Fabrication of a Liquid Scintillator based on 7-Diethylamino-4-Methylcoumarin for Radiation Detection.

Organic liquid scintillation detectors are widely used to measure the presence of radiation. With these devices, there are advantages in that they are easy to manufacture, large in size, and have a short fluorescence decay time. However, they are not suitable for gamma spectroscopy because they are composed of a low-atomic-number material. In this regard, alternative materials for the secondary solute used in basic organic liquid scintillators have been investigated, and the applicability of alternative materials, the detection characteristics, and neutron/gamma identification tests were all assessed. 7-Diethylamino-4-methylcoumarin (DMC), selected as an alternative material, is a benzopyrone derivative in the form of colorless crystals with high fluorescence, a high quantum yield in the visible region, and excellent light stability. In addition, it has a large Stokes shift, and solubility in a solvent is good. Through an analysis in this study, it was found that the absorption wavelength range of DMC coincides with the emission wavelength range of PPO, which is the primary solute used with DMC. Finally, it was confirmed that the optimal concentration of DMC was 0.08 wt%. As a result of performing gamma and neutron measurement tests using a DMC-based liquid scintillator, it was found to perform well (FOM = 1.42) compared to a commercial liquid scintillator, BC-501A.

Synthesis and evaluation of curcumin-based near-infrared fluorescent probes for the in vivo optical imaging of amyloid-ß plaques.

The abnormal self-assembly of amyloid-beta (Aß) peptides into oligomers, as well as insoluble fibrils, has been identified as a key factor for monitoring the progression of Alzheimer's disease (AD). The noninvasive imaging of Aß aggregates utilizing chemical probes can be a powerful and practical technique for accurately diagnosing and monitoring the progress of AD, as well as evaluating the effectiveness of therapeutic drug candidates in treating or managing it. Particularly, the near-infrared (NIR) fluorescence imaging of Aß plaques is a potentially promising approach toward the efficient detection of the biomarker. In this study, we describe a new NIR fluorophore, which was based on curcumin derivatives. The fluorophore is equipped with desirable optical properties for in vivo brain imaging. The emission wavelength of the probe, 8b, is 667 nm, and its fluorescent intensity is significantly increased through binding with the Aß aggregates. The probe allows the clear visualization of the Aß plaques 10 min post administration, and the intensity of the fluorescent signal in the brain of a 5XFAD transgenic mouse model is more than three times higher than that of the normal control group. These results demonstrate that the designed probe can be an effective tool for visualizing Aß plaques, as well as investigating the pathological progress of AD.

Development of a Squaraine-Based Molecular Probe for Dual-Modal in Vivo Fluorescence and Photoacoustic Imaging.

Dual-modular imaging approaches combining near-infrared (NIR) fluorescence (FLI) and photoacoustic imaging (PAI) require suitable contrast agents to produce dual-modular signals. Although nanoparticles have been used to develop PAI agents, small molecule-based imaging agents have not been extensively studied, highlighting the need to design new fluorophores with an enhanced multifunctional ability. Thus, in this study, we designed a novel squaraine (SQ)-based dye and reported its rational preparation and conjugation with a cancer targeting peptide. Specifically, benzoindole-derived SQ (BSQ) showed strong absorption and fluorescence properties at above 650 nm under aqueous conditions, with a maximum absorption and emission at 665 and 680 nm, respectively. Moreover, PA signal scanning experiments revealed a maximum signal intensity in the range 680-700 nm. BSQ was also conjugated with cyclic arginine-glycine-aspartic acid (cRGD) to improve its active targeting ability for the αvß3 integrin, which is overexpressed in various cancer and angiogenic cells. A series of in vitro, in vivo, and ex vivo FLI studies showed that the cRGD conjugated BSQ (BSQ-RGD2) successfully stained and targeted αvß3 integrin-overexpressing tumor cells and xenografts, which were clearly visualized by FLI and PAI. Therefore, BSQ-RGD2 can successfully be applied to dual-modular imaging of the specific biomarker in living animals.

