synthesis, pharmacological evaluation and QSAR modeling of mono-substituted 4-phenylpiperidines and 4-phenylpiperazines.


Input: A series of mono-substituted 4-phenylpiperidines and-piperazines have been synthesized and their effects on the dopaminergic system tested in vivo.

mono-substituted 4-phenylpiperidines and-piperazines


Input: The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3, 4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats.

3, 4-dihydroxyphenylacetic acid

DOPAC


Input: In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression.


Input: Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response.

dopamine

monoamine

DOPAC


Input: These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class.

DOPAC


Input: Magnetic field triggered drug release from polymersomes for cancer therapeutics.


Input: Local and temporal control of drug release has for long been a main focus in the development of novel drug carriers.


Input: Polymersomes, which can load both hydrophilic and hydrophobic species and, at the same time, be tailored to respond to a desired stimulus, have drawn much attention over the last decade.


Input: Here we describe polymersomes able to encapsulate up to 6% (w/w) of doxorubicin (DOX) together with 30% (w/w) of superparamagnetic iron oxide nanoparticles (USPIO; gamma-Fe (2) O (3)).

doxorubicin

DOX

iron oxide

gamma-Fe (2) O (3)


Input: Upon internalization in HeLa cells and when a high frequency AC magnetic field (14mT at 750kHz) was applied, the developed delivery system elicited an 18% increase in cell toxicity, associated with augmented DOX release kinetics.

DOX


Input: In order to ensure that the observed cytotoxicity arose from the increased doxorubicin release and not from a pure magnetic hyperthermia effect, polymersomes loaded with magnetic nanoparticles alone were also tested.

doxorubicin


Input: In this case, no increased toxicity was observed.


Input: We hypothesize that the magnetic field is inducing a very local hyperthermia effect at the level of the polymersome membrane, increasing drug release.


Input: This approach opens new perspectives in the development of smart delivery systems able to release drug upon demand and therefore, improving treatment control.


Input: Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension.

fasudil


Input: Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH.


Input: However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes.


Input: In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles.

fasudil


Input: Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient.

fasudil

ammonium sulfate


Input: Liposomes were then characterized for various physicochemical properties.


Input: Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH.

monocrotaline

MCT


Input: The entrapment efficiency of optimized liposomal fasudil formulations was between 68. 1 +/- 0. 8% and 73. 6 +/- 2. 3%, and the cumulative release at 37 degrees C was 98-99% over a period of 5 days.

fasudil


Input: Compared to intravenous (IV) fasudil, a ~ 10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols.

fasudil

fasudil


Input: The t1/2 of IV fasudil was 0. 39 +/- 0. 12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4. 71 +/- 0. 72 h.

fasudil


Input: One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37. 6 +/- 5. 7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats.

fasudil

MCT


Input: Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH.

fasudil


Input: Cystathionase mediates senescence evasion in melanocytes and melanoma cells.


Input: The development of malignant melanoma is a highly complex process, which is still poorly understood.


Input: A majority of human melanomas are found to express a few oncogenic proteins, such as mutant RAS and BRAF variants.


Input: However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence.


Input: This renders the understanding of senescence escape mechanisms an important point to understand tumor development.


Input: Here, we approached the question of senescence evasion by expressing the transcription factor v-myc myelocytomatosis viral oncogene homolog (c-MYC), which is known to act synergistically with many oncogenes, in melanocytes.


Input: We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling.

oxygen

tyrosine


Input: Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence.


Input: Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence.

oxygen


Input: We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects.


Input: Blocking CTH enzymatic activity in MYC-overexpressing and Miz1 knockdown cells increased intracellular stress and senescence.


Input: Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H (2) O (2) resistance and soft agar growth.

H (2) O (2)


Input: Thus, we identified CTH as new MYC target gene with an important function in senescence evasion. Oncogene advance online publication, 28 January 2013; doi: 10. 1038/onc. 2012. 641.


Input: Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2, 5-dimethoxy-4-iodoamphetamine elicited head-twitch response model.

2, 5-dimethoxy-4-iodoamphetamine


Input: There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2, 5-dimethoxy-4-iodoamphetamine (DOI).

serotonin

2, 5-dimethoxy-4-iodoamphetamine

DOI


Input: Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response.


Input: The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J.

DOI


Input: The expected results were considered in accordance with ligand functional selectivity.


Input: Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N, N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR.

CP 809101

Ro 60-0175

WAY 161503

mCPP

4-phenyl-2-N, N-dimethyl-aminotetralin

PAT

DOI


Input: In contrast, there were differential effects on locomotion across classes of compounds.


Input: The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion.


Input: In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells.

DOI

DOI


Input: Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species.


Input: Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI.

DOI

DOI


Input: Drug " supersaturation " states induced by polymeric micelles and liposomes: a mechanistic investigation into permeability enhancements.


Input: The objective of this study was to investigate if the increase in apparent solubility induced by liposomalization or micellization of the poorly soluble drug hydrocortisone (HC) would lead to an enhancement of its permeability through biological membranes.

hydrocortisone


Input: For this purpose phosphatidylcholine liposome formulations as well as d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelle dispersions and polyvinylpyrrolidone (PVP) supersaturated solutions were prepared in order to increase the apparent solubility of HC.

phosphatidylcholine

d-alpha-tocopheryl polyethylene glycol 1000 succinate

TPGS

polyvinylpyrrolidone

PVP


Input: Both the apparent solubility of hydrocortisone (i. e. amount of drug entrapped plus non-entrapped in the carriers) as well as the concentration of molecularly dissolved drug (i. e. fraction non-entrapped into carriers, truly molecularly dissolved fraction) were characterized.

hydrocortisone


Input: Subsequently, the permeability of hydrocortisone was assessed for each type of formulation using the in vitro sheep nasal mucosa permeability assay.

hydrocortisone


Input: In all formulations where solubilizing agents are present, an enhanced flux of HC (compared to the pure drug powder suspension) is observed.


Input: The expected linear correlation between apparent solubilities and fluxes was not found, whereas, the concentrations of molecularly dissolved HC were found to be directly proportional to the respective fluxes.


Input: This is an experimental proof for the hypothesis that, of all the strategies to increase the apparent solubility of poorly soluble drugs, enhancement of the molecularly dissolved drug concentration (induction of true supersaturation) would lead to better permeation though membranes.


Input: Pesticides and oncogenic modulation.


Input: Pesticides constitute a diverse class of chemicals used for the protection of agricultural products.


Input: Several lines of evidence demonstrate that organochlorine and organophosphate pesticides can cause malignant transformation of cells in in vitro and in vivo models.

organochlorine

organophosphate


Input: In the current minireview a comprehensive summary of recent in vitro findings is presented along with data reported from human population studies, regarding the impact of pesticide exposure on activation or dysregulation of oncogenes and tumor suppressor genes.


Input: Substantial mechanistic work suggests that pesticides are capable of inducing mutations in oncogenes and increase their transcriptional expression in vitro, whereas human population studies indicate associations between pesticide exposure levels and mutation occurrence in cancer-related genes.


