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PubMed1986

Modulation of luteinizing hormone immunoreactivity and bioactivity by dopamine but not norepinephrine in women.

It has been suggested that changes in bioactive luteinizing hormone in women occur toward midcycle and may result in increased bioactive/immunoreactive luteinizing hormone ratios. To determine whether dopamine or norepinephrine modulate immunoreactive and bioactive luteinizing hormone secretion, 15 ovulatory women were studied in the mid to late follicular phase. Dopamine in two doses (0.5 micrograms/kg/min and 4 micrograms/kg/min) and norepinephrine, 0.1 microgram/kg/min, were infused for 4 hours, and metoclopramide, 10 mg intravenously, was also given to determine whether dopamine receptor antagonism results in changes. Bioactive luteinizing hormone and the bioactive/immunoreactive luteinizing hormone ratio increased in women from the early to late follicular phase (p less than 0.05). Both intravenous doses of dopamine resulted in significant decrements in immunoreactive luteinizing hormone (20 +/- 2 and 20 +/- 3%, p less than 0.02) and bioactive luteinizing hormone (36.7% and 43.2%, p less than 0.05). With dopamine there was also a significant decrease in the bioactive/immunoreactive luteinizing hormone ratio (p less than 0.02). Intravenous norepinephrine, however, resulted in no changes in either immunoreactive or bioactive luteinizing hormone levels. Metoclopramide also did not change immunoreactive or bioactive luteinizing hormone levels. These data suggest that although endogenous dopaminergic blockade may not play a significant role in determining basal levels of luteinizing hormone, decreases in dopamine at the pituitary level may increase the bioactive/immunoreactive luteinizing hormone ratio. Norepinephrine does not appear to exert major changes in immunoreactive or bioactive luteinizing hormone.

Adult↗

PubMed1992

Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome.

Gilbert's syndrome occurs in 5%-7% of the human population and is caused by an inherited deficiency in the glucuronidation of endogenous bilirubin, resulting in its accumulation and jaundice. The authors of the present study have previously shown that rats with a similar deficiency in bilirubin glucuronidation (Gunn rats) had reduced glucuronidation and enhanced susceptibility to the toxicity of the widely used analgesic, acetaminophen. Acetaminophen is eliminated primarily by glucuronidation, which prevents its cytochrome P-450-catalysed bioactivation to a hepatotoxic reactive intermediate. The purpose of this study was to determine whether people with Gilbert's syndrome had reduced glucuronidation and enhanced bioactivation of acetaminophen. Therefore, the biotransformation of acetaminophen, 20 mg/kg IV, was investigated in six subjects with Gilbert's syndrome (total bilirubin, 41 +/- 6 mumol/L; mean +/- SE) and six normal controls (total bilirubin, 11 +/- 2 mumol/L; P less than 0.01). Formation of the acetaminophen glucuronide conjugate measured by high-performance liquid chromatography was quantified by the ratio of the area under the plasma concentration-time curve (AUC) from 0 to 2 hours for the acetaminophen glucuronide divided by the AUC for acetaminophen. Acetaminophen bioactivation was quantified by the molar percentage of acetaminophen excreted in the urine during 24 hours as glutathione-derived conjugates (cysteine and mercapturic acid). Acetaminophen glucuronide formation in subjects with Gilbert's syndrome was 31% lower than that in normal controls (0.27 +/- 0.05 vs. 0.39 +/- 0.03; P less than 0.05), and bioactivation was 1.7-fold higher (3.5% +/- 0.4% vs. 2.1% +/- 0.3%; P less than 0.05). One control subject with normal bilirubin glucuronidation had substantially decreased acetaminophen glucuronide formation (0.20) and enhanced bioactivation (4.8%). Among all subjects, glucuronidation correlated inversely with bioactivation (r = -0.84; P less than 0.001), indicating that a decrease in a major pathway of elimination can shunt more drug through the toxifying route. Thus, a deficiency in bilirubin UDP-glucuronosyltransferase, evidenced by jaundice, can be paralleled by a deficiency in glucuronidation of other compounds. In these cases, jaundice can be a phenotypic determinant of enhanced acetaminophen bioactivation. On the other hand, some people with normal bilirubin glucuronidation may have a deficiency in the glucuronidation of acetaminophen; these people are not easily recognized.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaminophen↗

PubMed1993

Bioactive glasses and glass-ceramics.

