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PubMed2007

Cell/surface interactions and adhesion on bioactive glass 45S5.

This paper examines the effects of surface texture (smooth versus rough) on cell/surface interactions on the bioactive glass, 45S5. The cell surface interactions associated with cell spreading are studied using cell culture experiments. Subsequent energy dispersive x-ray spectroscopy is also used to reveal the distributions of calcium, phosphorous, sodium and oxygen on the surfaces of the bioactive glasses. The implications of the results are then discussed for the applications of textured bioactive glasses in medicine.

3T3 Cells↗

PubMed1989

Bone resorption and circulating PTH-like bioactivity in an animal model of hypercalcaemia of malignancy.

An in vivo model of humoral hypercalcaemia of malignancy has been used to examine the role of circulating PTH-like bioactivity in the development of bone resorption and hypercalcaemia. After inoculation of cells from a renal carcinoma cell line into nude mice, circulating PTH-like bioactivity as measured by the sensitive renal and metatarsal cytochemical bioassays for PTH was elevated in only 18% and 53% of the mice respectively. Bone resorption was elevated in all the mice investigated irrespective of the level of PTH-like bioactivity. Thus, in this model, while the circulating PTH-like moiety is more potent when acting on bone, it did not correlate with the degree of bone resorption suggesting that it may not be the sole cause of the hypercalcaemia.

Animals↗

PubMed1988

Nephrotoxicity of mercapturic acids of three structurally related 2,2-difluoroethylenes in the rat. Indications for different bioactivation mechanisms.

The biotransformation and the hepato- and nephrotoxicity of the mercapturic acids (N-acetyl-1-cysteine S-conjugates) of three structurally related 2,2-difluoroethylenes were investigated in vivo in the rat. All mercapturic acids appeared to cause nephrotoxicity, without any measureable effect on the liver. The mercapturic acid of tetrafluoroethylene (TFE-NAC) appeared to be the most potent nephrotoxin, causing toxicity upon an i.p. dose of 50 mumol/kg. The mercapturic acids of 1,1-dichloro-2,2-difluoroethylene (DCDFE-NAC) and 1,1-dibromo-2,2-difluoroethylene (DBDFE-NAC) were nephrotoxic at slightly higher doses, i.e. at 75 and 100 mumol/kg, respectively. In the urine of TFE-NAC-treated rats significant amounts of difluoroacetic acid (DFAA) could be detected. With increasing doses, the relative amount of DFAA in urine increased progressively (5-18% of dose). In urine of rats treated with DCDFE-NAC and DBDFE-NAC, however, the corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected. Formation of DFAA and pyruvate could also be observed during in vitro metabolism of the cysteine conjugate of tetrafluoroethylene (TFE-CYS) by rat renal cytosol. Inhibition by aminooxyacetic acid (AOA) pointed to a beta-lyase dependency for the DFAA-formation. Next to DFAA and pyruvate, also formation of hydrogen sulfide and thiosulfate could be detected. These results suggest that TFE-CYS is bioactivated to a significant extent to difluorothionacyl fluoride, which most likely is subsequently hydrolysed to difluorothio(no)acetic acid and difluoroacetic acid. According to formation of pyruvate, the cysteine conjugates derived from DCDFE-NAC and DBDFE-NAC also were efficiently metabolized by rat renal beta-lyase. However, the formation of corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected in vitro at all. Only very small amounts of hydrogen sulfide and thiosulfate were detected. These results suggest that bioactivation of the latter two conjugates to a dichloro- or dibromothionoacyl fluoride represents only a minor route. Because of better leaving group abilities of chloride and bromide compared to fluoride, rearrangement of the initially formed ethanethiol to a thiirane might be favoured. Based on the present in vivo and in vitro data, it is concluded that the nephrotoxicity of the structurally related mercapturic acids of 2,2-difluoroethylenes is dependent on halogen substitution and presumably the result of at least two different mechanisms of bioactivation.

Acetylcysteine↗

PubMed1995

Bioactivation of nitroglycerin in vascular smooth muscle cells is different from that in non-vascular tissue.

