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PubMed2000

Cartilage degradation by stimulated human neutrophils: reactive oxygen species decrease markedly the activity of proteolytic enzymes.

BACKGROUND: Although neutrophilic granulocytes clearly contribute to cartilage degradation in rheumatic diseases, it is unclear if reactive oxygen species (ROS) or proteolytic enzymes are the most important components in cartilage degradation and how they interact. RESULTS: Neutrophils were stimulated by chemicals conferring a different degree of ROS formation and enzyme release. Supernatants of neutrophils were incubated with thin slices of pig articular cartilage. Supernatants of cartilage were assayed by NMR spectroscopy, MALDI-TOF mass spectrometry and relevant biochemical methods. Stimulation conditions of neutrophils correlated well with the extent of cartilage degradation. Due to the release of different enzymes, cartilage degradation could be best monitored by NMR since mainly low-mass degradation products were formed. Astonishingly, the suppression of the formation of ROS resulted in decreased cartilage degradation. CONCLUSION: ROS formed by neutrophils are not directly involved in cartilage degradation but influence the activity of proteolytic enzymes, which are the main effectors of cartilage degradation.

Animals↗
PubMed2006

A study of the reactions of H3O+, NO+ and O2+ ions with nine alkoxy alcohols.

Following a selected ion flow tube mass spectrometry (SIFT-MS), analysis of the headspace of a commercial available nail polish remover pad in which gamma-butyrolactone (GBL) and 2-butoxy-1-ethanol were found to be the major volatiles, a study of the reactions of H3O+, NO+ and O2+* ions with nine alkoxy alcohols (R1-O-R2OH) was carried out using selected ion flow tube (SIFT) at a carrier gas (helium) pressure of 9. 3 x 10(1) Pa. Experiments were also performed at various carrier gas pressures (4 x 10(1)-1.1 x 10(2) Pa) for some reactions and under moist air condition. The number and distribution of the hydrates for the product ions were used to identify their structures and to investigate reaction mechanisms. The H3O+ reactions proceed via nascent ion-molecule complex (H3O+ .M)*, then produce R1-O-R2OH. H+, ( R1-O-R2)+, HOR2OH. H+ and R2=O. H+ ions through various channels. Similarly, via a nascent complex (NO+.M)*, NO+. M, (M-H)+ and (M-ROH)+ ions were produced in the NO+ reactions. The collisions between the nascent complexes (H3O+ .M)* and (NO+.M)* with a third body (He, N2 and O2 etc) have influence on the product ion distributions. The O2+ reactions produce mainly dissociative product ions and it is uncertain whether they proceed via the nascent ion-molecule complex (O2+ . M)*. This study provides rate coefficients and product ions in the SIFT-MS database for the analysis of these compounds in normal and humid air samples. It will be further utilised into addiction and drug abuse, respiratory medicine and other research areas using SIFT-MS.

Air Pollutants↗
PubMed1994

The superoxide-generating system of human neutrophils possesses a novel diaphorase activity. Evidence for distinct regulation of electron flow within NADPH oxidase by p67-phox and p47-phox.

A dye reductase activity, independent of the production of superoxide, is induced in membranes prepared from stimulated human neutrophils or during activation of NADPH oxidase in a cell-free system. This diaphorase activity was greater under anaerobic as opposed to aerobic conditions. The activity has an absolute requirement for the membrane components of the oxidase, but does not appear to have an absolute dependence for the 47-kDa cytosolic factor p47-phox, suggesting the oxidase can be converted to a partial state of activation in the absence of this factor. The dye-reductase activity was inhibited at low concentration by the oxidase inhibitor, diphenylene iodonium. The electron acceptor, iodonitrotetrazolium violet (2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride) is both a substrate and a mixed inhibitor of NADPH oxidation.

Aerobiosis↗
PubMed1984

Inhibition of photosynthetic sulfide oxidation by organic cations.

Photosynthetic sulfide oxidation by the purple sulfur bacterium Chromatium vinosum is strongly inhibited by the organic cations benzyl viologen ( BV2 +) and tetraphenylphosphonium (TPP+) at micromolar concentrations. Both are much more inhibitory at pH 8 than at pH 7. Inhibition probably results from uptake of benzyl viologen and tetraphenylphosphonium in response to an electrical potential gradient across the plasma membrane which increases in magnitude with increasing pH. Although both compounds appear to have the same mode of action, the biochemical mechanism of their inhibition remains to be determined.

Benzyl Viologen↗
PubMed1996

The drug-binding activity of the multidrug-responding transcriptional regulator BmrR resides in its C-terminal domain.