Bioactive materials are designed to induce a specific biological activity; in most cases the desired biological activity is one that will give strong bonding to bone. A range of materials has been assessed as being capable of bonding to bone, but this paper is solely concerned with bioactive glasses and glass-ceramics. Firstly, the structure and processing of glasses and glass-ceramics are described, as a basic knowledge is essential for the understanding of the development and properties of the bioactive materials. The effect of composition and structure on the bioactivity is then discussed, and it will be shown that bioactivity is associated with the formation of an apatite layer on the surface of the implant. A survey of mechanical performance demonstrates that the structure and mechanical properties of glass-ceramics depend upon whether the processing involves casting or sintering and that the strength and toughness of glass-ceramics are superior to those of glasses. Attempts to further improve the mechanical performance by the use of non-monolithic components, i.e. bioactive coatings on metal substrates and glass and glass-ceramic matrix composites, are also reviewed and are shown to have varying degrees of success. Finally, some miscellaneous applications, namely bioactive bone cements and bone fillers, are briefly covered.

Biocompatible Materials↗

PubMed2006

Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration.

Bioactive glasses are potentially useful as bone defect fillers, and vascular endothelial growth factor (VEGF) has demonstrated benefit in bone regeneration as well. We hypothesized that the specific combination of prolonged localized VEGF presentation from a matrix coated with a bioactive glass may enhance bone regeneration. To test this hypothesis, the capacity of VEGF-releasing polymeric scaffolds with a bioactive glass coating was examined in vitro and in vivo using a rat critical-sized defect model. In the presence of a bioactive glass coating, we did not detect pronounced differences in the differentiation of human mesenchymal stem cells in vitro. However, we observed significantly enhanced mitogenic stimulation of endothelial cells in the presence of the bioactive glass coating, with an additive effect with VEGF release. This trend was maintained in vivo, where coated VEGF-releasing scaffolds demonstrated significant improvements in blood vessel density at 2 weeks versus coated control scaffolds. At 12 weeks, bone mineral density was significantly increased in coated VEGF-releasing scaffolds versus coated controls, while only a slight increase in bone volume fraction was observed. The results of this study suggest that a bioactive glass coating on a polymeric substrate participates in bone healing through indirect processes which enhance angiogenesis and bone maturation and not directly on osteoprogenitor differentiation and bone formation. The mass of bioactive glass used in this study provides a comparable and potentially additive, response to localized VEGF delivery over early time points. These studies demonstrate a materials approach to achieve an angiogenic response formerly limited to the delivery of inductive growth factors.

Animals↗

PubMed2006

Strontium-containing hydroxyapatite bioactive bone cement in revision hip arthroplasty.

Clinical outcome of cemented implants to revision total hip replacement (THR) is not as satisfactory as primary THR, due to the loss of bone stock and normal trabecular pattern. This study evaluated a bioactive bone cement, strontium-containing hydroxyapatite (Sr-HA) bone cement, in a goat revision hip hemi-arthroplasty model, and compared outcomes with polymethylmethacrylate (PMMA) bone cement. Nine months after operation, significantly higher bonding strength was found in the Sr-HA group (3.36+/-1.84 MPa) than in the PMMA bone cement group (1.23+/-0.73 MPa). After detached from the femoral component, the surface of PMMA bone cement mantle was shown relatively smooth, whereas the surface of the Sr-HA bioactive bone cement mantle was uneven, by SEM observation. EDX analysis detected little calcium and no phosphorus on the surface of PMMA bone cement mantle, while high content of calcium (14.03%) and phosphorus (10.37%) was found on the surface of the Sr-HA bone cement mantle. Even higher content of calcium (17.37%) and phosphorus (10.84%) were detected in the concave area. Intimate contact between Sr-HA bioactive bone cement and bone was demonstrated by histological and SEM observation. New bone bonded to the surface of Sr-HA cement and grew along its surface. However, fibrous tissue was observed between PMMA bone cement and bone. The results showed good bioactivity of Sr-HA bioactive bone cement in this revision hip replacement model using goats. This in vivo study also suggested that Sr-HA bioactive bone cement was superior to PMMA bone cement in terms of bone-bonding strength. Use of bioactive bone cement may be a possible solution overcoming problems associated with the use of PMMA bone cement in revision hip replacement.

Animals↗

PubMed2006

Hydrogen peroxide restrains endothelium-derived nitric oxide bioactivity -- role for iron-dependent oxidative stress.

