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At least 811 records · Page 45Linked to original sources
PubMed2005

Probing the interaction of kojic acid antibiotics with iron(III) chloride by using electrospray tandem mass spectrometry.

Kojic acid, 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one, has been used extensively as a clinical iron-chelating drug although the nature of the complexes of iron and kojic acid has not been established. In this article we demonstrate the complexation of kojic acid with iron(III) chloride by using electrospray ionization mass spectrometry (ESI-MS). The ESI-MS analysis revealed different reactions between iron(III) chloride and kojic acid (M), and the mass spectrum exhibited four complexes: [Fe+2(M-H)]+, [Fe+3(M-H)+H]+, [Fe2+4(M-H)+Cl]+, and [Fe2+5(M-H)]+. All these proposed complexes and the presence of chloride ion in one of the dinuclear complexes have been confirmed by isotopic patterns and fragmentation studies by means of tandem mass spectrometry (MSn).

Anti-Bacterial Agents↗
PubMed2007

A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence.

Previous studies established that Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) and (2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester (herkinorin) are fully efficacious mu-agonists. Herkinorin (HERK), unlike DAMGO, does not recruit beta-arrestin and promote mu-receptor internalization, even in cells that over express beta-arrestin. We hypothesized that chronic HERK and DAMGO treatment will differentially affect cellular markers of tolerance and dependence. CHO cells expressing the cloned human mu-receptor were treated for 20 h with 10 microM DAMGO, HERK, morphine, or medium. Both DAMGO and HERK acted as full agonists in the [(35)S]GTP-gamma-S binding assay with E(MAX) values of 230% and EC(50) values of 12.8 and 92.5 nM, respectively. In the cAMP assay, DAMGO and HERK had similar E(MAX) values of approximately 80% and EC(50) values of 3.23 and 48.7 nM, respectively. Chronic exposure to both drugs produced moderate tolerance to both drugs ( approximately 2 to 5 fold) in the [(35)S]GTP-gamma-S binding assay. In the cAMP assay, chronic DAMGO produced tolerance to both drugs ( approximately 3 to 4 fold). Chronic HERK eliminated the ability of either drug to inhibit forskolin-stimulated cAMP accumulation. Chronic DAMGO increased, and chronic HERK decreased, forskolin-stimulated cAMP accumulation. Naloxone, after chronic HERK (but not DAMGO) induced a large increase in forskolin-stimulated cAMP accumulation. Viewed collectively with published data, the current data indicate that both internalizing and noninternalizing mu-agonists produce cellular signs of tolerance and dependence.

Analgesics, Opioid↗
PubMed2001

Examination of Alternaria alternata mutagenicity and effects of nitrosylation using the Ames Salmonella test.

Molds of the genus Alternaria are common food pathogens responsible for the spoilage of fruits, vegetables, grains, and nuts. Although consumption of Alternaria alternata-contaminated foodstuffs has been implicated in an elevated incidence of esophageal carcinogenesis, the mutagenic potencies of several A. alternata toxins seem unable to account for the levels of activity found using crude mycelial extracts. In this study, the mutagenic effects of nitrosylation were examined with the major Alternaria metabolites Altenuene (ALT), Alternariol (AOH), Alternariol Monomethyl Ether (AME), Altertoxin I (ATX I), Tentoxin (TENT), Tenuazonic Acid (TA), and Radicinin (RAD) using the Ames Salmonella strains TA98 and TA100. In the absence of nitrosylation, ATX I was mutagenic when tested from 1 to 100 microg/plate in TA98 with rat liver S9 for activation, while AOH and ATX I were weakly mutagenic +/- S9 in TA100. Incubation with nitrite generally increased mutagenic potencies with ATX I strongly mutagenic +/- S9 in both TA98 and TA100, while ALT, AOH, AME, and RAD responses were enhanced in TA100 + S9. However, subsequent examination of three extracts made from A. alternata culture broth, acetone-washed mycelia, and the acetone washes showed a different mutagenic response with both broth and acetone washes directly mutagenic in TA98 and TA100 but with a reduced response + S9. The acetone-washed mycelial extract was found to have the lowest mutagenic activity of the three extracts tested. Nitrosylation had little effect on the mutagenicity of any of the extracts. Thus, while nitrosylation increases the mutagenicity of ATX I, and to a lesser extent that of several other Alternaria toxins, the results demonstrate that Alternaria produces a major mutagenic activity with a S. typhimurium response different from that found with the purified toxins. Efforts are currently underway to chemically identify this mutagenic species. Published 2001 Wiley-Liss, Inc.

