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At least 1,027 records · Page 57Linked to original sources
PubMed2004

Orally administrated aluminum-maltolate complex enhances oxidative stress in the organs of mice.

Recently, aluminum (Al) in drinking water has been proposed to be a risk factor for development of Alzheimer's disease (AD). Because the physiological role of Al in humans is not yet known, we previously examined this role using an experimental animal model. Our results revealed a greater accumulation of Al in the brain, liver, kidney and spleen of mice who received long-term (90 days) administration of an Al complex, aluminum-maltolate (ALM), than in untreated controls. This observation prompted us to examine the degree of injury in the organs of mice in terms of lipid peroxidation evaluated by thiobarbituric acid reactive substances (TBARS) and NOx levels in order to determine the effects of Al accumulation. Six-week-old mice were given drinking water containing AlCl3 or ALM for 120 days. TBARS and NOx levels were found to change depending on the organs and chemical forms of Al. In particular, TBARS and NOx levels in the brain of mice given ALM for 30, 60 and 120 days were significantly increased compared with those of the control group. In addition, nervous degeneration was detected in the brain of the ALM-treated group. These results indicate that the chemical form of Al alters the distribution and oxidative stress in the brain. In addition, we propose a more precise method of determining Al levels in biological systems using neutron activation analysis. When the biological samples are irradiated with a neutron flux, both 27Al and 31P can be counted to 28Al by the reactions, 27Al(n,gamma)28Al and 31P(n,alpha)28Al, respectively. The level of Al in the organs can then be determined by subtraction of the radioactivity due to 28Al originated in 31P from the total radioactivity of the samples.

Administration, Oral↗
PubMed2005

Syntheses, crystal structure and cytotoxicity of diamine platinum(II) complexes containing maltol.

The cationic complexes (1,2-diaminoethane)(maltolato)platinum(II) ([Pt(en)(ma)]+) and (1R,2R-1,2-diaminocyclohexane)(maltolato)platinum(II) ([Pt(R,R-DACH)(ma)]+) have been prepared and the structure of [Pt(R,R-DACH)(ma)]NO3 has been determined by single crystal X-ray diffraction. The geometry of the metal in [Pt(R,R-DACH)(ma)]NO3 is essentially square planar and the maltolate ligand has a geometry similar to other chelate complexes involving this ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and the IC50 values are approximately 32 microM in HeLa cells and 26 microM in K562 cells. In these cell lines the cytotoxicity of cisplatin is higher than the maltolate complexes by a factor of 2 to 3 whereas the cytotoxicity of carboplatin is lower than the maltolate complexes.

Cell Line, Tumor↗
PubMed2004

Analysis of plant extracts by NIRS: simultaneous determination of kavapyrones and water in dry extracts of Piper methysticum Forst.

A near-infrared reflection spectroscopy (NIRS) method was developed to determine the total content of kavapyrones, kavain and water in dry extracts of Piper methysticum Forst. (kava kava, Piperaceae). Based on the recorded spectra and the reference data, performed by HPLC and Karl Fischer titration, a chemometrical analysis was calculated using PLS 2 algorithm. In general, good calibration statistics are obtained for the prediction of the different contents presenting high correlation coefficients (r(2) > 0.9913) and low root mean square errors of prediction (RMSEP < 0.094%). Usually the main water bands are "cut out" of the spectra to improve the model, however this is associated with the loss of relevant spectroscopic information. Thus, the entire spectrum including the OH bands is used, as these are not only found in water but also in the kavapyrones. The use of this new strategy succeeds in overcoming the difficulties in NIRS and establishes NIRS as a valid alternative in the routine quality control of plant extracts.

Kava↗
PubMed2006

Prostacyclin production in tryptase and thrombin stimulated human bladder endothelial cells: effect of pretreatment with phospholipase A2 and cyclooxygenase inhibitors.

