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At least 181 records · Page 10Linked to original sources
PubMed2006

Cytotoxicity of iodinated and gadolinium-based contrast agents in renal tubular cells at angiographic concentrations: in vitro study.

PURPOSE: To test in vitro whether gadolinium-based contrast agents induce fewer toxic effects on renal tubular cells than does an iodinated contrast medium at concentrations used for angiography. MATERIALS AND METHODS: LLC-PK1 cells were incubated with iomeprol, gadopentetate dimeglumine, gadobenate dimeglumine, gadoterate meglumine, gadodiamide, and corresponding mannitol solutions for 24 hours at 37 degrees C in two experimental settings: measurements with equally attenuating solutions and measurements with equimolar solutions. Cytotoxicity was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, trypan blue testing, and an assay to detect apoptosis and necrosis. Data were analyzed with analyses of variance and post hoc tests. RESULTS: Yielding the same x-ray attenuation, iomeprol-300 and iomeprol-150 at concentrations of 2.34-18.75 mg of iodine per milliliter induced significantly (P < .001) lower inhibition of MTT conversion (74%-102% of undamaged control cells) compared with 15.63-125.00 mmol/L concentrations of the gadolinium-based agents (mean percentages of undamaged control cells: 48%-80%, 50%-87%, 60%-95%, and 56%-92% with gadopentetate dimeglumine, gadobenate dimeglumine, gadoterate meglumine, and gadodiamide, respectively). At equimolar concentrations (62.5 mmol/L), iomeprol-190 induced a mean extent of inhibition of MTT conversion (69% of undamaged control cells) similar to that induced by gadoterate meglumine (71%) and gadodiamide (70%), whereas gadopentetate dimeglumine and gadobenate dimeglumine induced stronger effects (63% and 64%, respectively; P < .001). At trypan blue testing, there were more dead cells after incubation with 125 mmol/L gadopentetate dimeglumine than after incubation with iomeprol-190 (57% vs 19%, P < .001). The 125 mmol/L gadopentetate and gadobenate formulations induced more necrosis and apoptosis than did gadoterate meglumine, gadodiamide, and iomeprol (mean percentage difference between treated and untreated control cells: for necrosis, +124%, +95%, +17%, -6%, and +3%, respectively; for apoptosis, +34%, +35%, +13%, +4%, and +5%, respectively; P < .001). CONCLUSION: At angiographic concentrations, gadolinium-based contrast agents do not induce fewer cytotoxic effects on cultured renal tubular cells than does iomeprol.

Angiography↗
PubMed2006

Dihydroimidazophenanthridinium (DIP)-based DNA binding agents with tuneable structures and biological activity.

We have synthesised a library of dihydroimidazophenanthridinium cations (DIPs) with large structural diversity (1-29) using a "one-pot" approach. The DNA binding constants of DIPs range from 2x10(4) to 1.3x10(5) M(-1), and the free energies for binding range from -5.9 to -6.40 kcal mol(-1). Viscosity measurements demonstrated that the binding of the compounds caused DNA lengthening, thus signifying binding by intercalation. The cytotoxicities of the compounds were determined by tetrazolium dye-based microtitration assays and showed a large range of values (0.09-11.7 microM). Preliminary molecular modelling studies of the DNA-DIP interactions suggested that the DIP moieties can interact with DNA by intercalation, and some R groups might facilitate binding by minor-groove binding. The results provide insight into how to design biologically active DNA binding agents that can interact in these ways.

Cell Line, Tumor↗
PubMed1990

A study of human small-cell lung carcinoma (hSCLC) cell lines with different sensitivities to detect relevant mechanisms of cisplatin (CDDP) resistance.

The cisplatin(CDDP)-resistant cell line GLC4-CDDP shows a variety of differences from the parent line GLC4. The aim of this study was to determine which of the observed changes correlated with the degree of resistance and was therefore relevant to the phenomenon of CDDP resistance. For these experiments we used cells of the sensitive hSCLC cell line GLC4 and the in vitro-acquired CDDP-resistant sublines GLC4-CDDP3 and GLC4-CDDP11, with a resistance factor (RF) of 3 and 11 respectively for CDDP and of 1.8 and 7.4 respectively for carboplatin. Carboplatin was used, in addition to CDDP in seeking relevant mechanisms. No consistency was found between the RF and the growth pattern or antigen expression, cellular volume, doubling time, cellular or nuclear platinum (Pt) content or the level of Pt-non-histone chromatin protein (NHCP) binding. A correlation was found between the RF and the level of glutathione (GSH), and a trend was found for the level of Pt-DNA binding, Pt-GG adduct content and the amount of interstrand cross-links (ISC). These changes might therefore be relevant for the development of resistance. These findings are compatible with a GSH-induced reduction of the amount of reactive Pt in the resistant cell, resulting in a lower net platination and toxic Pt-DNA adduct formation.

Antibodies, Monoclonal↗
PubMed2005

Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage.