Alternaria↗
PubMed1995

The absence of extracellular calcium potentiates the killing of cultured hepatocytes by aluminum maltolate.

Dose- and time-dependent killing of cultured rat hepatocytes was produced by aluminum maltolate (AlM), a neutral, water-soluble complex of aluminum 3-hydroxy-2-methyl-4H-pyran-4-one. Treatment with 10 mM AlM for 1 h killed 50% or more of the cells within 3 h. Removal of calcium from the culture medium or treatment with calcium channel blockers (verapamil, nifedipine, diltiazem) potentiated the cell killing. By contrast, inhibition by thapsigargin of the sequestration of intracellular calcium by the endoplasmic reticulum reduced the toxicity of AlM. In turn, activation of protein kinase C with 12-O-tetradecanoylphorbol 13-acetate or activation of protein kinase A with 8-[4-chlorophenyl-thio]adenosine 3',5'-cyclic monophosphate also reduced the toxicity of AlM. By contrast, inhibition of protein kinase activity by staurosporine potentiated the cell killing. Staurosporine, however, did not reverse the protection afforded by thapsigargin. Hepatocytes treated with AlM for 1 h were rescued by adding deferoxamine as late as 90 min following the removal of AlM, whereas pretreatment for 1 h with deferoxamine did not prevent the toxicity of AlM. ATP depletion did not precede loss of viability. Pharmacologic probes excluded oxidative stress as a mechanism of lethal injury by AlM, and inhibition of protein synthesis by cycloheximide did not protect the hepatocytes, thereby excluding activation of a cell death program. These data define a new model in which aluminum kills liver cells by a mechanisms distinct from previously recognized pathways of lethal cell injury. It is hypothesized that aluminum binds to cytoskeletal proteins intimately associated with the plasma membrane. This interaction eventually disrupts the permeability barrier function of the cell membrane, an event that heralds the death of the hepatocyte. The intracellular calcium ion concentration and protein phosphorylation may modify the interaction of aluminum with its critical targets. Alternatively, aluminum may inhibit the phosphorylation of cytoskeletal elements, thereby interfering with their function.

Aluminum↗
PubMed1996

Effect of NADPH-associated keto-reducing domain on substrate entry into 6-hydroxymellein synthase, a multifunctional polyketide synthetic enzyme involved in phytoalexin biosynthesis in carrot.

6-Hydroxymellein synthase is a polyketide biosynthetic enzyme induced in carrot cells which is organized as a homodimer composed of multifunctional subunits. The synthase liberates triacetic acid lactone, instead of 6-hydroxymellein, as a derailment product when the keto-reducing reaction at the triketide intermediate stage is interrupted. However, the efficiency of the triacetic acid lactone-forming reactions is markedly lower than that of the normal reaction, and the kinetic analyses have revealed that the affinity of the enzyme protein for acetyl-CoA is appreciably reduced in the abnormal reactions. It is assumed that the interaction of the NADPH-associated keto-reducing domain with a putative primary binding site(s) of the acyl-CoA in the enzyme structure affects the entry of the starter unit into the protein. The present finding should provide an example of the novel class of "subunit communication" of multimer enzymes.

Acetyl Coenzyme A↗
PubMed2000

Phospholipase A(2) is involved in thapsigargin-induced sodium influx in human lymphocytes.