PURPOSE: Thrombin and tryptase stimulation of human bladder microvascular endothelial cells (Cambrex Bioscience, Walkersville, Maryland) results in the production of multiple membrane phospholipid derived inflammatory mediators via the activation of a calcium independent phospholipase A2 that may have important implications in bladder inflammatory conditions, such as interstitial cystitis. We examined the effect of multiple phospholipase A2 and cyclooxygenase inhibitors on the immediate release of prostacyclin from human bladder microvascular endothelial cells. MATERIALS AND METHODS: We stimulated confluent human bladder microvascular endothelial cell monolayers with thrombin or tryptase and measured the immediate release of prostacyclin. Human bladder microvascular endothelial cells were pretreated with several selective phospholipase A2 and cyclooxygenase inhibitors before thrombin or tryptase stimulation to determine which combination of phospholipase A2/cyclooxygenase isoforms was involved in this process. Phospholipase A2 activity was measured using (16:0, [3H]18:1) plasmenylcholine substrate in the absence of calcium. [3H] arachidonic acid release was measured in the surrounding medium from prelabeled human bladder microvascular endothelial cell monolayers. Prostacyclin release into the surrounding medium was measured using a commercially available immunoassay kit. RESULTS: The immediate increase in prostacyclin release from thrombin or tryptase stimulated human bladder microvascular endothelial cells depended on the activation of membrane associated calcium independent phospholipase A2, resulting in an increase in arachidonic acid production. Constitutively active cyclooxygenase-1 was then responsible for further metabolism of free arachidonic acid to prostacyclin. CONCLUSIONS: These results show that the search for a suitable anti-inflammatory agent that selectively target specific phospholipase A2 isoforms requires rigorous testing in several cell types in response to various stimuli.

Arachidonic Acids↗
PubMed2004

IL-10 production induced by HIV-1 Tat stimulation of human monocytes is dependent on the activation of PKC beta(II) and delta isozymes.

The effect of HIV-1 Tat protein on the production of IL-10, an immunosuppressive cytokine, was examined in human primary monocytes obtained from healthy HIV-1-negative blood donors. As expected and in agreement with our previous data, a dose-dependent induction of IL-10 was observed. In addition, we showed that this induction is mediated by the PKC pathway: in the presence of Ro 31-8220, an inhibitor of all PKC isozymes, or after 48 h of PMA treatment, Tat protein becomes unable to stimulate IL-10 production. Among the 11 PKC isozymes, eight (PKC alpha, beta(I), beta(II), delta, epsilon, eta, zeta, mu) are expressed in monocytes. In this study, by analyzing the translocation to the membrane after Tat stimulation, we showed that PKC alpha, beta(I), beta(II), delta and epsilon isozymes are activated by Tat. Moreover, by combining different approaches including selective PKC inhibitors (Gö6983, Gö6976, hispidin and rottlerin), we showed that PKC beta(II) and delta isozymes are essential for the activation of IL-10 production in human monocytes following stimulation by HIV-1 Tat protein.

Acetophenones↗
PubMed2004

Opposed regulation of aluminum-induced apoptosis by glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor in rat brains.

When intracisternally injected to rat brain, aluminum induced apoptosis as assessed by DNA fragmentation and activation of caspase-3 and caspase-12. Co-administration of glial cell line-derived neurotrophic factor (GDNF) effectively prevented aluminum-induced cell death through reduced apoptosis whereas brain-derived neurotrophic factor (BDNF) accelerated aluminum-induced apoptosis, suggesting that the extent of aluminum neurotoxicity in vivo may depend on the biological activity of the neurotrophic factors.

Animals↗
PubMed2004

Genotoxicity of goniothalamin in CHO cell line.

Goniothalamin (GTN) is a styrylpyrrone derivative from Goniothalamus umbrosus and other Annonaceae species. It has been shown to have anti-cancer and apoptosis-inducing properties against various human tumour and animal cell lines. The compound has also been shown to be active in vivo against DMBA-induced rat mammary tumours and was reported as an anti-fertility agent in rats. The aim of our study was to assess the genotoxicity of GTN in CHO cells using the UKEMS guidelines. A metabolic activation fraction (S9) was prepared according to standard methods. The methylthiazoletetrazolium (MTT) screening assay was then carried out to determine the cytotoxicity index (IC50) of GTN. The average IC50 value was 12.45 (+/- 3.63)microM. The mitotic index (MI) assay was then performed to determine the clastogenicity indices (MI(C25), MI(C50) and MI(C100)) of GTN. The chromosome aberration (CA) induction assay using air-dried metaphase spread was then performed to investigate the clastogenic effects of goniothalamin. Benzo[a]pyrene (BaP) and ethylmethanesulphonate (EMS) were used as positive controls in the presence and absence of S9 metabolic activation, respectively. The anti-genotoxicity effect of GTN was also assessed using a combination of GTN and EMS, and GTN and BaP. Dose-responses of CA frequencies were determined for both, the genotoxicity and anti-genotoxicity effects. GTN on its own and when combined with positive controls, was found to induce and enhance CA, respectively. Chromatid and whole chromosome breaks/gaps, as well as interchanges, endoreduplications and ring chromosomes were the main types of aberration induced by GTN. The overall clastogenic effect of GTN was statistically significant. In conclusion, GTN is potentially a genotoxic or clastogenic substance without any anti-genotoxic properties.