Input: Further work is required to fully explore the exact mechanisms by which pesticide exposure affects the integrity and normal function of oncogenes and tumor suppressor genes in human populations.


Input: Caffeine increases liking and consumption of novel-flavored yogurt.

Caffeine


Input: RATIONALE: Caffeine has been shown to increase preference for beverages with which it is paired; however, it is not known if caffeine alters liking for foods with which it is paired indirectly.

Caffeine

caffeine


Input: OBJECTIVES: The purpose of the current experiment was to test the hypothesis that a caffeinated beverage paired with a novel-flavored yogurt will increase preference for that yogurt compared to one paired with placebo.


Input: We also tested the hypothesis that liking would increase more when caffeine was paired with high energy density yogurt.

caffeine


Input: METHODS: Men and women (n = 62) were randomized to receive a beverage containing placebo (PLA) or caffeine (CAF) and to consume a low (LED) or high energy density (HED), novel-flavored yogurt.

caffeine

CAF


Input: Participants rated, ranked, and consumed seven novel-flavored yogurts and then had a target yogurt paired with either PLA or CAF over four consecutive days.

CAF


Input: RESULTS: In general, yogurt liking increased over time, the HED yogurt was liked more than the LED yogurt, and yogurt paired with caffeine was liked more than yogurt paired with placebo.

caffeine


Input: Participants showed a significant increase in liking of LED yogurt paired with caffeine compared to those with LED yogurt paired with placebo.

caffeine


Input: CONCLUSIONS: Caffeine administration may increase liking and consumption of novel-flavored foods, particularly if the food is not highly liked at baseline.

Caffeine


Input: This suggests that caffeine pairing may be a way to increase liking of LED foods, such as vegetables and fruit.

caffeine


Input: Effects of repeated exposure to MDMA on 5HT1a autoreceptor function: behavioral and neurochemical responses to 8-OHDPAT.

MDMA


Input: A consistent effect of repeated exposure to 3, 4 methylenedioxymethamphetamine (MDMA) is a decrease in the tissue levels of serotonin (5-HT).

3, 4 methylenedioxymethamphetamine

MDMA

serotonin


Input: A variety of behavioural and neurochemical tests were conducted to determine whether the tissue deficits were accompanied by an increased sensitivity of the 5-HT1a autoreceptor.


Input: Tests were conducted 2 weeks following MDMA exposure (four injections of 10. 0 mg/kg, IP, administered at 2-h intervals in a single day).

MDMA


Input: The response to the 5-HT1a agonist, 8-OHDPAT (0. 003-0. 5 mg/kg, SC), was assessed using lower lip retraction (LLR), hypoactivity, and 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition.


Input: The 8-OHDPAT produced a dose-dependent increase in LLR and hypoactivity, but these effects were comparable for MDMA and saline pretreated groups.

MDMA


Input: MDMA decreased tissue levels of 5-HT and the accumulation of 5-HTP, but these effects were not reflected in the changes in autoreceptor sensitivity.

MDMA


Input: The data suggest that the decrease in tissue levels of 5-HT produced by MDMA is accompanied by a decrease in tryptophan hydroxylase activity but cannot be explained by supersensitivity of the 5-HT1a autoreceptor.

MDMA

tryptophan


Input: Age-related differences and relationships between elements in human amygdala and other limbic system or Basal Ganglia.


Input: To elucidate the compositional changes of the amygdala with aging, the authors investigated age-related differences of elements in human amygdalae.


Input: In addition, the relationships between the amygdala and other brain regions were investigated from a viewpoint of elements.


Input: After ordinary dissections at Nara Medical University were finished, the amygdalae were removed from the cerebra of the subjects who consisted of 22 men and 23 women, ranging in age from 70 to 101 years.


Input: In addition, the hippocampus, dentate gyrus, mammillary body of the limbic system and the caudate nucleus, putamen, and globus pallidus of the basal ganglia were also removed from the identical cerebra.


Input: After the brain samples were incinerated with nitric acid and perchloric acid, the element contents were determined by inductively coupled plasma-atomic emission spectrometry.

nitric acid

perchloric acid


Input: It was found that both the Ca and Mg contents increased significantly in the amygdalae with aging, but the other five element contents (P, S, Zn, Fe, and Na) did not change significantly in the amygdalae with aging.

Ca

Mg

P

S

Zn

Fe


Input: Regarding the relationships among elements, very significant or significant direct correlations were found among the Ca, P, and Mg contents in the amygdalae.

Ca

P

Mg


Input: To explore the relationships between the amygdala and either other limbic system or basal ganglia, the correlations between seven elements of the amygdala and hippocampus, dentate gyrus, or mammillary body, and between those of the amygdala and caudate nucleus, putamen, or globus pallidus which derived from the identical cerebra, were analyzed with Pearson' s correlation.


Input: It was found that regarding the four elements of Ca, P, Mg, and Fe, a close relationship existed between the amygdala and hippocampus, globus pallidus, or mammillary body.

Ca

P

Mg

Fe


Input: Investigational anti-hyperglycemic agents: the future of type 2 diabetes therapy?


Input: As the pandemic of type 2 diabetes spreads globally, clinicians face many challenges in treating an increasingly diverse patient population varying in age, comorbidities, and socioeconomic status.


Input: Current therapies for type 2 diabetes are often unable to alter the natural course of the disease and provide durable glycemic control, and side effects in the context of individual patient characteristics often limit treatment choices.


Input: This often results in the progression to insulin use and complex regimens that are difficult to maintain.


Input: Therefore, a number of agents are being developed to better address the pathogenesis of type 2 diabetes and to overcome limitations of current therapies.


Input: The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects.

glucose


Input: These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade.

sodium

glucose

fatty acid


Input: Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations.

glucose


Input: Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants.

piperacillin

tazobactam


Input: OBJECTIVES: To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population.

piperacillin

tazobactam


Input: METHODS: A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU).


Input: A total of 207 piperacillin and 204 tazobactam concentration-time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII).

piperacillin

tazobactam


Input: PK models were developed for piperacillin and tazobactam.

piperacillin

tazobactam


Input: The final models were evaluated using both bootstrap and visual predictive checks.


Input: External model evaluations were made in 20 additional patients.


Input: RESULTS: For neonates and young infants less than 2 months of age, the median central clearance was 0. 133 and 0. 149 L/h/kg for piperacillin and tazobactam, respectively.

piperacillin

tazobactam


Input: Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam.

piperacillin

tazobactam


Input: However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone.


Input: BW was the most important covariate for apparent central volume of distribution.


Input: Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models.

piperacillin

tazobactam


Input: The dosing strategy 44. 44/5. 56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations > 4 mg/L for more than 50% of the dosing interval) in about 67% of infants.

piperacillin

tazobactam

piperacillin


Input: CONCLUSIONS: Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age.

piperacillin

tazobactam


Input: The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.


Input: Decoupling cell and matrix mechanics in engineered microtissues using magnetically actuated microcantilevers.


Input: A novel bio-magnetomechanical microtissue system is described for magnetic actuation of arrays of 3D microtissues using microcantilevers.