Previously, we reported that emptying of intracellular Ca(2+) pools with endoplasmatic Ca(2+)-ATP-ase inhibitor thapsigargin leads to the Na(+) influx in human lymphocytes (M. Tepel et al., 1994, J. Biol. Chem. 269, 26239-26242). In the present study we examined the mechanism underlying the thapsigargin-induced Na(+) entry. We found that the thapsigargin-induced increase in Na(+) concentration was effectively inhibited by three structurally unrelated phospholipase A(2) (PLA(2)) inhibitors, p-bromophenacyl bromide, 3-(4-octadecyl)-benzoylacrylic acid (OBAA), and bromoenol lactone (BEL). The thapsigargin-induced Na(+) influx could be mimicked by PLA(2) exogenously added to the lymphocyte suspension. In addition, thapsigargin stimulated formation of arachidonic acid (AA), the physiological PLA(2) product. AA induced Na(+) entry in a time- and concentration-dependent fashion. Both, thapsigargin-induced Na(+) influx and AA liberation were completely inhibited in the presence of tyrosine kinase inhibitor genistein but not in the absence of extracellular Ca(2+). Collectively, these data show that thapsigargin-induced Na(+) entry is associated with tyrosine kinase-dependent stimulation of PLA(2).

Acetophenones↗
PubMed1996

The use of diethylaminoethyl-cellulose-membrane filters in a bioassay to quantify melanin synthesis.

Melanins are a class of extremely insoluble granular biopolymers with a yet ill-defined chemical structure, properties which render the isolation and quantification of these molecules very difficult. Based on their strong anionic character, however, a biophysical property shared by all melanins, we have developed a method allowing total recovery of the pigment. Soluble melanin is bound and granular melanin retained by DEAE-cellulose membrane filters. This approach provides an excellent means to quantify melanin synthesis in normal human melanocytes alone and in coculture with normal human keratinocytes.

DEAE-Cellulose↗
PubMed1999

A standardized protocol for assessing regulators of pigmentation.

Varied effects of chemical or biological compounds on mammalian pigmentation have been reported by many groups, but to date, no standardized method has established necessary and/or optimal parameters for testing such agents. A standardized method has been developed to screen compounds with potential effects on pigmentation. The protocol comprises basic parameters to analyze melanogenic effects and allows for further characterization of candidate compounds, providing important insights into their mechanism of action. In this protocol (termed STOPR, for standardized testing of pigmentation regulators), compounds are initially screened using purified tyrosinase and are then tested on melanocytes in culture. After treatment of melanocytes with potentially bioactive compounds, cell proliferation and viability, total melanin accumulated, and melanogenic potential are measured. This protocol is an important first step in characterizing chemical regulation of effects on melanogenesis. When bioactive candidate compounds are identified, testing may proceed for pharmacological or otherwise commercial applications in coculture and/or organ culture models followed by in vivo testing. As an application of this method, results for compounds known to stimulate and/or inhibit melanogenesis (including arbutin, hydroquinone, kojic acid, melanocyte-stimulating hormone, and thymidine dimers) as well as some commercial skin whiteners are reported.

Animals↗
PubMed2002

A melanocyte-keratinocyte coculture model to assess regulators of pigmentation in vitro.

Many melanocyte or skin equivalent models have been used to evaluate the potential efficacy of melanogenic compounds to regulate pigmentation, but there has been great variation in results, partially stemming from the use of different cell lines and diverse conditions for the melanogenic assays. In an earlier report, we optimized a microtiter format assay system to screen potential bioactive compounds using immortalized melan-a melanocytes. That assay system, termed the STOPR protocol, allowed effects on melanocyte proliferation and differentiation to be assessed in a highly sensitive, reproducible, and cost-effective manner. However, in the skin and hair, melanocytes interact with keratinocytes, fibroblasts, and other cell types, and testing of putative bioactive compounds on melanocytes alone in culture does not allow one to observe the interactions with those other cell types, such as would occur in vivo. Therefore, we developed a melanocyte-keratinocyte coculture protocol that allows testing of compounds for potential effects on pigmentation in a more physiologically relevant context. It is a sensitive, reproducible, and reliable model for testing melanogenic regulators, and we have standardized it with known melanogenic inhibitors (hydroquinone, arbutin, kojic acid, and niacinamide) and stimulators (alpha-melanocyte-stimulating hormone, 8-methoxypsoralen, and 3,4-dihydroxyphenylalanine). This coculture system allows for large-scale screening of candidate compounds in conjunction with the STOPR protocol and provides a more physiologically relevant system to study melanocyte-keratinocyte interactions and to elucidate the regulatory mechanisms of melanogenic compounds.

