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At least 1,135 records · Page 63Linked to original sources
PubMed1997

Contribution to the quantitative and enantioselective determination of kavapyrones by high-performance liquid chromatography on ChiraSpher NT material.

A simultaneous HPLC separation of the enantiomers of kavain, dihydrokavain, methysticin and dihydromethysticin, as well as the achiral dienolides yangonin and desmethoxyyangonin was carried out on a ChiraSpher NT column. For quantitative determinations, calibration curves with correlation coefficients between 0.9982 and 0.9996 were established for the genuine kavapyrones. Detection limits between 0.25 microg and 0.5 microg per injection were measured at 240 nm. The defined scopes of work corresponded with the different kavapyrone amounts, depending on growth factors of distinct plant locations. The precision of the method was verified by analysing a phytopharmacon with a nominal value of 40 mg kavapyrones per tablet. The evaluation revealed 39.62 mg per tablet by the sum of single calculated kavapyrones. Relative standard deviations between 1.06% and 2.39% were found for the compounds under investigation. The accuracy of the method was proved by a recovery of 99.7%. To simplify the determination of the total kavapyrone amount, response factors and correlation factors for (+)-dihydrokavain, (+)-methysticin, (+)-dihydromethysticin, yangonin and desmethoxyyangonin were calculated relative to (+)-kavain.

Anti-Anxiety Agents↗
PubMed1997

Behavioural effects of Passiflora incarnata L. and its indole alkaloid and flavonoid derivatives and maltol in the mouse.

Lyophilised hydroalcoholic and aqueous extracts of the aerial parts of Passiflora incarnata L. (Passifloraceae) (Passion-flower), as well as chemical constituents of the plant, indole alkaloids (harman, harmin, harmalin, harmol, and harmalol) maltol and flavonoids (orientin, isoorientin, vitexin and isovitexin) were assessed for behavioral effects in mice. The accordance with the traditional use of P. incarnata, psychotropic properties were confirmed by some behavioral tests in mice. The anxiolytic properties of hydroalcoholic extract were confirmed at 400 mg/kg by the increase of rears and steps climbed in the staircase test (non-familiar environmental test), and the increase in locomotion and time spent in light side in the light/dark box choice test (non-familiar environmental test). The sedative properties of aqueous extract were confirmed at 400 g/kg by decrease of rears and steps climbed in the staircase test and the decrease of rears and locomotion in the free exploratory test. Moreover, the aqueous extract induced sleep in mice after treatment with a sub-hypnotic dose of pentobarbital.

Alkaloids↗
PubMed2002

Simultaneous analysis of dehydroacetic acid, benzoic acid, sorbic acid and salicylic acid in cosmetic products by solid-phase extraction and high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for simultaneous determination of dehydroacetic acid (DHA), benzoic acid (BA), sorbic acid (SOA) and salicylic acid (SA) was developed for application to cosmetic products. Isocratic reversed-phase HPLC was employed for quantitative analysis using tetra-n-butylammonium (TBA) hydroxide as an ion-pair reagent. Cosmetic samples were purified by solid-phase extraction using Bond-Elut SI cartridges. Four acidic preservatives were eluted with methanol from cartridges. The HPLC assay was carried out using TSK gel ODS-80TM column (5 microm, 150 x 4.6 mm I.D.). The mobile phase consisted of a mixture of water and methanol (65:35, v/v) containing 2.5 mM TBA hydroxide adjusted with phosphoric acid to pH 7.0. The calibration curves of these preservatives showed good linearity with UV detection (235 nm). The correlation coefficients were better than 0.999 in all cases. The lower limits of detection (defined as a signal-to-noise ratio of about 3) were approximately 2.5 ng for DHA, 4.0 ng for BA, 2.0 ng for SOA and 5.5 ng for SA. The procedure described here is simple, selective and is suitable for quality control of finished cosmetic products.

Benzoic Acid↗
PubMed2003

Amino acid and peptide analysis using derivatization with p-nitrophenol-2,5-dihydroxyphenylacetate bis-tetrahydropyranyl ether and capillary electrophoresis with electrochemical detection.

The amine derivatization reagent p-nitrophenol-2,5-dihydroxyphenylacetate bis-tetrahydropyranyl ether (NDTE) was used in conjunction with capillary electrophoresis (CE) and electrochemical detection (EC) for the pre-separation derivatization of primary amine analytes present in aqueous solution. Glycine, several dipeptides and angiotensin II were used as model analytes. A miniaturized EC detection cell was designed and fabricated, which featured a fractured-joint field decoupler with a fixed end-column carbon fiber electrode. When a series of glycine and angiotensin II calibration solutions were derivatized with NDTE followed by CE-EC determination, linear calibration plots resulted with pre-derivatization concentration limits of detection of 500 nM (106 attomoles on-column) and 6 microM (1.275 femtomoles on-column), respectively.