Input: This system enables both in situ measurements of fundamental mechanical properties of engineered tissue, such as contractility and stiffness, as well as dynamic stimulation of the microtissues.


Input: Using this system, cell and extracellular matrix contributions to the tissue mechanical properties are decoupled for the first time under both static and dynamic loading conditions.


Input: Evaporation-induced self-alignment and transfer of semiconductor nanowires by wrinkled elastomeric templates.


Input: The evaporation-induced self-alignment of semiconductor nanowires is achieved using wrinkled elastomeric templates.


Input: The wrinkled templates, which have a surface topography that can be tuned via changes in the mechanical strain, are used as both a template to align the nanowires and as a stamp to transfer the aligned nanowires to target substrates.


Input: Self-healing polymer coatings based on crosslinked metallosupramolecular copolymers.


Input: Self-healing coating based on metallopolymers are prepared and fully characterized.


Input: Iron bisterpyridine complexes are incorporated into a polymer network based on methacrylates, resulting in self-healing properties of these materials.

Iron bisterpyridine

methacrylates


Input: Moreover, the influence of the comonomers on the thermal properties is studied in detail.


Input: The discovery of phenylbenzamide derivatives as Grb7-based antitumor agents.

phenylbenzamide


Input: Grb7 is a non-catalytic protein, the overexpression of which has been associated with the proliferative and migratory potentials of cancer cells.


Input: Virtual screening strategies involving a shape-based similarity search, molecular docking, and 2D-similarity searches complemented by experimental binding studies (Thermofluor and isothermal titration calorimetry) resulted in the identification of nine novel phenylbenzamide-based antagonists of the Grb7 SH2 domain.

phenylbenzamide


Input: Moderate binding affinities were observed, ranging from K (d) = 32. 3 mu M for lead phenylbenzamide NSC 104999 (1) to K (d) = 1. 1 mu M for a structurally related compound, NSC 57148 (2).

phenylbenzamide NSC 104999

NSC 57148


Input: Deconvolution of the affinity data into its components revealed differences in lead binding, from being entropy based (lead 1) to enthalpically driven (NSC 100874 (3), NSC 55158 (4), and compound 2).

NSC 100874

NSC 55158


Input: Finally, the lead compound 1 was found to decrease the growth of MDA-MB-468 breast cancer cells, with an IC (50) value of 39. 9 mu M.


Input: It is expected that these structures will serve as novel leads in the development of Grb7-based anticancer therapeutics.


Input: Structural Basis of Signaling Blockade by Anti-IL-13 Antibody Lebrikizumab.


Input: The cytokine interleukin 13 (IL-13) is a major effector molecule for T-helper type 2 inflammation and is pathogenic in allergic diseases such as asthma.


Input: The effects of IL-13 are mediated via a pathway that is initiated by binding to a heterodimeric receptor consisting of IL-13R alpha 1 and IL-4R alpha.


Input: Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides.


Input: Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit in a phase II study for the treatment of moderate-to-severe uncontrolled asthma.


Input: Here we report the molecular structure of IL-13 in complex with the Fab from lebrikizumab by X-ray crystallography at 1. 9 A resolution.


Input: We show that lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4R alpha.


Input: In addition, we use site-directed mutations to identify the most important antibody contributors to binding.


Input: Our studies define key features of lebrikizumab binding and its mechanism of action that may contribute to its clinical effects.


Input: The role of phosphodiesterases in hippocampal synaptic plasticity.


Input: Phosphodiesterases (PDEs) degrade cyclic nucleotides, signalling molecules that play important roles in synaptic plasticity and memory.

cyclic nucleotides


Input: Inhibition of PDEs may therefore enhance synaptic plasticity and memory as a result of elevated levels of these signalling molecules, and this has led to interest in PDE inhibitors as cognitive enhancers.


Input: The development of new mouse models in which PDE subtypes have been selectively knocked out and increasing selectivity of PDE antagonists means that this field is currently expanding.


Input: Roles for PDE2, 4, 5 and 9 in synaptic plasticity have so far been demonstrated and we review these studies here in the context of cyclic nucleotide signalling more generally.

cyclic nucleotide


Input: The role of other PDE families in synaptic plasticity has not yet been investigated, and this area promises to advance our understanding of cyclic nucleotide signalling in synaptic plasticity in the future.

cyclic nucleotide


Input: This article is part of a Special Issue entitled' GluR-dep synaptic plasticity'.


Input: beta-Asarone induces senescence in colorectal cancer cells by inducing lamin B1 expression.

beta-Asarone


Input: Colorectal cancer is a leading cause of cancer mortality with a complex carcinogenesis that includes reduced cellular senescence.


Input: Lamin proteins are decreased in senescing cells, and frequently decreased in malignancies.


Input: This study identified a new drug candidate for colorectal cancer that appears to target cell senescence via a lamin protein.


Input: beta-Asarone (1-propenyl-2, 4, 5-methoxybenzol) is a compound from the traditional medical herb Acorus calamus Linn.

beta-Asarone

1-propenyl-2, 4, 5-methoxybenzol


Input: This study tested the in vitro and in vivo effects of beta-asarone on colorectal cancer cells by testing cell viability using human colorectal cell lines HT29 and SW480 in MTT assays; tumorigenesis using xenografts in nude mice and a mouse model of colorectal cancer; cell senescence using senescence-associated beta-galactosidase activity; and expression of cancer and senescence-related proteins, specifically lamins, Oct-1, p53, p21, and p15, by Western blot.

beta-asarone

MTT


Input: beta-Asarone appeared to increase expression of lamin B1, p53, p21, but not lamin A/C.

beta-Asarone


Input: beta-Asarone regulates p15 expression by regulation of Oct-1 binding.

beta-Asarone


Input: Collectively, the results suggested that beta-asarone inhibits colon cancer formation in vivo and in vitro by inducing senescence.

beta-asarone


Input: Since beta-asarone induced lamin B1 expression, a model is proposed in which beta-asarone inhibits colorectal cancer by inducing senescence through lamin B1.

beta-asarone

beta-asarone


Input: Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum.

NO

triterpenes


Input: Four new lanostane triterpenes, butyl lucidenate P (1), butyl lucidenate D (2) (2), butyl lucidenate E (2) (3) and butyl lucidenate Q (4) along with 11 known compounds (5-15) were isolated from the fruiting bodies of Ganoderma lucidum.

lanostane triterpenes

butyl lucidenate P

butyl lucidenate D (2)

butyl lucidenate E (2)

butyl lucidenate Q


Input: Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry.


Input: Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW 264. 7 cells.

NO


Input: Compounds 1, 3, 4, 9, 10 and 15 showed inhibitory potency with IC (50) values of 7. 4, 6. 4, 4. 3, 9. 4, 9. 2 and 4. 5 mu M, respectively.


Input: Compounds 1, 3 and 15 dose-dependently reduced the LPS-induced iNOS expressions.


Input: Preincubation of cell with 1, 3 and 15 significantly suppressed LPS-induced expression of COX-2 protein.