Rhodamine and tetraphenylphosphonium, the substrates of the Bacillus subtilis multidrug efflux transporter Bmr, induce the expression of Bmr through direct interaction with its transcriptional activator BmrR. Here we show that the C-terminal domain of BmrR, expressed individually, binds both these compounds and therefore can be used as a model for molecular analysis of the phenomenon of multidrug recognition.

Bacillus subtilis↗
PubMed1985

Selective killing of carcinoma cells "in vitro" by lipophilic-cationic compounds: a cellular basis.

Lipophilic positively-charged compounds are facilitated across biological membranes by the transmembrane potential of intact cells. One such compound, rhodamine 123, has recently been shown to be selectively toxic toward a variety of transformed (carcinoma), epithelial cells in vitro (Lampidis et al., 1982; Bernal et al., 1982; Lampidis et al., 1983). A mechanism that could account for the selectivity of this agent would be a difference in the plasma membrane potential between normal and carcinoma cells. We report here that a significantly higher transmembrane potential has been found in a pair of carcinoma (83 mV for human breast and -99 mV for human cervix) as compared to normal (-56 mV for marsupial kidney and -48 mV for monkey kidney) epithelial cell lines. We also identified 3 other positively-charged lipophilic compounds, safranin 0, rhodamine 6G and tetraphenylphosphonium chloride (TPP+), which show selective toxicity toward carcinoma cells in vitro, while an uncharged lipophilic analog, rhodamine 116, does not. These data suggest that the higher plasma membrane potential of carcinoma cells may in part contribute to the preferential accumulation and selective toxicity of the lipophilic cationic compounds we have examined. An extension of this concept to an in vivo environment could lead to a class of cationic compounds which selectively exploit differences between normal and carcinoma cells.

Animals↗
PubMed2004

Role of a conserved membrane-embedded acidic residue in the multidrug transporter MdfA.

According to the current topology model of the Escherichia coli multidrug transporter MdfA, it contains a membrane-embedded negatively charged residue, Glu26, which was shown to play an important role in substrate recognition. To further elucidate the role of this substrate recognition determinant, various Glu26 replacements were characterized. Surprisingly, studies with neutral MdfA substrates showed that, unlike many enzymatic systems where the size and chemical properties of binding site residues are relatively defined, MdfA tolerates a variety of changes at position 26, including size, hydrophobicity, and charge. Moreover, although efficient transport of positively charged substrates requires a negative charge at position 26 (Glu or Asp), neutralization of this charge does not always abrogate the interaction of MdfA with cationic drugs, thus demonstrating that the negative charge does not play an essential role in the multidrug transport mechanism. Collectively, these results suggest a link between the broad substrate specificity profile of multidrug transporters and the structural and chemical promiscuity at their substrate recognition pockets.

Amino Acid Sequence↗
PubMed1995

NADPH oxidase activity of cytochrome P-450 BM3 and its constituent reductase domain.

Cytochrome P-450 BM3 from Bacillus megaterium catalyses NADPH oxidation in the absence of added substrate. This activity is also associated with the independently expressed flavin-containing reductase domain of the protein. The rates of these activities are more than two orders of magnitude lower than those in the presence of fatty acid P-450 substrates or artificial electron acceptors. Electrons derived from NADPH in this fashion are transferred onto oxygen, generating superoxide (O2-) anions. The formation of these active oxygen species is detectable by luminometry and the chemiluminescence can be inhibited through the addition of superoxide dismutase (but not catalase). This activity is reminiscent of the microbicidal NADPH oxidase activity associated with neutrophils and other leukocyte blood cell types. Diphenyliodonium, a potent inhibitor of the neutrophil NADPH oxidase, effectively inhibits fatty acid hydroxylase and electron transferase activities catalysed by P-450 BM3 and its reductase domain. CD studies on the native and NADPH-reduced P-450 BM3 and BM3 reductase indicate that no secondary structural alteration is caused by pre-incubation with the reductant. Therefore, the previously recognised reversible time-dependent inactivation of P-450 BM3 by NADPH may be attributed to the NADPH oxidase activity associated with the reductase domain of the enzyme.

Bacillus megaterium↗
PubMed1981

Synthesis and evaluation of some stable multisubstrate adducts as inhibitors of catechol O-methyltransferase.

A new series of methylase inhibitors has been designed in which the nucleophilic methyl acceptor is attached to the adenosine and/or homocysteine fragments of the methyl donor, S-adenosylmethionine, to form a "multisubstrate adduct". In the present case, catecholamine analogues attached through a phenethyl sulfide linkage to 5'-thioadenosine or homocysteine have been synthesized, together with the corresponding methylsulfonium salts. These compounds were assayed as inhibitors of catechol O-methyltransferase, and the adenosylsulfonium salts (4) were found to be inhibitors of the enzyme.

