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PubMed2004

Inhibition of Ca2+-independent phospholipase A2 results in insufficient insulin secretion and impaired glucose tolerance.

Islet Ca2+-independent phospholipase A2 (iPLA2) is postulated to mediate insulin secretion by releasing arachidonic acid in response to insulin secretagogues. However, the significance of iPLA2 signaling in insulin secretion in vivo remains unexplored. Here we investigated the physiological role of iPLA2 in beta-cell lines, isolated islets, and mice. We showed that small interfering RNA-specific silencing of iPLA2 expression in INS-1 cells significantly reduced insulin-secretory responses of INS-1 cells to glucose. Immunohistochemical analysis revealed that mouse islet cells expressed significantly higher levels of iPLA2 than pancreatic exocrine acinar cells. Bromoenol lactone (BEL), a selective inhibitor of iPLA2, inhibited glucose-stimulated insulin secretion from isolated mouse islets; this inhibition was overcome by exogenous arachidonic acid. We also showed that iv BEL administration to mice resulted in sustained hyperglycemia and reduced insulin levels during glucose tolerance tests. Clamp experiments demonstrated that the impaired glucose tolerance was due to insufficient insulin secretion rather than decreased insulin sensitivity. Short-term administration of BEL to mice had no effect on fasting glucose levels and caused no apparent pathological changes of islets in pancreas sections. These results unambiguously demonstrate that iPLA2 signaling plays an important role in glucose-stimulated insulin secretion under physiological conditions.

Animals↗
PubMed2001

Cryptofolione derivatives from Cryptocarya alba fruits.

Cryptofolione (1) and the new cryptofolione derivative 6-(4,6-dimethoxy-8-phenyl-octa-1,7-dienyl)-4-hydroxy-tetrahydro-pyran-2-one (2) were isolated from the fruits of Cryptocarya alba. The structures were elucidated by spectroscopic methods. Cryptofolione showed activity towards Trypanosoma cruzi trypomastigotes, reducing their number by 77% at 250 microg mL(-1). Cryptofolione showed moderate cytotoxicity in both macrophages and T. cruzi amastigotes. It also displayed a mild inhibitory effect on the promastigote form of Leishmania spp. As both cytotoxic and trypanocidal effects are similar, the compound presented little selectivity in our assay models.

Animals↗
PubMed2004

Design, synthesis and properties of novel iron(III)-specific fluorescent probes.

Bidentate chelators such as hydroxypyridinones and hydroxypyranones are highly iron selective. The synthesis of two novel fluorescent probes N-[2-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)ethyl]-2-(7-methoxy-2-oxo-2H-chromen-4-yl)acetamide (CP600) and N-[(3-hydroxy-6-methyl-4-oxo-4H-pyran-2-yl)methyl]-2-(7-methoxy-2-oxo-2H-chromen-4-yl)acetamide (CP610) is reported. The method involves coupling the bidentate ligands, 3-hydroxypyridin-4-one and 3-hydroxypyran-4-one, with the well-characterised fluorescent probe methoxycoumarin. Fluorescence emission of both probes at 380 nm is readily quenched by Fe(3+). The fluorescence was quenched to a greater extent by Fe(3+) than by Mn(2+), Co(2+), Zn(2+), Ca(2+), Mg(2+), Na(+) and K(+) and to approximately the same extent as Cu(2+). Comparison of the fluorescence-quenching ability by a range of metal ions on CP600 and CP610 and the hexadentate chelator, calcein, under in-vitro conditions, demonstrated advantages of the two novel fluorescent probes with respect to both iron(III) sensitivity and selectivity. Chelation of iron(III) by CP600 and CP610 leads to the formation of a complex with a metal-to-ligand ratio of 1:3. Fluorescence is quenched on formation of such complexes. These probes possess a molecular weight less than 400 and thus they are predicted to permeate biological membranes by passive diffusion, and have potential for reporting intracellular organelle labile iron levels.

Acetamides↗
PubMed2004

Peroxynitrite scavenging mode of alaternin isolated from Cassia tora.

Peroxynitrite (ONOO-), formed from the reaction of superoxide (.O2-) and nitric oxide (NO), is a potent oxidant that contributes to the oxidation of various cellular constituents, including lipids, amino acids, sulfhydryls and nucleotides. It can cause cellular injury, such as DNA fragmentation and apoptotic cell death. ONOO- toxicity is also reported to be involved in inflammatory and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and atherosclerosis. Moreover, the necessity for a strong ONOO- scavenger is important because of the lack of endogenous enzymes that protect against the damage caused by ONOO-. The aim of this study was to evaluate the ability of natural products to scavenge ONOO-. We tested various plant extracts for their ONOO- scavenging activity. Among them, extract from Cassia tora, which is well known as an oriental herb in traditional medicine, showed potent ONOO- scavenging activity. Further analysis identified the phenolic active components, alaternin and nor-rubrofusarin glucose, as potent ONOO- scavengers. Spectrophotometric analysis demonstrated that alaternin and nor-rubrofusarin glucose led to a decrease in the ONOO- -mediated nitration of tyrosine through electron donation. In bovine serum albumin, alaternin, but not nor-rubrofusarin glucose, showed significant inhibition of ONOO- -mediated nitration in a dose-dependent manner. We believe alaternin can be developed as an effective ONOO- scavenger for the prevention of ONOO- -associated diseases.