Amino Acids↗
PubMed1999

Equilibrium distribution of HIV antiviral drugs into human peripheral blood mononuclear cells (PBMC) is controlled by free drug concentration in the extracellular medium.

Effect of protein binding on the equilibrium distribution of selected HIV antiviral drugs into isolated human peripheral blood mononuclear cells (PBMC, mainly lymphocytes) was investigated. Human PBMC from a single healthy human donor were isolated, purified, and cryopreserved. Uptake of non-peptide HIV-1 protease inhibitors PNU-96988 and PNU-103017 by these cells in vitro was evaluated as a function of increasing concentration of human serum in the cell incubation media. Both PNU-96988 and PNU-103017 were extensively bound to serum proteins. Uptake/efflux kinetics were very rapid such that accumulation by the cells was thermodynamically, not kinetically, controlled. Accumulation by human PBMCs in vitro was directly proportional to the free and not the total drug concentration in the media. For comparative purposes, the serum protein binding effect on the distribution of two HIV reverse transcriptase (RT) inhibitors, delavirdine (RESCRIPTOR) and zidovudine (AZT), was also evaluated. Like the HIV-1 protease inhibitors, delavirdine was found to be extensively associated with serum proteins and its accumulation by human PBMCs in vitro to be proportional to the free and not total drug concentration. In contrast, AZT was not bound to serum proteins to any significant extent. The uptake of this drug by human PBMCs in vitro was independent of serum concentration. However, the intrinsic cellular accumulation of PNU-96988, PNU-103017 and delavirdine were all greater than AZT. Thus, the extent to which drugs uptake by cells is affected by serum appears proportional to the binding affinity of the serum proteins for the drug.

Adult↗
PubMedDate not supplied

Mechanisms of apoptosis in embryonic cortical neurons (E6 and E7) in culture involve lipid signalling, protein phosphorylation and caspase activation.

Cultured embryonic (E7) chick neurons, derived from cerebral hemispheres, underwent apoptosis in response to inhibitors of protein kinase C (staurosporine) and phosphatidylinositol-3-kinase (wortmannin and LY294002), in a dose- and time-dependent manner. This was monitored by loss of cell viability, increased DNA fragmentation, and activation of caspase-3-like activity, all of which were partially reversed by elevating the level of cAMP in the cells with Bt(2)cAMP or (Sp)cAMPS. Further studies revealed that an early step in apoptosis was the formation of ceramide from sphingomyelin, resulting from the activation of a neutral pH sphingomyelinase activity. Thus inhibitors of protein kinase C and phosphatidylinositol-3-kinase increased ceramide levels in the same time-frame as caspase-3 activation and DNA fragmentation. Neurons could also be killed by the addition of either water-soluble C2-ceramide (30 microM) or natural C22/24 ceramide (0.5 microM). In contrast to the apparent protective effect of ser/thr protein phosphorylation, a pro-apoptotic role for tyrosine phosphate phosphorylation was suggested by the ability of protein tyrosine phosphate phosphatase inhibitor, Bis(maltolato)oxovanadium (IV) (BMOV), to induce apoptosis in E7CH neurons. Thus BMOV (25 microM) killed 50% of E7CH neurons and B lymphocytes but not glial cells, or T-lymphocytes, suggesting the existence of a common apoptotic pathway in neurons and B-cells. We conclude that the major pathway for programmed cell death in embryonic chick neurons has many elements in common with that described for other cells but that there may be some unique aspects which can be used to protect embryonic neurons from opioid and other drug-enhanced apoptosis.

Androstadienes↗
PubMed2003

Loss of mitochondrial transmembrane potential and caspase-9 activation during apoptosis induced by the novel styryl-lactone goniothalamin in HL-60 leukemia cells.

Styryl-lactones such as goniothalamin represent a new class of compounds with potential anti-cancer properties. In this study, we investigated the mechanisms of goniothalamin (GTN), a plant styryl-lactone induced apoptosis in human promyelocytic leukemia HL-60 cells. This plant extract resulted in apoptosis in HL-60 cells as assessed by the externalisation of phosphatidylserine. Using the mitochondrial membrane dye (DIOC(6)) in conjunction with flow cytometry, we found that GTN treated HL-60 cells demonstrated a loss of mitochondrial transmembrane potential (Deltapsi(m)). Further immunoblotting on these cells showed activation of initiator caspase-9 and the executioner caspases-3 and -7. Pretreatment with the pharmacological caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.FMK) abrogated apoptosis as assessed by all of the apoptotic features in this study. In summary, our results demonstrate that goniothalamin-induced apoptosis occurs via the mitochondrial pathway in a caspase dependent manner.

