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PubMed1996

Longimicins A-D: novel bioactive acetogenins from Asimina longifolia (annonaceae) and structure-activity relationships of asimicin type of annonaceous acetogenins.

Bioactivity-directed fractionation of the ethanol extract of Asimina longifolia led to the isolation of four novel bioactive annonaceous acetogenins: longimicins A-D (1-4). Compounds 1-4 represent the asimicin type of acetogenins; however, the locations of the adjacent bis-tetrahydrofuran (THF) ring moieties are shifted along the aliphatic chains compared to the known compounds of this type. They are the first examples among this type of acetogenins with the placements of the ring systems altered. Compounds 1-4 showed bioactivities in several bioassays, but they are less active than their structural isomers. Study of their structure-activity relationships (SAR) reveals that the position of the adjacent bis-THF ring moiety is essential for maximization of the bioactivities among these asimicin type annonaceous acetogenins.

Animals↗

PubMedDate not supplied

3,3',5'-Tri-O-methylpiceatannol and 4,3',5'-tri-O-methylpiceatannol: improvements over piceatannol in bioactivity.

Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) (NSC 365798) has recently been isolated and was subsequently synthesized for NCI tumor panel testing as a new antileukemic natural product from the seeds of Euphorbia lagascae. During the synthesis, a bioactive reaction mixture of several partially O-methylated piceatannol analogues was obtained. This mixture has now been maximized and subjected to bioactivity-directed fractionation, using brine shrimp lethality, to yield 3,3',5'-tri-O-methylpiceatannol (NSC 381281); this new compound has improved stability and better bioactivity in several systems than piceatannol itself. To confirm the structure, 5 was synthesized from vanillin. In addition, the isovanillin analogue, 4,3',5'-tri-O-methylpiceatannol (NSC 381864), another new compound, was synthesized and found to be bioactive.

Animals↗

PubMed2003

Bioactivation of clozapine by murine cardiac tissue in vivo and in vitro.

Clozapine, an atypical neuroleptic, undergoes bioactivation to a chemically reactive nitrenium ion. This has been implicated in the pathogenesis of clozapine-induced agranulocytosis. Clozapine also causes myocarditis and cardiomyopathy, the mechanisms of which are unknown. To investigate this, we have evaluated whether clozapine undergoes bioactivation by murine cardiac tissue, in comparison to hepatic tissue. Mice were administered clozapine (5 and 50 mg/kg i.p.), and the extent of covalent binding was assessed by Western blotting. There was an increase in irreversible binding of clozapine to several proteins, ranging in mass from 30 to 250 kDa in both hepatic and cardiac tissue. Bioactivation by hepatic and cardiac microsomes was assessed by LC/MS using glutathione to trap the intermediate. Metabolism of radiolabeled clozapine to a glutathionyl conjugate by liver and cardiac microsomes was 30.5 +/- 3.3 and 3.6 +/- 0.3% of the initial incubation concentration, respectively. Ketoconazole (20 muM), a P450 inhibitor, significantly reduced binding in both hepatic and cardiac microsomes to 6.2 +/- 0.2 and 0.5 +/- 0.06%, respectively. These data indicate that clozapine undergoes bioactivation in the heart to a chemically reactive nitrenium metabolite that may be important in the pathogenesis of myocarditis and cardiomyopathy observed in man.

Animals↗

PubMed2005

Bioactivation of 4-ipomeanol by CYP4B1: adduct characterization and evidence for an enedial intermediate.