Input: Constitutively active group I mGlu receptors and PKMzeta regulate synaptic transmission in developing perirhinal cortex.


Input: Synaptic transmission is essential for early development of the central nervous system.


Input: However, the mechanisms that regulate early synaptic transmission in the cerebral cortex are unclear.


Input: PKM zeta is a kinase essential for the maintenance of LTP.


Input: We show for the first time that inhibition of PKM zeta produces a profound depression of basal synaptic transmission in neonatal, but not adult, rat perirhinal cortex.


Input: This suggests that synapses in early development are in a constitutive LTP-like state.


Input: Furthermore, basal synaptic transmission in immature, but not mature, perirhinal cortex relies on persistent activity of metabotropic glutamate (mGlu) receptor, PI3Kinase and mammalian target of rapamycin (mTOR).

glutamate

rapamycin


Input: Thus early in development, cortical synapses exist in an LTP-like state maintained by tonically active mGlu receptor-, mTOR-and PKM zeta-dependent cascades.


Input: These results provide new understanding of the molecular mechanisms that control synapses during development and may aid our understanding of developmental disorders such as autism and schizophrenia.


Input: This article is part of a Special Issue entitled' Metabotropic Glutamate Receptors'.

Glutamate


Input: Relative impact of incorporating pharmacokinetics on predicting in vivo hazard and mode of action from high-throughput in vitro toxicity assays.


Input: The use of high-throughput in vitro assays has been proposed to play a significant role in the future of toxicity testing.


Input: In this study, rat hepatic metabolic clearance and plasma protein binding were measured for 59 ToxCast phase I chemicals.


Input: Computational in vitro-to-in vivo extrapolation was used to estimate the daily dose in a rat, called the oral equivalent dose, which would result in steady-state in vivo blood concentrations equivalent to the AC 50 or lowest effective concentration (LEC) across more than 600 ToxCast phase I in vitro assays.


Input: Statistical classification analysis was performed using either oral equivalent doses or unadjusted AC 50/LEC values for the in vitro assays to predict the in vivo effects of the 59 chemicals.


Input: Adjusting the in vitro assays for pharmacokinetics did not improve the ability to predict in vivo effects as either a discrete (yes or no) response or a low effect level (LEL) on a continuous dose scale.


Input: Interestingly, a comparison of the in vitro assay with the lowest oral equivalent dose with the in vivo endpoint with the lowest LEL suggested that the lowest oral equivalent dose may provide a conservative estimate of the point of departure for a chemical in a dose-response assessment.


Input: Furthermore, comparing the oral equivalent doses for the in vitro assays with the in vivo dose range that resulted in adverse effects identified more coincident in vitro assays across chemicals than expected by chance, suggesting that the approach may also be used to identify potential molecular initiating events leading to adversity.


Input: The spectrum of circulating RNA: a window into systems toxicology.


Input: Adverse effects caused by therapeutic drugs are a serious and costly health concern.


Input: Despite the body' s systemic responses to therapeutics, the liver is often the focus of damage and is usually the focus of studies of toxic effects due to its active roles in the metabolism of xenobiotics.


Input: It is extremely difficult, however, to assess systemic responses with currently available methods.


Input: Comprehensive cataloging of cell-free circulating RNAs using next-generation sequencing technology may open a window to assess drug-associated adverse effects at the systems level.


Input: To explore this potential, we conducted an RNA profiling study using the well-characterized acetaminophen overdose mouse model on liver and plasma with microarray and next-generation sequencing platforms, respectively.

acetaminophen


Input: After drug treatment, the levels of a number of transcripts, both endogenous and exogenous RNAs, showed significant changes in plasma, reflecting not only the classical liver injury induced by acetaminophen overdose but also damage in tissues other than the liver.

acetaminophen


Input: The changes in exogenous RNAs also reflect alteration on dieting behavior after acetaminophen overdose.

acetaminophen


Input: Besides reporting an extensive list of circulating RNA-based biomarker candidates, this study illustrates the possibility of using circulating RNAs to assess global effects of therapeutics.


Input: This could also lead to a new approach for a more comprehensive assessment of the efficacy and safety of therapeutics.


Input: Inhibition of p-glycoprotein mediated multidrug resistance by stemofoline derivatives.

stemofoline


Input: Resistance to chemotherapy in cancer patients has been correlated to the overexpression of the ATP-binding cassette (ABC) drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells.

ATP


Input: We examined the mutidrug resistance reversing property of stemofoline derivatives in drug-resistance human cervical carcinoma (KB-V1) and human leukemic (K562/Adr) cell lines that overexpress P-gp.

stemofoline


Input: Didehydrostemofoline and eleven of its derivatives were synthesized and the cytotoxicity and their effect on doxorubicin, vinblastine and paclitaxel sensitivity in drug resistant (KB-V1 and K562/Adr) and drug sensitive (KB-3-1 and K562) cell lines by a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay were determined.

Didehydrostemofoline

doxorubicin

vinblastine

paclitaxel

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

MTT


Input: We found that three out of the twelve stemofoline derivatives including OH-A1, NH-B6 and NH-D6 showed commitment efficiency to increase sensitivity to doxorubicin, vinblastine and paclitaxel in KB-V1 cells and increase sensitivity to doxorubicin, and paclitaxel in K562/Adr cells whereas the effects have not been seen in their parental sensitive cancer cell lines (KB-3-1 and K562).

stemofoline

doxorubicin

vinblastine

paclitaxel

doxorubicin

paclitaxel


Input: These results indicate that stemofoline derivatives reversed P-gp-mediated multidrug resistance in vitro, and thus could be developed as effective chemosensitizers to treat multidrug-resistant cancers.

stemofoline


Input: The molecular mechanism of modulation of P-gp would be further determined.


Input: Partial peptide of alpha-synuclein modified with small-molecule inhibitors specifically inhibits amyloid fibrillation of alpha-synuclein.


Input: We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of alpha-synuclein, amyloid beta (1-42) (A beta (1-42)), and mouse prion protein.

pyrroloquinoline quinone

PQQ


Input: Moreover, PQQ-modified alpha-synuclein and a proteolytic fragment of the PQQ-modified alpha-synuclein are able to inhibit the amyloid formation of alpha-synuclein.

PQQ

PQQ


Input: Here, we identified the peptide sequences that play an important role as PQQ-modified specific peptide inhibitors of alpha-synuclein.

PQQ


Input: We demonstrate that the PQQ-modified alpha-Syn (36-46) peptide, which is a partial sequence of alpha-synuclein, prevented alpha-synuclein amyloid fibril formation but did not inhibit A beta (1-42) fibril formation.

PQQ


Input: In addition, the alpha-synuclein partial peptide modified with other small-molecule inhibitors, Baicalein and epigallocatechin gallate (EGCG), prevented alpha-synuclein fibril formation.

Baicalein

epigallocatechin gallate

EGCG


Input: Currently reported quinone amyloid inhibitors do not have selectivity toward protein molecules.

quinone


Input: Therefore, our achievements provide a novel strategy for the development of targeted specific amyloid formation inhibitors: the combination of quinone compounds with specific peptide sequence from target proteins involved in amyloid formation.

quinone


Input: Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4.

xanthine


Input: A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes.

xanthine

methylene

xanthine


Input: As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities.