The mechanism of biotransformation of nitroglycerin into the pharmacologically active radical nitric oxide (NO) or a related compound is still unclear. Different enzymes have been discussed to be involved in the bioactivation process. The effects of inhibition of glutathione-S-transferase and cytochrome P-450 enzymes were investigated on nitroglycerin-induced relaxation of bovine and porcine coronary arteries and on nitroglycerin-induced activation of guanylyl cyclase in cultivated porcine aortic smooth muscle cells. The glutathione-S-transferase inhibitor sulfobromophthalein had no effect on nitroglycerin-induced vascular relaxation, nor on nitroglycerin-induced elevation of cGMP levels in porcine coronary artery smooth muscle cells. The modulation of cytochrome P-450 activity by selective inhibitors as well as inducers did not alter the bioactivity of nitroglycerin in both systems. The data demonstrate that the isoenzymes of both enzyme families, which have been shown to be involved in the metabolism of nitroglycerin in different non-vascular tissues, do not play a role in bioactivation of nitroglycerin in the vascular system.

Animals↗

PubMed1989

Granulosa cell aromatase bioassay: changes of bioactive FSH levels in the female.

Some modified forms of follicle-stimulating hormone (FSH) may not cross react with the FSH antibody used in the radioimmunoassay (RIA), but still retain their biological activities. Therefore, estimates of immunoreactive FSH may not correspond with FSH bioactivity. The use of in vitro FSH bioassays may disclose possible roles of these heterogenous forms in vivo under various conditions. This review will focus on the history of FSH bioassays, and the widely used in vivo Steelman and Pohley bioassay, based on ovarian weight increase after injection into female rats, is discussed. Since 1971 different biological activities of FSH in various target tissues have been used for the in vitro estimates of FSH bioactivity. The aromatase bioassays involve the measurement of oestradiol in medium of FSH treated Sertoli cells or granulosa cells in culture. Estimates of FSH bioactivity, using the rat granulosa cell bioassay, in serum and urine or normally cycling women, during gonadotropin-releasing hormone-antagonist treatment in hypergonadotropic hypogonadal women and during different stages of female pubertal development will be discussed in more detail.

Animals↗

PubMed1996

Differential effect of adrenocorticosteroids on 11 beta-hydroxysteroid dehydrogenase bioactivity at the anterior pituitary and hypothalamus in rats.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) is a microsomal enzyme that catalyzes the dehydrogenation of cortisol (F) to cortisone (E) in man and corticosterone (B) to 11-dehydrocorticosterone (A) in rats. 11 beta-OHSD has been identified in a wide variety of tissues. The differential distribution of 11 beta-OHSD suggests that this enzyme has locally defined functions that vary from region to region. The aim of this study was to investigate the effects of the glucocorticoids B and dexamethasone (DM), the mineralocorticoid deoxycorticosterone (DOC), and the inhibitors of 11 beta-OHSD glycyrrhizic acid (Gl) and glycyrrhetinic acid (GE) on 11 beta-OHSD bioactivity at the hypothalamus (HT) and anterior pituitary (AP). Male Wistar rats were treated with GI or were adrenalectomized (ADX) and treated with either B, DM, or DOC for 7 days. All treatments were in vivo except GE, which was used in vitro. At the end of treatment, homogenates of HT and AP were assayed for 11 beta-OHSD bioactivity, expressed as the percentage conversion of B to A in the presence of NADP, 11 beta-OHSD bioactivity is significantly higher (P < 0.0001) in the AP compared with the HT. Adrenalectomy significantly increased the enzyme activity in the AP (P < 0.05), an effect reversed by B or DM. ADX rats treated with DOC showed decreased enzyme activity in the AP (P < 0.001) but increased the activity in the HT (P < 0.0001). Gl increased activity in both HT and AP, whereas GE decreased activity significantly. We conclude that the modulation of 11 beta-OHSD is both steroid specific and tissue specific.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1984

Profenofos insecticide bioactivation in relation to antidote action and the stereospecificity of acetylcholinesterase inhibition, reactivation, and aging.

