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金沢大学先端科学・社会共創推進機構, Table-top, femtosecond lasers provide the highest light intensities capable of extreme excitation of matter. A key challenge, however, is the efficient coupling of light to matter, a goal addressed by target structuring and laser pulse-shaping. Nanostructured surfaces enhance coupling but require “high contrast” (e.g., for modern ultrahigh intensity lasers, the peak to picosecond pedestal intensity ratio >1012) pulses to preserve target integrity. Here, we demonstrate a foam target that can efficiently absorb a common, low contrast 105 (in picosecond) laser at an intensity of 5 × 1018 W/cm2, giving ∼20 times enhanced relativistic hot electron flux. In addition, such foam target induced “micro-optic” function is analogous to the miniature plasma-parabolic mirror. The simplicity of the target—basically a structure with voids having a diameter of the order of a light wavelength—and the efficacy of these micro-sized voids under low contrast illumination can boost the scope of high intensity lasers for basic science and for table-top sources of high energy particles and ignition of laser fusion targets.

A Monte Carlo (MC) code simulating the kinetics of two-particle collisions has shown to have certain advantages in the spectral analysis of neutrons from fast-ignition inertial confinement fusion (ICF). The MC code quickly displays neutron spectra produced in the expected fusion plasma kinetics (incl. ion energy spectrum, anisotropy, and collision geometry). This allows to explore various potential mechanisms of neutron production without using time-consuming hydrodynamic or particle simulations and makes it possible to give a feedback to ongoing experiments. The validity of this model was demonstrated in the ”cone-free-shell” fast ignition experiment at the GEKKO-XII - LFEX laser facility, where the model provided a clear explanation for the significant spectral modulation of D(d, n)3He neutrons generated through the interaction between a high-power laser and a long-scale plasma.

Our previous studies have demonstrated the oxidative stress properties of sodium ascorbate (SAA) and its benzaldehyde derivative (SBA) on cancer cell lines, but the molecular mechanisms mediating their cytotoxicity remain unclear. In this study, we treated human colon cancer HT-29 cells with SAA and SBA, and found a significant exposure time-dependent increase of cytotoxicity in both treatments, with a higher cytotoxicity for 24 h with SAA (IC(50) = 5 mM) than SBA (IC(50) = 10 mM). A short-term treatment of cells with 10 mM SAA for 2 h revealed a destabilization of the lysosomes and subsequent induction of cell death, whereas 10 mM SBA triggered a remarkable production of reactive oxidative species, phosphorylation of survival kinase AKT, expression of cyclin kinase-dependent inhibitor p21, and induction of transient growth arrest. The crucial role of p21 mediating this cytotoxicity was confirmed by isogenic derivatives of the human colon carcinoma HCT116 cell lines (p21(+/+) and p21(-/-)), and immunoprecipitation studies with p21 antibody. The SAA cytotoxicity was blocked by co-incubation with catalase, whereas the SBA cytotoxicity and its subsequent growth arrest were abolished by N-acetyl-L-cysteine (NAC), but was not affected by PI3K phosphorylation inhibitor LY294002, or catalase, suggesting two separated oxidative stress pathways were mediated by these two ascorbates. In addition, neither active caspase 3 nor apoptotic bodies but autophagic vacuoles associated with increased LC3-II were found in SBA-treated HT-29 cells; implicating that SBA induced AKT phosphorylation-autophagy and p21-growth arrest in colon cancer HT-29 cells through an NAC-inhibitable oxidative stress pathway.

Results of study of pore waters of bottom sediments from different Baikal basins are presented. The most typical ion distribution patterns reflecting the Baikal sediment diagenesis are given. We have established that in areas with regular sedimentation, in the absence of faults and inflows, the sediment pore waters of three lake basins inherit the chemical composition of the Baikal water, which is stable in time and space. Changes in pore water composition mark general natural anomalies, such as the presence of active faults, tectonic movements, and inflows along permeable zones. In areas with the subsurface occurrence of gas hydrates, thorough long-term research has revealed an anomalous composition of pore waters. It has been established that the anomalies are caused by a discharge of deep-level mud-volcanic fluids. The ejected mud-volcanic waters differ from each other in mineralization, ion composition, and sources, which determines the difference in hydrate formation and the composition of gas hydrates.

Isothermal enthalpy relaxation and density relaxation were investigated for bulk Pd42.5Cu30Ni7.5P20 and Pd40Ni40P20 metallic glasses. The density was measured at room temperature after relaxing the sample for a given time. Enthalpy relaxation data of Pd42.5Cu30Ni7.5P20 glass and density relaxation data of Pd40Ni40P20 glass were well fitted by a non-Debye type relaxation function. A fit to a stretched exponential relaxation function of density relaxation data at 549 K of Pd40Ni40P20 glass gave the exponential index of 0.66. Isochoric Kauzmann temperature TK was estimated from density measurements for nearly fully relaxed bulk glasses and TK = 456 ± 10 K was obtained.

