Nonpeptidic Lysosomal Modulators Derived from Z-Phe-Ala-Diazomethylketone for Treating Protein Accumulation Diseases

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Benzylamide derivative compound attenuates the ultraviolet B-induced hyperpigmentation in the brownish guinea pig skin

This study evaluated the effects of synthetic benzylamide compound I (2,6-dimethoxy-N-phenylbenzamide) on the ultraviolet B (UV B)-induced hyperpigmentation of the skin. UV B-induced hyperpigmentation was elicited on brownish guinea pig skin according to the method reported by Hideya et al. [Arch Dermatol Res 290 (1998) 375] with minor modifications. A lightening effect was observed following the topical application of compound I on UV-stimulated hyperpigmentation. The skin returned to its original color after treatment with compound I. Fontana-Masson staining indicated that melanin level in the hyperpigmented area was significantly decreased in the compound I-treated animals. However, the number of melanocytes were not changed in the compound I-treated groups using the S-100 stain, which is an immunohistochemical method. In vitro experiments using the cultured melanoma cells showed a 31.7% inhibition of melanin production by compound I at 100 microM. In addition, this compound had no effect on the tyrosinase enzyme function. However, it exhibited a catalyzing effect on the dopachrome transformation into 5,6-dihydroxyindole-2-carboxylic acid. Overall, the pigment-lightening effects of the compound I may due to the dopachrome tautomerase stimulation.     

Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior.

Striatal dopamine D2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D2 receptor availability promotes cocaine self-administration. Here, D2 receptor availability was assessed with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.     

Capsaicin potentiates wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride-channel currents

To examine the effects of capsaicin on cystic fibrosis transmembrane conductance regulator (CFTR), we recorded wild-type and mutant CFTR chloride-channel currents using patch-clamp methods. The effects of capsaicin were compared with those of genistein, a well-characterized CFTR activator. In whole-cell experiments, capsaicin potentiates cAMP-stimulated wild-type CFTR currents expressed in NIH 3T3 cells or Chinese hamster ovary cells in a dose-dependent manner with a maximal response approximately 60% of that with genistein and an apparent Kd of 48.4 +/- 6.8 microM. In cell-attached recordings, capsaicin alone fails to activate CFTR in cells that show negligible basal CFTR activity, indicating that capsaicin does not stimulate the cAMP cascade. The magnitude of potentiation with capsaicin depends on the channel activity before drug application; the lower the prestimulated Po, the higher the potentiation. Single-channel kinetic analysis shows that capsaicin potentiates CFTR by increasing the opening rate and decreasing the closing rate of the channel. Capsaicin may act as a partial agonist of genistein because the maximally enhanced wild-type CFTR currents with genistein are partially inhibited by capsaicin. Capsaicin increases DeltaR-CFTR, a protein kinase A (PKA)-independent, constitutively active channel, in cell-attached patches. In excised inside-out patches, capsaicin potentiates the PKA-phosphorylated, ATP-dependent CFTR activity. Both capsaicin and genistein potentiate the cAMP-stimulated G551D-CFTR, DeltaF508-CFTR, and 8SA mutant channel currents. The binding site for capsaicin is probably located at the cytoplasmic domain of CFTR, because pipette application of capsaicin fails to potentiate CFTR activity. In conclusion, capsaicin is a partial agonist of genistein in activation of the CFTR chloride channel. Both compounds affect ATP-dependent gating of CFTR.     