Cassia↗
PubMed2006

Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase.

The G1 phase of the cell cycle is characterized by a high rate of membrane phospholipid turnover. Cells regulate this turnover by coordinating the opposing actions of CTP:phosphocholine cytidylyltransferase and the group VI Ca2+-independent phospholipase A2 (iPLA2). However, little is known about how such turnover affects cell-cycle progression. Here, we show that G1-phase phospholipid turnover is essential for cell proliferation. Specific inhibition of iPLA2 arrested cells in the G1 phase of the cell cycle. This G1-phase arrest was associated with marked upregulation of the tumour suppressor p53 and the expression of cyclin-dependent kinase inhibitor p21cip1. Inactivation of iPLA2 failed to arrest p53-deficient HCT cells in the G1 phase and caused massive apoptosis of p21-deficient HCT cells, suggesting that this G1-phase arrest requires activation of p53 and expression of p21cip1. Furthermore, downregulation of p53 by siRNA in p21-deficient HCT cells reduced the cell death, indicating that inhibition of iPLA2 induced p53-dependent apoptosis in the absence of p21cip1. Thus, our study reveals hitherto unrecognized cooperation between p53 and iPLA2 to monitor membrane-phospholipid turnover in G1 phase. Disrupting the G1-phase phospholipid turnover by inhibition of iPLA2 activates the p53-p21cip1 checkpoint mechanism, thereby blocking the entry of G1-phase cells into S phase.

Cell Cycle↗
PubMed2006

Ca2+-independent phospholipase A2 enhances store-operated Ca2+ entry in dystrophic skeletal muscle fibers.

Duchenne muscular dystrophy is caused by deficiency of dystrophin and leads to progressive weakness. It has been proposed that the muscle degeneration occurring in this disease is caused by increased Ca2+ influx due to enhanced activity of cationic channels that are activated either by stretch of the plasma membrane (stretch-activated channels) or by Ca2+-store depletion (store-operated channels). Using both cytosolic Ca2+ measurements with Fura-2 and the manganese quench method, we show here that store-operated Ca2+ entry is greatly enhanced in dystrophic skeletal flexor digitorum brevis fibers isolated from mdx(5cv) mice, a mouse model of Duchenne muscular dystrophy. Moreover, we show for the first time that store-operated Ca2+ entry in these fibers is under the control of the Ca2+-independent phospholipase A2 and that the exaggerated Ca2+ influx can be completely attenuated by inhibitors of this enzyme. Enhanced store-operated Ca2+ entry in dystrophic fibers is likely to be due to a near twofold overexpression of Ca2+-independent phospholipase A2. The Ca2+-independent phospholipase A2 pathway therefore appears as an attractive target to reduce excessive Ca2+ influx and subsequent degeneration occurring in dystrophic fibers.

Anilides↗
PubMed1997

Phospholipase A2 inhibition results in sequestration of plasma membrane into electronlucent vesicles during IgG-mediated phagocytosis.

Arachidonic acid is essential for antibody-mediated phagocytosis but its role in this process has not been defined. The phospholipase A2 inhibitor bromoenol lactone decreases arachidonic acid release and arrests phagocytosis; this effect is bypassed by the addition of arachidonic acid to bromoenol lactone-treated cells. In this morphological study, monocytes treated with bromoenol lactone accumulate electronlucent vesicles in the cytoplasm underlying bound targets. The vesicles are not contiguous with the plasma membrane as they are not labeled with cationized ferritin and are not connected to the plasma membrane as determined by high voltage electron microscopy imaging. However, if the plasma membrane is decorated with wheat germ agglutinin-gold prior to vesicle formation, virtually all vesicles contain the gold marker, indicating that they are plasma membrane-derived. The number of vesicles decreases dramatically upon addition of arachidonic acid to phospholipase A2-inhibited monocytes and phagocytosis is restored. Time course studies reveal electronlucent regions surrounding targets at early timepoints and a morphology consistent with fusion of electronlucent vesicles into the developing phagosome. These results are consistent with the following model: during the early stages of antibody-mediated phagocytosis, plasma membrane is sequestered in intracellular vesicles that provide membrane for the forming phagosome via fusion events that require arachidonic acid.

Animals↗
PubMed2002

Nobiletin as a tyrosinase inhibitor from the peel of Citrus fruit.

A tyrosinase inhibitor was isolated from the peel of Citrus fruit by activity-guided fractionation, and identified as 3',4',5,6,7,8-hexamethoxyflavone (nobiletin) by comparison with reported spectral data. Nobiletin (IC50 of; 46.2 microM) exhibited more potency than Kojic acid (IC50; 77.4 microM) used as a positive control, and it was found to be potentially an effective inhibitor of the production of melanin.