Here, we report a novel target of the drug memantine, ATP-sensitive K

Target design and the fabrication scheme are discussed aiming an application for the future laser fusion reactor KOYO-F that has 4 modular chambers with a wet wall operated with fast ignition scheme. Gain estimation and load of fusion output from the non-symetric burn on the first wall are shown.

It is widely believed that depletion force causes formation of colloidal crystal or flocculation in the stable colloidal suspension mixed with nonadsorbing polymers. This force works between a colloidal particle and plane, which can be regarded as a sphere with infinite radius. We report a novel technique that enables us to measure the depletion force working between a colloidal particle and a glass surface using laser radiation pressure. We found that the observed force almost coincides with the predicted one. {copyright} {ital 1997} {ital The American Physical Society}

Isomerization of heptane was carried out at 573 K under atmospheric pressure using molybdenum oxides as catalysts. MoO3 was inactive for this reaction. H2 reduction of MoO3 at 623 K, however, enhanced the isomerization activity and selectivity, which became almost constant after the reduction for 24 h. The reduced MoO3 exhibited a higher isomerization activity than a typical bifunctional catalyst, 0.5 wt%Pt/USY zeolite, while there was no appreciable difference in product distribution between these two catalysts. These results indicate that the reduced MoO3 catalyzed the isomerization of heptane via a conventional bifunctional mechanism.

A plasma channel created by a high intensity infrared laser beam was observed in a long scale-length plasma (L ~ 240 μm) with the angular filter refractometry technique, which indicated a stable channel formation up to the critical density. We analyzed the observed plasma channel using a rigorous ray-tracing technique, which provides a deep understanding of the evolution of the channel formation.

Thermonuclear ignition and subsequent burn are key physics for achieving laser fusion. In fast ignition, a highly compressed fusion fuel generated with multiple ns‐laser beams is rapidly heated with a large energy, ps‐laser pulse in prior to core disassembly. This scheme has a high potential to achieve ignition and burn since driver energy required for high fusion gain is predicted to be about one tenth of that needed for the central ignition scheme. In Japan, Fast Ignition Realization Experiment (FIREX) project has been started to clarify the physics of energy transport and deposition in the core plasma and to demonstrate fuel temperature of above 5 keV. After the success, FIREX‐I will be followed by the second phase of the project (FIREX‐II) to demonstrate ignition and burn. LFEX laser, designed to deliver a laser pulse of 10 kJ in 10 ps, are operational and the first phase of FIREX experiments has been stated. A new target is proposed to attain dense compression of fuel and improve laser‐core coupling efficiency by adopting double‐cone structure, a low‐density inner liner, low‐Z outer coating, and Br‐doped fuel shell. In this paper, present status and near term prospects of the FIREX‐I project will be reported together with activities on target designing, laser development, and plasma diagnostics.

Hollow cone-shaped overdense plasma targets were used to investigate the generation and transport of fast particles in a high-intensity laser-matter interaction. Using 2d PIC simulations we examine cone, cone-wire and cone with an open tip target designs. Localization of electron jets and an angular spread are found in all cases of the laser-cone interaction. However, in the cone-wire geometry, at later times, the charge separation and radial electric fields around the wire collimate electron streams with an electron hot spot at the front end of the wire. The main mechanism of the electron transport in the targets is the reflection of electrons from the potential walls of the cone surface, and no significant surface electron transport is observed. Furthermore, the presence of harmonics in the reflected light suggests that the field intensity in the cone can be enhanced not only by simple multiple reflection but also by the field modulation due to harmonics generation. Moreover, it is found that the laser interaction with the open-tip cone can efficiently generate trains of short ( LT lambda) attosecond electron sheets close to the laser axis. 5th International Conference on Inertial Fusion Sciences and Applications(IFSA 2007), Sep 09-14, 2007, Kobe, Japan

The fast ignition scheme is one of the most fascinating and feasible ignition schemes for the inertial fusion energy. At ILE Osaka University, FIREX (Fast Ignition Realization Experiment) project is in progress. Implosion experiments of the cryogenic target are scheduled in near future. There are two key issues for the fast ignition. One is controlling the implosion dynamics to form high density core plasma in non‐spherical implosion, and the other is heating the core plasma efficiently by the short pulse high intense laser. The time and space scale in the fast ignition scheme vary widely from initial laser irradiation to solid target, to relativistic laser plasma interaction and final fusion burning. The numerical simulation plays an important role in demonstrating the performance of the fast ignition, designing the targets, and optimizing laser pulse shapes for the scheme. These all the physics are desired to be self‐consistently described. In order to study these physics of FI, we have developed “Fast Ignition Integrated Interconnecting code” (FI3), which consists of collective Particle‐in‐Cell (PIC) code (FISCOF1D/2D), Relativistic Fokker‐Planck with hydro code (FIBMET), and 2‐dimensional Arbitrary‐Lagrangian‐Eulerian (ALE) radiation hydrodynamics code (PINOCO). Those codes are sophisticated in each suitable plasma parameters, and boundaries conditions and initial conditions for them are imported/exported to each other by way of DCCP, a simple and compact communication tool which enable these codes to communicate each others under executing different machines. We show the feature of the FI3 code, and numerical results of whole process of fast ignition. Individual important physics behind the FI are explained with the numerical results also.

