PE859, A Novel Curcumin Derivative, Inhibits Amyloid-ß and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8.

Aggregation of amyloid-ß (Aß) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aß and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aß and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aß aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aß and tau aggregation in vivo. PE859 inhibited Aß aggregation in vitro and protected cultured cells from Aß-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aß and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

Oligomer formation of a tea polyphenol, EGCG, on its sensing molecule 67 kDa laminin receptor.

Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) has been attributed to the activation of its cell surface sensing receptor 67 kDa laminin receptor (67LR). However, the action of EGCG to activate 67LR remains unknown. Here we show that EGCG undergoes oligomer formation on its surface receptor 67LR.

Unconventional Charge-Density-Wave Transition in Monolayer 1T-TiSe2.

Reducing the dimension in materials sometimes leads to unexpected discovery of exotic and/or pronounced physical properties such as quantum Hall effect in graphene and high-temperature superconductivity in iron-chalcogenide atomically thin films. Transition-metal dichalcogenides (TMDs) provide a fertile ground for studying the interplay between dimensionality and electronic properties, since they exhibit a variety of electronic phases like semiconducting, superconducting, and charge-density-wave (CDW) states. Among TMDs, bulk 1T-TiSe2 has been a target of intensive studies due to its unusual CDW properties with the periodic lattice distortions characterized by the three-dimensional (3D) commensurate wave vector. Clarifying the ground states of its two-dimensional (2D) counterpart is of great importance not only to pin down the origin of CDW, but also to find unconventional physical properties characteristic of atomic-layer materials. Here, we show the first experimental evidence for the realization of 2D CDW phase without Fermi-surface nesting in monolayer 1T-TiSe2. Our angle-resolved photoemission spectroscopy (ARPES) signifies an electron pocket at the Brillouin-zone corner above the CDW-transition temperature (TCDW ∼ 200 K), while, below TCDW, an additional electron pocket and replica bands appear at the Brillouin-zone center and corner, respectively, due to the back-folding of bands by the 2 × 2 superstructure potential. Similarity in the spectral signatures to bulk 1T-TiSe2 implies a common driving force of CDW, i.e., exciton condensation, whereas the larger energy gap below TCDW in monolayer 1T-TiSe2 suggests enhancement of electron-hole coupling upon reducing dimensionality. The present result lays the foundation for the electronic-structure engineering based with atomic-layer TMDs.

Mouse Models for Assessing the Protective Efficacy of Lactobacillus gasseri SBT2055 against Helicobacter suis Infection Associated with the Development of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

BACKGROUND: Helicobacter suis strain TKY infection has been strongly associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in a C57BL/6J mouse model. MATERIALS AND METHODS: 1. C57BL/6J mice were intragastrically administered Lactobacillus strains once daily with 10(8)-10(9) colony-forming units (CFU), starting 2 days before intragastric infection with H. suis TKY (approximately 1 × 10(4) copies of 16S rRNA genes) or H. pylori Sydney strain 1 (SS1; 3 × 10(8) CFU) and continuing for 14 days after infection. 2. C57BL/6J mice were given powdered feed mixed with lyophilized L. gasseri SBT2055 (LG2055) cells (5 × 10(8) CFU/g), starting 2 weeks before intragastric infection with H. suis TKY and continuing 12 months after infection. RESULTS: 1. Among the 5 Lactobacillus strains that we examined, only LG2055 exhibited significantly preventive efficacy against both H. suis TKY and H. pylori SS1 at day 15 after infection. 2. Dietary supplementation with LG2055 protected mice from the formation of round protrusive lesions in the gastric fundus 12 months after infection with H. suis TKY, whereas such lesions had developed in the gastric fundus of nonsupplemented mice 12 months after infection. In addition, the formation of lymphoid follicles in gastric mucus layers was suppressed by dietary LG2055 at 3 months after infection. CONCLUSIONS: LG2055 administration is effective for suppressing the progression of gastric MALT lymphoma by reducing H. suis colonization.

Toll-like receptors as a target of food-derived anti-inflammatory compounds.

Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for TLR-inhibiting activity in HEK293 cells co-expressing TLR with the NF-κB reporter gene, we found cabbage and onion extracts to be the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin 4'-O-ß-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain insight into the inhibitory mechanism of TLR dimerization, we developed a novel probe combining an isothiocyanate-reactive group and an alkyne functionality for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds.

Development of dual targeting inhibitors against aggregations of amyloid-ß and tau protein.