Agaricales↗
PubMed2005

Glutathione depletion promotes aluminum-mediated cell death of PC12 cells.

Exposure of rat phenochromocytoma cells (PC12 cells) to aluminum maltolate complex, Al(maltol)3, induced a decrease in intracellular glutathione (GSH) concentration, resulting in a facilitated release of lactate dehydrogenase (LDH) from the cell and an increase in trypan blue-stained cells. Similar phenomena were observed as the cells were treated with L-buthione-[S,R]-sulfoximine (BSO) in the presence of Al(maltol)3. On the other hand, treatment of PC 12 cells with BSO alone in the absence of Al(maltol)3 did not affect the cell viability. Pre-treatment of PC12 cells with N-acetylcysteine (NAC) for 30 min before a 48 h-exposure to Al(maltol)3 effectively protected the cells from Al(maltol)3 toxicity by increasing intracellular GSH concentration. NAC also effectively inhibited reactive oxygen species (ROS) generation induced by treatment of the cells with Al(maltol)3. However, several lipophilic radical scavengers such as alpha-tocopherol and 3(2)-tert-butyl-4-hydroxyanisole, and an iron chelator, desferrioxamine, did not prevent Al(maltol)3-mediated ROS production or the decrease of cell viability. Based on these results, we discussed the role of intracellular GSH against the onset of aluminum toxicity in the context of ROS production.

Animals↗
PubMed2006

Dykellic acid inhibits cell migration and tube formation by RhoA-GTP expression.

Dykellic acid, a novel factor initially identified from the culture broth of Westerdykella multispora F50733, has been shown to inhibit matrix metalloprotease 9 activity, caspase-3 activity, B cell proliferation and LPS-induced IgM production, suggesting that this factor may have anti-cancer effects. In an effort to further address the possible anti-tumoral effects of dykellic acid, we used wound healing, invasion and RhoA-GTP assays to examine the effects of dykellic acid on cell migration, invasion and angiogenesis. Our results revealed that dykellic acid dose-dependently inhibits B16 cell migration and motility, and inhibits HUVEC tube formation. Western blot analysis of the active form of RhoA (RhoA-GTP) showed that dykellic acid treatment decreased the levels of RhoA-GTP. These findings collectively suggest that dykellic acid may have both anti-metastatic and anti-angiogenic acitivites, and provides the first evidence for the involvement of RhoA in dykellic acid-induced effects.

Animals↗
PubMed2006

Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells.

Kojic acid is a natural product and normally used as a food additive and preservative, a skin-whitening agent in cosmetics, a plant growth regulator and a chemical intermediate. Using DNA microarray technology, the overall biological effects of kojic acid on the gene expression profiling of a human skin A375 malignant melanoma cells were examined. After treatment with kojic acid, a total of 361 differentially expressed genes were distinctively changed with 136 up-regulated genes and 225 down-regulated genes. We used the bioinformatics tool to search the gene ontology and category classification of differentially expressed genes that provided the useful information of expressed genes belonging to cellular component, molecular function and biological process in regulation of melanogenesis. Seven down-regulated genes of APOBEC1, ARHGEF16, CD22, FGFR3, GALNT1, UNC5C and ZNF146 that were typically validated by the real-time quantitative PCR (RT-qPCR) analysis technology showed to be the tumor suppressor genes in melanoma cancer cells. Thus, microarray technology coupled with RT-qPCR offered a high throughput method to explore the number of differentially expressed genes responding to kojic acid and their biological functions, and led to more understanding of kojic acid effects on skin cancer therapy and related side effects. Moreover, the differentially expressed genes may become useful markers of skin malignant melanoma for further diagnostic and therapeutic applications.

Antioxidants↗
PubMed1991

Evaluation of new pasty-type implantable devices consisting of poly(epsilon-caprolactone/delta-valerolactone) and Estracyt or estramustine.

Biodegradable pasty-type copolyesters with a relatively low molecular weight of 4500 were synthesized by direct copolycondensation of epsilon-caprolactone (CL) and delta-valerolactone (VL) in the absence of catalysts to evaluate in vivo capabilities of the polymer for implantable controlled release devices in drug delivery systems. The devices in cylindrical shape were prepared by the melt-pressing technique using pasty-type copoly(CL/VL) with 53 mol% CL unit, in which Estracyt and estramustine were used as a water soluble and insoluble drug, respectively. The degradation and drug release in vivo of the devices were examined by subcutaneous implantation in the backs of male rats. The degradation of the device was remarkably accelerated by the presence of hydrophilic Estracyt, and was slightly suppressed by hydrohobic estramustine. The estramustine release profile roughly corresponded to the polymer degradation one. It was found that the degradation of the polymer in the device was affected by hydrophilicity of the drug. A reasonable release of estramustine from the device was kept for a period of more than 20 weeks. Furthermore, the release of the drugs in vivo was able to lead to an atrophy of accessory sex organs such as ventral prostates (VP) and right-side seminal vesicle (SV), resulting in pharmacological influence.

Animals↗