A three-dimensional fluid code, IMPACT-3D has been parallelized with high performance Fortran (HPF) on the Earth Simulator. IMPACT-3D is an implosion analysis code using TVD scheme, which performs three-dimensional compressible and inviscid Eulerian fluid computation with the explicit 5-point stencil scheme for spatial differentiation and the fractional time step for time integration. The third dimension of an array was distributed for the parallelization, but the first dimension was preserved for the vector processing. Shift communications were manually tuned to get best performance by using HPF/JA extensions, which was designed to give the users more control over sophisticated parallelization and communication optimizations. Even the Earth Simulator Center claims more than 95% of vectorization ratio and more than 50% of parallelization efficiency to run the simulation code on the Earth Simulator, we have cleared these severe criteria for using 128 nodes of the Earth Simulator. We are very encouraged to get this outstanding performance on a real-world scientific application parallelized with HPF

In this paper, we propose a parallelized rule extraction method from trained neural networks for high-dimensional pattern classification problems. In the rule extraction method, we have to examine all combinations of antecedent fuzzy sets for extracting fuzzy rules. For high-dimensional problems, the number of possible combinations is increased exponentially. To address this difficulty, we parallelize the rule extraction method.

Almost all alveolar macrophages in the mouse lung were strongly immunoreactive for epidermal-type fatty acid binding protein. At the electron microscope level, the immunoreactive material was localized diffusely in the cytoplasm but not within the nucleus. A certain number of alveolar type II epithelial cells were also immunoreactive for the protein with variable immunointensity, while a substantial number of the type II cells were immunonegative. No immunoreactive interstitial fibroblasts were encountered. Based on the present findings, possible roles of epidermal-type fatty acid binding protein in the host-defence mechanism played by alveolar macrophages are suggested.

Chlorogenic acid (CGA) induced apoptotic cell death in human oral squamous cell carcinoma (HSC-2) and salivary gland tumor (HSG) cell lines. CGA exhibited oxidation potential in the culture medium, as demonstrated by NO monitor. Both cytotoxic activity and oxidation potential were significantly reduced by the addition of CoCl2. ESR spectroscopy showed that CGA produced seven peaks of radicals under alkaline condition, while addition of CoCl2 altered the spectral pattern and diminished the radical intensity of CGA. CoCl2 accelerated the CGA-induced coloration of the culture medium and modified the difference spectrum at around 325 nm, an absorption maximum characteristic of CGA. These data suggest that CoCl2 induced conformational changes in the CGA molecule.

We investigated the combination effect of sodium ascorbate (vitamin C) and menadione (vitamin K3) on the viability of various cultured cells. Human oral squamous cell carcinoma (HSC-2, HSC-3) and human promyelocytic leukemia (HL-60) cells were more sensitive to these vitamins as compared to normal cells (human gingival fibroblast HGF, human periodontal ligament fibroblast HPLF, human pulp cell HPC). The combination of vitamin C and vitamin K3 produced synergistic cytotoxicity against all these 6 cell lines. Treatment with vitamin C or vitamin K3, or their combination, induced internucleosomal DNA fragmentation only in HL-60 cells, but not in the oral tumor cell lines (HSC-2, HSC-3, HSG). ESR spectroscopy showed that vitamins C and K3 produce radicals under alkaline conditions and that the combination of these two vitamins synergistically enhanced their respective radical intensities.

Allium victorialis L. (Liliaceae, "Hon-Gyoujya Nin-Niku" in Japanese) was successively extracted with hexane, acetone, methanol and 70% methanol and the extracts were further separated into a total of twenty-five fractions by silica gel and ODS column chromatographies. The biological activities of these four extracts and 25 column fractions were compared. The cytotoxic activity of all extracts and fractions against two oral tumor cell lines was significantly higher than that against normal human gingival fibroblasts, suggesting their tumor-specific action. Three methanol column fractions [M2, M3, M6] and a 70% methanol column fraction [70M6] most effectively reversed the multidrug resistance (MDR) against L5178 mouse T cell lymphoma. The electron spin resonance (ESR) spectroscopy showed that methanol column fractions and 70% methanol extracts produced the highest amount of radical(s) and most efficiently scavenging O2*-, generated by the hypoxanthine-xanthine reaction system, suggesting that the same substances in these fractions display both prooxidant and antioxidant properties. They showed no anti-human immunodeficiency virus (HIV) or anti-Helicobacterpylori activity. These data suggest the medicinal efficacy of Allium victorialis extract.