Animals↗
PubMed1994

New cytochrome P450-dependent reactions from wheat: terminal and sub-terminal hydroxylation of oleic acid by microsomes from naphthalic acid anhydride and phenobarbital induced wheat seedlings.

Incubation of the microsomal fraction from etiolated wheat shoots (Triticum aestivum L. cv Etoile de Choisy) with [1-14C]oleic acid led to the formation of three polar metabolites which were identified as 18-, 17- and 16-hydroxyoleic acids by gas chromatography/mass spectra analysis. They were generated in a molar ratio of 1.4/4.6/4, respectively. Terminal and sub-terminal hydroxylation of oleic acid and the cytochrome P450 content were strongly enhanced in microsomes from wheat shoots treated with naphthalic acid anhydride and phenobarbital. The involvement of cytochrome P450 is demonstrated by the dependence of hydroxylation upon O2 and NADPH, and by their light-reversible inhibition by carbon monoxide. In addition, the hydroxylation of oleic acid, but not of lauric acid and cinnamic acid, was inhibited when microsomes where incubated with 9-octadecen-16-ynoic acid, a substrate analogue displaying an acetylenic function at the carbon position of major enzyme attack. Our results suggest that at least two different P450 enzymes are involved in the oxidation of oleic and lauric acids in wheat.

Cytochrome P-450 Enzyme System↗
PubMed1996

Nonpeptidic HIV protease inhibitors: 4-hydroxy-pyran-2-one inhibitors with functional tethers to P1 phenyl ring to reach S3 pocket of the enzyme.

A systematic study of tethering various groups on 6-phenyl ring of 4-hydroxy-6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to increase the binding affinity with HIV protease. This tethering approach was aimed to fill S3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as tethering substituents to alter the physical properties as well as to enhance the binding affinity with HIV protease. Inhibitor 24, 4-hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(3-pyridinylmethoxy+ ++ ) phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological properties of this class of HIV protease inhibitors.

Cell Line↗
PubMed1999

Ca(2+)-independent phospholipase A2 is required for alpha2-adrenergic-induced preadipocyte spreading.

In the present study, we studied the involvement of A2 phospholipases (PLA2) in alpha2-adrenergic receptor-control of preadipocyte actin cytoskeleton. For that, various PLA2 inhibitors were tested on the ability of the selective alpha2-adrenergic agonist UK14304 to induce the spreading in alpha2AF2 preadipocytes. We observed that, whereas several Ca(2+)-dependent PLA2 blockers were ineffective, the Ca(2+)-independent phospholipase A2 (iPLA2) inhibitor, broenolactone (BEL), specifically blocked alpha2-adrenergic-dependent preadipocyte spreading without affecting the spreading activity of lysophosphatidic acid (LPA) or serum. BEL inhibition was completely restored by lysophosphatidic acid, but not by arachidonic acid or other fatty acids. The presence of the lysophospholipase (phospholipase B) suppressed the effect of LPA on preadipocyte spreading, but had no influence on alpha2-adrenergic-induced spreading. Thus, the extracellular production of LPA or fatty acids is not involved in iPLA2-dependent preadipocyte spreading. iPLA2 protein was found in preadipocytes but, conversely to cPLA2, did not exhibit any modification of its electrophoretic mobility after alpha2-adrenergic stimulation. We concluded that iPLA2 is involved in alpha2-adrenergic control of preadipocyte actin cytoskeleton.

