Solid-state NMR analysis of the β-strand orientation of the protofibrils of amyloid β-protein.

Alzheimer's disease (AD) is caused by abnormal deposition (fibrillation) of a 42-residue amyloid β-protein (Aβ42) in the brain. During the process of fibrillation, the Aβ42 takes the form of protofibrils with strong neurotoxicity, and is thus believed to play a crucial role in the pathogenesis of AD. To elucidate the supramolecular structure of the Aβ42 protofibrils, the intermolecular proximity of the Ala-21 residues in the Aβ42 protofibrils was analyzed by (13)C-(13)C rotational resonance experiments in the solid state.

Suppression of nanosilica particle-induced inflammation by surface modification of the particles.

It has gradually become evident that nanomaterials, which are widely used in cosmetics, foods, and medicinal products, could induce substantial inflammation. However, the roles played by the physical characteristics of nanomaterials in inflammatory responses have not been elucidated. Here, we examined how particle size and surface modification influenced the inflammatory effects of nanosilica particles, and we investigated the mechanisms by which the particles induced inflammation.

Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure.

We previously reported that well-dispersed amorphous nanosilicas with particle size 70 nm (nSP70) penetrate skin and produce systemic exposure after topical application. These findings underscore the need to examine biological effects after systemic exposure to nanosilicas. The present study was designed to examine the biological effects.

Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils.

Aggregation of 42-residue amyloid β-protein (Aβ42) plays a pivotal role in the etiology of Alzheimer's disease (AD). Curcumin, the yellow pigment in the rhizome of turmeric, attracts considerable attention as a food component potentially preventing the pathogenesis of AD. This is because curcumin not only inhibits the aggregation of Aβ42 but also binds to its aggregates (fibrils), resulting in disaggregation.

Silica and titanium dioxide nanoparticles cause pregnancy complications in mice.

The increasing use of nanomaterials has raised concerns about their potential risks to human health. Recent studies have shown that nanoparticles can cross the placenta barrier in pregnant mice and cause neurotoxicity in their offspring, but a more detailed understanding of the effects of nanoparticles on pregnant animals remains elusive. Here, we show that silica and titanium dioxide nanoparticles with diameters of 70 nm and 35 nm, respectively, can cause pregnancy complications when injected intravenously into pregnant mice.

Systemic distribution, nuclear entry and cytotoxicity of amorphous nanosilica following topical application.

Currently, nanomaterials (NMs) with particle sizes below 100 nm have been successfully employed in various industrial applications in medicine, cosmetics and foods. On the other hand, NMs can also be problematic in terms of eliciting a toxicological effect by their small size. However, biological and/or cellular responses to NMs are often inconsistent and even contradictory.

The effect of surface modification of amorphous silica particles on NLRP3 inflammasome mediated IL-1beta production, ROS production and endosomal rupture.

Although amorphous silica particles (SPs) are widely used in cosmetics, foods and medicinal products, it has gradually become evident that SPs can induce substantial inflammation accompanied by interleukin-1beta (IL-1beta) production. Here, to develop safe forms of SPs, we examined the mechanisms of SP-induced inflammation and the relationship between particle characteristics and biological responses. We compared IL-1beta production levels in THP-1 human macrophage like cells in response to unmodified SP of various diameters (30- to 1000-nm) and demonstrated that unmodified microsized 1000-nm SP (mSP1000) induced higher levels of IL-1beta production than did smaller unmodified SPs.

[Safety assessment of nanomaterials using toxicokinetics and toxicoproteome analysis].

With recent development of the nanotechnology, nanomaterials have been successfully employed in various industrial applications such as medicine and cosmetics. Nanomaterials show the useful properties such as electronic reactivity and the tissue permeability that were not provided by micromaterials. Thus, nanomaterials are expected as innovative materials for the development of medicine and cosmetics.

Varicella-zoster virus glycoprotein M homolog is glycosylated, is expressed on the viral envelope, and functions in virus cell-to-cell spread.

Although envelope glycoprotein M (gM) is highly conserved among herpesviruses, the varicella-zoster virus (VZV) gM homolog has never been investigated. Here we characterized the VZV gM homolog and analyzed its function in VZV-infected cells. The VZV gM homolog was expressed on virions as a glycoprotein modified with a complex N-linked oligosaccharide and localized mainly to the Golgi apparatus and the trans-Golgi network in infected cells.

Deletion in open reading frame 49 of varicella-zoster virus reduces virus growth in human malignant melanoma cells but not in human embryonic fibroblasts.