Vascular diseases are characterized by impairment of endothelial-derived nitric oxide (NO) bioactivity and increased vascular levels of hydrogen peroxide (H(2)O(2)). Here we examined the implications of H(2)O(2) for agonist-stimulated endothelial NO bioactivity in rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC). Vessels pre-treated with H(2)O(2) exhibited impaired endothelial-dependent relaxation induced by acetylcholine or calcium ionophore. In contrast, H(2)O(2) had no effect on endothelium-independent relaxation induced by a NO donor, indicating a defect in endothelium-derived NO. This defect was not related to eNOS catalytic activity; treatment of PAEC with H(2)O(2) enhanced agonist-stimulated eNOS activity indicated by increased eNOS phosphorylation at Ser-1177 and de-phosphorylation at Thr-495 and enhanced conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline that was prevented by inhibitors of Src and phosphatidylinositol-3 kinases. Despite activating eNOS, H(2)O(2) impaired endothelial NO bioactivity indicated by attenuation of the increase in intracellular cGMP in PAEC stimulated with calcium ionophore or NO. The decrease in cGMP was not due to impaired guanylyl cyclase as H(2)O(2) treatment increased cGMP accumulation in response to BAY 41-2272, a NO-independent activator of soluble guanylyl cyclase. At concentrations that impaired endothelial NO bioactivity H(2)O(2) increased intracellular oxidative stress and size of the labile iron pool in PAEC. The increase in oxidative stress was prevented by the free radical scavenger's tempol or tiron and the iron chelator desferrioxamine and these antioxidants reversed the H(2)O(2)-induced impairment of NO bioactivity in PAEC. This study shows that despite promoting eNOS activity, H(2)O(2) impairs endothelial NO bioactivity by promoting oxidative inactivation of synthesized NO. The study highlights another way in which oxidative stress may impair NO bioactivity during vascular disease.

Animals↗

PubMed2006

The ratio of P40 monomer to dimer is an important determinant of IL-12 bioactivity.

IL-12 is a 75 kDa heterodimer (IL12p70) comprised of independently regulated disulfide-linked 40 kDa (p40) and 35 kDa (p35) subunits. The p40 subunit exists extracellularly as a monomer (IL12p40) or dimer (IL12(p40)2) and can antagonize the action of IL12p70. Given the disagreement in the literature over the physiologic roles for IL12p70, IL12p40, and IL12(p40)2, we asked whether the bioactivity of IL-12 depended only on the concentration of the IL12p70 subunit alone or whether the relative concentrations of IL12p70, IL12p40, and IL12(p40)2 and their competitive binding with the IL-12 receptor are essential for determining IL-12 bioactivity under simulated human physiologic conditions. A mathematical model for IL-12 bioactivity was created by incorporating the production of IL12p70, IL12p40, and IL12(p40)2 by mature human DC and the interaction of these species with the IL-12 receptor. Using this model, we explored the effects of IFN-gamma, IL-4, and PGE2 concentrations on the bioactivity of IL-12. The simulations suggest that the concentration of IL12p70 alone is not indicative of IL-12 bioactivity; rather, the bioactivity of IL-12 produced by mature DC depends on IL12p70, IL12p40, and IL12(p40)2 production and their competitive interaction with the IL-12 receptor. In addition to the typically measured quantities of total p40 (IL12p40 + IL12(p40)2) and IL12p70, the ratio of IL12p40 to IL12(p40)2 is an equally important, yet underreported, determinant of IL-12 bioactivity.

Dendritic Cells↗

PubMed2003

Effects of added bioactive glass on the setting and mechanical properties of resin-modified glass ionomer cement.

In this study, the effects of added bioactive glass on the basic setting properties of a commercially available resin-modified glass ionomer cement were investigated with respect to setting time, mechanical strength, and setting mechanism. It was found to be clinically acceptable whether the setting time was extended or shortened depending on the type of bioactive glass added. The compressive strength of the set cement containing the bioactive glass decreased and was much higher when compared with the conventional type glass ionomer cement containing bioactive glass. The Fourier-transform infrared and 13C CP/MAS-NMR spectroscopies revealed that the extent of the acid-base reaction was larger in the cements containing bioactive glass than in the commercial resin-modified glass ionomer cement because of its high basicity in the bioactive glass. The 27Al MAS-NMR showed that crosslinking of the carboxylates in the polymeric acid by Al proceeded less in the cement containing the bioactive glass.

Biocompatible Materials↗

PubMed1994

Biochemistry of cytosolic sulfotransferases involved in bioactivation.