Activatable red emitting fluorescent probe for rapid and sensitive detection of intracellular peroxynitrite.

Peroxynitrite (ONOO-), a highly reactive oxygen species generated by the reaction of nitric oxide and superoxide radical anion, is involved in numerous physiological and pathological processes in the human body. To identify important pathogenic mechanisms, it is crucial to develop a reliable tool for detecting peroxynitrite in living systems. In the present study, a new difluoroboron ß-diketonate-based fluorescent probe for detecting exogenous and endogenous peroxynitrite in living systems was designed. The red emitting fluorophore can be synthesized in a simple three-step procedure. This probe reacts quickly and selectively with peroxynitrite and its detection limit is determined to be as low as 19.8 nM. It allows for clear imaging of peroxynitrite in RAW 264.7 cells and was successfully applied to visualize changes of intracellular peroxynitrite induced by reactive oxygen species inhibitors. This designed probe is an effective tool for investigating the physiological and pathological role of peroxynitrite in living cells.

A Pyridazine-Based Fluorescent Probe Targeting Aß Plaques in Alzheimer's Disease.

Accumulation of ß-amyloid (Aß) plaques comprising Aß40 and Aß42 in the brain is the most significant factor in the pathogenesis of Alzheimer's disease (AD). Thus, the detection of Aß plaques has increasingly attracted interest in the context of AD diagnosis. In the present study, a fluorescent pyridazine-based dye that can detect and image Aß plaques was designed and synthesized, and its optical properties in the presence of Aß aggregates were evaluated. An approximately 34-fold increase in emission intensity was exhibited by the fluorescent probe after binding with Aß aggregates, for which it showed high affinity (KD = 0.35 µM). Moreover, the reasonable hydrophobic properties of the probe (log P = 2.94) allow it to penetrate the blood brain barrier (BBB). In addition, the pyridazine-based probe was used in the histological costaining of transgenic mouse (APP/PS1) brain sections to validate the selective binding of the probe to Aß plaques. The results suggest that the pyridazine-based compound has the potential to serve as a fluorescent probe for the diagnosis of AD.

Discovery of boronic acid-based fluorescent probes targeting amyloid-beta plaques in Alzheimer's disease.

A boronic acid-based fluorescent probe was developed for diagnosis of amyloid-ß (Aß) plaques from Alzheimer's disease (AD). Probe 4c, which included boronic acid as a functional group, exhibited a significant increase (64.37-fold, FAß/F0) in fluorescence intensity as a response to Aß aggregates, with a blue shift (105nm) in the maximum emission wavelength. We found that boronic acid as a functional group improved the binding affinity (KD value=0.79±0.05µM for 4c) for Aß aggregates and confirmed that 4c selectively stained Aß plaques in brain sections from APP/PS1 mice. Ex vivo fluorescence imaging using mice (normal and APP/PS1) also revealed that 4c was able to penetrate the blood-brain barrier (BBB) and to stain Aß plaques in the brain. From these results, we believe that 4c will be useful as a fluorescent probe in preclinical research related to AD. Furthermore, we believe that our results with boronic acid also provide valuable information for the development of a probe for Aß plaques.

Development of fluorescent probes that bind and stain amyloid plaques in Alzheimer's disease.

ß-amyloid (Aß) plaques in the brain are composed of Aß40 and Aß42 peptides, and are the defining pathological feature of Alzheimer's disease (AD). Fluorescent probes that can detect Aß plaques have gained increasing interest as potential tools for in vitro and in vivo monitoring of the progression of AD. In this study, chalcone-mimic fluorescent probe 5 was designed and prepared. Probe 5 exhibited an approximately 50-fold increase in emission intensity after mixing with Aß42 aggregates, a high affinity for Aß42 aggregates (K D = 1.59 µM), and reasonable lipophilicity (log P value = 2.55). Probe 5 also exhibited specific staining of Aß plaques in the transgenic mice (APP/PS1) brain sections. Ex vivo fluorescence imaging of the brain from normal and TG mice revealed that probe 5 was able to penetrate the BBB and stain the Aß plaques. These results suggest that chalcone-mimic probe 5 possessed the requirements of a fluorescent probe for Aß plaques and may be useful in AD research.