Animals↗
PubMed2005

Evaluation of liver and peripheral blood micronucleus assays with 9 chemicals using young rats. A study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study Group (MMS).

We conducted simultaneous liver and peripheral blood micronucleus assays in young rats with seven rodent hepatocarcinogens-4,4'-methylenedianiline (MDA), quinoline, o-toluidine, 4-chloro-o-phenylenediamine (CPDA), dimethylnitrosamine (DMN), p-dimethylaminoazobenzene (DAB), and di(2-ethylhexyl)phthalate (DEHP)-and two mutagenic chemicals-kojic acid and methylmethanesulfonate (MMS). Quinoline, DMN, and DAB were positive in the liver assay, while o-toluidine, kojic acid, DAB, and MMS were positive in the peripheral blood assay. o-Toluidine, kojic acid, and DAB are reportedly negative in mouse bone marrow micronucleus assays, indicating a species difference. Our results revealed a correlation between micronucleus induction in hepatocytes and hepatocarcinogenicity. This technique can be useful for the detection of micronucleus-inducing chemicals that require metabolic activation, and it enables simultaneous comparison of the micronucleus-inducing potential of chemicals in the liver and peripheral blood in the same individual.

Aniline Compounds↗
PubMed2004

Aluminum maltolate-induced toxicity in NT2 cells occurs through apoptosis and includes cytochrome c release.

Aluminum (Al) compounds are neurotoxic and have been shown to induce experimental neurodegeneration although the mechanism of this effect is unclear. In order to study this neurotoxic effect of Al, we have developed an in vitro model system using Al maltolate and human NT2 cells. Al maltolate at 500 microM caused significant cell death with a 24-h incubation and this toxicity was even more evident after 48 h. Lower doses of Al maltolate were also effective, but required a longer incubation for cell death. Nuclear fragmentation suggestive of apoptosis was observed as early as three hours and increased substantially through 24 h. Chromatin condensation and nuclear fragmentation were confirmed by electron microscopy. In addition, TUNEL positive nuclei were also observed. The release of cytochrome c was demonstrated with Western blot analysis. This in vitro model using human cells adds to our understanding of Al neurotoxicity and could provide insight into the neurodegenerative processes in human disease.

Aluminum↗
PubMed2006

Neuroprotection of rat hippocampal slices exposed to oxygen-glucose deprivation by enrichment with docosahexaenoic acid and by inhibition of hydrolysis of docosahexaenoic acid-containing phospholipids by calcium independent phospholipase A2.

Polyunsaturated fatty acids play an important role in the development of pathological states in brain after hypoxia/ischemia. Here, we investigated the role of docosahexaenoic acid (22:6n-3) in brain phospholipids for neuronal survival. We used organotypic cultures of rat brain hippocampal slices exposed to 40 min of oxygen-glucose deprivation, to study the consequences of experimental ischemia. In [14C]docosahexaenoic acid-labeled cultures, oxygen-glucose deprivation induced significant release of radioactive docosahexaenoic acid. This release could be blocked by the selective inhibitor of the Ca2+-independent phospholipase A2, 4-bromoenol lactone (10 microM), when it was added 30 min prior to oxygen-glucose deprivation. Addition of 4-bromoenol lactone at 30 min prior to oxygen-glucose deprivation markedly decreased the neuronal damage induced by oxygen-glucose deprivation. The protective effect was substantially higher in dentate gyrus than in CA1 and CA3 areas. Enrichment of the hippocampal tissue with docosahexaenoic acid by incubation with 10 microM docosahexaenoic acid for 24 h exerted the same neuroprotective effect, which was observed after treatment with 4-bromoenol lactone. In contrast to the 24 h-preincubation, simultaneous addition of docosahexaenoic acid with the onset of oxygen-glucose deprivation had no protective effect. This suggests that incorporation of docosahexaenoic acid into phospholipids is required for the protective effect observed. Then the possible involvement of arachidonic acid metabolism in docosahexaenoic acid-induced neuroprotection was tested. Inhibition of prostaglandin production by ibuprofen produced no change in neuroprotection after 24-h incubation of the hippocampal slices with docosahexaenoic acid. Simultaneous inhibition of Ca2+-independent and Ca2+-dependent phospholipases A2 by treatment with the general phospholipase A2 inhibitor methyl arachidonyl fluorophosphonate (3 microM, 30 min prior to oxygen-glucose deprivation) resulted in significant enhancement of the neuroprotective effect in the dentate gyrus, but not in the CA1 and CA3 areas. In summary, the results reported here indicate that docosahexaenoic acid and docosahexaenoic acid-containing phospholipids provide potent protection against neurodegeneration after hypoxia/hypoglycemia. Furthermore, our data suggest that Ca2+-independent phospholipase A2, the isoform, which has been largely ignored so far, is a possible target for treatment of ischemia-related pathologies in brain.