Numerous studies have indicated that two classes of cytosolic STs are involved in the bioactivation of procarcinogens and drugs to reactive electrophiles, especially in rodent tissues. These two classes of STs are the hydroxysteroid STs, which are involved in the conjugation of hydroxymethyl PAHs, and the phenol STs involved in the sulfation of alkenylbenzenes and N-hydroxyarylamines. Purification studies of rat liver STs have clearly indicated that specific isoforms of hydroxysteroid and phenol STs are capable of sulfating procarcinogens in vitro. Rat liver STa and BAST I are structurally similar hydroxysteroid STs, which have been shown to sulfate and bioactive HMBA. Molecular cloning studies of the rat hydroxysteroid STs indicate that these enzymes are probably part of a family of closely related genes. The single human hydroxysteroid ST that has been characterized is very similar to the rat enzymes, but its role in the bioactivation of hydroxymethyl PAHs has not been established. Phenol STs have been demonstrated to have an important role in the bioactivation of alkenylbenzenes and N-hydroxyarylamines. Purification of rat phenol STs has identified several different forms, but only some appear to be involved in bioactivation of procarcinogens. Four isoforms (HAST I and II, AST III and IV) are apparently responsible for the majority of N-hydroxyarylamine sulfation. The relationship between these enzymes has not been established but they may represent similar enzymes. Different isoforms of rat phenol ST are also involved in the bioactivation of procarcinogens and drugs. However, the role of these phenol STs, PST-1, Mx-ST, and paracetamol ST, in carcinogenesis requires further study. In human tissues, only two phenol STs, P-PST and M-PST, have been identified. The role of these enzymes or unidentified STs in the sulfation of N-hydroxyarylamine procarcinogens has not yet been established. Initial reports of the molecular cloning and expression of the rat and human phenol ST genes will provide a valuable mechanism for the characterization of roles of the individual enzymes in bioactivation.

Amino Acid Sequence↗

PubMed2002

Human-osteoblast proliferation and differentiation on grit-blasted and bioactive titanium for dental applications.

Physico-chemical and topographical surface quality of commercially pure titanium (c.p. Ti) dental implants is one of the most influencing factors in the improvement of their osseointegration. In this sense, previously, a two-step method (2S) for obtaining bioactive blasted-rough titanium surfaces was developed for improving short-term (due to its bioactivity) and long-term (due to its roughness) osseointegration. This 2S-method consists of: (1) Grit blasting on titanium surface in order to roughen it, and (2) thermo-chemical (TCh) treatment in order to obtain a bioactive surface with bone-bonding ability. The aim of the present work is to evaluate the in vitro human-osteoblast response (proliferation, differentiation - ALP activity- and cell morphology-studied by environmental scanning electron microscopy) of rough c.p. Ti (grit blasted), bioactive c.p. Ti (thermo-chemically treated) and rough-bioactive c.p. Ti (2S-treated). Different grit materials (Al(2)O(3) and SiC) have been used in order to investigate their influence. The results showed that cell adhesion was statistically higher for the rough and bioactive surfaces, whatever the grit used. Cells proliferated very well on all the c.p. Ti surfaces. If comparing groups with and without TCh (all other treatments being equal) the ALP was always higher in the groups with TCh, indicating stimulation of osteoblast differentiation because of TCh, more significantly in the groups that were first blasted. Those ALP results were accompanied by a decrease in the value of proliferation, which shows the good behavior of the cells. This results suggest that a rough and bioactive-titanium surface obtained by 2S-treatment enhances adhesion and differentiation activity of human osteoblasts cells.

Journal Article↗

PubMed1999

Rational design, conformational studies and bioactivity of highly potent conformationally constrained calcitonin analogues.

Calcitonin is known for its hypocalcaemic effect and the inhibition of bone resorption, and is used therapeutically for the treatment of osteoporosis and Paget's disease. Our studies on the conformational features of human calcitonin (hCt) bioactivity have led to the conformationally constrained hCt analogue cyclo17,21-[Asp17, Lys21]hCt (1), which had a 5-10 times higher in vivo hypocalcaemic potency than hCt [Kapurniotu, A. & Taylor, J.W. (1995) J. Med. Chem. 38, 836-847]. We hypothesized that a stabilized, possibly type I beta turn/beta sheet conformation between residues 17 and 21 could play a crucial role in hCt bioactivity. Here, we designed, synthesized and studied the conformation and bioactivity of 19-member to 17-member ring-size analogues of 1 with the structure cyclo17,21-[Asp17,XX21]hCt with XX = Orn (2), Dab (3) and Dap (4), of the control peptide [Asp17,Orn21]hCt (5), and of the 19-member cyclo17,21-[Glu17,Dab21]hCt (6). Analyses of the far-UV CD spectra indicated increased type I beta turn and antiparallel beta sheet content in the bicyclic analogues compared with hCt. In the in vivo hypocalcaemic assay, cyclo17,21-[Asp17,Orn21]hCt (2) was found to have a 400-fold higher potency than hCt and was fourfold more potent than salmon calcitonin (sCt), which has been the most potent known Ct. Analogue 3 had a 30-fold higher potency than hCt, whereas the highly constrained analogue 4 was as potent as hCt. Bioactivity was not enhanced for the nonbridged compound [Asp17, Orn21]hCt (5), whereas cyclo17,21-[Glu17,Dab21]hCt (6) showed the same bioactivity as 1. This study identifies 2 as exhibiting the highest in vivo potency among currently known Cts, while it differs in only one amino acid residue from hCt, strongly suggesting that the introduced constraint may have served in 'freezing' hCt in a bioactive conformation. Our findings provide evidence for the first time that a beta turn/beta sheet conformation in region 17-21 of hCt and the topological features of the side chain of Asn17 are strongly associated with in vivo bioactivity, and offer a novel lead structure for a hCt-based drug for the treatment of osteoporosis and other bone-disorder-related diseases.