Poisoning signs in chicks administered the organophosphorus insecticide profenofos correlated with in vivo inhibition of brain acetylcholinesterase (AChE) activity. Mixtures of atropine with eserine, pyridinium oximes, or the bispyridinium compound SAD-128 increased the LD50 of coadministered profenofos by up to sevenfold in chicks and fourfold in mice. Atropine and the oximes were less effective as profenofos antidotes, indicating that profenofos-inhibited AChE may undergo rapid aging. Brain AChE from chicks poisoned with profenofos was not reactivated by pralidoxime methanesulfonate, although it was from chicks poisoned with the phosphoramidothiolate, methamidophos. Similarly, eel AChE, inhibited in vitro by bioactivated (-)-profenofos, the most toxic isomer, did not reactivate in contrast to that inhibited by methamidophos, nonbioactivated (-)-profenofos, and (+)-profenofos, with or without bioactivation. It appears that the action of eserine and possibly SAD-128 was due to protecting AChE or cholinergic receptors from profenofos or bioactivated profenofos and that oximes may work in the same way rather than as reactivators due to rapid aging of the inhibited AChE.

Aging↗

PubMed1989

Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and alpha-phenyl-N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase.

Teratogenicity of the anticonvulsant drug phenytoin is thought to involve its bioactivation by cytochromes P-450 to a reactive arene oxide intermediate. We hypothesized that phenytoin also may be bioactivated to a teratogenic free radical intermediate by another enzymatic system, prostaglandin synthetase. To evaluate the teratogenic contribution of this latter pathway, an irreversible inhibitor of prostaglandin synthetase, acetylsalicylic acid (ASA), 10 mg/kg intraperitoneally (ip), was administered to pregnant CD-1 mice at 9:00 AM on Gestational Days 12 and 13, 2 hr before phenytoin, 65 mg/kg ip. Other groups were pretreated 2 hr prior to phenytoin administration with either the antioxidant caffeic acid or the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). Caffeic acid and PBN were given ip in doses that respectively were up to 1.0 to 0.05 molar equivalents to the dose of phenytoin. Dams were killed on Day 19 and the fetuses were assessed for teratologic anomalies. A similar study evaluated the effect of ASA on the in vivo covalent binding of radiolabeled phenytoin administered on Day 12, in which case dams were killed 24 hr later on Day 13. ASA pretreatment produced a 50% reduction in the incidence of fetal cleft palates induced by phenytoin (p less than 0.05), without significantly altering the incidence of resorptions or mean fetal body weight. Pretreatment with either caffeic acid or PBN resulted in dose-related decreases in the incidence of fetal cleft palates produced by phenytoin, with maximal respective reductions of 71 and 82% at the highest doses of caffeic acid and PBN (p less than 0.05). Caffeic acid and PBN also significantly reduced the incidence of fetal resorptions produced by phenytoin, but not the fetal weight loss. In viable embryos, ASA pretreatment reduced the covalent binding of phenytoin to embryonic protein by 43% (p less than 0.05). Binding of phenytoin to embryonic resorptions was equally high with and without ASA pretreatment, and within each treatment group was 3- to 10-fold higher than that in the respective placentas and associated viable embryos (p less than 0.05). These results suggest that prostaglandin synthetase may contribute to the enzymatic bioactivation of phenytoin to a teratogenic free radical intermediate.

Abnormalities, Drug-Induced↗

PubMed1991

Isolation of a mercapturate adduct produced subsequent to glutathione conjugation of bioactivated 3-methylindole.