Aggregations of both amyloid-ß (Aß) and hyper-phosphorylated tau proteins are recognized as key pathological manifestations of Alzheimer's disease (AD). Agents that inhibit both those forms of aggregation show promise as drug candidates. Seventeen oligo heteroaromatic compounds were rapidly synthesized via a one-pot, 3- or 4-component coupling procedure. Evaluations showed that compounds E16 and E18 were the most potent inhibitors of Aß and tau aggregations (E16: IC50s = 0.38, 0.29 µM against Aß, tau, respectively, E18: IC50s = 0.55, 0.30 µM against Aß, tau, respectively).

Anti-cytomegalovirus effects of tricin are dependent on CXCL11.

It has been reported that treatment with tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone), a derivative of Sasa albo-marginata, after human cytomegalovirus (HCMV) infection significantly suppressed both infectious virus production and HCMV replication in the human embryonic fibroblast cell line MRC-5. In this paper, we examined the mechanisms for the anti-HCMV effects of tricin in MRC-5 cells. Exposure of fibroblasts to tricin inhibited infectious HCMV production, with concomitant decreases in levels of transcripts of the CXC chemokine IFN-inducible T cell alpha chemoattractant (I-TAC or CXCL11) gene. We also found that the transcripts of the HCMV immediate early (IE) gene and replication of HCMV were lower in CXCL11 gene-knockdown cells. These results suggest that tricin is a novel compound with potential anti-HCMV activity and that CXCL11 is one of the chemokines involved in HCMV replication. In addition, it is possible that CXCL11 is the one of the targets of tricin.

Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells.

Neuroimaging evidence showed structural and/or functional abnormalities existing in the central nervous system, especially the hippocampus, in chronic fatigue syndrome (CFS) patients. However, its pathophysiologic mechanisms are unclear in part due to the lack of an applicable animal model. We established a chronic fatigue murine model by six repeated injections of Brucella abortus antigen to mice, which was manifested as reduced daily running activity and hippocampal atrophy. Thereafter, resveratrol, a polyphenolic activator of sirtuin 1, was used for treatment in this model. Daily running activity was increased by more than 20%, and the hippocampus was enlarged after 4-week resveratrol therapy. Furthermore, resveratrol inhibited neuronal apoptosis and expression of hippocampal acetylated p53 in the fatigue mice. Resveratrol also improved neurogenesis and expression of brain-derived neurotrophic factor mRNA in the hippocampus. We concluded that repeated injection of B. abortus antigen could induce hypoactivity and hippocampal atrophy in mice. Resveratrol may be effective for improving fatigue symptoms and enlarging the atrophic hippocampus by repressing apoptosis and promoting neurogenesis.

Mao-to Prolongs the Survival of and Reduces TNF-alpha Expression in Mice with Viral Myocarditis.

Goal of this study was to evaluate effects of Mao-to on development of myocarditis induced by encephalomyocarditis (EMC) virus in mice. Mice were randomly divided into five groups. Group N included uninfected controls (n = 18), while group A, B and C underwent intraperitoneal injection of EMC virus. Group A was administered oral saline from day 0 to day 4. Group B was administered oral Mao-to (500 mg(-1) kg(-1) day(-1)) from day 0 to day 4. Group C was administered Mao-to from day 2 to day 6. Group D was administered Mao-to from day 5 to day 10. Treated mice were followed for survival rates during 2 weeks after infection. Body weight (BW) and organ weights including heart (HW), lungs, thymus and spleen were examined on days 4, 6 and 14. Survival rate of group C (36.4%) was significantly improved compared with group A, B or D (0% of each, P < 0.05). HW and HW/BW ratio in group C was significantly (P < 0.05) lower than those in group A, B or D. Viral titers of hearts were significantly different among groups A, B and C. Cardiac expression in tumor necrosis factor-alpha (TNF-alpha) was significantly reduced in group C in comparison with group A, B or D on day 6 by immunohistochemical study. Administration of Mao-to starting on day 2 improves mortality resulting from viral myocarditis in mice with reduced expression of cardiac TNF-alpha. These findings suggest that timing of Mao-to is crucial for preventing cardiac damage in mice with viral myocarditis.

A Kampo Medicine, Boi-ogi-to, Inhibits Obesity in Ovariectomized Rats.