Catechol O-Methyltransferase Inhibitors↗
PubMed2006

Endothelin-A and -B receptors, superoxide, and Ca2+ signaling in afferent arterioles.

It is unknown if endothelin-A and -B receptors (ET(A)R and ET(B)R) activate the production of superoxide via NAD(P)H oxidase and subsequently stimulate the formation of cyclic adenine diphosphate ribose (cADPR) in afferent arterioles. Vessels were isolated from rat kidney and loaded with fura 2. Endothelin-1 (ET-1) rapidly increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) by 303 nM. The superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and nicotinamide, an inhibitor of ADPR cyclase, diminished the response by approximately 60%. The ET(B)R agonist sarafotoxin 6c (S6c) increased peak [Ca(2+)](i) by 117 nM. Subsequent addition of ET-1 in the continued presence of S6c caused an additional [Ca(2+)](i) peak of 225 nM. Neither nicotinamide or 8-bromo- (8-Br) cADPR nor apocynin decreased the [Ca(2+)](i) response to S6c, but inhibited the subsequent [Ca(2+)](i) response to ET-1. The ET(B)R blockers BQ-788 and A-192621 prevented the S6c [Ca(2+)](i) peak and reduced the ET-1 response by more than one-half, suggesting an ET(B)R/ET(A)R interaction. In contrast, the ET(A)R blocker BQ-123 had no effect on the S6c [Ca(2+)](i) peak and obliterated the subsequent ET-1 response. ET-1 immediately stimulated superoxide formation (measured with TEMPO-9-AC, 68 arbitrary units) that was inhibited 95% by apocynin or diphenyl iodonium. S6c or IRL-1620 increased superoxide by 8% of that caused by subsequent ET-1 addition. We conclude that ET(A)R activation of afferent arterioles increases the formation of superoxide that accounts for approximately 60% of subsequent Ca(2+) signaling. ET(B)R activation appears to result in only minor increases in superoxide production. Nicotinamide and 8-Br-cADPR results suggest that ET-1 (and primarily ET(A)R) causes the activation of vascular smooth muscle cell-ADPR cyclase.

ADP-ribosyl Cyclase↗
PubMed2005

New transport assay demonstrates vesicular acetylcholine transporter has many alternative substrates.

The acetylcholine-binding site in vesicular acetylcholine transporter faces predominantly toward the outside of the vesicle when resting but predominantly toward the inside when transporting. Transport-related reorientation is detected by an ATP-induced decrease in the ability of saturating substrate to displace allosterically bound [(3)H]vesamicol. The assay was used here to determine whether structurally diverse compounds are transported by rat VAChT expressed in PC12(A123.7) cells. Competition by ethidium, tetraphenylphosphonium and other monovalent organic cations with [(3)H]vesamicol is decreased when ATP is added, and the effect depends on proton-motive force. The results indicate that many organic molecules carrying +1 charge are transported, even though the compounds do not resemble acetylcholine in structural details.

Acetylcholine↗
PubMed1978

Fungal toxicity of phosfon D and its reversion by lipids.

The growth retardant Phosfon D inhibits the growth of some yeasts and human pathogenic filamentous fungi. The toxic effects of the compound on the dermatophyte Microsporum cookei were completely reversed by adding ergosterol and oleic acid to the medium. The significance of these findings is discussed.

Ergosterol↗
PubMed2000

Azo reduction of methyl red by neuronal nitric oxide synthase: the important role of FMN in catalysis.

Nitric oxide synthase (NOS) is composed of an oxygenase domain and a reductase domain. The reductase domain has NADPH, FAD, and FMN binding sites. Wild-type nNOS reduced the azo bond of methyl red with a turnover number of approximately 130 min(-1) in the presence of Ca(2+)/calmodulin (CaM) and NADPH under anaerobic conditions. Diphenyleneiodonium chloride (DPI), a flavin/NADPH binding inhibitor, completely inhibited azo reduction. The omission of Ca(2+)/CaM from the reaction system decreased the activity to 5%. The rate of the azo reduction with an FMN-deficient mutant was also 5% that of the wild type. NADPH oxidation rates for the wild-type and mutant enzymes were well coupled with azo reduction. Thus, we suggest that electrons delivered from the FMN of the nNOS enzyme reduce the azo bond of methyl red and that this reductase activity is controlled by Ca(2+)/CaM.

Animals↗
PubMed2001

Oxidative processes in human promonocytic cells (THP-1) after differentiation into macrophages by incubation with Chlamydia pneumoniae extracts.

