Antiproliferative and Anti-Invasive Effect of Piceatannol, a Polyphenol Present in Grapes and Wine, against Hepatoma AH109A Cells

Piceatannol is a stilbenoid, a metabolite of resveratrol found in red wine. Piceatannol and sera from rats orally given piceatannol were found to dose-dependently suppress both the proliferation and invasion of AH109A hepatoma cells in culture. Its antiproliferative effect was based on cell cycle arrest at lower concentration (25~50 μM) and on apoptosis induction at higher concentration (100 μM). Piceatannol suppressed reactive oxygen species-potentiated invasive capacity by scavenging the intracellular reactive oxygen species. These results suggest that piceatannol, unlike resveratrol, has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction. They also suggest that the antioxidative property of piceatannol, like resveratrol, may be involved in its anti-invasive action. Subsequently, piceatannol was found to suppress the growth of solid tumor and metastasis in hepatoma-bearing rats. Thus, piceatannol may be a useful anticancer natural product

Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions

Gene therapy is expected to open a new strategy for the treatment of refractory vascular diseases, so the development of appropriate gene vectors for vascular lesions is needed. To realize this requirement with a non-viral approach, cyclo(RGDfK) peptide (cRGD) was introduced to block copolymer, poly(ethylene glycol)-block-polycation carrying ethylenediamine units (PEG-PAsp(DET)). cRGD recognizes αvβ3 and αvβ5 integrins, which are abundantly expressed in vascular lesions. cRGD-conjugated PEG-PAsp(DET) (cRGD-PEG-PAsp(DET)) formed polyplex micelles through complexation with plasmid DNA (pDNA), and the cRGD-PEG-PAsp(DET) micelles achieved significantly more efficient gene expression and cellular uptake as compared with PEG-PAsp(DET) micelles in endothelial cells and vascular smooth muscle cells. Intracellular tracking of pDNA showed that cRGD-PEG-PAsp(DET) micelles were internalized via caveolae-mediated endocytosis, which is associated with a pathway avoiding lysosomal degradation, and that PEG-PAsp(DET) micelles were transported to acidic endosomes and lysosomes via clathrin-mediated endocytosis. Further, in vivo evaluation in rat carotid artery with a neointimal lesion revealed that cRGD-PEG-PAsp(DET) micelles realized sustained gene expression, while PEG-PAsp(DET) micelles facilitated rapid but transient gene expression. These findings suggest that introduction of cRGD to polyplex micelles might create novel and useful functions for gene transfer and contribute to the establishment of efficient gene therapy for vascular diseases

Hypoglycemic effect of resveratrol in type 2 diabetic model db/db mice and its actions in cultured L6 myotubes and RIN-5F pancreatic β-cells

Resveratrol, a phytoalexin present in the skin of grapes and red wine, has been demonstrated to possess a wide range of health promoting activities including anti-diabetic properties. In the present study, we investigated the effect of resveratrol in both type 2 diabetic mice and cell culture systems. In cultured L6 myotubes, we studied the effect of resveratrol on glucose uptake and translocation of glucose transporter 4 to plasma membrane from the aspects of insulin signaling and AMP-activated protein kinase signaling. In cultured RIN-5F cells, we examined whether resveratrol would protect the pancreas-derived β-cells from oxidative stress. Resveratrol significantly suppressed the elevation in the fasting blood glucose level and the serum triglyceride and lipid peroxide levels in db/db mice. Resveratrol stimulated glucose uptake and glucose transporter 4 translocation by activating both insulin signaling and AMP-activated protein kinase signaling. Moreover, resveratrol could protect pancreatic β-cells from advanced glycation end products-induced oxidative stress and apoptosis. From these results, resveratrol is suggested to show anti-diabetic effect by stimulating both insulin-dependent and -independent glucose uptake in muscles and by protecting pancreatic β-cells from advanced glycation end products-induced oxidative stress and apoptosis

Anti-invasive activity of α-tocopherol against hepatoma cells in culture via protein kinase C inhibition

Effects of α-, β-, γ- and δ-tocopherols on the proliferation and invasion of AH109A hepatoma cells and their modes of action were investigated. Four tocopherols inhibited the invasion as well as the proliferation of AH109A cells. Their inhibitory effects were more prominent on the invasion than on the proliferation. At 1 µM, α-tocopherol showed most potent anti-invasive activity without any influence on the proliferation. We have previously demonstrated that reactive oxygen species increase the invasion of AH109A cells. α-Tocopherol suppressed the reactive oxygen species-induced invasion but failed to suppress the reactive oxygen species-induced rises in intracellular peroxide level. GF 109203X, a protein kinase C inhibitor, decreased the invasive activity of AH109A cells. In contrast, phorbol-12-myristate-13-acetate, a protein kinase C activator, increased the invasive capacity of AH109A cells. α-Tocopherol suppressed the phorbol-12-myristate-13-acetate-induced increase in the invasion, and canceled the phorbol-12-myristate-13-acetate-induced rises in protein kinase C activity and phosphorylation of extracellular signal-regulated kinase. These results suggest that tocopherols, especially α-tocopherol, possess inhibitory effect more strongly on the invasion of AH109A cells than on the proliferation. They also suggest that the anti-invasive activity of α-tocopherol is raised through suppression of PKC/ERK signaling