3T3 Cells↗
PubMed2001

Arachidonyltrifluoromethy ketone, a phospholipase A(2) antagonist, induces dispersal of both Golgi stack- and trans Golgi network-resident proteins throughout the cytoplasm.

Arachidonyltrifluoromethy ketone (AACOCF(3)), a phospholipase A(2) antagonist, reversibly induced dispersal of Golgi stack- and trans Golgi network (TGN)-resident proteins throughout the cytoplasm in NRK cells as followed by immunocytochemical staining of ManII and TGN38, respectively. The action of AACOCF(3) was partly blocked by other PLA(2) antagonists, suggesting it be not caused by a general inhibition of phospholipase A(2). AACOCF(3) neither dissociated beta-COP from membranes nor prevented brefeldin A-induced beta-COP release. Action of AACOCF(3) on the Golgi stack and TGN is different from that of brefeldin A and nordihydroguaiaretic acid. The most prominent difference is that the Golgi stack and TGN showed a similar sensitivity to AACOCF(3), while the TGN was dispersed more slowly than the Golgi stack in brefeldin A- or nordihydroguaiaretic acid-treated NRK cells. This novel action of AACOCF(3) may be used as pharmacological tool and give new insights into vesicle-mediated traffic and Golgi membrane dynamics.

Aminobenzoates↗
PubMed2001

Insulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing effect in KK-A(y) mice with type 2 diabetes mellitus.

High blood glucose levels of KK-A(y) mice with type 2 diabetes mellitus were normalized by daily intraperitoneal (ip) administration of a zinc(II) complex, bis(maltolato)zinc(II) (Zn(Mal)(2)) with a Zn(O(4)) coordination mode, following the finding of strong in vitro insulinomimetic activity in isolated rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. The blood glucose level was maintained in the normal range during administration of the Zn(Mal)(2) complex for 14 days and improvements in the glucose tolerance were confirmed by an oral glucose tolerance test.

Adipocytes↗
PubMed1997

Comparison of in vitro preconditioning responses of isolated pig and rabbit cardiomyocytes: effects of a protein phosphatase inhibitor, fostriecin.

Calcium tolerant pig and rabbit cardiomyocytes were isolated using retrograde aortic perfusion of nominally calcium-free collagenase. Preconditioning protocols used 1 or 3x10-min episodes of ischemic pelleting or pre-incubation with 100 micro M adenosine, followed by a 15-min post-incubation and 180-240-min ischemic pelleting. Control cells were incubated and washed in parallel with the experimental groups. Injury was assessed by determination of cell morphology, trypan blue permeability following osmotic swelling, lactate and HPLC analysis of adenine nucleotides. Preconditioned pig cardiomyocytes had a reduced rate of ischemic contracture, but protection occurred without conservation of ATP. Preconditioned rabbit cardiomyocytes were protected without significant changes in rates of ischemic contracture or ATP depletion. Incubation of ischemic cells with the protein phosphatase inhibitor, fostriecin, at PP2A-selective concentrations (0.1-10 micro M), mimicked preconditioning in both rabbit and pig cardiomyocytes. In rabbits, the KATP channel blocker, 5-hydroxydecanoate (5-HD), did not block preconditioning or fostriecin protection. In the pig, 5-HD blocked both preconditioning and fostriecin protection, with return of the rates of ischemic contracture to control. However, 5-HD was an effective blocker of protection only in early ischemia. Fostriecin mimicked preconditioning in the rabbit and the early responses of the preconditioned pig. Preconditioning appears associated with protein phosphorylation in both the rabbit and the pig, but major pathways leading to protection may differ in the two species.

Alkenes↗
PubMed1998

Protein phosphatase inhibitors calyculin A and fostriecin protect rabbit cardiomyocytes in late ischemia.