The ORF49 gene product (ORF49p) of the varicella-zoster virus (VZV) is likely a myristylated tegument protein, and its homologs are conserved across the herpesvirus subfamilies. The UL11 gene of herpes simplex virus type 1 and of pseudorabies virus and the UL99 gene of human cytomegalovirus are the homologs of ORF49 and have been well characterized by using mutant viruses; however, little research on the VZV ORF49 gene has been reported. Here we report on VZV ORF49p expression, subcellular localization, and effect on viral spread in vitro.

Dose-dependent promotion of rat forestomach carcinogenesis by combined treatment with sodium nitrite and ascorbic acid after initiation with N-methyl-N'-nitro-N-nitrosoguanidine: possible contribution of nitric oxide-associated oxidative DNA damage.

Dose-dependent promotion effects of combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) on gastric carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Groups of 15 6-week-old F344 male rats were given 0.01% MNNG in their drinking water for 10 weeks to initiate carcinogenesis in the glandular stomach and a single intragastric administration of 100 mg/kg/bodyweight of MNNG by stomach tube at week 9 to initiate carcinogenesis in the forestomach.

Enhancing effects of simultaneous treatment with sodium nitrite on 2-amino-3-methylimidazo[4,5-f]quinoline-induced rat liver, colon and Zymbal's gland carcinogenesis after initiation with diethylnitrosamine and 1,2-dimethylhydrazine.

Combined effects of sodium nitrite (NaNO2) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) on liver, colon and Zymbal's gland carcinogenesis were assessed using a rat two-stage carcinogenesis model, with a focus on involvement of oxidative stress. Male 6-week-old F344 rats were given a single intraperitoneal injection of 200 mg/kg of diethylnitrosamine and 4 subcutaneous injections of 40 mg/kg of 1,2-dimethylhydrazine for initiation. Then, they were administered 0 or 300 ppm IQ in the diet or 0, 0.

Effects of N-acetylcysteine, quercetin, and phytic acid on spontaneous hepatic and renal lesions in LEC rats.

The effects of anti-oxidants were examined in Long-Evans Cinnamon (LEC) rats, which develop acute hepatic injury, and subsequent hepatic and renal tumors due to accumulation of excess Cu. The rats, at the age of 15 weeks, were supplied a diet containing either 1% of N-acetylcysteine (NAC), quercetin (QC), or phytic acid (PA), or basal diet alone. At weeks 2 and 6 posttreatment, animals were sacrificed for collection of blood and tissue samples.

Lack of enhancing effects of sodium nitrite on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in female Sprague-Dawley rats.

A number of heterocyclic amines (HCAs) have been shown to exert enhanced carcinogenic and mutagenic potential when given simultaneously with sodium nitrite (NaNO(2)). In the present experiment, effects of combined treatment with NaNO(2) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the most prevalent carcinogenic HCAs in the human environment, were assessed with regard to mammary tumor induction in female Sprague-Dawley (SD) rats. Animals at 6 weeks of age were given intragastric doses of 100mg/kg body weight of PhIP twice a week for 4 weeks, during which period 0 or 0.

Pronounced synergistic promotion of N-bis(2-hydroxypropyl)nitrosamine-initiated thyroid tumorigenesis in rats treated with excess soybean and iodine-deficient diets.

We have reported that excess soybean treatment and iodine deficiency synergistically interact, resulting in remarkable induction of thyroid hyperplasias in rats. In the present study, modifying effects of excess soybean and iodine-deficient diets were investigated in the post-initiation phase of N-bis(2-hydroxypropyl)nitrosamine [DHPN]-initiated thyroid tumorigenesis in rats. AIN-93G in which casein was replaced with gluten was used as a basal diet to avoid possible iodine contamination.

Induction of colon tumors in C57BL/6J mice fed MeIQx, IQ, or PhIP followed by dextran sulfate sodium treatment.

Heterocyclic amines (HCAs) have been shown to induce tumors in several organs of rodents, but except for MeIQ and PhIP, other HCAs such as MeIQx and IQ consistently failed to induce colon tumors in mice, whereas MeIQ, IQ, and PhIP exerted colon tumorigenicity in rats. Recently, we found that dietary MeIQx induces genotoxicity in the colon as well as the liver of two different types of reporter gene transgenic mice at subcarcinogenic doses such as 300 ppm. However, in the present study, dietary MeIQx did not significantly induce any tumors in C57BL/6J mice or gpt delta mice even when fed at 300 ppm for 78 weeks, suggesting that the treatment of MeIQx alone was not sufficient to promote colon tumors.

In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N-nitrosopyrrolidine, 2-amino-3-methylimidazo[4,5-f]quinoline, and di(2-ethylhexyl)phthalate.