In women facing menopause, end of menstrual activity is accompanied by lower levels of estrogen and gradual weight gain. Postmenopausal weight gain sounds an alarm for women's health and may lead to hyperlipidemia, a lipid increase and glucose intolerance. These phenomena are connected to lifestyle-related diseases such as hypertension, type II diabetes mellitus, arteriosclerosis and metabolic syndrome, making it essential to prevent weight gain in women. A Kampo medicine, Boi-ogi-to, is traditionally used to treat obese conditions, but the mechanism has not yet been investigated. In this experiment, we tested the antiobesity properties of Boi-ogi-to in ovariectomized rats by measuring changes of serum cytokine levels and adipocytokines in fat cells. After treatment with this extract for 6 weeks (20-week-old rats), we found that there was a significant weight decrease in rats treated with Boi-ogi-to as compared with that in the control group. Serum tumor necrosis factor (TNF)-α levels increased significantly in a dose-dependent manner. Gene expression of adipose tissue in uterus also dose dependently showed a significant increase of TNF-α levels, suggesting that secretion of TNF-α by fat cells might play a role in the ability of Boi-ogi-to to inhibit weight gain. While peroxisome proliferators-activated receptor-γ and adiponectin levels did not show a significant difference as compared with those in the control, levels of mRNA expression showed a tendency to increase dose dependently. Resistin did not show any significant change. These results suggest that Boi-ogi-to might be useful for the prevention of obesity that occurs in women with reduction of estrogen.

Traditional chinese medicine for chronic fatigue syndrome.

More and more patients have been diagnosed as having chronic fatigue syndrome (CFS) in recent years. Western drug use for this syndrome is often associated with many side-effects and little clinical benefit. As an alternative medicine, traditional Chinese medicine (TCM) has provided some evidences based upon ancient texts and recent studies, not only to offer clinical benefit but also offer insights into their mechanisms of action. It has perceived advantages such as being natural, effective and safe to ameliorate symptoms of CFS such as fatigue, disordered sleep, cognitive handicaps and other complex complaints, although there are some limitations regarding the diagnostic standards and methodology in related clinical or experimental studies. Modern mechanisms of TCM on CFS mainly focus on adjusting immune dysfunction, regulating abnormal activity in the hypothalamic-pituitary-adrenal (HPA) axis and serving as an antioxidant. It is vitally important for the further development to establish standards for 'zheng' of CFS, i.e. the different types of CFS pathogenesis in TCM, to perform randomized and controlled trials of TCM on CFS and to make full use of the latest biological, biochemical, molecular and immunological approaches in the experimental design.

Screening and evaluation of new inhibitors of hepatic glucose production.

In the course of our screening program for inhibitors of hepatic glucose production in rat hepatoma H4IIE-C3 cells, which were used as model liver cells, five naphtoquinone derivatives-javanicin, solaniol, 9-O-methylfusarubin, 5,10-dihydroxy-1,7-dimethoxy-3-methyl-1H-naphtho[2,3-c]pyran-6,9-dione, 9-O-methylbostrycoidin-and vanillin were selected from our natural product library. These naphtoquinone derivatives inhibited hepatic glucose production at IC(50) values of 3.8-29 microM, but showed cytotoxicity against hepatic cells after incubation for 48 h. However, vanillin showed an IC(50) value of 32 microM without exhibiting cytotoxicity at 50 microM. Therefore, we examined 12 vanillin derivatives to investigate their inhibitory activities against glucose production. Among these analogs, 4-hydro-3-methoxyacetophenone and 5-nitrosalicylaldehyde exhibited stronger inhibition than the other compounds at IC(50) values of 25 and 24 microM, respectively, with no cytotoxicity at a concentration of 50 microM. Hence, 4-hydro-3-methoxyacetophenone and 5-nitrosalicylaldehyde may be useful as a lead compound of anti-type 2 diabetic drugs.

Hochu-ekki-to combined with interferon-gamma moderately enhances daily activity of chronic fatigue syndrome mice by increasing NK cell activity, but not neuroprotection.

The purpose of this study was to evaluate the beneficial effect of Hochu-ekki-to (TJ-41) combined with interferon-gamma (IFN gamma) on daily activity, immunological and neurological alternation in a mouse model of chronic fatigue syndrome (CFS). CFS was induced by 6 times of repeated injection of Brucella abortus antigen every 2 weeks. Both single TJ-41 and TJ-41 combined with IFN gamma increased running activity and thymus weight of CFS mice, while thicker thymic cortex together with elevation of natural killer cell activity was only found in the combined treatment group. No significant improvement was observed in the atrophic brain and decreased expression level of brain-derived neurotrophic factor and Bcl-2 mRNA in hippocampus in both treatment groups. Our results suggest that TJ-41 combined with IFN gamma might have a protective effect on the marked reduction in the activity in a model of CFS via normalization of host immune responses, but not neuroprotection.

The Kampo medicines Orengedokuto, Bofutsushosan and Boiogito have different activities to regulate gene expressions in differentiated rat white adipocytes: comprehensive analysis of genetic profiles.