Calcium-tolerant rabbit cardiomyocytes were isolated using retrograde aortic perfusion with a nominally calcium-free, collagenase buffer. In vitro ischemic preconditioning was induced by a 10-min episode of ischemic pelleting, followed by a 15-min post-incubation and a prolonged period of ischemic pelleting. Injury was assessed by determination of cell contracture and trypan blue permeability following hypotonic swelling and correlated with metabolic assays of lactate and adenine nucleotides. The protein phosphatase PP1/2A inhibitor calyculin A and PP2A-selective fostriecin protected isolated rabbit cardiomyocytes from lethal injury after a 10-min pre-incubation and when added late into ischemic pellets after a delay of 75 min. At the time of late drug addition, cells were severely ATP-depleted and in rigor contracture. Protection with Calyculin A from 1 nM to 1 microM was dose-related. Cells pre-incubated with 10 nM to 10 microM fostriecin 10 min prior to ischemic pelleting were protected with an EC50 approximating 71 nM, implying protection at a PP2A-selective dose. The selective protein kinase C inhibitor, calphostin C, blocked ischemic preconditioning protection but not protection from 1 microM calyculin A. Protection of severely ischemic cardiomyocytes following protein phosphatase inhibition appears not to require PKC activity or ATP conservation. Pre-incubation of cells with calyculin A induced high levels of phosphorylation in p38 mitogen activated protein kinase (MAPK), as compared to the ischemia-induced phosphorylation observed in the untreated group only at 30 min of ischemia, providing evidence of protein phosphatase activity in cardiomyocytes. Pharmacological protection in late ischemia has been demonstrated, but the mechanism of protection is undetermined.

Adenosine Triphosphate↗
PubMed1998

Phospholipase A2-mediated activation of phospholipase D in rat heart sarcolemma.

The effect of phospholipase A2 (PLA2)-dependent release of unsaturated fatty acids (FA) on phospholipase D (PLD) function was examined in purified sarcolemmal (SL) membranes isolated from rat heart. PLD hydrolytic activity was determined by measuring either [14C] phosphatidic acid formation from exogenous [14C] phosphatidylcholine (PtdCho) or [3H] choline release from prelabelled SL Ptd[3H]choline. SL membranes with endogenous [3H] PtdCho that were prelabelled with [3H] myristic acid were used for testing PLD transphosphatidylation activity. Exogenous cis-unsaturated FA, arachidonate and oleate, significantly enhanced the [3H] choline formation at 50 and 100 microM, respectively; their effect was maximal at 250 microM and declined at higher concentrations. Use of melittin (which stimulates membrane-bound PLA2, thus releasing FA) or exogenous PLA2 reproduced the stimulatory effect of added arachidonate and oleate. Under melittin, PLA2-dependent FA release was strongly correlated (r = 0.99) to the PLD-dependent phosphatidic acid formation. Arachidonate- or melittin-enhanced PLD transphosphatidylation activity confirmed the augmented catalytic rate of PLD by these agents. Melittin-evoked PLD activation was completely blocked by 1 microM E-6-(bromomethylene) tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one, a selective inhibitor of Ca(2+)-independent v Ca(2-)-dependent PLA2, thus indicating that PLD stimulation under melittin occurred via PLA2. Activity measurement and Western blotting studies revealed the presence of a Ca(2+)-independent, high molecular weight (110 kDa) PLA2 in the SL membrane, and its immunoprecipitation by monoclonal antibodies significantly reduced the melittin-related PLD stimulation. These results suggest that Ca(2+)-independent PLA2 and subsequent endogenous mobilization of sn-2 unsaturated FA modulate PLD activity in heart SL membranes. This event may occur in physiological conditions via hormonal stimulation of membranal PLA2 as well as in heart diseases characterized by PLA2 pathological dysfunction.

Animals↗
PubMed1994

A neutral water-soluble broadening agent for spin-label studies.

Cr(maltolate)3 is proposed as a neutral water-soluble reagent for the broadening of accessible nitroxyl spin labels or spin probes in biological experiments. For situations in which the molecular charge is important, it supplements Cr(oxalate)3(3-), which is somewhat more effective on a molar basis. The interaction of the two reagents with spin-labeled creatine kinase is an example of a case in which the charge of the broadening agent is important.

Animals↗