Design, synthesis, and anti-influenza viral activities of 1,3-diarylprop-2-en-1-ones: a novel class of neuraminidase inhibitors.

A series of 1,3-diarylprop-2-en-1-one derivatives 3a-v have been synthesized and evaluated for their ability to inhibit neuraminidase (NA). Among the prepared compounds, the less lipophilic derivative 3k showed the most potent in vitro inhibitory activity against NA with an IC(50) value of 1.5 µM.

Fluorescent 2-styrylpyridazin-3(2H)-one derivatives as probes targeting amyloid-beta plaques in Alzheimer's disease.

Amyloid plaques, which are primarily composed of aggregated amyloid-beta (Aß) peptide, are the neuropathological hallmarks of Alzheimer's disease (AD). Fluorescent markers containing 2-styrylpyridazin-3(2H)-ones were developed to detect intracellular aggregated Aß peptides. Nine compounds exhibited a greater than 10-fold increase of in emission spectra before and after mixing with Aß aggregates compared with before mixing. Among these compounds, compound 9n exhibited the highest affinity for Aß aggregates (K(d)=1.84 µM) and selectively stained both aggregated intracellular Aß and Aß plaques in the transgenic AD model mice (APP/PS1). These preliminary results indicate that 2-styrylpyridazin-3(2H)-one derivatives are promising alternative fluorescence imaging agent for the study of AD.

Biological evaluation of isoegomaketone isolated from Perilla frutescens and its synthetic derivatives as anti-inflammatory agents.

The anti-inflammatory activities of a prepared isoegomaketone 3a and its derivatives 3b-3f were evaluated in RAW 264.7 cells. Among these, the compound 3d was displayed the most potent inhibitory activities against production of nitric oxide, monocyte chemoattractant protein-1 and interleukin-6. Based on these results, the abilities of compounds 3a-3f to modulate NF-κB and AP-1-mediated gene transcription using a luciferase reporter assay were investigated. The transcriptional activities of NF-κB and AP-1 decreased when pretreated with 3a-3f. Interestingly, at 10 µM, compound 3d markedly suppressed the lipopolysaccharide-induced NF-κB and activator protein-1 DNA binding activities. Some preliminary structure-activity relationships were proposed that may provide a direction for further study.

Isoegomaketone induces apoptosis through caspase-dependent and caspase-independent pathways in human DLD1 cells.

Isoegomaketone (IK) is an essential oil component of Perilla frutescens (L.), but the mechanism by which IK induces apoptosis has never been studied. The purpose of this study was to elucidate the IK-induced apoptotic pathway in DLD1 human colon cancer cells. We observed that IK treatment over 24 h significantly inhibited cell viability in a dose-dependent manner. We also found that IK triggered cleavage of PARP. Moreover, IK treatment resulted in cleavage of caspase-8, -9, and -3 in a dose- and time-dependent manner. IK treatment also resulted in cleavage of Bid and translocation of Bax, and triggered the release of cytochrome c from the mitochondria to the cytoplasm. Furthermore, it resulted in the translocation of apoptosis inducing factor (AIF), a caspase-independent mitochondrial apoptosis factor, from the mitochondria into the nucleus. Overall, these results suggest that IK induces apoptosis through caspase-dependent and capase-independent pathways in DLD1 cells.

Isoegomaketone inhibits lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages through the heme oxygenase-1 induction and inhibition of the interferon-beta-STAT-1 pathway.

Isoegomaketone (IK) is an essential oil component of Perilla frutescens (L.) Britt., and there have been no studies investigating its biological activities. We found that IK inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages, and moreover, when IK was injected into animals prior to LPS administration, NO serum levels decreased in a dose-dependent manner. These results indicate that IK possesses anti-inflammatory activity both in vitro and in vivo. IK suppressed the phosphorylation of STAT-1 and the production of IFN-beta. Treatment with IK also inhibited the activation of NF-kappaB and activator protein-1, but more IK was required for inhibition than for STAT-1 inhibition, indicating that downregulation of inducible nitric oxide synthase gene expression by IK is mainly attributed to the blockade of STAT-1 activation. Furthermore, IK also induced the expression of heme oxygenase-1 (HO-1) through the activation of nuclear factor E2-related factor 2. Treatment with SnPP, a selective inhibitor of HO-1, reversed the IK-induced suppression of STAT-1 phosphorylation and NO production. Taken together, IK isolated from P. frutescens inhibits NO production in LPS-treated RAW 264.7 macrophages through simultaneous induction of HO-1 and inhibition of the IFN-beta-STAT-1 pathway.

Device fabrication with solid-liquid-solid grown silicon nanowires.

High quality, single-crystal silicon nanowires were successfully grown from silicon wafers with a nickel catalyst by utilizing a solid-liquid-solid (SLS) mechanism. The nanowires were composed of a crystalline silicon core with an average diameter of 10 nm and a thick outer oxide layer of between 20 and 30 nm at a growth temperature of 1000 °C. When utilizing the SLS growth mechanism, the diameter of the silicon nanowire is dependent solely upon the growth temperature, and has no relation to either the size or the shape of the catalyst. The characteristics of the silicon nanowires are highly dependent upon the properties of the silicon substrate, such as the crystal phase of silicon itself, as well as the doping type. The possibility of doping of silicon nanowires grown via the SLS mechanism without any external dopant source was demonstrated by measuring the electrical properties of a silicon nanowire field effect transistor.

Human acyl-CoA: cholesterol acyltransferase inhibitory activities of aliphatic acid amides from Zanthoxylum piperitum DC.

Acyl-CoA: cholesterol acyltransferase (ACAT) plays an important role in the esterification of cholesterol with its substrates, cholesterol and fatty acyl coenzyme A, to facilitate both intracellular storage and intercellular transport. ACAT-1 is more involved in macrophage foam cell formation and ACAT-2 plays a critical role in the cholesterol absorption process in intestinal enterocytes. Three aliphatic acid amides, beta-sanshool (1), gamma-sanshool (2), and hydroxy-beta-sanshool (3), were isolated by bioassay-guided fractionation of the ethanolic extracts of Zanthoxylum piperitum DC. Compounds 1 and 2 inhibited human ACAT-1 and -2 activities with IC50 values of 39.0 and 79.7 microM for 1 and of 12.0 and 82.6 microM for 2, respectively. However, the hACAT-1 and -2 inhibitory activities of compound 3 having hydroxyl group were relatively less than those of compounds 1 and 2. A semi-synthetic compound 4, which has acetyl residue at 2'-OH of compound 3, exhibited the increased hACAT-1 and -2 inhibitory activities with IC50 values of 28.1 and 87.5 microM, respectively.

Human ACAT inhibitory effects of shikonin derivatives from Lithospermum erythrorhizon.

Three naphthoquinones were isolated by bioassay-guided fractionation from the CHCl(3) extracts of roots of Lithospermum erythrorhizon. They were identified as acetylshikonin (1), isobutyrylshikonin (2), and beta-hydroxyisovalerylshikonin (3) on the basis of their spectroscopic analyses. The compounds 1-3 were tested for their inhibitory activities against human ACAT-1 (hACAT-1) or human ACAT-2 (hACAT-2). Compound 2 preferentially inhibited hACAT-2 (IC(50)=57.5microM) than hACAT-1 (32% at 120microM), whereas compounds 1 and 3 showed weak inhibitory activities in both hACAT-1 and -2. To develop more potent hACAT inhibitor, shikonin derivatives (5-11) were synthesized by semi-synthesis of shikonin (4), which was prepared by hydrolysis of 1-3. Among them, compounds 5 and 7 exhibited the strong inhibitory activities against hACAT-1 and -2. Furthermore, we demonstrated that compound 7 behaved as a potent ACAT inhibitor in not only in vitro assay system but also cell-based assay system.

Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime.

A series of multi-substituted oximes were prepared and their potencies for inhibiting lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity were evaluated in vitro. Among them, compounds 3a, 3b, and 3m were identified to display a micromolar potency for inhibiting Lp-PLA(2) in whole human plasma and isolated human LDL. Based on these results, structure-activity relationship was studied on modification of three parts of R(1), R(2), and R(3) to identify a potent pharmacophore for Lp-PLA(2). In an attempt to introduce various functional groups at R(2) and R(3), we discovered that replacement of less lipophilic groups led to an increase of inhibitory activity. Among the tested oxime derivatives, cyano- and morpholino-substituted analogue 4f at R(2) and R(3) had the highest potency with an IC(50) value of 0.05 microM in whole human plasma.

Anti-atherosclerotic and anti-inflammatory activities of catecholic xanthones and flavonoids isolated from Cudrania tricuspidata.

The catecholic xanthones and flavonoids 1-13 were isolated from the root bark of Cudrania tricuspidata. Compounds 1 and 3-8 exhibited significant antioxidant activity against low-density lipoprotein (LDL) oxidation in the thiobarbituric acid-reactive substance (TBARS) assay. Among them, prenylated flavonoids 10-12 showed an inhibitory effect on the NO production and iNOS expression in RAW264.7 cells. Also, compounds 1, 2, 5, 7, 9, and 11 preferentially inhibited hACAT-2 than hACAT-1, whereas compounds 3, 4, 6, and 8 showed a similar specificity against hACAT-1 and -2. However, flavonoids 10, 12, and 13 dominantly inhibited hACAT-2, not hACAT-1.

Human ACAT-1 and ACAT-2 inhibitory activities of pentacyclic triterpenes from the leaves of Lycopus lucidus TURCZ.

Acyl-CoA: cholesterol acyltransferase (ACAT) catalyzes the acylation of cholesterol to cholesteryl ester with long chain fatty acids and ACAT inhibition is a useful strategy for treating hypercholesterolemia or atherosclerosis. Pentacyclic triterpenes, ursolic acid (1), oleanolic acid (2), and betulinic acid (3) were isolated from the methanol extracts of the leaves of Lycopus lucidus TURCZ. by bioassay-guided fractionation. The structures of compounds 1-3 were elucidated by their spectroscopic data analysis. Among them, betulinic acid (3) exhibited more potent human ACAT-1 and ACAT-2 inhibitory activities with IC(50) values of 16.2+/-0.6 and 28.8+/-1.3 microM, respectively.

Lp-PLA2 inhibitory activities of fatty acid glycerols isolated from Saururus chinensis roots.

(R)-Glycerol-monolinoleate 4 and (R)-glycerol-monostearate 5 were isolated from the ethyl acetate extracts of Saururus chinensis roots and (R)- or (S)-fatty acid glycerols 4 and 5 were synthesized for confirming their structures and evaluating their inhibitory activities against Lp-PLA(2). The (R)-4 and (S)-4 exhibited Lp-PLA(2) inhibitory activities with IC(50) values of 45.0 and 52.0 microM, respectively.

A one-pot synthesis of pyrido[2,3-b][1,4]oxazin-2-ones.

Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently prepared in excellent yields by a one-pot annulation of N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyridines with use of cesium carbonate in refluxing acetonitrile. The key transformation features a Smiles rearrangement of the initial O-alkylation product and subsequent cyclization.