The neuroprotective effects of minocycline-which is broadly protective in neurologic-disease models featuring cell death and is being evaluated in clinical trials-were investigated both in vitro and in vivo. For the in vivo study, focal cerebral ischemia was induced by permanent middle cerebral artery occlusion in mice. Minocycline at 90 mg/kg intraperitoneally administered 60 min before or 30 min after (but not 4 h after) the occlusion reduced infarction, brain swelling, and neurologic deficits at 24 h after the occlusion. For the in vitro studies, we used cortical-neuron cultures from rat fetuses in which neurotoxicity was induced by 24-h exposure to 500 microM glutamate. Furthermore, the effects of minocycline on oxidative stress [such as lipid peroxidation in mouse forebrain homogenates and free radical-scavenging activity against diphenyl-p-picrylhydrazyl (DPPH)] were evaluated to clarify the underlying mechanism. Minocycline significantly inhibited glutamate-induced cell death at 2 microM and lipid peroxidation and free radical scavenging at 0.2 and 2 microM, respectively. These findings indicate that minocycline has neuroprotective effects in vivo against permanent focal cerebral ischemia and in vitro against glutamate-induced cell death and that an inhibition of oxidative stress by minocycline may be partly responsible for these effects.

Animals↗
PubMed2004

Morphometric characterization of the neuromuscular junction of rodents intoxicated with 2,4-dithiobiuret: evidence that nerve terminal recycling processes contribute to muscle weakness.

2,4-Dithiobiuret (DTB) causes ascending motor weakness when given chronically to rodents. In muscles of animals with DTB-induced weakness, quantal release of acetylcholine (ACh) is impaired. We examined in detail the structural changes that occurred at neuromuscular junctions and their associated Schwann cells of extensor digitorum longus (EDL) muscles of male rats treated with DTB to the onset of muscle weakness, 5-8 days. Our objective was to assess the involvement of the Schwann cells and to determine the most likely primary targets of DTB. At the onset of muscle weakness, nerve terminals exhibited some enlarged regions, but did not sprout. Terminal Schwann cells became flatter and expanded to cover most of the endplate. The extent of invasion of the synaptic cleft by Schwann cell processes was not significantly different from controls; extension of Schwann cell sprouts away from the junction was not seen. Thus, the morphology of the Schwann cells, although clearly affected by DTB, does not suggest that they contribute directly to the physiological defects of DTB-treated terminals. Abnormal tubulovesicular structures or tangles of neurofilaments were clustered in the centers of about 25% of treated terminals. Fewer synaptic vesicles occupied the region opposite the postsynaptic folds. Vesicle volumes were variable and included some very large vesicles, corresponding with the variable MEPP amplitudes reported previously for terminals of DTB-treated rodents. The postsynaptic area stained by rhodamine-labeled alpha-bungarotoxin expanded with terminal swelling, apparently by unpleating of the postsynaptic folds. No loss of ACh receptors or spread of ACh receptors beyond terminal boundaries was detected. Morphometric data are consistent with the conclusion that DTB affects, either directly or indirectly, vesicular release of ACh and the subsequent vesicular recycling process.

Animals↗
PubMed2002

Superoxide dismutase activity and electrochemical study of the binuclear [Cu(TSA)2py]2 complex.

The superoxide dismutase-mimetic activity and the electrochemical behavior of the binuclear complex [Cu(TSA)2py]2 is reported. The complex exhibits a marked SOD activity in the nitroblue tetrazolium assay. Its redox response is in agrement with two copper atoms partially coupled through the carboxylate moieties. The electrode reactions lie in the range of the superoxide/peroxide and oxygen/superoxide couples. This fact is indicative that this complex can act as catalyst for the SOD reaction.

Animals↗
PubMed1999

3-Nitropropionic acid (3-NPA) produces hypothermia and inhibits histochemical labeling of succinate dehydrogenase (SDH) in rat brain.

3-Nitropropionic acid (3-NPA) is a toxin sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neurological disorders when consumed by humans. In vitro, 3-NPA irreversibly inactivates SDH, a Complex II respiratory enzyme required for mitochondrial energy production. A single dose of 3-NPA (30 mg/kg s.c.) was given to singly-caged adult male Sprague-Dawley rats. Rectal temperature was measured after dosing as a potential biomarker of exposure to 3-NPA, and animals were sacrificed at various times after 3-NPA exposure for histochemical visualization of SDH activity. 3-NPA-treated rats experienced a progressive hypothermia, which reached a loss of 3 degrees C or more in core body temperature by 3 hours after dosing. The optical density of the SDH stain in brain was reduced according to a similar time-course, most prominently in the cerebellum and least sharply in the thalamus. The caudate nucleus had the greatest density of SDH staining that we measured in brain; it also has been reported to be the region most consistently lesioned by 3-NPA. However, within other areas of brain such as subdivisions of the hippocampus, neither endogenous SDH activity nor its sensitivity to inhibition by 3-NPA could predict the susceptibility to neurodegenerative changes. Although SDH activity remained significantly reduced in most areas of brain (except thalamus) for up to 5 days after dosing, core temperatures had returned to control values by 5 days suggesting that animals can utilize an alternate method of heat production to withstand insult by 3-NPA.