A total of 23 newly-synthesized 2-aminomethylene-3(2H)-benzofuranone and structurally-related compounds were compared for their cytotoxic activity against both normal (human gingival fibroblast HGF) and tumor cells (human oral squamous cell lines HSC-2, HSC-3 and human salivary gland tumor cells HSG). There was a significant variability of drug sensitivity among the oral tumor cell lines. In general, HSC-2 cells were the most sensitive, followed by HSG cells, while HSC-3 cells were the most resistant. HGF normal cells were highly resistant to all compounds, suggesting their tumor-specific cytotoxic action. The cytotoxic activity of the compounds with morpholine, 1-methylpiperazine or piperidine structure was generally elevated by the introduction of fluorine, but not chlorine and methoxy functional groups, to the benzofuranone structure, whereas that of compounds attached by 1-phenylpiperazine or 1-(2-pyridyl)piperazine was rather reduced. The most active compounds induced internucleosomal DNA fragmentation in human promyelocytic leukemia HL-60 cells, but not in HSG, further confirming that oral tumor cell lines are resistant to DNase digestion.

People in the Katayama area of Hiroshima Prefecture had been afraid of a curious disease for a long time. The causative agent for the disease had not been identified through the beginning of the 20th century when it turned out that a human parasitic trematode, Schistosoma japonicum, had been afflicting the inhabitants, causing this disease. This was made clear mainly by two medical doctors, Akira Fujinami and Ryuzo Yoshida, much before 1909. The memoir on the disease described by a herb doctor, Yoshinao Fujii (1847), was made known by A. Fujinami to medical scientists in 1909.

Hot electron transport in a high density plasmas has been studied using a two dimensional hybrid code. The results show that the initially cylindrical solid beam evolves into a hollow, annular beam due to the Weibel instability and generates strong magnetic fields on both sides of the annular ring. The annular structure subsequently breaks up into several beamlets due to a mechanism similar to a tearing instability. It is found that the magnetic fields parallel to the direction of beam propagation also grow during the tearing process. These beamlets are attract each other and finally they merged into a single beam which carries a net electric current. The tearing and merging processes have also been analyzed by the hybrid code for a uniform initial condition to determine an asymptotic behaviors of the total number of hot electron beams. We also have performed a three dimensional particle-in-cell (PIC) simulation to compare with the results of 2D hybrid code. It shows that the spatial variation of cold electron density is much more uniform than that obtained by 2D code.

Six new phenol (anthraquinone or stilbene) glycosides with an acyl group at 6-position of the glucopyranose moiety were isolated from rhubarb (the roots of Rheum palmatum) cultivated in Japan, together with 22 known compounds. Most of these compounds were evaluated for cytotoxic activity against tumor and normal cells and for induction of DNA damage by spore rec-assay. Among them, emodin and aloe-emodin showed higher cytotoxic activities against human oral squamous cell carcinoma (HSC-2) and salivary gland tumor (HSG) cell lines than against normal human gingival fibroblasts (HGF). Chrysophanol 8-O-beta-(6'-acetyl)glucopyranoside, 4-(4'-hydroxyphenyl)-2-butanone 4'-O-beta-D-(2"-O-galloyl-6"-O-cinnamoyl) glucopyranoside, and 6"-O-(4'''-hydroxybenzoyl) resveratroloside exhibited relatively higher cytotoxic activities against all these cells. The other glycosides of anthraquinone or stilbene showed weaker cytotoxic activity against these tumor cell lines, but may be considered as cancer chemopreventive agents. Spore rec-assay with a recombination deficient mutant of Bacillus subtilis M45 demonstrated the DNA damage-inducing activity of emodin and aloe-emodin 15-O-beta-D-glucopyranoside among, rhubarb phenols.

Among 11 isoflavones tested, genistein [YS13] produced higher cytotoxic activity against human oral tumor cell lines (HSC-2, HSG) than against normal cells (human gingival fibroblast, HGF), suggesting its tumor-specific action. Electron spin resonance (ESR) spectroscopy showed that YS13 did not produce radical, nor scavenged O2*- generated by hypoxanthine-xanthine oxidase reaction system, suggesting that radical-mediated oxidation mechanism is not be involved in the YS13-induced cytotoxicity. Addition of one prenyl group produced YS18 and YS19 with higher anti-Helicobacter pylori activity. Addition of two prenyl groups produced YS21 with the highest cytotoxic activity but lower tumor-specificity. Since YS21 produced the highest amount of radical and most efficiently scavenged O2*-, this compound may induce cytotoxicity by radical-mediated oxidation mechanism. All isoflavones failed to induce anti-human immunodeficiency virus (HIV) activity. These data suggest the medicinal efficacy of isoflavones.