Three Kampo medicines, Boiogito (BOT), Bofutsushosan (BTS) and Orengedokuto (OGT), used for obese patients were investigated for their effects on adipogenesis in cultured rat white adipocytes. Administration of the three extracts suppressed adipogenesis in concentration-dependent manners (1-100 microg/ml) without any cytotoxicity. Changes in mRNA expression levels were analyzed using a Rat 230 2.0 Affymetrix GeneChip microarray system. DNA microarray analysis (total probe set: 31099) using cDNAs prepared from adipocytes revealed that BOT, BTS and OGT increased the expression of 133-150 genes and decreased the expression of 42-110 genes by > or =2-fold. We identified 329 downregulated genes and 189 upregulated genes among a total set of 514 probes (overlap: 4). Overall, genes related to cellular movement, cell death, cell growth/differentiation and immune responses were the most downregulated, while those related to lipid metabolism and cell signaling were the most upregulated. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assays were conducted to confirm the microarray results. Analysis of the clustering profiles of the microarray results revealed that BOT and BTS changed the expression levels of similar genes mainly involved in small molecule biochemistry and cell differentiation, while OGT altered 10 genes related to lipid metabolism, in contrast to the effects of BOT and BTS. We also measured mRNA expression levels of seven selected genes highly contributing to the lipid metabolism by using semiquantitative RT-PCR assay, that were acetyl-Coenzyme A carboxylase alpha (ACACA), AE binding protein 1 (AEBP1), patatin-like phospholipase domain containing 8 (PNPLA8), secretoglobin (SCGB1A1), adrenergic (ADRB3), adiponectin (ADIPOQ), monoglyceride lipase (MGLL). Beta-actin (ACTB) gene was used as an endogenous internal standard. The present findings indicate that these three herbal extracts have the potential to prevent adipogenesis in rat white adipocytes through different mechanisms via modulation of gene expression levels.

Brain atrophy in a murine model of chronic fatigue syndrome and beneficial effect of Hochu-ekki-to (TJ-41).

Brain-derived neurotrophic factor (BDNF) is associated with the main symptoms of chronic fatigue syndrome (CFS) and neuron apoptosis. Nevertheless, no study has been performed directly to explore the relationship between CFS, BDNF and neuron apoptosis. We induced a CFS model by six injections of killed Brucella abortus antigen in BALB/c mice and treated them with Hochu-ekki-to (TJ-41). Daily running activity, body weight (BW), ratio of cerebral weight to BW (CW/BW) and expression levels of BDNF and Bcl-2 mRNA in the hippocampus were determined. The daily activity and CW/BW decreased significantly in the CFS model. BDNF and Bcl-2 mRNA expression levels in the hippocampus were suppressed in the CFS model and TJ-41 treated mice, while no significant difference was found between them. We improved a murine model to investigate the relationship between CFS and brain dysfunction. In this model, reduced daily activity might have been associated with decreased hippocampal BDNF mRNA expression, hippocampal apoptosis and brain atrophy. TJ-41 increased the daily running activity of the model, which was independent of brain recovery.

Acupuncture regulates leukocyte subpopulations in human peripheral blood.

Acupuncture has recently been attracting more and more people throughout the world as an alternative treatment, however little is known about its physiological activities (i.e. immune system). We examined acupuncture both quantitatively and qualitatively by measuring CD-positive cell counts and cytokine expression levels in the blood, to determine the activity of T cells, B cells, macrophages and natural killer (NK) cells. Fifteen milliliters of peripheral blood obtained from 17 healthy volunteers aged 21-51 years, were analyzed using flow cytometry before and after acupuncture treatment. There was a statistically significant increase in the number of CD2(+), CD4(+), CD8(+), CD11b(+), CD16(+), CD19(+), CD56(+) cells as well as IL-4, IL-1beta and IFN-gamma levels in the cells after acupuncture stimulation of meridian points. These observations indicate that acupuncture may regulate the immune system and promote the activities of humoral and cellular immunity as well as NK cell activity. In this article, we discussed how acupuncture regulated leukocyte numbers and functions since they are considered to be potential indicators for evaluating complementary and alternative medicine.

Randomized trial of the efficacy of adjuvant chemotherapy for colon cancer with combination therapy incorporating the oral pyrimidine 1-hexylcarbamoyl-5-fluorouracil.