4-Ipomeanol (IPO) is a pneumotoxin that is bioactivated to a reactive intermediate that binds to DNA and other cellular macromolecules. Despite over 30 years of research in this area, detailed structural information on the nature of the IPO reactive intermediate is still lacking. In the present study, we reacted IPO with rabbit CYP4B1 in the presence of exogenous nucleophiles and analyzed the products by liquid chromatography/electrospray ionization-mass spectrometry. Coincubation of IPO and rabbit CYP4B1 with glutathione gave rise to multiple products due likely to the presence of both sulfur and nitrogen nucleophiles in the same trapping molecule. Reaction mixtures containing equimolar N-acetyl cysteine (NAC) and N-acetyl lysine (NAL) provided a major NADPH- and CYP4B1-dependent product. A combination of high-resolution mass spectrometry and two-dimensional NMR analysis following large-scale isolation of the biologically derived material provided evidence for an N-substituted cysteinyl pyrrole derivative of IPO, analogous to that characterized previously in model chemical studies conducted with cis-2-butene-1,4-dial. Purified native rabbit lung CYP4B1 and purified recombinant rabbit CYP4B1 produced the trapped NAC/NAL-IPO pyrrole adduct at rates of 600-700 nmol/nmol P450/30 min. A panel of 14 commercially available recombinant human CYPs was also studied, and substantial rates of IPO bioactivation (>100 nmol/nmol/30 min) were observed with CYP1A2, CYP2C19, CYP2D6, and CYP3A4. These studies provide evidence for the formation of an enedial reactive intermediate during CYP-mediated IPO bioactivation, identify multiple human liver P450s capable of IPO bioactivation, and demonstrate that the same reactive intermediate is formed by both rabbit CYP4B1 and human P450s.

Acetylcysteine↗

PubMed2006

Human cytochrome p450 enzymes of importance for the bioactivation of methyleugenol to the proximate carcinogen 1'-hydroxymethyleugenol.

In vitro studies were performed to elucidate the human cytochrome P450 enzymes involved in the bioactivation of methyleugenol to its proximate carcinogen 1'-hydroxymethyleugenol. Incubations with Supersomes, expressing individual P450 enzymes to a high level, revealed that P450 1A2, 2A6, 2C9, 2C19, and 2D6 are intrinsically able to 1'-hydroxylate methyleugenol. An additional experiment with Gentest microsomes, expressing the same individual enzymes to roughly average liver levels, indicated that P450 1A2, 2C9, 2C19, and 2D6 contribute to methyleugenol 1'-hydroxylation in the human liver. A study, in which correlations between methyleugenol 1'-hydroxylation in human liver microsomes from 15 individuals and the conversion of enzyme specific substrates by the same microsomes were investigated, showed that P450 1A2 and P450 2C9 are important enzymes in the bioactivation of methyleugenol. This was confirmed in an inhibition study in which pooled human liver microsomes were incubated with methyleugenol in the presence and absence of enzyme specific inhibitors. Kinetic studies revealed that at physiologically relevant concentrations of methyleugenol P450 1A2 is the most important enzyme for bioactivation of methyleugenol in the human liver showing an enzyme efficiency (kcat/Km) that is approximately 30, 50, and > 50 times higher than the enzyme efficiencies of, respectively, P450 2C9, 2C19, and 2D6. Only when relatively higher methyleugenol concentrations are present P450 2C9 and P450 2C19 might contribute as well to the bioactivation of methyleugenol in the human liver. A 5-fold difference in activities was found between the 15 human liver microsomes of the correlation study (range, 0.89-4.30 nmol min(-1) nmol P450(-1)). Therefore, interindividual differences might cause variation in sensitivity toward methyleugenol. Especially lifestyle factors such as smoking (induces P450 1A) and the use of barbiturates (induces P450 2C) can increase the susceptibility for adverse effects of methyleugenol.

Aryl Hydrocarbon Hydroxylases↗

PubMed1998

A proposed bioactive conformation of peptide T.

The conformational profiles of Peptide T, (5-8)Peptide T, [Abu5](4-8)Peptide T and (4-8)Peptide T were computed independently to assess the geometrical characteristics of the bioactive conformation of Peptide T. The conformational profiles of the peptides were computed within the molecular mechanics framework using an effective dielectric constant of 80. The conformational space was thoroughly sampled using an iterative simulated annealing protocol. The bioactive conformation was assessed by pairwise cross comparisons of each of the unique low energy conformations found for each of the different analogs studied. After a putative bioactive conformation was selected, in order to further validate our hypothesis the conformational profile of the potent compound cyclo(Thr-Thr-Asn-Tyr-Thr-Asp) was computed and the putative bioactive conformation was found. The conformation exhibits a pseudo beta-turn involving the side chain of Thr5 and the carbonyl oxygen of Tyr7 forming a C12 ring.

Amino Acid Sequence↗

PubMed1999

Influence of sodium oxide content on bioactive glass properties.

The rate of in vivo degradation and level of bioactivity of bioactive glasses are composition dependent [1]. By altering bioactive glass composition, the rate of resorption can be controlled. The network connectivity of a glass can be used to predict various physical properties of the glass including its solubility and, hence, its bioactivity [2]. Glass solubility increases as network connectivity is reduced. Glasses in the soda-lime phosphosilicate system were studied. The initial choice of composition was based on phosphate content and low network connectivity. A systematic substitution of calcium oxide for sodium oxide on a molar basis was made in order to examine the influence of sodium oxide content on the glass properties while keeping the network connectivity constant. The glass transition temperature and the peak crystallization temperature were seen to decrease linearly with increasing sodium oxide content. Thermal expansion coefficient and glass density were also seen to be related to sodium oxide content. Preliminary in vitro biocompatibility studies revealed that the glasses of higher sodium oxide content were associated with a cytotoxic response. The measurement of media pH indicated that this cytotoxic effect was due to ion exchange reactions at the glass surface.

Journal Article↗

PubMed1999

Bioactivity and glycosylation of circulating prolactin in various physiological and pathological conditions.

Multiple posttranslational processes modify native PRL and result in the secretion of several PRL isoforms with different bioactivity. Since we observed that serum samples contain non-lactogenic substances able to interfere in Nb2 cell bioassay, in this study we extracted PRL molecules from sera of pregnant and non-pregnant normal adults, fetuses and patients with prolactinoma and evaluated the ability of partially purified PRL to stimulate Nb2 cell proliferation. The preliminary immunopurification of PRL samples, conferred good sensitivity and specificity to PRL biological assay. Whenever possible, bioactivity values were correlated with glycosylated-PRL levels (G-PRL), the major posttranslational modification known to reduce PRL bioactivity. The ratio of bioactive (B-) vs immunoreactive PRL (I-PRL) (B/I) in normal subjects was 0.9 +/- 0.1 (mean +/- SD), and not affected by TRH and sulpiride administration. PRL B/I ratio did not change during pregnancy, both in maternal (0.8 +/- 0.1) and fetal circulation (1.0 +/- 0.01). In patients with prolactinoma PRL B/I ratios (0.8 +/- 0.18) were in the normal range. However, in 2 women with microprolactinoma, with a clear discrepancy between high I-PRL levels and mild clinical features, a significantly reduced PRL B/I ratio was observed (0.51 +/- 0.08 and 0.52 +/- 0.1 respectively). Conversely, a woman with clear clinical features of hyperprolactinemia, but border-line elevated I-PRL levels had a PRL B/I ratio in the upper limit of normal range. No variation in G-PRL vs NG-PRL percentages was observed in all the cases studied. In conclusion, our data show that physiological and pathological conditions of hyperprolactinemia, including fetal life, are associated in the majority of cases, with the secretion of PRL molecules with unchanged mitogenic activity on Nb2 cells. Nb2 PRL bioassay may be an useful tool to explain the discrepancies between clinical features and immunoreactive PRL levels in some particular cases.

Adolescent↗

PubMed2001

Energy dispersive analysis (EDX) of a degradable bioactive-glass coating on Ti6Al4V in-vivo.

The bioactive-glass coating of metallic substrates provides a gradually degrading interface which can be used to favor the bony integration of the implant by the physiologic processes of bone turn-over and remodeling. Twelve New Zealand White rabbits, about 2700 g of weight, were operated by the sagittal insertion of a bioactive-glass coated plate of Ti6Al4V. Retrievals were performed at 4, 8 and 12 weeks. Undecalcified specimens were embedded in methyl-metacrylate and sectioned at 100 microns of thickness. Blocks were grinded and had an electroconductive coating to be examined by scanning electron microscopy (SEM), back scattering electron microscopy (BSEM) and X-ray energy dispersive spectroscopy microanalysis (EDX). EDX allows to evaluate quantitatively the gradual process of coating degradation. Areas of 200 microns in square were analyzed at the interface between bone and coating to determine their elemental composition. Silicon was the key marker for the presence of the glass. Morphological analysis confirms that a tight apposition with bone can be obtained by utilizing the bioactive glass coating of metal. Results of energy dispersive analysis support the mechanism of a gradual degradation of the bioactive glass coating and its integration with bone, since the presence of silicon can be documented within the newly formed bone after the coating has disappeared.

Journal Article↗

PubMed2002

Interaction between bioactive glasses and human dentin.

This study explores the interaction between bioactive glasses and dentin from extracted human teeth in simulated oral conditions. Bioactive glasses in the Na(2)O-CaO-P(2)O(5)-SiO(2) and MgO-CaO-P(2)O(5)-SiO(2) systems were prepared as polished disks. Teeth were prepared by grinding to expose dentin and etching with phosphoric acid. A layer of saliva was placed between the two, and the pair was secured with an elastic band and immersed in saliva at 37 degrees C for 5, 21 or 42 days. The bioactive glasses adhered to dentin, while controls showed no such interaction. A continuous interface between the bioactive glass and dentin was imaged using cryogenic-scanning electron microscopy (SEM). However, after alcohol dehydration and critical point drying, fracture occurred due to stresses from dentin shrinkage. SEM investigations showed a microstructurally different material at the fractured interface. Chemical analyses revealed that ions from the glass penetrated into the dentin and that the surface of the glass in contact with the dentin was modified. Microdiffractometry showed the presence of apatite at the interface. Bonding appears to be due to an affinity of collagen for the glass surface and chemical interaction between the dentin and glass, leading to apatite formation at the interface.

Journal Article↗

PubMed2002

Mechanical properties of biodegradable polymer sutures coated with bioactive glass.

Combining commercially available Polyglactin 910 (Vicryl) sutures with bioactive glass powder offers new possibilities for application of composite materials in tissue engineering. Commercial bioactive glass (45S5 Bioglass) powder was used to coat Vicryl sutures and the tensile strength of the sutures was tested before and after immersion in simulated body fluid (SBF) as a means to assess the effect of the bioactive glass coating on suture degradation. Different gauge lengths (126.6 and 111.6 mm) and strain rates (2.54, 11.4 and 25.4 mm/min) were tested. The tensile strength of composite sutures was slightly lower than that of as-received Vicryl sutures (404 MPa versus 463 MPa). However after 28 days immersion in SBF the residual tensile strength of the coated sutures was significantly higher, indicating a protective function of the Bioglass coating. The tensile strength results were similar for the different gauge lengths and strain rates investigated. A qualitative explanation for the effect of bioactive glass coating on polymer degradation is offered.

Journal Article↗

PubMed1997

Evaluation of in vitro bioactivity and biocompatibility of Bioglass-reinforced polyethylene composite.

The bioactivity and biocompatibility of Bioglass-reinforced high-density polyethylene composite (Bioglass/HDPE) have been evaluated in simulated body fluid (SBF) and by in vitro cell culture, respectively. The formation of a biologically active hydroxy-carbonate apatite (HCA) layer on the composite surface after immersion in SBF was demonstrated by thin-film X-ray diffraction, infrared spectroscopy and scanning electron microscopy, indicating the in vitro bioactivity of Bioglass/HDPE composites. The HCA layer was formed on the 40 vol% composite surface within 3 days immersion in SBF at a formation rate comparable to those on bioactive glass-ceramics, showing that in vitro bioactivity could be obtained in a composite. Furthermore, the composite was biocompatible to primary human osteoblast-like cells. In comparison with unfilled HDPE and tissue culture plastic control, a significant increase in cellular metabolic activity was found on the composite. Therefore, Bioglass/HDPE composites have a promising biological response as a potential implant material.

Journal Article↗

PubMed2002

Novel starch thermoplastic/Bioglass composites: mechanical properties, degradation behavior and in-vitro bioactivity.

The present research aims to evaluate the possibility of creating new degradable, stiff and highly bioactive composites based on a biodegradable thermoplastic starch-based polymeric blend and a Bioglass filler. Such combination should allow for the development of bioactive and degradable composites with a great potential for a range of temporary applications. A blend of starch with ethylene-vinyl alcohol copolymer (SEVA-C) was reinforced with a 45S5 Bioglass powder presenting a granulometric distribution between 38 and 53 microm. Composites with 10 and 40 wt % of 45S5 Bioglass were compounded by twin-screw extrusion (TSE) and subsequently injection molded under optimized conditions. The mechanical properties of the composites were evaluated by tensile testing, and their bioactivity assessed by immersion in a simulated body fluid (SBF) for different periods of time. The biodegradability of these composites was also monitored after several immersion periods in an isotonic saline solution. The tensile tests results obtained indicated that SEVA-C/Bioglass composites present a slightly higher stiffness and strength (a modulus of 3.8 GPa and UTS of 38.6 MPa) than previously developed SEVA-C/Hydroxylapatite (HA) composites. The bioactivity of SEVA-C composites becomes relevant for 45S5 amounts of only 10 wt %. This was observed by scanning electron microscopy (SEM) and confirmed for immersion periods up to 30 days by both thin-film X-ray diffraction (TF-XRD) (where HA typical peaks are clearly observed) and induced coupled plasma emission (ICP) spectroscopy used to follow the elemental composition of the SBF as function of time. Additionally, it was observed that the composites are biodegradable being the results correlated with the correspondent materials composition.

Journal Article↗

PubMed1991

The paradoxical effects of somatostatin on the bioactivity and production of cytotoxins derived from human peripheral blood mononuclear cells.

Somatostatin (SMS), a naturally occurring peptide is known to inhibit the production of certain protein molecules and to diminish the ability of peripheral blood mononuclear cells to proliferate. We tested the effects of three forms of SMS on the bioactivity of both lymphotoxin (LT) and tumour necrosis factor (TNF). We also tested the effects of these agents on production of cytotoxins by peripheral blood mononuclear cells. We found the 28 amino acid form of SMS significantly enhanced the bioactivity of both LT and TNF (10(-9) M concentration) when tested in mouse L cells. The 14 amino acid form of SMS enhanced LT (10(-9) M concentration) activity but not TNF activity. The first 14 amino acid form of SMS-28 (amino terminal) did not affect bioactivity of the cytotoxin. In contrast, the naturally occurring 14 amino acid form of SMS (10(-8) M concentration) significantly diminished production of cytotoxin by human peripheral blood mononuclear cells. Cytotoxin produced by the latter was shown to be a combination of both LT and TNF. Similarly after SMS exposure, the cytotoxin produced remained a mixture of LT and TNF in roughly similar proportions. It thus appears that certain forms of SMS can enhance the bioactivity of cytotoxins, but at the same time decrease the production of these cytotoxins.

Cytotoxicity, Immunologic↗

PubMed2003

Site-specific PEGylation of a lysine-deficient TNF-alpha with full bioactivity.

Addition of polyethylene glycol to protein (PEGylation) to improve stability and other characteristics is mostly nonspecific and may occur at all lysine residues, some of which may be within or near an active site. Resultant PEGylated proteins are heterogeneous and can show markedly lower bioactivity. We attempted to develop a strategy for site-specific mono-PEGylation using tumor necrosis factor-alpha (TNF-alpha). We prepared phage libraries expressing TNF-alpha mutants in which all the lysine residues were replaced with other amino acids. A fully bioactive lysine-deficient mutant TNF-alpha (mTNF-alpha-Lys(-)) was isolated by panning against TNF-alpha-neutralizing antibody despite reports that some lysine residues were essential for its bioactivity. mTNF-alpha-Lys(-) was site-specifically mono-PEGylated at its N terminus. This mono-PEGylated mTNF-alpha-Lys(-), with superior molecular uniformity, showed higher bioactivity in vitro and greater antitumor therapeutic potency than randomly mono-PEGylated wild-type TNF-alpha. These results suggest the usefulness of the phage display system for creating functional mutant proteins and of our site-specific PEGylation approach.

Animals↗

PubMed1985

Participation of cellular thiol/disulphide groups in the uptake, degradation and bioactivity of insulin in primary cultures of rat hepatocytes.