Human monocytes differentiated into macrophages by Chlamydia pneumoniae were able to oxidize blood lipoproteins, as discovered by Kalayoglu et al. (1998). Using a model of human promonocytic cells (THP-1), the cells were differentiated into macrophages by preincubation with C. pneumoniae extract, and further stimulated by phorbol myristate acetate. In these conditions, the differentiated cells oxidized a thiol compound and released superoxide anion as demonstrated respectively by gas liquid chromatography and electron spin resonance. The thiol oxidation and superoxide anion release were inhibited by diphenyliodonium, a NADPH oxidase and NOsynthase inhibitor, proving that the respiratory burst and the NOsynthase were involved in the oxidation processes occurring in the differentiated THP-1. The role of H(2)O(2) (derived from superoxide anion) was indicated by the enhancing effect of a peroxidase on the thiol oxidation. The presence of alpha-tocopherol in the surrounding medium strongly diminished the oxidation of the thiol target.

Anti-Bacterial Agents↗
PubMed1986

The phosphonium ion efflux system of Escherichia coli: relationship to the ethidium efflux system and energetic studies.

The extent of accumulation of methyltriphenylphosphonium ion by Escherichia coli was shown to be dependent on the permeability of the outer membrane and the activity of an efflux system for this compound. Evidence consistent with the operation of a single efflux system for compounds such as phosphonium ions, phenanthridiniums and flavines is presented. Studies on the energy coupling mechanism for this efflux system indicated that it was driven by the transmembrane proton electrochemical gradient.

Energy Metabolism↗
PubMed1991

Enhanced in vitro uptake and retention of 3H-tetraphenylphosphonium by nervous system tumor cells.

Photodynamic therapy is a promising treatment for human brain tumors because of the selective retention of certain compounds by tumor cells. Certain lipophilic cationic compounds, such as tetraphenylphosphonium (TPP), are selectively taken up by a variety of carcinomas. Although preferential retention of TPP has been demonstrated for the breast carcinoma cell line MCF-7, this compound had not been tested previously on cells derived from nervous system tumors. In the present study, tritiated-TPP (3H-TPP) uptake and retention for eight different cell cultures of three histologically different types of nervous system tumors was measured and the data were compared to a positive control (MCF-7) and negative controls (normal African Green monkey kidney epithelium (CV-1) and the normal human fibroblast (WI-38) cell lines). Uptake and retention characteristics could be grouped by specific pathological tumor types, but individual tumor variability was notable. Malignant astrocytoma (grade III/III glioblastoma) and malignant neurofibrosarcoma cells showed preferential uptake and retention of 3H-TPP relative to meningioma cells and normal controls. A clonogenic assay utilizing the cytotoxic lipophilic cationic compound dequalinium showed strong retainers of 3H-TPP to be more susceptible to the effects of dequalinium than weak retainers. These data demonstrate that certain human and experimental animal nervous system tumor cell lines retain lipophilic compounds possessing a delocalized positive charge. Lipophilic cationic compounds may be useful in the intraoperative delineation of tumor margins and in the photodynamic therapy of certain nervous system tumors.

Animals↗
PubMed2005

Reactive oxygen species-linked regulation of the multidrug resistance transporter P-glycoprotein in Nox-1 overexpressing prostate tumor spheroids.

Expression of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) has been demonstrated to be regulated by hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibited by intracellular reactive oxygen species (ROS). Herein, P-gp and HIF-1alpha expression were investigated in multicellular prostate tumor spheroids overexpressing the ROS-generating enzyme Nox-1 in comparison to the mother cell line DU-145. In Nox-1-overexpressing tumor spheroids (DU-145Nox1) generation of ROS as well as expression of Nox-1 was significantly increased as compared to DU-145 tumor spheroids. ROS generation was significantly inhibited in the presence of the NADPH-oxidase antagonists diphenylen-iodonium chloride (DPI) and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). Albeit growth kinetic of DU-145Nox1 tumor spheroids was decreased as compared to DU-145 spheroids, elevated expression of Ki-67 was observed indicating increased cell cycle activity. In DU-145Nox1 tumor spheroids, expression of HIF-1alpha as well as P-gp was significantly decreased as compared to DU-145 spheroids, which resulted in an increased retention of the anticancer agent doxorubicin. Pretreatment with the free radical scavengers vitamin E and vitamin C increased the expression of P-gp as well as HIF-1alpha in Nox-1-overexpressing cells, whereas no effect of free radical scavengers was observed on mdr-1 mRNA expression. In summary, the data of the present study demonstrate that the development of P-gp-mediated MDR is abolished under conditions of elevated ROS levels, suggesting that the MDR phenotype can be circumvented by modest increase of intracellular ROS generation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