Oki-Dozen Dike Swarm: Effect of the Regional Stress Field on Volcano-Tectonic Orientations

This article presents new field, geochronological, and geochemical data for the Late Miocene Oki-dozen dike swarm (ODS), southwest Japan. This swarm is part of a volcanic suite comprising mafic and silicic dikes, sills, and pyroclastic cones from which we obtained structural measurements at a various genetic orders and scales. The mafic magmas generated three dike swarms with dikes oriented to NW-SE, N-S, and NE-SW. In comparison, the silicic intrusions do not have a preferred orientation but instead appear to radiate from the center of the volcanic suite. Comparison of the maximum thickness of 37 dikes with SiO2 content (wt%) yielded a critical thickness (T cr ) value of T cr = 0.2 × (SiO2 − 40). These data indicate that the orientations of dikes were controlled by the magnitude of dike tip pressure and magma overpressure, both of which positively correlate with SiO2 concentrations. The silicic units yield estimated pressures (up to 15–60 MPa) that are large enough to have counteracted the regional stress field, whereas the mafic dike swarm only yielded lower pressures. This result suggests that comparative analysis at a range of scales is essential for the accurate determination on the tectonic stress field by igneous rocks

Nuclear translocation of ATBF1 is a potential prognostic maker for skin cancer

The AT motif binding factor 1 (ATBF1) is expressed in varioustissues, such as brain, liver, lung, and gastrointestinal tract, and hasan important role in cell differentiation in organs. ATBF1 interacts withPIAS3, a protein inhibitor for activated signal transducer and activatorof transcription (STAT3), to suppress STAT3 signaling, which has criticalroles in cell proliferation, migration, and survival. We hypothesized thatATBF1 is a useful prognostic marker for skin cancer. We performed immunohistochemicalanalyses of squamous cell carcinoma (SCC, n=7),basal cell carcinoma (BCC, n=4), and Bowen’s disease (n=4) tissues usingan anti-ATBF1 monoclonal antibody. All cases of BCC and Bowen’sdisease exhibited intense nuclear ATBF1 staining, whereas only someSCC cases exhibited weakly positive nuclear ATBF1 staining. SCC andBowen’s disease showed intense nuclear STAT3 staining, while BCC hadfew STAT3-positive nuclei. Based on these observations, nuclear ATBF1staining was associated with low malignancy profiles. The pattern ofATBF1 staining is a potential prognostic marker for skin cancer

Novel Treatment Criteria for Persistent Ductus Arteriosus in Neonates

BackgroundThe indications for ductus arteriosus ligation in very-low-birth-weight infants (VLBWIs) with persistent ductus arteriosus (PDA) are unclear. Increased left ventricular end-diastolic dimension (LVDd) is commonly found in patients with PDA. Here, the enlargement of LVDd in term and preterm neonates without congenital heart disease was estimated by two-dimensional echocardiography.MethodsThe value of the measured LVDd was divided by the normal LVDd as an index (LVDd ratio) to compare 30 patients who underwent PDA ligation with 30 patients treated with indomethacin and 30 patients who did not undergo radical therapy.ResultsAn LVDd ratio between 122% and 197% (mean, 142%) was considered to be an indication for the ligation procedure. The proportion of patients exceeding 130% in the LVDd ratio was 87% (26/30) in those patients who underwent ligation. Catecholamines and/or vasodilators were required in 83% patients for the treatment of low ejection fraction or hypertension after operations, suggesting that patients had been in preload and/or afterload remodeling failure during the operation. The percentage of patients with less than 115% in the LVDd ratio was 90% in the non-radical-therapy patients. The LVDd ratios of 130% and 115% were regarded as cut-off values for surgical ligation and indomethacin treatment.ConclusionThe LVDd ratio is a useful measure to determine the treatment of VLBWIs with PDA

Isolation and characterization of a yeast gene, MPD1, the overexpression of which suppresses inviability caused by protein disulfide isomerase depletion

AbstractMPD1, a yeast gene the overexpression of which suppresses the inviability caused by the loss of protein disulfide isomerase (PDI) was isolated and characterized. The MPD1 gene product retained a single disulfide isomerase active site sequence (APWCGHCK), an N-terminal putative signal sequence, and a C-terminal endoplasmic reticulum (ER) retention signal, and was a novel member of the PDI family. The gene product, identified in yeast extract, contained core size carbohydrates. MPD1 was not essential for growth, but overexpression of the gene suppressed the maturation defect of carboxypeptidase Y caused by PDI1 deletion, indicative of the related function to PDI in the yeast ER

Right-sided infective endocarditis as a potentially fatal complication in patients with long-term refractory severe bradyarrhythmia after cervical spinal cord injury: A case report

AbstractBradyarrhythmia is usually a spontaneously subsiding complication of cervical spinal cord injury. However, in severe cases, it can lead to cardiac arrest. We report a case of cervical spinal cord injury, complicated by right-sided infective endocarditis after the placement of a temporary pacing catheter in the right ventricle for severe bradyarrhythmia that led to cardiac arrest. Although the patient׳s condition was successfully treated by pacing catheter removal and pharmacological therapy, right-sided infective endocarditis would be a fatal complication in cases of cervical spinal cord injury where cardiac pacing is required for long-term refractory severe bradyarrhythmia

Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons

Background: Recently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown. Results: We found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM. Conclusions: To the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD