Cu3 MS4 (M=V, Nb, Ta) and its Solid Solutions with Sulvanite Structure for Photocatalytic and Photoelectrochemical H2 Evolution under Visible-Light Irradiation.

Solid solutions with of Cu3 VS4 with either Cu3 NbS4 or Cu3 TaS4 (Cu3 Nb1-x Vx S4 or Cu3 Ta1-x Vx S4 ) were prepared by a solid-state reaction and adopted a sulvanite structure. Their band gaps were 1.6-1.7 eV corresponding to the absorption of a wide range of visible light. Ru cocatalyst-loaded Cu3 MS4 (M=V, Nb, Ta), Cu3 Nb1-x Vx S4 , and Cu3 Ta1-x Vx S4 showed photocatalytic activities for sacrificial H2 evolution under visible-light irradiation. Most solid solutions showed better activities than the single-component Cu3 MS4 (M=V, Nb, Ta). Cu3 MS4 (M=V, Nb), Cu3 Nb1-x Vx S4 , and Cu3 Ta1-x Vx S4 also functioned as photoelectrodes and gave cathodic photocurrents under visible-light irradiation, indicating a p-type semiconductor character. Cu3 Nb0.9 V0.1 S4 showed the best photocatalytic and photoelectrochemical performances. When Ru-loaded Cu3 Nb0.9 V0.1 S4 was used as a photocathode with a CoOx -loaded BiVO4 photoanode, photoelectrochemical water splitting proceeded under simulated sunlight irradiation without an external bias.

Lavender Essential Oil and Its Main Constituents Inhibit the Expression of TNF-α-induced Cell Adhesion Molecules in Endothelial Cells.

Lavender essential oil (Lvn) has anti-inflammatory effects in an ovalbumin-sensitized murine model of asthma, and inhibits inflammatory cell infiltration into the lungs. The anti-inflammatory effects of Lvn on cell adhesion molecules are not clear. Here we evaluated the effects of Lvn and its main constituents, linalyl acetate (LA) and linalool (LO), on the expression of tumor necrosis factor-alpha (TNF-α)-induced cell adhesion molecules in murine brain endothelial bEnd.3 cells and human umbilical vein endothelial cells (HUVECs). The bEnd.3 cells were treated with Lvn, LA, or LO and subsequently stimulated with TNF-α. The mRNA expression levels of cell adhesion molecules were detected using RT-PCR. E-selectin and P-selectin protein and phosphorylated-NF-κB p65 were detected by western blotting. The effects of Lvn on HUVECs were measured by RT-PCR. In bEnd.3 cells, Lvn and LA suppressed TNF-α-induced E-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and phosphorylated-NF-κB p65 in the nucleus; LO did not suppress P-selectin or phosphorylated-NF-κB p65. Lvn inhibited TNF-α-induced E-selectin mRNA in HUVECs. These results indicate that Lvn and LA inhibit TNF-α-induced cell adhesion molecules in endothelial cells through the suppression of NF-κB activation. Consequently, Lvn or other essential oils including LA may be useful as alternative anti-inflammatory medicines.

A case of non-cardiogenic pulmonary edema provoked by intravenous acetazolamide.

Case: A 61-year-old man was diagnosed with severe chest trauma after a car accident and had had difficulty in weaning from a ventilator because of flail chest and dilated cardiomyopathy. On the 17th day in the intensive care unit, he received i.v. acetazolamide to increase urine output. One hour after the injection, he suddenly developed severe hypoxia. Chest radiography revealed a butterfly shadow. He received other diuretics and a vasodilator, which seemed slowly to resolve the respiratory failure. Five days later, acetazolamide was again given and he experienced the same deterioration. Outcome: We concluded that the episodes were attributed to pulmonary edema provoked by acetazolamide. Conclusion: Acute non-cardiogenic pulmonary edema is an uncommon and lethal adverse effect of acetazolamide. Careful attention may be warranted when administering acetazolamide to critically ill patients.

Fabrication of White Light-emitting Electrochemical Cells with Stable Emission from Exciplexes.

The authors present an approach for fabricating stable white light emission from polymer light-emitting electrochemical cells (PLECs) having an active layer which consists of blue-fluorescent poly(9,9-di-n-dodecylfluorenyl-2,7-diyl) (PFD) and π-conjugated triphenylamine molecules. This white light emission originates from exciplexes formed between PFD and amines in electronically excited states. A device containing PFD, 4,4',4''-tris[2-naphthyl(phenyl)amino]triphenylamine (2-TNATA), Poly(ethylene oxide) and K2CF3SO3 showed white light emission with Commission internationale de l'éclairage (CIE) coordinates of (0.33, 0.43) and a Color Rendering Index (CRI) of Ra = 73 at an applied voltage of 3.5 V. Constant voltage measurements showed that the CIE coordinates of (0.27, 0.37), Ra of 67, and the emission color observed immediately after application of a voltage of 5 V were nearly unchanged and stable after 300 sec.

Aflatoxins in Rice Artificially Contaminated with Aflatoxin-producing Aspergillus flavus under Natural Storage in Japan.

Aflatoxin (AFT) contamination is frequent in foods grown in tropical regions, including rice. Although AFTs are generally not found in temperate-region foods, global warming has affected typical temperate-region climates, potentially permitting the contamination of foods with AFT-producing Aspergillus flavus (A. flavus). Here we investigated the AFT production in rice during storage under natural climate conditions in Japan. We examined AFTs in brown rice and rough rice artificially contaminated with A. flavus for 1 year in Japan, and we subjected AFTs in white rice to the same treatment in airtight containers and examined the samples in warm and cold seasons, simulating the storage of white rice in general households. In the brown rice, AFTs increased after 2 months (March) and peaked after 9 months (October). The AFT contamination in the rough rice was minimal. After the polishing and cooking of the brown rice, AFTs were undetectable. In the white rice stored in airtight containers, AFTs increased after 1 month (August) and peaked after 2 months (September). Minimal AFTs were detected in the cold season. Thus, AFT contamination in rice may occur in temperate regions following A. flavus contamination. The storage of rice as rough rice could provide be useful for avoiding AFT contamination.

Highly Efficient and Stable Solar Cells Based on Thiazolothiazole and Naphthobisthiadiazole Copolymers.

A critical issue in polymer-based solar cells (PSCs) is to improve the power conversion efficiency (PCE) as well as the stability. Here, we describe the development of new semiconducting polymers consisting of thiophene, thiazolothiazole and naphthobisthiadiazole in the polymer backbone. The polymers had good solubility and thus solution-processability, appropriate electronic structure with narrow band gaps of ~1.57 eV and low-lying HOMO energy levels of ~-5.40 eV, and highly ordered structure with the favorable face-on backbone orientation. Solar cells based on the polymers and PC71BM exhibited quite high PCEs of up to 9%. More interestingly, the cells also demonstrated excellent stability as they showed negligible degradation of PCE when stored at 85˚C for 500 hours in the dark under nitrogen atmosphere. These results indicate that the newly developed polymers are promising materials for PSCs in the practical use.

Utilization of Metal Sulfide Material of (CuGa)(1-x)Zn(2x)S2 Solid Solution with Visible Light Response in Photocatalytic and Photoelectrochemical Solar Water Splitting Systems.

Upon forming a solid solution between CuGaS2 and ZnS, we have successfully developed a highly active (CuGa)(1-x)Zn(2x)S2 photocatalyst for H2 evolution in the presence of sacrificial reagents under visible light irradiation. The Ru-loaded (CuGa)0.8Zn0.4S2 functioned as a H2-evolving photocatalyst in a Z-scheme system with BiVO4 of an O2-evolving photocatalyst and Co complexes of an electron mediator. The Z-scheme system split water into H2 and O2 under visible light and simulated sunlight irradiation. The (CuGa)(1-x)Zn(2x)S2 possessed a p-type semiconductor character. The photoelectrochemical cell with a Ru-loaded (CuGa)0.5ZnS2 photocathode and a CoO(x)-modified BiVO4 photoanode split water even without applying an external bias. Thus, we successfully demonstrated that the metal sulfide material group can be available for Z-scheme and electrochemical systems to achieve solar water splitting into H2 and O2.

N'-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide is a dynamin GTPase inhibitor that suppresses cancer cell migration and invasion by inhibiting actin polymerization.

Dynasore, a specific dynamin GTPase inhibitor, suppresses lamellipodia formation and cancer cell invasion by destabilizing actin filaments. In search for novel dynamin inhibitors that suppress actin dynamics more efficiently, dynasore analogues were screened. N'-[4-(dipropylamino)benzylidene]-2-hydroxybenzohydrazide (DBHA) markedly reduced in vitro actin polymerization, and dose-dependently inhibited phosphatidylserine-stimulated dynamin GTPase activity. DBHA significantly suppressed both the recruitment of dynamin 2 to the leading edge in U2OS cells and ruffle formation in H1299 cells. Furthermore, DBHA suppressed both the migration and invasion of H1299 cells by approximately 70%. Furthermore, intratumoral DBHA delivery significantly repressed tumor growth. DBHA was much less cytotoxic than dynasore. These results strongly suggest that DBHA inhibits dynamin-dependent actin polymerization by altering the interactions between dynamin and lipid membranes. DBHA and its derivative may be potential candidates for potent anti-cancer drugs.

Splenic artery ligation: A protection against hepatic ischemia/reperfusion injury in partially hepatectomized rats.

AIM: In liver resection, the temporary occlusion of the hepatoduodenal ligament (Pringle maneuver) is often used. However, the maneuver causes ischemia/reperfusion (I/R) injury in the remnant liver. Heme oxygenase (HO)-1 has a cytoprotective role against this injury. Our aim is to investigate whether splenic artery ligation induces HO-1 expression in the liver and ameliorates the hepatic I/R injury in partially hepatectomized rats. METHODS: Rats underwent splenic artery ligation by occluding the main splenic artery. Two days later, the total hepatic ischemia (Pringle maneuver) was conducted, and then a two-thirds partial hepatectomy (PH) was performed just before the start of reperfusion. HO inhibitor was twice injected s.c. at 3 and 16 h before the Pringle maneuver. HO-1 levels were determined by western blotting. Liver injury was biochemically assessed. RESULTS: In normal rats, HO-1 was highly expressed in the spleen, but not in the liver. Splenic artery ligation induced HO-1 in the livers. When rats underwent 20 and 30 min of Pringle maneuver/PH, survival rates were 28% and 8%, respectively. Splenic artery ligation significantly improved both the survival rates: 73% and 56%, respectively. Under these conditions, administration of HO-1 inhibitor at least partly negated the efficacy of splenic artery ligation. Splenic artery ligation also increased the recovery rate of the remnant liver mass and platelet counts in Pringle maneuver/PH-treated rats. CONCLUSION: Splenic artery ligation was significantly effective on the hepatic I/R injury in partially hepatectomized rats. Induction of HO-1 may be at least partly involved in the improvement of this injury.

Distribution pattern of urine albumin creatinine ratio and the prevalence of high-normal levels in untreated asymptomatic non-diabetic hypertensive patients.

BACKGROUND: Even high-normal albuminuria is reportedly associated with cardiovascular events. OBJECTIVE: We determined the urine albumin creatinine ratio (UACR) in spot urine samples and analyzed the UACR distribution and the prevalence of high-normal levels. PATIENTS AND METHODS: The UACR was determined using immunoturbidimetry in 332 untreated asymptomatic non-diabetic Japanese patients with hypertension and in 69 control subjects. The microalbuminuria and macroalbuminuria levels were defined as a UCAR ≥30 and <300 µg/mg·creatinine and a UCAR ≥300 µg/mg·creatinine, respectively. RESULTS: The distribution patterns showed a highly skewed distribution for the lower levels, and a common logarithmic transformation produced a close fit to a Gaussian distribution with median, 25th and 75th percentile values of 22.6, 13.5 and 48.2 µg/mg·creatinine, respectively. When a high-normal UACR was set at >20 to <30 µg/mg·creatinine, 19.9% (66/332) of the hypertensive patients exhibited a high-normal UACR. Microalbuminuria and macroalbuminuria were observed in 36.1% (120/336) and 2.1% (7/332) of the patients, respectively. UACR was significantly correlated with the systolic and diastolic blood pressures and the pulse pressure. A stepwise multivariate analysis revealed that these pressures as well as age were independent factors that increased UACR. CONCLUSION: The UACR distribution exhibited a highly skewed pattern, with approximately 60% of untreated, non-diabetic hypertensive patients exhibiting a high-normal or larger UACR. Both hypertension and age are independent risk factors that increase the UACR. The present study indicated that a considerable percentage of patients require anti-hypertensive drugs with antiproteinuric effects at the start of treatment.

Investigation of interferon-α response by a single amino acid substitution of nonstructural protein 5A in hepatitis C virus-infected patients.

The therapeutic efficacy of interferon (IFN) for the hepatitis C is closely related with mutations in interferon sensitivity determining region or V3 domain of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A). However, the relationship between alanine aminotransferase (ALT) normalization and the NS5A variability remains unclear. To clarify these features of NS5A, we examined the genetic variability of the patients' NS5A from 33 HCV genotype 1b-infected patients: 11 sustained virological response (SVR), 11 end-of-treatment response (ETR) with normal ALT (<40 IU/L), and 11 non-response (NR) with abnormal ALT (>40 IU/L) after IFN treatment for >24 weeks. The amino acid in position 2378 (followed by HCV-J prototype strain) with alanine (A2378) before IFN treatment was frequent in both SVR and ETR after IFN treatment, whereas that with threonine (T2378) was significant in NR. Moreover, substitution of threonine for alanine in HCV subgenomic replicon showed a 3- to 4-fold reduction of IFN transactivation and replication even in the presence of IFN, suggesting an IFN-resistant phenotype. These observations suggest that a single amino acid in position 2378 of NS5A plays important roles for both ALT normalization and IFN response in HCV-1b infected patients.

Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors.

Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto-enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited marked antiretroviral activity. Here, we show the synthesis and the detailed structure-activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nM in the strand transfer assay and an ED50 of 0.6 nM in the antiviral assay, and 6-(3-chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 49, which had an IC50 of 7.2 nM and an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrase-catalyzed strand transfer processes than 3'-processing reactions, as is the case with the keto-enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.

MDM2 is a novel E3 ligase for HIV-1 Vif.

The human immunodeficiency virus type 1 (HIV-1) Vif plays a crucial role in the viral life cycle by antagonizing a host restriction factor APOBEC3G (A3G). Vif interacts with A3G and induces its polyubiquitination and subsequent degradation via the formation of active ubiquitin ligase (E3) complex with Cullin5-ElonginB/C. Although Vif itself is also ubiquitinated and degraded rapidly in infected cells, precise roles and mechanisms of Vif ubiquitination are largely unknown. Here we report that MDM2, known as an E3 ligase for p53, is a novel E3 ligase for Vif and induces polyubiquitination and degradation of Vif. We also show the mechanisms by which MDM2 only targets Vif, but not A3G that binds to Vif. MDM2 reduces cellular Vif levels and reversely increases A3G levels, because the interaction between MDM2 and Vif precludes A3G from binding to Vif. Furthermore, we demonstrate that MDM2 negatively regulates HIV-1 replication in non-permissive target cells through Vif degradation. These data suggest that MDM2 is a regulator of HIV-1 replication and might be a novel therapeutic target for anti-HIV-1 drug.

Association between serum retinol-binding protein 4 and small dense low-density lipoprotein cholesterol levels in young adult women.

BACKGROUND: Serum retinol-binding protein 4 (RBP4) and small dense low-density lipoprotein (sdLDL) have been suggested to be associated with insulin resistance, but no information is available on the relationship between RBP4 and sdLDL. METHODS: We determined serum RBP4, sdLDL-cholesterol, and other metabolic variables on 38 young women, aged 19-29 years. The homeostatic model assessment of insulin resistance (HOMA-IR) was used for the estimation of insulin resistance. RESULTS: In simple regression analyses, RBP4 levels had significant correlations with total cholesterol (r=0.354, P=0.029), LDL-cholesterol (r=0.396, P=0.014), and sdLDL-cholesterol (r=0.510, P=0.001) levels. The sdLDL-cholesterol levels also correlated significantly with total cholesterol (r=0.402, P=0.012), LDL-cholesterol (r=0.627, P<0.001) and triglycerides (r=0.449, P=0.005). Stepwise multiple regression analyses showed only sdLDL-cholesterol (beta coefficient (ss)=0.510, P=0.001) level was a significant independent predictor of RBP4 levels (adjusted R(2)=0.240), whereas RBP4 (ss=0.289, P=0.026) level was one of major factors affecting sdLDL-cholesterol levels (adjusted R(2)=0.519). There was no significant association of HOMA-IR with RBP4 or sdLDL levels. CONCLUSIONS: We showed an independent linkage between serum RBP4 and sdLDL-cholesterol levels in young adult women. These findings may contribute to understanding of lipoprotein metabolisms involved in diabetes and cardiovascular disease.

Isolation and gene analysis of interferon alpha-resistant cell clones of the hepatitis C virus subgenome.

Hepatitis C virus (HCV) proteins appear to play an important role in IFN-resistance, but the molecular mechanism remains unclear. To clarify the mechanism in HCV replicon RNA harboring Huh-7 cells (Huh-9-13), we isolated cellular clones with impaired IFNalpha-sensitivity. Huh-9-13 was cultured for approximately 2 months in the presence of IFNalpha, and 4 IFNalpha-resistant cell clones showing significant resistances were obtained. When total RNA from clones was introduced into Huh-7 cells, the transfected cells also exhibited IFNalpha-resistance. Although no common mutations were present, mutations in NS3 and NS5A regions were accumulated. Transactivation of IFNalpha and IFNalpha-stimulated Stat-1 phosphorylation were reduced, and the elimination of HCV replicon RNA from the clones restored the IFNalpha signaling. These results suggest that the mutations in the HCV replicon RNA, at least in part, cause an inhibition of IFN signaling and are important for acquisition of IFNalpha resistance in Huh-9-13.

Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137).

Integrase (IN), an essential enzyme of human immunodeficiency virus (HIV), is an attractive antiretroviral drug target. The antiviral activity and resistance profile in vitro of a novel IN inhibitor, elvitegravir (EVG) (also known as JTK-303/GS-9137), currently being developed for the treatment of HIV-1 infection are described. EVG blocked the integration of HIV-1 cDNA through the inhibition of DNA strand transfer. EVG inhibited the replication of HIV-1, including various subtypes and multiple-drug-resistant clinical isolates, and HIV-2 strains with a 50% effective concentration in the subnanomolar to nanomolar range. EVG-resistant variants were selected in two independent inductions, and a total of 8 amino acid substitutions in the catalytic core domain of IN were observed. Among the observed IN mutations, T66I and E92Q substitutions mainly contributed to EVG resistance. These two primary resistance mutations are located in the active site, and other secondary mutations identified are proximal to these primary mutations. The EVG-selected IN mutations, some of which represent novel IN inhibitor resistance mutations, conferred reduced susceptibility to other IN inhibitors, suggesting that a common mechanism is involved in resistance and potential cross-resistance. The replication capacity of EVG-resistant variants was significantly reduced relative to both wild-type virus and other IN inhibitor-resistant variants selected by L-870,810. EVG and L-870,810 both inhibited the replication of murine leukemia virus and simian immunodeficiency virus, suggesting that IN inhibitors bind to a conformationally conserved region of various retroviral IN enzymes and are an ideal drug for a range of retroviral infections.

Potent and selective inhibition of Tat-dependent HIV-1 replication in chronically infected cells by a novel naphthalene derivative JTK-101.

In search for effective human immunodeficiency virus type 1 (HIV-1) transcription inhibitors, we have evaluated more than 100,000 compounds for their inhibitory effects on HIV-1 long terminal repeat (LTR)-driven reporter gene expression, and identified a novel naphthalene derivative, JTK-101. This compound could suppress tumour necrosis factor (TNF)-alpha-induced HIV-1 production in latently infected OM-10.1 cells at nanomolar concentrations. JTK-101 could also potently inhibit constitutive HIV-1 production in MOTL-4/IIIB. However, the antiviral activity of JTK-101 was found to be much weaker in acutely infected cells and the chronically infected cells U937/IIIB cells than in OM-10.1 and MOLT-4/IIIB cells. JTK-101 selectively suppressed TNF-alpha-induced HIV-1 mRNA synthesis in OM-10.1 cells in a dose-dependent fashion. JTK-101 modestly inhibited TNF-alpha-induced HIV-1 LTR-driven reporter gene expression, but potently inhibited Tat-induced gene expression. Immunoblot analysis revealed that low-level expression of the Tat cofactors CDK9 and cyclin T1 might contribute to the diminished antiviral activity in U937/IIIB cells. Furthermore, JTK-101 could not inhibit HIV-1 replication in chronically infected monocytes/macrophages, in which CDK9 and cyclin T1 were undetectable. These results suggest that JTK-101 exerts its anti-HIV-1 activity through the inhibition of known or unknown Tat cofactors, presumably CDK9/cyclin T1.

Enhanced replication of human T-cell leukemia virus type 1 in T cells from transgenic rats expressing human CRM1 that is regulated in a natural manner.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). To develop a better animal model for the investigation of HTLV-1 infection, we established a transgenic (Tg) rat carrying the human CRM1 (hCRM1) gene, which encodes a viral RNA transporter that is a species-specific restriction factor. At first we found that CRM1 expression is elaborately regulated through a pathway involving protein kinase C during lymphocyte activation, initially by posttranscriptional and subsequently by transcriptional mechanisms. This fact led us to use an hCRM1-containing bacterial artificial chromosome clone, which would harbor the entire regulatory and coding regions of the CRM1 gene. The Tg rats expressed hCRM1 protein in a manner similar to expression of intrinsic rat CRM1 in various organs. HTLV-1-infected T-cell lines derived from these Tg rats produced 100- to 10,000-fold more HTLV-1 than did T cells from wild-type rats, and the absolute levels of HTLV-1 were similar to those produced by human T cells. We also observed enhancement of the dissemination of HTLV-1 to the thymus in the Tg rats after intraperitoneal inoculation, although the proviral loads were low in both wild-type and Tg rats. These results support the essential role of hCRM1 in proper HTLV-1 replication and suggest the importance of this Tg rat as an animal model for HTLV-1.

Further studies on hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors toward improved replicon cell activities: benzimidazole and structurally related compounds bearing the 2-morpholinophenyl moiety.

Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).