Antiplatelet and antithrombotic activities of CP201, a newly synthesized 1,4-naphthoquinone derivative

The antiplatelet and antithrombotic activities of a newly synthesized CP201, 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone on human platelet aggregation in vitro and murine pulmonary thrombosis in vivo were examined. In addition, the antiplatelet activity of CP201 involved in calcium-signaling cascade was also investigated. CP201 showed concentration-dependent inhibitory effects on platelet aggregation induced by collagen and thrombin, with IC50 values of 4.1+/-0.3 and 4.6+/-0.4 microM, respectively. Orally administered CP201 protected mice against the collagen plus epinephrine-induced thromboembolic death in a dose-dependent manner. On the other hand, CP201 did not alter such coagulation parameters as activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in human plasma in vitro. These results suggest that the antithrombotic activity of CP201 may be due to antiplatelet rather than anticoagulation activity. CP201 potently inhibited platelet aggregation challenged by calcium ionophore A23187 and thapsigargin, which is a selective inhibitor of the Ca(2+)-ATPase pump, in a concentration-dependent manner, indicating that CP201 may have an inhibitory effect on calcium-signaling cascade. This was supported by measuring [Ca2+]i in platelets loaded with fura-3AM, where CP201 inhibited the rise in cytosolic Ca2+ mediated by thrombin. Taken together, these results suggest that CP201 may be a promising antithrombotic agent, and the antithrombotic effect of CP201 may be due to antiplatelet activity, which was mediated, at least partly, by the inhibition of cytosolic calcium mobilization.     

A novel method for determining the blood/gas partition coefficients of inhalation anesthetics to calculate the percentage of loss at different temperatures

The loss by blood/gas (lambda) partition of inhalation anesthetics can be estimated by an equation for the percentage of loss. However, because lambdas of inhalation anesthetics at different temperatures have not been fully determined so far, the percentage of loss at varying temperature in various headspace volumes cannot be estimated. Therefore, a novel method was developed for the determination of inhalation anesthetic lambda, in this study. The method was precise, with a relative standard deviation of less than 5%. The average of lambda from seven distinct blood samples at 4 degrees C, 25 degrees C, and 37 degrees C were determined as 6.68, 2.04, and 1.32 of isoflurane; 3.47, 1.10, and 0.65 of sevoflurane; and 2.31, 0.75, and 0.46 of desflurane, respectively. In addition, increasing temperature was found to decrease lambda profoundly by a secondary order mechanism. Using the obtained value of lambda, the percentage of loss of isoflurane, sevoflurane, and desflurane were then predicted using a 5-mL vacuum tube as a collecting container for an example. In conclusion, a novel method was developed here for lambda determination, and lambdas of isoflurane, sevoflurane, and desflurane at various temperatures were given for estimating the loss resulting from liquid/gas partitioning.     

Kuwanon G: an antibacterial agent from the root bark of Morus alba against oral pathogens

Kuwanon G was isolated from the ethyl acetate fraction of methanol extract of Morus alba and its structure was elucidated by 13C-NMR, 1H-NMR and FAB-MS. Antibacterial activity of kuwanon G was investigated by the minimum inhibitory concentration (MIC) test and the viable cell count method. MIC of kuwanon G against Streptococcus mutans causing dental caries was determined to be 8.0 microg/ml. The bactericidal test showed that kuwanon G completely inactivated S. mutans at the concentration 20 microg/ml in 1 min. Kuwanon G also significantly inhibited the growth of other cariogenic bacteria such as Streptococcus sobrinus and Streptococcus sanguis, and Porpyromonas gingivalis causing periodontitis. Transmission electron microscopy (TEM) of kuwanon G treated cells demonstrated remarkable morphological damage of the cell wall and condensation of the cytoplasm.     

Methylalpinumisoflavone Inhibits Lipopolysaccharide‐Induced Inflammation in Microglial Cells by the NF‐kappaB and MAPK Signaling Pathway