Animals↗
PubMed2005

Kavalactones fail to inhibit alcohol dehydrogenase in vitro.

In recent years, Kava kava (Piper methysticum, Forst. f., Piperaceae), a folkloric beverage and popular herbal remedy, has been implicated in a number of liver failure cases. Many hypotheses as to the mechanism of its hepatotoxicity, for example interactions with other co-ingested medication, have been postulated. This present study investigated whether pharmacokinetic interactions between kava constituents and alcohol via alcohol dehydrogenase (ADH) inhibition by individual kavalactones might explain its claimed hepatotoxic effects. Four kavalactones, (+/-)-kavain, methysticin, yangonin and desmethoxyyangonin, fail to inhibit ADH in vitro at 1, 10 or 100 microM concentrations.

Alcohol Dehydrogenase↗
PubMed2005

The cytotoxicity of naturally occurring styryl lactones.

We extracted and isolated three natural styryl lactones from Goniothalamus griffithii Hook f. Thoms and investigated their cytotoxicity on a panel of three hepatocyte cell lines, HepG2, drug resistant HepG2 (HepG2-R) and primary cultured normal mice hepatocyte in order to find candidates of potential anti-cancer drugs which have low toxicity on normal cells and high effect on tumors or drug resistant tumors. All the three styryl lactones showed evident cytotoxic activities on both HepG2 and HepG2-R cell lines; however, gonithalamin and goniodiol shows less toxicity on normal mice hepatocyte as the IC(50) values of them on normal mice hepatocyte were about three times of that on HepG2. Morphological observation and cell cycle analysis were employed to elucidate the mechanisms of cytotoxicity of the tested compounds. Many apoptotic cells were observed in gonithalamin- and altholactone-treated cells, whereas, cells with chromosomes gathered at the equator were easily found in goniodiol-treated cultures. The analysis of cell cycle showed that G(2)/M arrest contributed to goniothalimin- and gonidiol-caused cell death and apoptosis was the cause of gonithalamin- and altholactone-induced cell death. Our results suggest that the three styryl lactones may be prospectively developed into anti-tumor drugs, especially on treating drug-resistance tumor after structure modification.

Animals↗
PubMed2004

Maltol glucosides from the tuber of Smilax bockii.

Two maltol glucosides, bockiosides A and B, along with 10 known compounds, were isolated from the tuber of Smilax bockii (Liliaceae), and their structures were elucidated by spectral experiments, chemical analysis and comparison with literature data.

Glucosides↗
PubMed2006

Inhibition of phospholipase A2 reduces neurite outgrowth and neuronal viability.

Phospholipase A2 (PLA(2)) has been implicated in neurodevelopmental processes and in the early development of the nervous system. We investigated the effects of the inhibition of calcium-dependent and calcium-independent subtypes of cytosolic PLA2 (cPLA2 and iPLA2) on the development and viability of primary cultures of cortical and hippocampal neurons. PLA2 in these cultures was continuously inhibited with methylarachidonyl-fluorophosphonate (MAFP), an irreversible inhibitor of cPLA2 and iPLA2, or with bromoenol lactone (BEL), an irreversible selective iPLA2 inhibitor. The effect of PLA2 inhibitors on the development of neuronal cultures was ascertained by total cell count and morphological characterisation. Neuronal viability was quantified with MTT assays. Inhibition of PLA2 resulted in reduction of neuritogenesis and neuronal viability, disrupting neuronal homeostasis and leading to neuronal death. We conclude that the functional integrity of both calcium-dependent and calcium-independent cytosolic PLA2 is necessary for the in vitro development of cortical and hippocampal neurons.