Bioactivation of the pneumotoxin 3-methylindole (3MI) to a methylene imine intermediate has been demonstrated previously by trapping the electrophile with glutathione in goat lung microsomal incubations. To determine whether the same bioactivation process occurs in whole animals, 3MI was administered to goats, mice, and rats, and the urinary metabolites from these three species were analyzed by HPLC for the presence of the mercapturate that would be expected as the processed and excreted form of the 3MI-glutathione adduct. The mercapturate, 3-[(N-acetylcysteine-S-yl)-methyl]indole (3MI-NAC), was identified in the urine from all three species and was isolated from rat urine for structural identification by uv, NMR, and mass spectrometry. Synthetic 3MI-NAC had uv, NMR, and chromatographic characteristics identical to the isolated metabolite. The presence of this mercapturate in the urine of treated animals unequivocally demonstrates that 3MI is bioactivated to the methylene imine in vivo and that the glutathione adduct is also formed, presumably to detoxify the methylene imine.

Acetylcysteine↗

PubMed1994

Analysis of surface layers on bioactive glasses.

FT-Raman spectroscopy proves to be a powerful technique to study surface reactions on bioactive glasses and it eliminates the fluorescence of the organic phase of whole bone, thereby making it possible to compare the reaction layers formed on bioactive glasses with the mineral phase of bone. The spectrum of hydroxycarbonate apatite (HCA) developed on the bioactive glasses is closer to that of bone than synthetic hydroxyapatite (HA) and closely matches that of bone mineral obtained by deproteination of whole human femoral cortical bone.

Apatites↗

PubMed1996

Protection by coffee against somatic genotoxicity in Drosophila: role of bioactivation capacity.

The protective effects of coffee against somatic mutation and mitotic recombination induced by cyclophosphamide (CPH), mitomycin C (MMC) and urethane (URE) were evaluated in the standard (ST) and high bioactivation (HB) crosses of the wing spot test in Drosophila melanogaster. These two crosses are characterized by different constitutive levels of cytochrome )-450-dependent enzyme activities. 3-day old larvae transheterozygous for the wing cell markers mwh (multiple wing hairs) and flr3 (flare3) were fed until pupation on medium containing a genotoxin alone or its combination with different concentrations of instant coffee. subsequently, the wings of the resulting adult flies were analysed for detecting single spots (mwh or flr3) originating from mutational or recombinational events as well as twin spots (mwh and flr3) originating exclusively from recombination. The results showed high sensitivity of the HB cross to URE. Co-administration of instant coffee was effective in exerting significant dose-related inhibitory effects on the genotoxicity of URE in the ST and the genetically susceptible HB cross. Similarly, coffee showed significant dose-related inhibitory effects on the genotoxicity of MMC in both crosses. The same protective effect was also observed with one concentration of coffee in combination with CPH. Pretreatment of 2-day-old HB larvae with coffee for 24 hr followed by treatment with URE was also effective in significantly reducing the induction of mutation and recombination. The magnitude of the protective effects of coffee against these three genotoxins was independent of the genotype of the larvae used for treatment, that is it was independent of the bioactivation capacity of these larvae. The study demonstrates the suitability of this assay for obtaining qualitative and quantitative data on the result of interactions among a genotoxin, an inhibitor of genotoxicity and bioactivation capacity of the host.

Animals↗

PubMedDate not supplied

Aging and eliciting agents: effect on murine peritoneal macrophage monokine bioactivity.

Decreased responsiveness of the aged to infection may be associated with a decline in monokine production. Prior studies in macrophages have used different eliciting agents, and results have varied. We assessed the effect of age on interleukin-1 (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6) in unelicited, thioglycollate (TG)-elicited, and complete Freund's adjuvant (CFA)-elicited peritoneal macrophages. Resident macrophages or CFA-elicited macrophages from middle aged or aged mice produced significantly less monokine bioactivity than resident or CFA-elicited macrophages from young mice. Monokine bioactivity from TG-elicited macrophages from aged and middle aged mice was significantly increased when compared with macrophages of young mice. Eliciting agents may alter macrophage populations and interactions with other cells leading to changes in monokine bioactivity with aging.

Aging↗

PubMedDate not supplied

TCDD alters pituitary-adrenal function. II: Evidence for decreased bioactivity of ACTH.