Input: Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.


Input: Synthesis, DNA binding and antitumor evaluation of styelsamine and cystodytin analogues.

styelsamine

cystodytin


Input: A series of N-14 sidechain substituted analogues of styelsamine (pyrido [4, 3, 2-mn] acridine) and cystodytin (pyrido [4, 3, 2-mn] acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines.

styelsamine

pyrido [4, 3, 2-mn] acridine

cystodytin

pyrido [4, 3, 2-mn] acridin-4-one


Input: Overall it was found that styelsamine analogues were stronger DNA binders, with the natural products styelsamines B and D having particularly high affinity (K (app) 5. 33 x 10 (6) and 3. 64 x 10 (6) M (-1), respectively).

styelsamine

styelsamines B and D


Input: In comparison, the cystodytin iminoquinone alkaloids showed lower affinity for DNA, but were typically just as active as styelsamine analogues at inhibiting proliferation of tumor cells in vitro.

cystodytin iminoquinone alkaloids

styelsamine


Input: Sub-panel selectivity towards non-small cell lung, melanoma and renal cancer cell lines were observed for a number of the analogues.


Input: Correlation was observed between whole cell activity and clogP, with the most potent antiproliferative activity being observed for 3-phenylpropanamide analogues 37 and 41 (NCI panel average GI (50) 0. 4 mu M and 0. 32 mu M, respectively) with clogP ~ 4. 0-4. 5.


Input: Variation in the alpha 5 nicotinic acetylcholine receptor subunit gene predicts cigarette smoking intensity as a function of nicotine content.

acetylcholine

nicotine


Input: A single-nucleotide polymorphism (SNP) in the alpha 5 nicotinic acetylcholine receptor subunit gene, rs16969968, has been repeatedly associated with both smoking and respiratory health phenotypes.

acetylcholine


Input: However, there remains considerable debate as to whether associations with lung cancer are mediated through effects on smoking behavior.


Input: Preclinical studies suggest that alpha 5 receptor subunit expression and function may have a direct role in nicotine titration during self administration.

nicotine


Input: The present study investigated the association of CHRNA5 polymorphisms and smoking topography in 66 smokers asked to smoke four nicotine-containing (nicotine yield = 0. 60 mg) and four placebo (nicotine yield < 0. 05 mg) cigarettes, during separate experimental sessions.

nicotine

nicotine

nicotine


Input: Genotype at rs16969968 predicted nicotine titration, with homozygotes for the major allele (G: G) displaying significantly reduced puff volume in response to nicotine, whereas minor allele carriers (A: G or A: A) produced equivalent puff volumes for placebo and nicotine cigarettes.

nicotine

nicotine

nicotine


Input: The present results suggest that puff volume may be a more powerful objective phenotype of smoking behavior than self-reported cigarettes per day and nicotine dependence.

nicotine


Input: Further, these results suggest that the association between rs16969968 and lung cancer may be mediated by the quantity of smoke inhaled. The Pharmacogenomics Journal advance online publication, 29 January 2013; doi: 10. 1038/tpj. 2012. 50.


Input: Dynamic pH mapping in microfluidic devices by integrating adaptive coatings based on polyaniline with colorimetric imaging techniques.

polyaniline


Input: In this paper we present a microfluidic device that has integrated pH optical sensing capabilities based on polyaniline.

polyaniline


Input: The optical properties of polyaniline coatings change in response to the pH of the solution that is flushed inside the microchannel offering the possibility of monitoring pH in continuous flow over a wide pH range throughout the entire channel length.

polyaniline


Input: This work also features an innovative detection system for spatial localisation of chemical pH gradients along microfluidic channels through the use of a low cost optical device.


Input: Specifically, the use of a microfluidic channel coated with polyaniline is shown to respond colorimetrically to pH and that effect is detected by the detection system, even when pH gradients are induced within the channel.

polyaniline


Input: This study explores the capability of detecting this gradient by means of imaging techniques and the mapping of the camera' s response to its corresponding pH after a successful calibration process.


Input: The provision of an inherently responsive channel means that changes in the pH of a sample moving through the system can be detected dynamically using digital imaging along the entire channel length in real time, without the need to add reagents to the sample.


Input: This approach is generic and can be applied to other chemically responsive coatings immobilised on microchannels.


Input: Agrochemicals in field margins-assessing the impacts of herbicides, insecticides, and fertilizer on the common buttercup (ranunculus acris).


Input: The effects of herbicide, insecticide, and fertilizer inputs on the common buttercup Ranunculus acris in field margins were studied in an experimental field study.


Input: The test design allowed us to investigate the single and combined effects of repeated herbicide, insecticide, and fertilizer applications in successive growing seasons.


Input: To assess the effects of the agrochemical applications on R. acris, plant community assessments were carried out and a photodocumentation of the flowering intensity was performed over two years.


Input: In addition, the authors conducted a monitoring survey of R. acris in field margins in the proximity of the study site.


Input: In the field experiment, R. acris plant density decreased significantly with treatments including fertilizer.


Input: The herbicide caused a sublethal effect by reducing flower intensity by 85%.


Input: In the long run, both effects will result in a decline of R. acris and lead to shifts in plant communities in field margins.


Input: This was confirmed by the monitoring survey, where R. acris could hardly be observed in field margins directly adjacent to cereal fields, whereas in margins next to meadows the species was recorded frequently.


Input: Besides the implications for the plants, the sublethal effects may also affect many flower-visiting insects.


Input: The results indicate that the current risk assessment for nontarget plants is insufficiently protective for wild plant species in field margins and that consideration of sublethal effects is crucial to preserve biodiversity in agricultural landscapes.


Input: Environ.


Input: Toxicol.


Input: Chem.


Input: 2013; 32: 1124-1131.


Input: (c) 2013 SETAC.


Input: Effect propagation in a toxicokinetic/toxicodynamic model explains delayed effects on the growth of unicellular green algae scenedesmus vacuolatus.


Input: Ecotoxicological standard tests assess toxic effects by exposing an organism to high concentrations over defined periods of time.


Input: To evaluate toxicity under field conditions such as fluctuating and pulsed exposures, process-based toxicokinetic/toxicodynamic (TK/TD) models may be used for extrapolation from the existing evidence.


Input: A TK/TD model was developed that simulates the effect on growth of the green algae Scenedesmus vacuolatus continuously exposed to the model chemicals norflurazon, triclosan, and N-phenyl-2-naphthylamine.

norflurazon

triclosan


Input: A pharmacological time-response model describing the effects of anticancer treatments on cancer cell growth was adapted and modified to model the affected growth of synchronized algae cells.


Input: The TK/TD model simulates the temporal effect course by linking the ambient concentration of a chemical to the observable adverse effect via an internal concentration and a sequence of biological events in the organism.


Input: The parameters of the toxicodynamic model are related to the growth characteristics of algae cells, a no effect concentration, the chemical efficacy as well as the ability of recovery and repair, and the delay during damage propagation.


Input: The TK/TD model fits well to the observed algae growth.


Input: The effect propagation through cumulative cell damage explained the observed delayed responses better than just the toxicokinetics.


Input: The TK/TD model could facilitate the link between several effect levels within damage propagation, which prospectively may be helpful to model adverse outcome pathways and time-dependent mixture effects.


Input: Environ.


Input: Toxicol.


Input: Chem.


Input: 2013; 32: 1161-1172.


Input: (c) 2013 SETAC.


Input: Pharmacologic therapy for nonalcoholic fatty liver disease in adults.


Input: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in hepatocytes in the absence of excessive alcohol intake, ranging in severity from simple steatosis to nonalcoholic steatohepatitis (NASH).

triglycerides

alcohol


Input: Nonalcoholic steatohepatitis can ultimately progress to cirrhosis and hepatocellular carcinoma.


Input: NAFLD is associated with cardiometabolic risk factors and is the most common chronic liver disease among adults in the Western Hemisphere.


Input: Although simple steatosis is generally considered a self-limiting disease, evidence suggests an increased risk of cardiovascular disease, and, less conclusively, mortality, among individuals with NAFLD and/or NASH.


Input: The current standard of care for the treatment of patients with NAFLD focuses on lifestyle interventions, particularly diet and exercise.


Input: There is a lack of consensus regarding the most effective and appropriate pharmacologic therapy.


Input: A PubMed search was conducted using the medical subject heading terms " fatty liver " and " steatohepatitis. " This review focuses on the current pharmacologic options available for treating adults with NAFLD and/or NASH.


Input: Continued investigation of drugs or combinations that improve NAFLD progression is crucial.


Input: Clinicians, particularly pharmacists, must take an active role in identification and appropriate selection of pharmacotherapy for NAFLD.


Input: PEG-Modified Macroporous Poly (Glycidyl Methacrylate) and Poly (2-Hydroxyethyl Methacrylate) Microspheres to Reduce Non-Specific Protein Adsorption.

PEG

Poly (Glycidyl Methacrylate)

Poly (2-Hydroxyethyl Methacrylate)


Input: To minimize non-specific protein adsorption on macroporous poly (glycidyl methacrylate) and poly (2-hydroxyethyl methacrylate) microspheres containing amino and/or carboxyl groups, the microspheres are coated with alpha, omega-bis-carboxy poly (ethylene glycol) and amino-terminated poly (ethylene glycol-co-propylene glycol) or alpha-methoxy-omega-amino poly (ethylene glycol).

poly (glycidyl methacrylate)

poly (2-hydroxyethyl methacrylate)

amino

carboxyl

alpha, omega-bis-carboxy poly (ethylene glycol)

amino

poly (ethylene glycol-co-propylene glycol)

alpha-methoxy-omega-amino poly (ethylene glycol)


Input: Adsorption of bovine serum albumin (BSA), gamma-globulin, (125) I-BSA, pepsin, and chymotrypsin on neat and PEGylated microspheres is determined by UV-VIS spectroscopy of supernatants and eluates or by measurement of radioactivity in an ionization chamber.

(125) I


Input: Neat and PEGylated microspheres adsorb 0. 8-70% and 0. 02-44% of protein, respectively.


Input: Electronic structure of individual hybrid colloid particles studied by near-edge X-ray absorption fine structure (NEXAFS) spectroscopy in the X-ray microscope.


Input: The electronic structure of individual hybrid particles was studied by nanoscale near-edge X-ray absorption spectromicroscopy.


Input: The colloidal particles consist of a solid polystyrene core and a cross-linked poly-N-(isopropylacrylamide) shell with embedded crystalline titanium dioxide (TiO (2)) nanoparticles (d = 6 +/- 3 nm).

polystyrene

poly-N-(isopropylacrylamide)

titanium dioxide

TiO (2)


Input: The TiO (2) particles are generated in the carrier network by a sol-gel process at room temperature.

TiO (2)


Input: The hybrid particles were imaged with photon energy steps of 0. 1 eV in their hydrated environment with a cryo transmission X-ray microscope (TXM) at the Ti L (2, 3)-edge.

Ti


Input: By analyzing the image stacks, the obtained near-edge X-ray absorption fine structure (NEXAFS) spectra of our individual hybrid particles show clearly that our synthesis generates TiO (2) in the anastase phase.

TiO (2)


Input: Additionally, our spectromicroscopy method permits the determination of the density distribution of TiO (2) in single carrier particles.

TiO (2)


Input: Therefore, NEXAFS spectroscopy combined with TXM presents a unique method to get in-depth insight into the electronic structure of hybrid materials.


Input: Assessing the regioselectivity of OleD-catalyzed glycosylation with a diverse set of acceptors.


Input: To explore the acceptor regioselectivity of OleD-catalyzed glucosylation, the products of OleD-catalyzed reactions with six structurally diverse acceptors flavones-(daidzein), isoflavones (flavopiridol), stilbenes (resveratrol), indole alkaloids (10-hydroxycamptothecin), and steroids (2-methoxyestradiol)-were determined.

flavones

daidzein

isoflavones

flavopiridol

stilbenes

resveratrol

indole alkaloids

steroids


Input: This study highlights the first synthesis of flavopiridol and 2-methoxyestradiol glucosides and confirms the ability of OleD to glucosylate both aromatic and aliphatic nucleophiles.

flavopiridol

2-methoxyestradiol glucosides

glucosylate


Input: In all cases, molecular dynamics simulations were consistent with the determined product distribution and suggest the potential to develop a virtual screening model to identify additional OleD substrates.


Input: Nonhuman targets in allergic lung conditions.


Input: Existing therapies for allergic asthma are far from perfect: the global prevalence of disease increases despite them and they are poorly effective in dealing with the exacerbations that account for hospitalization and asthma deaths.


Input: Commercially, there are pressures on these existing medicines too-a growing threat from generics and reluctance by payers to reimburse for increasingly marginal improvements in medicines with precedented mechanisms.


Input: Experience shows that attempts to devise selective small-molecule interventions directed at the myriad of downstream effector pathways has not been a fertile ground for the development of effective new medicines.


Input: An alternative strategy, exploiting breakthroughs in understanding the molecular basis of allergenicity and the key role of innate immune mechanisms in asthma, is to direct new approaches to the disease triggers themselves: allergens.


Input: This raises interesting possibilities for anti-Lipinski drug design (extracellular nonhuman targets, inhaled delivery) and creates unprecedented pharmacological opportunities in the therapeutic area.


Input: Macroporous silk fibroin cryogels.


Input: Silk fibroin cryogels with remarkable properties were obtained from frozen fibroin solutions (4. 2-12. 6%) at subzero temperatures between-5 and-22 degrees C.


Input: This was achieved by the addition of ethylene glycol diglycidyl ether (EGDE) into the cryogelation system.

ethylene glycol diglycidyl ether

EGDE


Input: EGDE triggers the conformational transition of fibroin from random coil to beta-sheet structure and hence fibroin gelation.

EGDE


Input: One of the unique features of fibroin cryogels is their elasticity that allows them to resist complete compression without any crack development, during which water inside the cryogel is removed.


Input: The compressed cryogel immediately swells during unloading to recover its original shape.


Input: The scaffolds obtained by freeze-drying of the cryogels consist of regular, interconnected pores of diameters ranging from 50 to 10 mu m that could be regulated by the synthesis parameters.


Input: The mechanical compressive strength and the modulus of the scaffolds increase with decreasing pore diameter, that is, with decreasing gelation temperature or, with increasing fibroin or EGDE concentrations in the feed.

EGDE


Input: The scaffolds produced at 12. 6% fibroin exhibit a very high compressive modulus (50 MPa) making them good candidates as bone scaffold materials.


Input: Effects of polymer end-group chemistry and order of deposition on controlled protein delivery from layer-by-layer assembly.


Input: Layer-by-layer (LBL) assembly is an attractive platform for controlled release of biologics given its mild fabrication process and versatility in coating substrates of any shape.


Input: Proteins can be incorporated into LBL coatings by sequentially depositing oppositely charged polyelectrolytes, which self-assemble into nanoscale films on medical devices or tissue engineering scaffolds.


Input: However, previously reported LBL platforms often require the use of a few hundred layers to avoid burst release, which hinders their broad translation due to the lengthy fabrication process, cost, and batch-to-batch variability.


Input: Here we report a biodegradable LBL platform composed of only 10 layers with tunable protein release kinetics, which is an order of magnitude less than previously reported LBL platforms.


Input: We performed a combinatorial study to examine the effects of polymer chemistry and order of deposition of poly (beta-amino) esters on protein release kinetics under 81 LBL assembly conditions.

poly (beta-amino) esters


Input: Using the optimal " polyelectrolyte couples " for constructing the LBL film, basic fibroblast growth factor (bFGF) was released gradually over 14 days with retained biological activity to stimulate cell proliferation.


Input: The method reported herein is applicable for coating various substrates including metals, polymers, and ceramics and may be used for a broad range of biomedical and tissue engineering applications.


Input: Epitaxial silicon dots self-assembled on aluminum nitride/Si (111).

silicon

aluminum nitride

Si (111)


Input: Si nanoscale dots are synthesized on AlN/Si (111) by molecular beam epitaxy.

Si

AlN

Si (111)


Input: A dot density of 2. 2 x 10 (11) cm (-2) with a mean radius of 5. 6 +/- 2. 8 nm is obtained in Volmer-Weber growth mode.


Input: A double Si coverage leads to a decrease in dot density and increase in dot size.

Si


Input: The dot orientations are [11 [overline] 0] (Si) (or [1 [overline] 10] (Si))//[112 [overline] 0] (AlN) and (111) (Si)//(0001) (AlN), which are similar (or identical) to the orientation of AlN relative to the Si substrate.

Si

Si

AlN

(111) (Si)

AlN

AlN

Si


Input: Safety of posaconazole.

posaconazole


Input: INTRODUCTION: The increasing number of invasive fungal infections (IFI) among immunocompromised hosts is a significant clinical issue.


Input: Diagnosis of IFI, choosing among the available antifungal drugs, and the high morbidity/mortality associated with IFI pose clinical challenges for healthcare providers.


Input: Besides efficacy, a thorough knowledge of the pharmacokinetics, drug-drug interactions and safety profile of the antifungal drugs is critical for appropriate drug selection.


Input: Among the commonly used triazoles, the recently released posaconazole is relatively less well investigated in terms of its safety.

triazoles

posaconazole


Input: With expanding clinical use of posaconazole, the present review examines the safety of the drug and its propensity for drug-drug interaction.

posaconazole


Input: AREAS COVERED: This paper mainly discusses the safety profile of posaconazole, its adverse effects and drug-drug interaction.

posaconazole


Input: EXPERT OPINION: Posaconazole is generally safe and well tolerated.

Posaconazole


Input: Lack of an intravenous formulation and unpredictable bioavailability of the suspension form are significant factors limiting the widespread use of posaconazole.

posaconazole


Input: Mass transfer and adsorption equilibrium for low volatility alkanes in BPL activated carbon.

alkanes

carbon


Input: The structure of a molecule and its concentration can strongly influence diffusional properties for transport in nanoporous materials.


Input: We study mass transfer of alkanes in BPL activated carbon using the concentration-swing frequency response method, which can easily discriminate among mass transfer mechanisms.

alkanes

carbon


Input: We measure concentration-dependent diffusion rates for n-hexane, n-octane, n-decane, 2, 7-dimethyloctane, and cyclodecane, which have different carbon numbers and geometries: straight chain, branched chain, and cyclic.

n-hexane

n-octane

n-decane

2, 7-dimethyloctane

cyclodecane

carbon


Input: Micropore diffusion is determined to be the controlling mass transfer resistance except at low relative saturation for n-decane, where an external mass transfer resistance also becomes important, showing that the controlling mass transfer mechanism can change with system concentration.

n-decane


Input: Micropore diffusion coefficients are found to be strongly concentration dependent.


Input: Adsorption isotherm slopes obtained from measured isotherms, the concentration-swing frequency response method, and a predictive method show reasonably good agreement.


Input: Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents.

tryptanthrins


Input: The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb).

tryptanthrin

tryptanthrin


Input: However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB.


Input: Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds.

tryptanthrin


Input: Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB.


Input: The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products.


Input: Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents.

tryptanthrin

tryptanthrin


Input: However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks.


Input: Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.

tryptanthrin


Input: pi-Conjugated nickel bis (dithiolene) complex nanosheet.

nickel bis (dithiolene)


Input: A pi-conjugated nanosheet comprising planar nickel bis (dithiolene) complexes was synthesized by a bottom-up method.

nickel bis (dithiolene)


Input: A liquid-liquid interfacial reaction using benzenehexathiol in the organic phase and nickel (II) acetate in the aqueous phase produced a semiconducting bulk material with a thickness of several micrometers.

benzenehexathiol

nickel (II) acetate


Input: Powder X-ray diffraction analysis revealed that the crystalline portion of the bulk material comprised a staggered stack of nanosheets.


Input: A single-layer nanosheet was successfully realized using a gas-liquid interfacial reaction.


Input: Atomic force microscopy and scanning tunneling microscopy confirmed that the pi-conjugated nanosheet was single-layered.


Input: Modulation of the oxidation state of the nanosheet was possible using chemical redox reactions.


Input: Comparative surface thermodynamic analysis of new fluid phase formation between a sphere and a flat plate.


Input: This paper investigates the behavior of confined fluid in the gap between a sphere and a flat plate by examining the curve of free energy of the system versus size of the new phase.


Input: Four possible situations corresponding to new phase formation out of confined liquid or vapor at pressures above or below the saturation pressure are studied.


Input: Using surface thermodynamics, the feasible shape of the meniscus (concave/convex), the possibility of phase transition, as well as the number and the nature (unstable/stable) of equilibrium states have been determined for each of these four situations.