Neuroinflammation is chronic inflammation within the brain that is attributed to prolonged activation of microglial cells and results in neurodegenerative events, such as neuronal dysfunction and neuronal loss. Therefore, suppression of neuroinflammation would theoretically slow progression of neurodegenerative disease. In this study, we investigated the anti‐inflammatory effects of 4′‐O‐methylalpinumisoflavone (methylalpinumisoflavone), isolated from Cudrania tricuspidata, against LPS‐induced microglial activation in BV2 cells. Exposure of BV2 cells to LPS (0.5 µg/mL) significantly increased production of pro‐inflammatory mediators, including NO, PGE₂, and pro‐inflammatory cytokines. Conversely, pre‐treatment with methylalpinumisoflavone (10 and 20 µg/mL) prior to treatment with LPS resulted in a significant decrease of LPS‐induced production of pro‐inflammatory mediators in a dose‐dependent manner. In addition, reduction of pro‐inflammatory mediators by treatment with methylalpinumisoflavone prior to treatment with LPS was accompanied by a decrease in translocation of NF‐κB p50 and p65 from the cytoplasm to the nucleus and by a decrease in activation of mitogen‐activated protein kinases (MAPKs), such as ERK1/2 and JNK. Taken together, these results suggest that methylalpinumisoflavone suppressed LPS‐induced microglial activation and production of pro‐inflammatory mediators by decreasing NF‐κB signaling and by phosphorylation of MAPKs. These results suggest the potential of methylalpinumisoflavone as an anti‐inflammatory drug candidate. Copyright © 2012 John Wiley & Sons, Ltd.     

Risks of interleukin-1 genetic polymorphisms and Helicobacter pylori infection in the development of gastric cancer

BACKGROUND: The host genetic factors that determine the clinical outcomes of Helicobacter pylori-infected individuals remain unclear. AIM: To elucidate the risks of host interleukin-1 (IL-1) genetic polymorphisms and H. pylori infection in the development of gastric cancer. METHODS: In a case-control study of 164 controls and 142 patients with gastric cancer, the IL-1B-511 biallelic polymorphisms and the IL-1RN penta-allelic variable number of tandem repeats were genotyped. RESULTS: The carriage of IL-1RN*2, male gender, old age and H. pylori infection independently increased the risk of gastric cancer, with odds ratios of 3.3 [95% confidence interval (CI), 1.4-7.7], 2.1 (95% CI, 1.2-3.8), 5.3 (95% CI, 3.1-9.0) and 2.2 (95% CI, 1.3-3.8), respectively. H. pylori-infected individuals who were carriers of IL-1RN*2 showed increased risks of both intestinal and diffuse types of gastric cancer, with odds ratios of 11.0 and 8.7, respectively. In addition, these individuals also had a higher score of intestinal metaplasia in the corpus than did uninfected non-carriers. CONCLUSIONS: This study is the first to verify IL-1RN*2 as an independent factor governing the development of gastric cancer in Asian individuals. A combination of H. pylori testing and host genotyping may target the eradication of H. pylori to high-risk individuals.     

Citrus unshiu peel suppress the metastatic potential of murine melanoma B16F10 cells in vitro and in vivo

The peel of Citrus unshiu Marcow. fruits (CU) has long been used as a traditional medicine that has therapeutic effects against pathogenic diseases, including asthma, vomiting, dyspepsia, blood circulation disorders, and various types of cancer. In this study, we investigated the effect of CU peel on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells, and in B16F10 cells inoculated‐C57BL/6 mice. Our results show that ethanol extracts of CU (EECU) inhibited cell growth and increased the apoptotic cells in B16F10 cells. EECU also stimulated the induction of mitochondria‐mediated intrinsic pathway, with reduced mitochondrial membrane potential and increased generation of intracellular reactive oxygen species. Furthermore, EECU suppressed the migration, invasion, and colony formation of B16F10 cells. In addition, the oral administration of EECU reduced serum lactate dehydrogenase activity without weight loss, hepatotoxicity, nor nephrotoxicity in B16F10 cell‐inoculated mice. Moreover, EECU markedly suppressed lung hypertrophy, the number and expression of metastatic tumor nodules, and the expression of inflammatory tumor necrosis factor‐alpha in lung tissue. In conclusion, our findings suggest that the inhibitory effect of EECU on the metastasis of melanoma indicates that it may be regarded as a potential therapeutic herbal drug for melanoma.