Epigallocatechin gallate (EGCG) induced apoptosis-associated characteristics in human oral tumor cell lines more efficiently than ascorbates, gallic acid, vitamin K, flavonoids or steroidal saponins. Since catalase partially inhibited the cytotoxic activity of EGCG, the possible involvement of hydrogen peroxide (H2O2) in cell death induction was investigated, using TCPO chemiluminescence method. Production of H2O2 by EGCG, sodium ascorbate, gallic acid or catechin reached a maximum level within 30 minutes, and was increased up to a plateau level above pH 8. Under optimal conditions, 1 mM EGCG was converted to 1 mM H2O2. At neutral pH, EGCG produced the highest amount of H2O2, followed by gallic acid, sodium ascorbate and catechin. EGCG produced methionine sulfoxide from methionine in the culture medium, while the methionine oxidation by EGCG was significantly reduced in the presence of serum. ESR spectroscopy showed that EGCG, gallic acid and sodium ascorbate, but not catechin, produced radicals under alkaline condition and that all these compounds scavenged superoxide anion, produced by hypoxanthine-xanthine oxidase reaction. EGCG also effectively scavenged the ascorbate and gallate radicals, more efficiently than other compounds. These data suggest that the apoptosis induction by EGCG may be mediated by H2O2 produced in the culture medium.

A total of 11 newly synthesized benzothiepins and structurally-related compounds were investigated for cytotoxic activity against both normal and tumor cells. All these compounds showed higher cytotoxic activity against three human oral tumor cell lines (HSC-2, HSC-3, HSG) than against normal human gingival fibroblast (HGF), suggesting tumor-specific cytotoxic action. In general, 3,4-dihydro-1-benzothiepin-5(2H)-ones [1-6] showed higher cytotoxic activity than 2,3-dihydro-1-benzothiepins [7-11]. Compounds 4 (4-bromo-3,4-dihydro-2-(2-oxo-2-phenylethyl)-1-benzothiepin-5(2H)-one), 5 (4-bromo-3,4-dihydro-2-(2-oxopropyl)-1-benzothiepin-5(2H)-one) and 6 (4-bromo-3,4-dihydro-2-[1-(methoxycarbonyl)-1-methylethyl]-1-benzothiepin-5(2H)-one), showed higher cytotoxic activity than compounds 1, 2 and 3, respectively, which had Cl instead of Br at C-4 position. Agarose gel electrophoresis demonstrated that these compounds induced large DNA fragments in oral tumor cells, whereas they produced smear pattern of smaller DNA fragments in human promyelocytic leukemia cells HL-60. These data suggest the medicinal efficacy of benzothiepins.

Russian green sweet pepper (Anastasia Green) was successively extracted with hexane, acetone, methanol and 70% methanol and the extracts were further separated into a total of twenty fractions by silica gel or ODS column chromatographies. The biological activities of these extracts and fractions were compared. The extracts and fractions showed higher cytotoxic activity against two human oral tumor cell lines than against normal human gingival fibroblasts, suggesting their tumor-specific action. Several fractions [H3, H4, A4] reversed the multidrug resistant gene (MDR1) against L5178 mouse T-cell lymphoma more effectively than (+/-) verapamil (positive control). All extracts and fractions showed no anti-human immunodeficiency virus (HIV) nor anti-Helicobacter pylori activity. These data suggest the medicinal importance of an Anastasia Green extract.

Diverse biological activities of moxa extracts and smoke (gas phase) were investigated. Moxa was extracted with hot water (Fr. I), or ethanol (Fr. II), or extracted with hot water after ethanol wash (Fr. III) and then lyophilized to obtain the dried powders. Moxa smoke (containing a lot of gaseous components obtained by burning Moxa) (Fr. IV) was collected into phosphate-buffered saline and quantified spectrophotometrically. These extracts and Moxa smoke showed comparable cytotoxic activity against human oral tumor cell lines (HSC-2, HSG). Human gingival fibroblasts (HGF) were more resistant to any Moxa fractions. Neither of the extracts showed anti-HIV activity. Pretreatment of mice with Fr. I significantly reduced the lethal effect of E. coli infection. All extracts produced radicals under alkaline condition, with a maximum intensity at pH 10.5, and enhanced the radical intensity of sodium ascorbate. It was unexpected that these extracts show significant O2- scavenging activities. These data suggest the medicinal efficacy of Moxa extracts and smoke.