Apoptosis↗
PubMed2002

Delayed ERK activation by ceramide reduces melanin synthesis in human melanocytes.

Sphingolipid metabolites regulate many aspects of cell growth and differentiation. However, the effects of sphingolipids on the growth and melanogenesis of human melanocytes are not known. In the present study, we investigated the effects of sphingolipid metabolites and the possible signalling pathways involved in human melanocytes. Our data show that C(2)-ceramide inhibits cell growth in a dose-dependent manner, whereas sphingosine-1-phosphate (SPP) has no effect. Moreover, we observed that the melanin content of the cells was significantly decreased by C(2)-ceramide. The pigmentation-inhibiting effect of C(2)-ceramide at 1-10 microM was stronger than that of kojic acid, tested at 1-100 microM. The tyrosinase activity of cell extracts was reduced by C(2)-ceramide treatment. However, in the cell-free system, C(2)-ceramide could not suppress tyrosinase, whereas kojic acid directly inhibited tyrosinase. These results suggest that C(2)-ceramide decreases the pigmentation of melanocytes indirectly regulating tyrosinase. Furthermore, we found that C(2)-ceramide decreased the protein expression of microphthalmia-associated transcription factor (MITF), which is required for tyrosinase expression. To identify the signalling pathway of ceramide, we studied the ability of C(2)-ceramide to influence extracellular signal-regulated protein kinase (ERK) and Akt/protein kinase B (PKB) activation. C(2)-ceramide induced a delayed activation of ERK ( > 1 h) and a much later activation of Akt/PKB ( > 3 h) in human melanocytes. In addition, the specific inhibition of the ERK and the Akt signalling pathways by PD98059 and LY294002, respectively, increased melanin synthesis. Thus, it seems that sustained ERK and Akt activation may lead to the suppression of cell growth and melanogenesis.

Adolescent↗
PubMed2003

Downregulation of NF-kappaB activation in human keratinocytes by melanogenic inhibitors.

BACKGROUND: Exposure of skin cells, particularly keratinocytes to various nuclear factor-kappaB (NF-kappaB) activators (e.g. tumor necrosis factor-alpha, interleukin-1, lipopolysaccharides, and ultraviolet light) leads to phosphorylation and degradation of the inhibitory protein, IkappaB. Liberated NF-kappaB is translocated into the nucleus where it can change or alter expression of target genes, resulting in the secretion of extracellular signaling molecules including melanotrophic factors affecting melanocyte. OBJECTIVE: In order to demonstrate the possible role of NF-kappaB activation on the synthesis of melanotrophic factors from the keratinocytes, the activities of NF-kappaB induced by melanogenic inhibitors (MIs) were determined in human HaCaT keratinocytes transfected with pNF-kappaB-SEAP-NPT plasmid. Transfectant cells released the secretory alkaline phosphatase (SEAP) as a transcription reporter in response to the NF-kappaB activity and contain the neomycin phosphotransferase (NPT) gene for the dominant selection marker for geneticin resistance. METHODS: MIs such as niacinamide, kojic acid, hydroquinone, resorcinol, arbutin, and glycolic acid were preincubated with transfectant HaCaT cells for 3 h and then ultraviolet B (UVB) was irradiated. NF-kappaB activation was measured with the SEAP reporter gene assay using a fluorescence detection method. RESULTS: Of the MIs tested, kojic acid (IC(50)=60 microM) was found to be the most potent inhibitor of UVB-upregulating NF-kappaB activation in transfectant HaCaT cells, which is followed by niacinamide (IC(50)=540 microM). Pretreatment of the transfectant HaCaT cells with the MIs, especially kojic acid and niacinamide, effectively lowered NF-kappaB binding measured by electrophoretic mobility shift assay. Furthermore, these two inhibitors remarkably reduced the secretion level of IL-6, one of melanotrophic factors, triggered by UV-radiation of the HaCaT cells. CONCLUSION: These observations suggest that MIs working at the in vivo level might act partially through the modulation of the synthesis of melanotrophic factors in keratinocyte.

Arbutin↗
PubMed2002

Molecular understanding of aluminum-induced topological changes in (CCG)12 triplet repeats: relevance to neurological disorders.