The effects on the uptake (cell-associated 125I) and degradation (125I-labelled products released into the medium) of 125I-insulin and bioactivity (protein, glycogen and lipid synthesis) of insulin caused by altering the cellular thiol/disulphide status in primary cultures of rat hepatocytes were studied. Incubation of hepatocyte cultures with various exogenous thiol compounds (reduced glutathione, 2-mercaptoethanol, cysteamine, dithiothreitol) resulted in increased insulin binding, but markedly decreased degradation and bioactivity. These effects could be reversed by washing or by the addition of oxidized glutathione, which alone had no effect. When cultures were exposed to certain thiol-modifying reagents (N-ethylmaleimide, p-chloromercuribenzoate, p-chloromercuribenzenesulphonate, iodoacetamide, iodoacetate), some decreases in bioactivity were evident, but the pronounced decrease in insulin degradation observed with the thiol-containing compounds was not observed with this class of compounds. None of the thiol-containing or -modifying agents tested had any significant effect on cellular ATP concentrations, indicating that the effects observed were due to perturbation of the thiol/disulphide status. Depletion of intracellular glutathione by DL-buthionine SR-sulphoximine (a specific inhibitor of glutathionine biosynthesis) decreased the syntheses of glycogen and lipid by about one-half, while having essentially no effect on protein synthesis, ATP concentrations or on the binding and degradation of insulin. The data presented here indicate that although intracellular thiol (glutathione) concentrations may be important for the maintenance of full expression of certain biological activities (glycogen and lipid synthesis), the thiol/disulphide groups on the cell surface and those immediately inside the cell membrane may be more critical in the mediation of insulin action, including the degradation and bioactivity of insulin in primary cultures of rat hepatocytes.

Animals↗

PubMed2000

Local bioactive tumour necrosis factor (TNF) in corneal allotransplantation.

The aim of this study was to examine the kinetic profile of bioactive TNF levels in aqueous humour of rabbit eyes undergoing corneal allograft rejection and to investigate the effect of locally blocking TNF activity after corneal transplantation. In a rabbit corneal transplantation, endothelial allograft rejection was identified and correlated with increase in central graft thickness. Samples of aqueous humour obtained on alternate days following transplantation were tested for TNF mRNA and bioactive TNF protein. To investigate the effect of locally blocking TNF activity in allograft recipients, the fusion protein TNFR-Ig was administered by injections into the anterior chamber after transplantation. Pulsatile increases in levels of this cytokine were found in 14 of 15 allograft recipients. Peaks of TNF bioactivity preceded by varying intervals the observed onset of rejection in allograft recipients. TNF levels were not elevated in aqueous humour from corneal autograft recipient controls or in serum of allografted animals. mRNA levels were elevated before onset of and during clinically observed allograft rejection. In three of seven animals receiving TNFR-Ig injections on alternate days from day 8 to day 16 post-transplant, clear prolongation of corneal allograft survival was demonstrated. Bioactive TNF is present in aqueous humour following rabbit corneal allotransplantation. Rather than correlating directly with endothelial rejection onset, pulsatile peak levels of TNF precede and follow the observed onset of endothelial rejection. Blockade of TNF activity prolongs corneal allograft survival in some animals, indicating that this cytokine may be a suitable target in local therapy of corneal allograft rejection.

Animals↗

PubMed2003

Apatite formation on dental ceramics modified by a bioactive glass.

Restorative dental materials are considered biocompatible without exhibiting any bioactive behaviour. The aim of this study was the investigation of surface structure changes on conventional dental ceramics used in metal-ceramic restorations modified by a bioactive glass, after immersion in SBF for various time periods. Bioactive glass powder was mixed with porcelain powder with three different weight ratios: 1:1, 1:2, and 2:1. The two powders were mixed with porcelain modelling liquid and the mixture was transferred and spread on the surface of pre-fabricated ceramic disks. Coated ceramic specimens after being exposed to a specific thermal cycle as it is recommended for dental ceramics were soaked in Simulated Body Fluid (SBF) at 37 degrees C for various periods of time. After soaking, specimens were studied using Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS). Results revealed the development of a non-stoichiometric, biological apatite layer on their surface after exposure in SBF for several time periods. The onset of apatite-layer formation is directly dependent on the amount of bioglass in the coating and its thickness reduces within the specimens of the same bioactive glass-porcelain proportion with time, reaching an average thickness of 15 microm at the longest immersion time, for all the specimens.

Apatites↗