Animals↗
PubMed2006

Kinetics of the substitution of dehydroacetic acid in tris (dehydroacetato) Fe(III) complex by 8-hydroxyquinoline, di- and tetra-hydroxyquinone.

The ligand substitution reactions of dehydroacetic acid (Hdha) in [Fe(dha)(3)] with second ligand such as 8-hydroxyquinoline (Hquin), 1,4-dihydroxyanthraquinone (H(2)dhaq) and 1,4,5,8-tetra-hydroxyanthraquinone (H(4)thaq) were investigated spectrophotometrically by in low polarity solvents like benzene, chloroform and dichloromethane. It is deduced that the substitution reaction takes place through one successive step. The reaction was performed at four different temperatures (5-25) degrees C, and it exhibits a first order dependence on the concentration of the starting complex. The observed rate constant depends on the concentration of both leaving and entering ligands. The evaluation of the kinetic data gives activation parameters which support an associative mechanism in the transition states and the higher rate of substitution of the dha in Fe(dha)(3) complex is due to entropy effect. The solid complexes were synthesized and characterized by elemental analysis, IR and UV-vis spectral techniques.

Anthraquinones↗
PubMed2006

Phospholipase A2-catalyzed hydrolysis of plasmalogen phospholipids in thrombin-stimulated human platelets.

In the present study, phospholipase A(2) (PLA(2))-catalyzed hydrolysis of platelet membrane phospholipids was investigated by measuring PLA(2) activity, phospholipid hydrolysis, arachidonic acid release and choline lysophospholipid production in thrombin-stimulated human platelets. Thrombin-stimulated platelets demonstrated selective hydrolysis of arachidonylated plasmenylcholine and plasmenylethanolamine, with little change in diacyl phospholipids. Accelerated plasmalogen hydrolysis was accompanied by increased arachidonic acid and thromboxane B(2) release and increased lysoplasmenylcholine production. Thrombin stimulation caused an increase in PLA(2) activity measured in the cytosolic fraction with plasmenylcholine only; no increase in activity was measured with phosphatidylcholine. No change in membrane-associated PLA(2) activity was observed with either substrate tested. Pretreatment with the Ca(2+)-independent PLA(2)-selective inhibitor, bromoenol lactone, inhibited completely any thrombin-stimulated phospholipid hydrolysis. Thus, thrombin stimulation of human platelets activates a cytosolic PLA(2) that selectively hydrolyzes arachidonylated plasmalogen phospholipids.

Arachidonic Acid↗
PubMed2026

Hologenomic interactions promote the higher-order evolvability of phenotypic complexity.

Current models for evolvability and complexity generally focus on mutational and regulatory processes in the host genome alone, limiting their ability to explain the origin, inheritance, and dynamics of many phenotypes. We describe a framework treating multigenome interactions in the holobiont as a central process that impacts the genotype-phenotype map, expanding the dimensionality of mechanisms producing heritable variation, generating novel traits, and exploring adaptive trajectories. These mechanisms can promote both complex phenotypic innovation and evolutionary systems drift. Many evolutionary pathways and novelties cannot be fully understood from host data alone but require consideration of hologenomic targets of selection. We outline hypotheses and methods to quantify and evaluate their impacts as a fundamental macroevolutionary process.

cellular innovation↗
PubMed2006

Emerging cancer therapeutic opportunities target DNA-repair systems.

DNA-damaging agents have a central role in non-surgical cancer treatment. The balance between DNA damage and repair determines the final therapeutic consequences. An elevated DNA-repair capacity in tumor cells leads to drug or radiation resistance and severely limits the efficacy of these agents. Interference with DNA repair has emerged as an important approach in combination therapy against cancer. Anticancer targets in DNA-repair systems have emerged, against which several small-molecule compounds are currently undergoing clinical trials.

Animals↗