We investigated the effect of lignin F, isolated from the alkaline extract of the cone of Pinus parviflora Sieb. et Zucc, on the cytotoxic activity and radical intensity (measured by ESR spectroscopy) of various natural products. Lignin F slightly inhibited the proliferation of human oral tumor cell lines (human squamous cell carcinoma HSC-2, human salivary gland tumor HSG), but not that of human gingival fibroblast HGF, suggesting its tumor specific cytotoxic action. Lignin F enhanced the cytotoxic activity of vitamin K2, vitamin K3, sodium ascorbate (vitamin C), epigallocatechin gallate (EGCG) (a major component of green tea), gallic acid (structural unit of tannin), chlorogenic acid, and 6 tea extracts (Japanese green tea, Japanese barley tea, black tea, Chinese green tea, Chinese Jasmin tea, Chinese Oolong tea), to various extents. On the other hand, lignin inhibited the cytotoxic activity of curcumin and dopamine. ESR spectroscopy demonstrated that combination of lignin and vitamin K3, EGCG or gallic acid synergistically augmented the radical intensity. Lignin F enhanced the bactericidal activity of EGCG against E. coli. These data suggest the beneficial effect of the combination of lignin F and natural products.

Five steroidal saponins from Camassia leichtlinii showed higher cytotoxicity against human oral squamous cell carcinoma cells HSC-2, as compared to normal human gingival fibroblasts HGF. The tumor specificity of saponins varied considerably from sample to sample, but was generally higher than that of tannins, flavonoids and prenylated compounds such as geranylgeraniol and vitamin K2 (MK-2). Agarose gel electrophoresis showed that the saponins failed to induce internucleosomal DNA fragmentation, but produced large DNA fragments in HSC-2 cells, whereas two saponin samples (compounds 1 and 5) induced internucleosomal DNA fragmentation in human promyelocytic leukemic HL-60 cells. In contrast to epigallocatechin gallate or gallic acid, the cytotoxic activity of saponins was not significantly affected by metals (Co2+, Cu2+, Fe3+) or by antioxidants (sodium ascorbate, N-acetyl-L-cysteine, catalase). Furthermore, the saponins did not produce radicals (detected by ESR spectroscopy) nor oxidation potential (measured by NO monitor). These data suggest that an oxidation-mediated mechanism is not involved in the cytotoxicity induced by the steroidal saponins.

Millimolar concentrations of alkaline extract of Cacao husk (polycaphenol) were more cytotoxic to human oral tumor cells (human oral squamous cell carcinoma HSC-2, human salivary gland tumor HSG), than to human gingival fibroblast (HGF), suggesting its tumor-specific action. Polycaphenol enhanced the radical intensity and cytotoxic activity of vitamin K3 more effectively than that of sodium ascorbate (vitamin C). Polycaphenol effectively scavenged the superoxide anion, produced by the hypoxanthine-xanthine oxidase reaction, indicating bimodal (prooxidant and antioxidant) action of polycaphenol. Polycaphenol inhibited the cytopathic effect of HIV (human immunodeficiency virus) infection in MT-4 cells, to a comparable extent as that achieved by lignin. Pretreatment of mice with polycaphenol protected them from lethal infection of Eschericia coli. These data suggest the medicinal efficacy of polycaphenol.

To clarify the possible link between radicals and cytotoxicity of eugenol-related compounds, dimeric compounds were synthesized from eugenol (4-allyl-2-methoxy-phenol), butylated hydroxyanisole (BHA) (2-t-butyl-4-methoxyphenol) or MMP (2 methoxy-4-methylphenol); bis-EUG (3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol), bis-BHA (3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diol), and bis-MMP (3,3'-di-methoxy-5,5'-dimethyl-1,1'-biphenyl-2,2'-diol). The cytotoxic activity of these compounds was determined using a salivary gland tumor cell line (HSG), oral squamous cell carcinoma cell line (HSC-2) and human promyelocytic leukemia cell line (HL-60). A parabolic relationship between the cytotoxicity and log P (the octanol-water partition coefficient) was observed, showing that both BHA and bis-MMP, with a log P of 3-4, were the most cytotoxic. The cytotoxic activity of the 2-methoxy derivatives, eugenol, MMP and bis-MMP, against HSG cells was significantly enhanced by visible-light irradiation, possibly due to their high redox potential. Electron spin resonance (ESR) spectroscopy indicated that eugenol and BHA alone produced radicals under alkaline conditions (pH9.5), and eugenol most efficiently scavenges reactive oxygen species (O2-). Antioxidative reactivity of eugenol-related compounds was determined by measuring the inhibiting periods of the AIBN (2,2'-azobisisobutyronitrile)/MMA (methyl methacrylate) polymerization system, and the number of moles of peroxy radical trapped by moles of the relevant phenols (stoichiometric factor, n). It was found that the n values of eugenol and MMP were approximately 1, whereas those of BHA2, suggesting that eugenol and MMP undergo dimerization through radical-radical couplings through quinone methides, whereas BHA undergoes the competitive interaction with poly-MMA radicals after oxidation by AIBN-peroxy radicals. BHA was an efficient peroxy radical-scavenger, but possibly reacted with polymer radicals of the lipid, thus mediating the cytotoxicity. The n value of bis-BHA was two, whereas those of bis-EUG and bis-MMP were 1.6-1.7, suggesting that the latter were further oxidized. The enthalpies of phenoxyl radical formation were determined using the semi-empirical PM3 quantum-mechanical method and the possible link to redox potential was discussed.