Input: The effects of equilibrium contact angle, separation distance of confinement surfaces, and sphere size have been studied.


Input: We show that the number and nature of equilibrium states, along with the effect of different parameters in these four possible situations, can be well described under two categories of new phase formation with (a) concave or (b) convex meniscus.


Input: Our results reveal that in the sphere-plate gap, stable coexistence of the liquid and vapor phases is only possible when the meniscus is concave (which corresponds to either capillary condensation or capillary evaporation), and when the sphere and plate are separated by a distance less than a critical amount (where that critical amount is always less than the Kelvin radius).


Input: With convex menisci, no stable coexistence of liquid and vapor phase is possible.


Input: In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D, L-alpha-peptide architecture.

cyclic D, L-alpha-peptide


Input: Misfolding of the A beta protein and its subsequent aggregation into toxic oligomers are related to Alzheimer' s disease.


Input: Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction.


Input: Given the significant similarities between amyloids and the architecture of self-assembled cyclic D, L-alpha-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of A beta, thereby preventing its aggregation into toxic forms.

cyclic D, L-alpha-peptide


Input: By screening a focused library of six-residue cyclic D, L-alpha-peptides and optimizing the activity of a lead peptide, we found one cyclic D, L-alpha-peptide (CP-2) that interacts strongly with A beta and inhibits its aggregation.

cyclic D, L-alpha-peptides

cyclic D, L-alpha-peptide


Input: In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of A beta aggregates, entirely disassembles preformed aggregated and fibrillar A beta, and protects rat pheochromocytoma PC12 cells from A beta toxicity, without inducing any toxicity by itself.

thioflavin T


Input: Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2' s antiamyloidogenic activity.

SDS


Input: NMR spectroscopy indicates that CP-2 interacts with A beta through its self-assembled conformation and induces weak secondary structure in A beta.


Input: Upon coincubation, CP-2 changes the aggregation pathway of A beta and alters its oligomer distribution by stabilizing small oligomers (1-3 mers).


Input: Our results support studies suggesting that toxic early oligomeric states of A beta may be composed of antiparallel beta-peptide structures and that the interaction of A beta with CP-2 promotes formation of more benign parallel beta-structures.


Input: Further studies will show whether these kinds of abiotic cyclic D, L-alpha-peptides are also beneficial as an intervention in related in vivo models.

cyclic D, L-alpha-peptides


Input: Anti-inflammatory effects of a special carbohydrate-whey protein cake after exhaustive cycling in humans.

carbohydrate


Input: Intense exercise induces increased levels of pro-inflammatory and anti-inflammatory cytokines.


Input: Thus, the purpose of this study was to examine the effects of a special cake (consisting of carbohydrate to whey protein 3. 5: 1) vs. an isocaloric carbohydrate cake on inflammatory markers after exhaustive cycling in humans.

carbohydrate

carbohydrate


Input: Nine subjects received either the experimental or placebo cake in a counterbalanced fashion using a crossover, double-blind, repeated-measures design.


Input: They performed one trial involving a 2h exercise on a cycle ergometer at 60-65% VO2max followed by a 4h recovery and then a second trial involving an 1h exercise at 60-65% VO2max which was increased at 95% VO2max.


Input: Blood samples were collected pre-exercise, 30min and 4h post-exercise, post-time Trial and 48h post-time Trial.


Input: Cakes were consumed immediately post-exercise and every 1h for the next 3h.


Input: The results showed that consumption of the experimental cake reduced significantly (p < 0. 05), 4h post-exercise, the pro-inflammatory protein levels IL-6 and CRP compared to the control group by 50% and 46% respectively.


Input: Moreover, in the experimental cake group, the level of the anti-inflammatory cytokine IL-10 was higher by 118%, 4h post-exercise, compared to the control group but not statistically significant.


Input: X-ray absorption spectroscopy and energy storage of Ni-doped cobalt nitride, (Ni (0. 33) Co (0. 67)) N, prepared by a simple synthesis route.

Ni

cobalt nitride

(Ni (0. 33) Co (0. 67)) N


Input: Metal nitride (Ni (0. 33) Co (0. 67)) N nanoparticles are prepared by nitridation using NiCo (2) O (4) as a precursor material by heating at 335 degrees C for 2 h in flowing NH (3) + N (2) gas and characterized by X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), high resolution-transmission electron microscopy (HR-TEM), along with selective area electron diffraction (SAED) and X-ray absorption spectroscopy (XAS) techniques.

Metal nitride (Ni (0. 33) Co (0. 67)) N

NiCo (2) O (4)

NH (3)

N (2)


Input: The X-ray absorption near edge structure (XANES) at the Co K-edge showed that the oxidation state of cobalt is close to 3 +.

Co

cobalt


Input: The (Ni (0. 33) Co (0. 67)) N showed a shift in edge energy towards lower values due to Ni-doping to cobalt site.

(Ni (0. 33) Co (0. 67)) N

Ni


Input: The Li-storage behaviour of (Ni (0. 33) Co (0. 67)) N nanoparticles was evaluated by galvanostatic cycling and cyclic voltammetry in the cells with Li-metal as counter electrode in the voltage range of 0. 005-3. 0 V at ambient temperature.

Li

(Ni (0. 33) Co (0. 67)) N

Li


Input: When cycled at 250 mA g (-1), the first-cycle reversible capacity of 700 (+/- 5) mA h g (-1) (~ 1. 9 moles of Li) is obtained.

Li


Input: It showed an initial decrease in capacity until the 10 (th) cycle and a stable capacity of 400 (+/- 5) mA h g (-1) (~ 1. 09 moles of Li) is observed at the end of the 50 (th) cycle.

Li


Input: Excellent rate capability is also shown when cycling at 500 mA g (-1) (up to 50 cycles).


Input: The materials showed excellent Li-ion insertion/extraction, with the coulombic efficiency reaching almost 99% in the range of 10-50 cycles.

Li


Input: The average charge and discharge potentials are ~ 2. 03 and ~ 1. 0 V, respectively for the decomposition/formation of Li (3) N as determined by electroanalytical techniques.

Li (3) N


Input: Self-assembly of mesoporous CuO nanosheets-CNT 3D-network composites for lithium-ion batteries.

CuO

lithium


Input: A facile, flexible and large-scale technique was proposed to prepare a CuO-CNT 3D-network composite with the aid of electrostatic interactions in aqueous solution.

CuO


Input: The composite greatly improves the electrochemical performance.


Input: At a rate of 0. 1 C, the cycling discharge capacity of the optimal composite is more than 2. 3 times of that of unmodified mesoporous CuO nanosheets as the active material in an anode after 40 cycles.

CuO


Input: Adsorbed and near surface structure of ionic liquids at a solid interface.


Input: The structure of solid-ionic liquid (IL) interfaces has been characterised with unprecedented clarity by employing a range of atomic force microscopy (AFM) imaging techniques and tip pressures appropriate for the system under study.


Input: Soft contact and amplitude-modulation (AM) AFM imaging have been used to elucidate the lateral structure of ILs adsorbed onto mica, and in the near surface ion layers.