The present study assessed the ability of primary cultures of rat anterior pituitary cells to secrete bioactive ACTH in the presence of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). The bioactivity of the secreted pituitary cell ACTH was determined by its ability to stimulate secretion of corticosterone from primary cultures of rat adrenal cells. ACTH from basal or CRH stimulated pituitary cells treated with TCDD was found to be less capable of stimulating corticosterone secretion from primary rat adrenal cell cultures than equimolar concentrations of ACTH purchased from a commercial supplier. Corticosterone secretion from adrenal cell cultures treated with ACTH from basal or CRH stimulated pituitary cell cultures exposed to TCDD was decreased by 60 and 70%, respectively. The decreased ability to stimulate corticosterone secretion can be overcome when extracts of ACTH from pituitary cell cultures treated with TCDD are supplemented with commercial ACTH. These findings indicate that TCDD may alter the bioactivity of secreted ACTH from the anterior pituitary gland.

Adrenal Glands↗

PubMed2006

The in vitro bioactivity of two novel hydrophilic, partially degradable bone cements.

Composite bone cements were prepared with bioactive glasses (MgO-SiO(2)-3CaO.P(2)O(5)) of different reactivities. The matrix of these so-called hydrophilic, partially degradable and bioactive cements was composed of a starch/cellulose acetate blend and poly(2-hydroxyethyl methacrylate). The addition of 30 wt.% of glasses to this system made them bioactive in acellular medium: a dense apatite layer formed on the surface after 7 days of immersion in simulated body fluid. This was demonstrated both by microscopic and infrared spectroscopic techniques. The composition of the glass and, consequently, its structure was found to have important effects on the rate of the apatite formation. The combination of reactivity obtained by one formulation with the hydrophilic and degradable character of these cements makes them a very promising alternative to conventional acrylic bone cements, by allowing a better stabilization of the implant and a stronger adhesion to the bone.

Apatites↗

PubMed2004

Nodule formation and mineralisation of human primary osteoblasts cultured on a porous bioactive glass scaffold.

The aim of this study was to analyse human osteoblast responses to a porous bioactive glass scaffold. It was hypothesised that osteoblasts would attach, proliferate and form mineralised nodules in response to culture on the bioactive glass. As dissolution products are a key feature of bioactive glasses, this was measured by inductively coupled plasma optical emission spectroscopy to determine effects of both the glass surface and ion release. Osteoblasts attached and proliferated on the foams as demonstrated by scanning electron microscopy. Nodule formation was also observed in the pores of the glass and also in conditioned medium containing dissolution products at certain concentrations and these nodules were shown to be mineralised by alizarin red staining. Undiluted dissolution products from the foams however caused significant apoptosis suggesting an ion concentration dependent response.

Apoptosis↗

PubMed2004

Fabrication and characterization of bioactive wollastonite/PHBV composite scaffolds.

Composite scaffolds of polyhydroxybutyrate-polyhydroxyvalerate (PHBV) with bioactive wollastonite were fabricated by a compression moulding, thermal processing, and salt particulate leaching method. Structure and mechanical properties of the scaffolds were determined. The bioactivity of the composites was evaluated by soaking in a simulated body fluid (SBF), and the formation of the hydroxyapatite (HAp) layer was determined by Scanning Electron Microscope (SEM) and Energy-Dispersive Spectrometer (EDS). The results showed that the wollastonite/PHBV composites were bioactive as it induced the formation of HAp on the surface of the composite scaffolds after soaking in SBF for 14 days. In addition, the measurements of the water contact angles suggested that incorporation of wollastonite into PHBV could improve the hydrophilicity of the composites and the enhancement was dependent on the wollastonite content. Furthermore, the pH and ion concentration changes of SBF solutions with composite scaffolds showed that the composites released Ca and Si ions, which could neutralize the acidic by-products of the PHBV and stabilize the pH of the SBF solutions between 7.2 and 7.8 within a 3-week soaking period. All of these results suggest that the incorporation of wollastonite was a useful approach to obtain composite scaffolds with improved properties.

Biocompatible Materials↗

PubMed2004

Strong and bioactive composites containing nano-silica-fused whiskers for bone repair.