The biological activity of ten prenylflavanones purified from Sophora tomentosa L., and Sophora moorcroftiana Benth. ex Baker (Leguminosae) was investigated. The flavanones with prenyl-, lavandulyl- or geranyl groups on A ring, and two bioactive flavonostilbenes on ring B and stilbene (resveratrol) showed tumor-specific cytotoxic activity, antimicrobial activity, and anti-HIV activity, radical generation, and O2- scavenging activity. There was a positive relationship between radical generation and O2- scavenging activity in these prenylflavanones. These data suggest the medicinal significance of prenylflavanones.

In order to elucidate the mechanisms of antitumor action of sodium 5,6-benzylidene-L-ascorbate (SBA), we established a mouse hepatocellular carcinoma model by oral administration of N-nitrosodiethylamine (NDA) and examined the ascorbate radical intensity and putrescine content in the liver. The oral intake of NDA induced precancerous lesion and a significant increase in putrescine content among three major polyamines. When the oral intake of NDA was stopped, morphological changes were reversed. ESR spectroscopy showed that the homogenate of precancerous tissues produced greater amounts of ascorbate radical than that of normal liver tissue. Intravenous administration of SBA 30 minutes before removal of the liver prolonged the higher level of ascorbate radical generation in the homogenate of precancerous tissue. The antitumor activity of SBA might be due to the long-term production of radicals in tumor tissues by its prooxidant action.

Diverse biological activities of 7 healthy foods [powdered pine needle, citrate-fermented sesame, powdered coffee, royal jelly, propolis, pollen and white sesame oil (extracted by super critical state (40 degrees C, 350 atmospheric pressure))] were investigated. The pine needle, sesame and powdered coffee was also extracted successively by ethanol and hot water, and lyophilized. The pine needle and coffee extracts, and propolis showed higher in vitro cytotoxic, bactericidal and oxidation activity, as compared with other 4 lipophilic healthy foods. However, propolis showed slightly lower, but significant cytotoxic and bactericidal activity with much reduced oxidation potential. ESR spectroscopy demonstrated that the cytotoxic activity of these extracts was closely related to their radical generation and O2- scavenging activities. Healthy food components may have both pro-oxidant and anti-oxidant properties. Pre-treatment of mice with pine needle, sesame or powdered coffee extract significantly reduced the lethality of bacterial infection, possibly due to their host-mediated action. These extracts failed to reduce the cytophatic effect of HIV-1 (human immunodeficiency virus) infection in MT-4 cells. No apparent acute toxicity was detected in mice by oral administration of 10 g/kg of these extracts. This data suggest the medicinal efficacy of healthy foods.

Three steroidal saponins showed higher cytotoxicity against human oral squamous cell carcinoma cell lines (HSC-2), as compared with normal human gingival fibroblasts HGF. Tumor specificity of saponins exceeded that of tannins and flavonoids. Agarose gel electrophoresis showed that saponins failed to induce internucleosomal DNA fragmentation, but produced large DNA fragments in both HSC-2 cells and human promyelocytic leukemic HL-60 cells. In contrast to epigallocatechin gallate or gallic acid, cytotoxic activity of saponins was not significantly affected by metals (Co2+, Cu2+, Fe3+) nor by antioxidants (sodium ascorbate, N-acetyl-L-cysteine, catalase). Furthermore, saponins did not produce radicals (detected by ESR spectroscopy) nor oxidation potential (measured by NO monitor). These data suggest that an oxidation-mediated mechanism is not involved in the cytotoxicity induced by steroidal saponins.

Cytotoxic activity of 9 polyprenylalcohols and 6 vitamin K2 derivatives (MK-1 to MK-6) with various lengths of prenyl units was investigated. Among these compounds, geranylgeraniol with 4 prenyl units, and MK-2 with 2 prenyl units, showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), without induction of internucleosomal DNA fragmentation. Higher molecular weight compounds showed selective cytotoxicity against tumor cell lines than normal human gingival fibroblasts HGF. ESR spectroscopy showed that all polyprenylalcohols did not produce radical, nor scavenged O2- generated by hypoxanthine and xanthine oxidase reaction, and only slightly enhanced the radical intensity of sodium ascorbate. Vitamin K2 derivatives scavenged O2- more efficiently, but did not produce radical (except MK-3) and only slightly modified the ascorbate radical intensity. Cytotoxic activity of these compounds might be affected by the molecular weight, hydrophobicity, van der Waals area and stabilization of hydration of the molecule.