BACKGROUND AND AIMS: The purpose of the present trial was to clarify the efficacy of postoperative adjuvant chemotherapy including an oral fluoropyrimidine anticancer drug, the 1-hexylcarbamoyl-5-fluorouracil (HCFU), for the treatment of colon cancer. METHOD: Patients with clinical stage Dukes' B and C colon cancer, who had been treated surgically, were assigned to a chemotherapy group treated with mitomycin C, 5-fluorouracil (5-FU), and HCFU and to a control group that received no postoperative adjuvant chemotherapy. RESULTS: Of the 1,001 patients registered for the study, 17 (1.7%) were ineligible. The incidence of toxicity was significantly higher in the chemotherapy group than in the control group. However, there were few severe side effects and no deaths related to the treatment. Overall survival showed no significant difference between the groups. The disease-free survival or the recurrence-free intervals was significantly higher in the chemotherapy group than in the control group. The incidence of hepatic recurrence was significantly (P=0.003) lower in the chemotherapy group than in the control group. CONCLUSION: The results of this study demonstrated the efficacy of adjuvant chemotherapy for colon cancer, i.e., combined chemotherapy that included the 5-FU oral anticancer drug HCFU.

Beneficial effect of brewers' yeast extract on daily activity in a murine model of chronic fatigue syndrome.

The aim of this study was to assess the effect of Brewers' yeast extract (BYE) on daily activity in a mouse model of chronic fatigue syndrome (CFS). CFS was induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. BYE was orally administered to mice in a dose of 2 g per kg per day for 2 weeks before injecting BA and for 4 weeks thereafter. We evaluated daily running activity in mice receiving BYE as compared with that in untreated mice. Weekly variation of body weight (BW) and survival in both groups was monitored during the observation period. Spleen weight (SW), SW/BW ratio, percent splenic follicular area and expression levels of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice. The daily activity during 2 weeks after the second BA injection was significantly higher in the treated group than in the control. There was no difference in BW between both groups through the experimental course. Two mice in the control died 2 and 7 days after the second injection, whereas no mice in the treated group died. Significantly decreased SW and SW/BW ratio were observed in the treated mice together with elevation of splenic follicular area. There were suppressed IFN-gamma and IL-10 mRNA levels in spleens from the treated mice. Our results suggest that BYE might have a protective effect on the marked reduction in activity following repeated BA injection via normalization of host immune responses.

Caffeine stimulates the proliferation of human lung adenocarcinoma cells and small airway epithelial cells via activation of PKA, CREB and ERK1/2.

The incidence of pulmonary adenocarcinoma (PAC) has increased dramatically over the last three decades. Recent studies have shown that human PAC cells with phenotypic features of bronchiolar Clara cells and experimentally induced PAC of Clara cell origin are under beta-adrenergic growth control. The phosphodiesterase inhibitor, theophylline, which is contained in tea, asthma/allergy medications and numerous dietary supplements selectively stimulated the growth of this cancer type in vivo and in vitro. The current study has tested the hypothesis that another environmentally prominent phosphodiesterase inhibitor, caffeine, has similar effects. Using a cell line derived from a human PAC with Clara cell features (PACC) and immortalized human small airway epithelial cells (SAECs), our data show that caffeine activated protein kinase A (PKA), the mitogen-activated kinases ERK1/2, the nuclear transcription factor cyclic AMP response element binding protein (CREB) and stimulated cell proliferation in these cell lines. These findings suggest that exposure to caffeine may contribute to the prevalence of PAC observed today.

Glucose oxidase assisted homogeneous electrochemical receptor binding assay for drug screening.

Although the idea of homogeneous electrochemical immunoassay using antibody and an electroactive modified antigen as a probe looks to be very useful for high-throughput drug screening, there have been few reports. One reason for this is the difficulty experienced making an electroactive probe, because the introduction of electroactive compounds to antigens often interferes with the antigen-antibody interaction. To apply a homogeneous electrochemical assay to drug screening, we have designed new probes referring to the information of immobilization on beads which could identify the drug receptor. FK506 (also called Tacrolimus), immunosuppressive agent is modified with ferrocene derivatives as an electron mediator between glucose oxidase and an electrode, at a non-obstructing part. One of the probes still indicated the electrochemical activity as a mediator and had the specific binding capability for FKBP12 (FK506 binding protein). The current decrease in response to the additional FKBP12, detected with constant voltage amperometry using the probe, was observed within 5 min. Then, free FK506 as a leader drug, rapamycin and cyclosporine A as unknown drugs were used as a model for drug screening. Since the order of response currents at the same concentration of each drug reflected their binding constants, it was shown that binding capacity of an unknown drug candidate could be estimated by comparison of response currents between the leader drug and the unknown drug candidate. Thus, this glucose oxidase assisted homogeneous electrochemical drug-receptor binding assay has been proved to be a useful tool for drug screening.