Animals↗
PubMed2002

Mechanism of superoxide anion production by hepatic sinusoidal endothelial cells and Kupffer cells during short-term ethanol perfusion in the rat.

BACKGROUND/AIMS: The aim of this study was to clarify the candidate cells for and the mechanism of superoxide anion (O2*-) release into the hepatic sinusoids during short-term exposure to ethanol. METHODS: The rat liver was perfused continuously with ethanol (a substrate for alcohol dehydrogenase) or tert-buthanol (not a substrate for alcohol dehydrogenase) for 20 min at a final concentration of 40 mM. In order to detect O2*- production, MCLA (2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-a]pyrazin-3-one), a Cypridina luciferin analogue, was simultaneously infused and MCLA-enhanced chemiluminescence was measured. The effects of gadolinium chloride (GdCL3) (a suppressor of Kupffer cells (KCs)), staurosporine (ST) (an inhibitor of serine-threonine kinases, including protein kinase C), diphenyleneiodonium chloride (DPI) (an inhibitor of NADPH oxidase), ibuprofen (IB) (an inhibitor of cyclooxygenase) and 4-methylpyrazole (4MP) (an inhibitor of ethanol metabolism) on the ethanol-induced chemiluminescence were also evaluated. Sites where O2*- could be released were determined by histochemical detection of nitro blue tetrazolium reduction. RESULTS: Both ethanol and tert-buthanol rapidly caused O2*- release. GdCL3 suppressed the ethanol-induced O2*- release by 61%. Staurosporine and DPI, but neither IB nor 4-MP, also significantly inhibited the ethanol-induced O2*- release. In the histochemical examination, ethanol-stimulated liver showed blue formazan precipitate on both sinusoidal endothelial cells (SECs) and Kupffer cells (KCs), whereas the GdCl3-pretreated liver had the precipitate only on SECs. CONCLUSIONS: This study shows that ethanol itself stimulates both SECs and KCs to release O2*- via activation of NADPH oxidase probably involving protein kinase C (PKC).

Animals↗
PubMed2000

Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein.

Linkage of alpha-synuclein (alpha-SN) mutations to familial Parkinson's disease (PD) and presence of alpha-SN as a major constituent of Lewy body in both sporadic and familial PD implicate alpha-SN abnormality in PD pathogenesis. Here we demonstrate that overexpression of wild-type or mutant alpha-SN does not cause any deleterious effect on the growth or continued propagation of transfected human cells, but overproduction of mutant alpha-SN heightens their sensitivity to menadione-induced oxidative injury. Such enhanced vulnerability is more pronounced in neuronal transfectants than in their nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated alpha-SN, especially with an alanine-to-proline substitution at residue 30, sensitizes neuronal cells to oxidative damage.

Cell Line↗
PubMed2002

Effects of antioxidants on surfactant peroxidation by stimulated human polymorphonuclear leukocytes.

Production of oxygen radicals by stimulated phagocytes followed by surfactant lipid peroxidation (LPO) and loss of surfactant function have all been implicated in the pathogenesis of acute lung injury. We studied the interactions between natural lung surfactant (Curosurf) and neutrophils in vitro, and compared various antioxidants; (superoxide dismutase (SOD), vitamin E, vitamin C, ebselen and melatonin), or combinations of them in duplicate and triplicate regarding their ability to decrease superoxide production and the peroxidation level of surfactant caused by activated phagocytes. The superoxide production of neutrophils activated by Candida albicans was measured with the nitroblue tetrazolium (NBT) test. The subsequent LPO was estimated as the content of malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNE). We found that lung surfactant decreased the superoxide production by activated neutrophils (29.7%) and that Curosurf was peroxidized with elevated MDA/4-HNE values. With supplements of antioxidants (except vitamin C), superoxide radical production and the surfactant LPO level fell in a dose-dependent manner. The protective effect of the antioxidants differed in each test. SOD had a slight effect in both tests. The findings with vitamin E, melatonin and ebselen were similar. The best combination was that of a natural and a synthetic antioxidant (melatonin-ebselen) with a 60% decrease in comparison to the corresponding control. These findings suggest that antioxidants, particularly in combination, prevent LPO of lung surfactant.

Animals↗
PubMed2000

Highly stereoselective synthesis and biological properties of nucleoside analogues bearing a spiro inserted oxirane ring.

Starting from 2',5'-di-O-TBDMS-3'-ketouridine 1 or its thymine analogue 2, both xylo (3-10) and ribo (20) epimers of a series of 3"-substituted 3'-spironucleosides have been obtained in good yields and with a total stereoselectivity. Most new compounds were moderately cytotoxic with in some cases slightly selective antiproliferative activities. None of these compounds was active against HIV, but some other antiviral activities against HSV-2, CMV, EBV, or VZV, in the micromolar range, were noted in specific cases.

Antibody-Dependent Cell Cytotoxicity↗