Recent studies have shown that gene mutations are involved in the pathology of neurological disorders. CCG repeats cause genetic instability and are localized at the 5' end of the non-coding regions of the FMR1 gene in fragile X syndrome. Our studies for the first time showed that aluminum (Al) levels were elevated in the serum samples of fragile X syndrome and also provide evidence for the interaction of aluminum with (CCG)12-repeats. Circular dichroism spectroscopic studies of (CCG)12 indicated B-DNA conformation and in the presence of Al (10(-5) M) CCG repeats attained Z-DNA conformation. Further spectroscopic studies, which included melting profiles, ethidium bromide binding patterns and interaction of Z-DNA specific polyclonal antibodies confirmed the Z-conformation in (CCG)12-repeats in the presence of Al (10(-5) M). It is interesting to mention that Al-induced Z-conformation is stable even after the total removal of Al from CCG by desferoximine, a chelating drug. This is the first report to proof the role of Al in modulating the DNA (CCG repeats) topology and this information provides a clue about the possible involvement of Al at a molecular level in neurological/neurodegenerative disorders.

Aluminum↗
PubMed2003

6-Alkyl, alkoxy, or alkylthio-substituted 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors.

A novel class of 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones possessing a central six-membered lactone (pyran-2-one) ring system, in conjunction with C-6 alkyl (Me, Et or i-Pr), alkoxy (OMe, OEt or O-i-Pr), and alkylthio (SMe, SEt or S-i-Pr) substituents, were designed for evaluation as selective COX-2 inhibitors.

Alkanes↗
PubMed2003

2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK).

6-aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC(50)=0.23 microM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. A multiple-parallel synthesis approach, employing Suzuki cross-coupling methodology, was utilised to prepare libraries of thiopyran-4-ones with a range of aromatic groups at the 3'- and 4'-positions on the thiopyran-4-one 6-aryl ring. Screening of the libraries resulted in the identification of 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones bearing naphthyl or benzo[b]thienyl substituents at the 4'-position, as potent DNA-PK inhibitors with IC(50) values in the 0.2-0.4 microM range.

Animals↗
PubMed1998

Benzothiopyran-4-one based reversible inhibitors of the human cytomegalovirus (HCMV) protease.

A novel class of CMV protease inhibitors based on a benzothiopyran-S,S-dioxide nucleus has been discovered. Enzyme kinetic data supports a reversible mode of inhibition for a representative member of this class, 2-(3-pyridyl-N-oxide)benzothiopyran-4-one-S,S-dioxide, 1. Experiments in the presence and absence of the disulfide reducing agent DTT suggest that the inhibition by 1 is not due to oxidative inactivation of the enzyme. Also presented are results of some SAR studies of the benzothiopyranone ring system.

Amino Acid Sequence↗
PubMed1999

4-hydroxy-5,6-dihydro-2H-pyran-2-ones.3. Bicyclic and hetero-aromatic ring systems as 3-position scaffolds to bind to S1' and S2' of the HIV-1 protease enzyme.

5,6-Dihydro-2H-pyran-2-ones are potent inhibitors of HIV-1 protease, which bind to the S1, S2, S1', and S2' pockets and have a unique binding mode with the catalytic aspartyl groups and the flap region of the enzyme. Efforts to explore 3-position heterocyclic scaffolds that bind to the S1' and S2' pockets have provided a number of selected analogs that display high HIV-1 protease inhibitory activity. reserved.

Binding Sites↗
PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety.

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.

Animals↗
PubMed1993

Conformationally constrained analogues of diacylglycerol (DAG)--II. Differential interaction of delta-lactones and gamma-lactones with protein kinase C (PK-C).

Starting with L- or D-tri-O-acetylglucal, the corresponding L- and D-isomers of 4-O-tetradecanoyl-2,3-dideoxyglucono-1,5-lactone (2a and 2b) were synthesized as rigid diacylglycerol (DAG) analogues. Consistent with results obtained previously with the equivalent L- and D-1,4-lactones (1a and 1b), the L-isomer (2a) was more potent in activating protein kinase C (PK-C) and inhibiting the binding of [3H]phorbol-12,13-dibutyrate to the enzyme's regulatory domain. In these experiments the difference in potency observed between the optical antipodes of the gluconolactones (2a and 2b) was greatly increased relative to the corresponding ribonolactones (1a and 1b). These results indicate that PK-C is more able to discriminate between optical antipodes, in favor of the L-isomer, as the lactone ring increases from five to six.

Binding Sites↗