In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative.

Dose-related changes of oxidative stress and cell proliferation in kidneys of male and female F344 rats exposed to potassium bromate.

It is still of importance to investigate renal carcinogenesis by potassium bromate (KBrO3), a by-product of water disinfection by ozonation, for assessment of the risk to man. Five female F344 rats in each group were given KBrO3 at a dose of 300 mg/kg by single i.g.

Enhancement of urinary bladder carcinogenesis by combined treatment with benzyl isothiocyanate and N-butyl-N-(4-hydroxybutyl)nitrosamine in rats after initiation.

Previously we reported that benzyl isothiocyanate (BITC) strongly enhanced rat urinary bladder carcinogenesis after initiation with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), while potently inhibiting BBN-induction of lesions when given simultaneously with the carcinogen. In the present experiment, the effects of simultaneous treatment with BITC and low-dose BBN on the post-initiation period of rat urinary bladder carcinogenesis were examined. After treatment with 500 ppm BBN for 4 weeks for initiation, groups of 20, 6-week-old, F344 male rats were given 25 ppm BBN alone, basal diet alone, or 100 or 1000 ppm BITC in the diet together with or without 25 ppm BBN in their drinking water for 36 weeks and then killed for autopsy.

Sequential alteration of apoptosis, p53 expression, and cell proliferation in the rat pancreas treated with 4-hydroxyaminoquinoline 1-oxide.

Changes in p53 expression, apoptosis and cell proliferation after treatment with 4-hydroxyaminoquinoline 1-oxide (4HAQO) were investigated in the rat pancreas and liver, target and nontarget organs for tumorigenesis, respectively. Male rats were given a single intravenous injection of 4HAQO at a dose of 20 mg/kg body weight and control rats received vehicle alone and were euthanized after 2-72 hours. Pancreata and livers were removed for histopathological examination, immunohistochemistry for p53 protein, PCNA and Ki-67, and TUNEL labeling and electron microscopic observation for detecting apoptosis.

Lack of significant inhibitory effects of a plant lignan tracheloside on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in female Sprague-Dawley rats.

Tracheloside, one of the plant lignans which can be extracted from the debris after safflower oil is produced from the seeds of Carthamus tinctorious, is an analogue of another plant lignan, arctiin, the side-chain C-2 of the five-membered ring being changed from a hydrogen to a hydroxyl group. We have already demonstrated that arctiin has chemopreventive effect on mammary carcinogenesis. Therefore, chemopreventive effects of tracheloside on the initiation or post-initiation period of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in female rats were examined.

Lack of modifying effects of atrazine and/or tamoxifen on thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN).

The modifying effects of atrazine, and/or tamoxifen, on thyroid carcinogenesis were investigated in a rat two-stage carcinogenesis model following N-bis(2-hydroxypropyl)nitrosamine (DHPN) initiation. Five-week-old male F344 rats were given a single subcutaneous injection of DHPN (2800 mg/kg, body weight) or vehicle alone. Starting 1 week later, the animals were fed a diet supplemented with 0, 5, 50 or 500 ppm of atrazine, 500 ppm atrazine plus 5 ppm tamoxifen, or 5 ppm tamoxifen in the DHPN-treated groups, and 0 or 500 ppm of atrazine in the DHPN-untreated groups for 24 weeks.

A 13-week subchronic toxicity study of paprika color in F344 rats.

The fruit of the paprika (Capsicum annuum) has been widely used in various countries as a spice and food-coloring additive. As a part of the safety assessment of paprika color (Paprika oleoresin), a 13-week subchronic toxicity study was performed in F344 rats. To establish a no-observed-adverse-effect level (NOAEL) for application in subsequent long-term studies, rats were fed powder diet containing paprika color at dose levels of 0 (basal diet), 0.

Chemoprevention of lung carcinogenesis by cacao liquor proanthocyanidins in a male rat multi-organ carcinogenesis model.

The effects of cacao liquor proanthocyanidins (CLPr) on tumorigenesis were investigated using a multi-organ carcinogenesis model in male F344 rats receiving combined treatment with a single i.p. injection of diethylnitrosamine (100 mg/kg body wt), four i.

Prolonged effects of beta-estradiol 3-benzoate on thyroid tumorigenesis in gonadectomized rats pretreated with N-bis(2-hydroxypropyl)nitrosamine.

The prolonged modulatory effects of beta-estradiol 3-benzoate (EB), a synthetic estrogenic compound, were investigated in a rat two-stage thyroid tumorigenesis model. One week after a single subcutaneous (s.c.