Fractionated extracts of Feijoa peels were studied for cytotoxic activity, anti-human immunodeficiency virus (HIV) activity and antibacterial activity. Two most cytotoxic fractions A3 of acetone extract and M2 of methanol extract had potent inhibitory activity against Gram-positive and Gram-negative bacteria as well as fungi tested. Fraction A4 of acetone extract showed multidrug resistance (MDR)-reversal activity comparable with that of verapamil (positive control). These results indicate the therapeutic value of Feijoa peel extracts as potential antimicrobial and MDR-modulating agents.

Hydroquinone (HQ) dose-dependently reduced the viable cell number of oral tumor cell lines (HSC-2, HSG). HQ induced internucleosomal DNA fragmentation in human promyelocytic leukemic HL-60 cells, but not in HSC-2 nor HSG cells. Cytotoxic activity of HQ was slightly reduced by catalase, but was enhanced by superoxide dismutase, suggesting the possible involvement of hydrogen peroxide in HQ-induced cytotoxicity. This was supported by slight increase or decrease of cytotoxicity of HQ in the presence of Cu2+ and Fe3+, respectively. Lower concentrations of sodium ascorbate, ascorbic acid and ascorbic acid 6-palmitate reduced both the radical intensity and cytotoxic activity of HQ, more efficiently than ascorbic acid 2,6-dipalmitate, in contrast to the cytotoxic action of these ascorbates at higher (millimolar) concentrations. Popular antioxidants such as N-acetyl-L-cysteine and cysteine also reduced the radical intensity and cytotoxic activity of HQ. The present study suggests that cytotoxic activity of HQ is generated by radical-mediated oxidation mechanism.

The ability of nine synthetic eugenol-related compounds to scavenge O2- (generated by the hypoxanthine-xanthine oxidase reaction) was compared with their radical generation and cytotoxic activity. ESR spectroscopy showed that eugenol (4-allyl-2-methoxyphenol), 2-allyl-4-methoxyphenol, 2-allyl-4-t-butylphenol and 2,4-dimethoxyphenol efficiently scavenged O2- and produced radicals under alkaline conditions. 2-allyl-4-t-butylphenol showed the highest cytotoxic activity and DNA-synthesis inhibitory activity, possibly due to the hydrophobic radical reactivity. 2-allyl-4-methoxyphenol and 2,4-dimethoxyphenol showed higher antioxidant activity than 3-t-butyl-4-hydroxyanisol (BHA), but all these compounds showed comparable cytotoxic activity with each other. These findings suggest a possible link between the cytotoxic activity and radical generation/scavenging activity in eugenol-related compounds.

The effect of CoCl2 on the cytotoxic activity of various antioxidants against human oral tumor cell lines (HSC-2, HSG) and normal human gingival fibroblasts (HGF) was investigated. Noncytotoxic concentrations of CoCl2 significantly reduced the cytotoxic activity of sodium ascorbate, gallic acid, epigallocatechin gallate (EGCG), curcumin and dopamine, but not that of sodium 5,6-benzylidene-L-ascorbate (SBA) and benzaldehyde. Among these compounds, benzaldehyde showed the most prominent tumor-specific cytotoxic action. ESR spectroscopy showed that these antioxidants produced radicals under alkaline condition and that their radical intensity was transiently enhanced and finally disappeared by addition of CoCl2. Antioxidants which are sensitive to CoCl2 generally had higher cytotoxic activity and oxidation potential (measured by NO monitor) and addition of CoCl2 significantly reduced their oxidation potential. The present study suggests that cobalt ion stimulates the oxidation of antioxidants to their inactive products.

Among 11 benzothiepins/benzoxepins, 4-chloro-3,4-dihydro-2-(2-oxo-2-phenylethyl)-1-benzothiepin-5-(2H)-one [1] showed the highest cytotoxicity against human oral squamous cell carcinoma HSC-2 cells, followed by 2,3-dihydro-2-(2-oxopropyl)-2-phenyl-1-benzoxepin [2]. Popular antioxidants, such as N-acetyl-L-cysteine and sodium ascorbate significantly reduced the cytotoxic activity of [1] but not that of [2]. Compound [1] induced internucleosomal DNA fragmentation in human promyelocytic leukemic HL-60 cell line, but produced large DNA fragmentation in human oral tumor cell lines (HSC-2, HSG). Compounds [1] and doxorubicin additively reduced the viable cell number of HSC-2 cells. These data, taken together with their tumor specific action, demonstrate for the first time, the medicinal efficacy of benzothiepins/benzoxepins.