Self-hardening calcium phosphate cement (CPC) sets to form hydroxyapatite with high osteoconductivity, but its brittleness and low strength limit its use to only non-stress bearing locations. Previous studies developed bioactive composites containing hydroxyapatite fillers in Bis-GMA-based composites for bone repair applications, and they possessed higher strength values. However, these strengths were still lower than the strength of cortical bone. The aim of this study was to develop strong and bioactive composites by combining CPC fillers with nano-silica-fused whiskers in a resin matrix, and to characterize the mechanical properties and cell response. Silica particles were fused to silicon carbide whiskers to roughen the whisker surfaces for enhanced retention in the matrix. Mass ratios of whisker:CPC of 1:2, 1:1 and 2:1 were incorporated into a Bis-GMA-based resin and hardened by two-part chemical curing. Composite with only CPC fillers without whiskers served as a control. The specimens were tested using three-point flexure and nano-indentation. Composites with whisker:CPC ratios of 2:1 and 1:1 had flexural strengths (mean+/-SD; n=9) of (164+/-14) MPa and (139+/-22) MPa, respectively, nearly 3 times higher than (54+/-5) MPa of the control containing only CPC fillers (p<0.05). The strength of the new whisker-CPC composites was 3 times higher than the strength achieved in previous studies for conventional bioactive composites containing hydroxyapatite particles in Bis-GMA-based resins. The mechanical properties of the CPC-whisker composites nearly matched those of cortical bone and trabecular bone. Osteoblast-like cell adhesion, proliferation and viability were equivalent on the non-whisker control containing only CPC fillers, on the whisker composite at whisker:CPC of 1:1, and on the tissue culture polystyrene control, suggesting that the new CPC-whisker composite was non-cytotoxic.

3T3 Cells↗

PubMed2005

Synthesis, bioactivity and specificity of glucagon-like peptide-1 (7-37)/polymer conjugate to isolated rat islets.

In order to increase the functionality of islets encapsulated in a biohybrid artificial pancreas (BAP), it was proposed that co-encapsulation with insulinotropic agents would improve insulin secretion from islets. To prevent agents from leaking out, conjugation with high-molecular-weight polymers was inevitable. In this study, synthetic glucagon-like peptide-1 (GLP-1) (7-37) was conjugated to a water-soluble polymer, poly(N-vinyl-2-pyrroridone-co-acrylic acid) (5 mol% acrylic acid, M(w) 445 kDa), via poly(ethylene glycol, M(w) 3.4 kDa) spacer. The chemical conjugation was confirmed by reverse phase-HPLC and the GLP-1 content in the GLP-1/polymer conjugate (VAPG) was determined by UV spectrophotometry at 280 nm (ca. 29 wt/wt%). In a static insulin secretion test, the VAPG increased insulin secretion up to 200% over a control (no stimulation) at high glucose levels, although the insulinotropic activity of VAPG was slightly lower than that of native GLP-1. The bioactivity of VAPG was prolonged for at least 2 weeks, which was examined by co-encapsulation of the conjugate into islet microcapsules. Dose-response curve revealed that the half-maximal effective dose (ED(50)) of VAPG was about 55 nm (25 nm for native GLP-1). By N-terminal analysis using aminopeptidase and RP-HPLC, it was confirmed that the lowered bioactivity of VAPG stemmed from the polymer conjugation to N-terminal histidine moieties, which actively participate in binding to GLP-1 receptors, resulting in only 16% of N-terminal histidine remaining intact after the conjugation reaction. Finally, the specific interaction of the VAPG with isolated rat islets was investigated. Total cellular cyclic AMP levels were measured and confocal microscopy was conducted using GLP-1 and VAPG labeled with fluorescent probes. It was found that VAPG effectively increased the cAMP level in islet cells in a glucose concentration-dependent manner. Moreover, the confocal microscopy study showed that the binding of VAPG occurs at the same location where GLP-1 binds but with less affinity than that of native GLP-1. In summary, a GLP-1/polymer conjugate was synthesized for the first time, and its bioactivity was examined, which must result from its specific interaction with isolated islets.

Animals↗