Animals↗

PubMed1995

Association of the "major histocompatibility complex subregion" I-J determinant with bioactive glycosylation-inhibiting factor.

Murine suppressor T-cell hybridoma cells (231F1) secrete not only bioactive glycosylation-inhibiting factor (GIF) but also an inactive peptide comparable to bioactive GIF peptide in its molecular size and reactivity with anti-GIF; the amino acid sequence of the inactive peptide is identical to that of the bioactive homologue. The inactive GIF peptide in culture supernatant of both the 231F1 cells and a stable transfectant of human GIF cDNA in the murine suppressor T hybridoma selectively bound to Affi-Gel 10, whereas bioactive GIF peptides from the same sources failed to bind to the gel. The inactive cytosolic human GIF from the stable transfectant and Escherichia coli-derived recombinant human GIF also had affinity for Affi-Gel 10. Both the bioactive murine GIF peptide from the suppressor T hybridoma and bioactive recombinant human GIF from the stable transfectant bound to the anti-I-J monoclonal antibody H6 coupled to Affi-Gel. However, bioactive hGIF produced by a stable transfectant of human GIF cDNA in BMT10 cells failed to be retained in H6-coupled Affi-Gel. These results indicate that the I-J specificity is determined by the cell source of the GIF peptide and that the I-J determinant recognized by monoclonal antibody H6 does not represent a part of the primary amino acid sequence of GIF. It appears that the epitope is generated by a posttranslational modification of the peptide.

Amino Acid Sequence↗

PubMed1997

Conversion of inactive glycosylation inhibiting factor to bioactive derivatives by modification of a SH group.

Escherichia coli-derived recombinant human glycosylation inhibiting factor (rhGIF) contains three cysteine residues (Cys-57, -60, and -81). All SH groups in the cysteine residues are free, and the GIF molecule had no biologic activity. Carboxymethylation of the SH group of Cys-60 in the molecule resulted in the generation of bioactivity, although the activity of the carboxymethylated GIF was 10- to 20-fold less than that of suppressor T cell (Ts)-derived GIF. However, treatment of the inactive rhGIF with ethylmercurithiosalicylate or 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) resulted in the generation of derivatives whose bioactivity was comparable to that of the Ts-derived bioactive GIF. The activity of these derivatives was lost by treatment with DTT. Isolation and chemical analysis of the DTNB-treated GIF derivative revealed that binding the 5-thio-2-nitrobenzoic acid group with Cys-60 was responsible for the generation of the highly bioactive derivative. Inactive cytosolic GIF from mammalian cells could also be converted to bioactive derivative by treatment with the SH reagent, while Ts-derived bioactive GIF was inactivated by DTT. These results, together with an x-ray crystal structure of GIF molecules, strongly suggest that the generation of bioactivity of GIF in Ts cells is due to posttranslational modifications that result in conformational changes in the molecule.

Amino Acid Sequence↗

PubMed2006

Bone powder enhances the effectiveness of bioactive glass S53P4 against strains of Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans in suspension.

OBJECTIVE: To assess whether bone powder in suspension enhances the antimicrobial efficacy of bioactive glass S53P4 against Gram-negative microbiota commonly associated with peri-implant disease. METHODS: Standardized suspensions of Porphyromonas gingivalis ATCC 33277 and YH 3, as well as Actinobacillus actinomycetemcomitans ATCC 29523 and KK 2 were added to 24-h suspensions of bioactive glass S53P4 with ground bovine bone powder, decalcified bone, or hydroxylapatite powder. Recovery of viable bacteria was assessed using anaerobic culture methods. As a reference, the antibacterial effect of an inert borosilicate powder with a particle size corresponding to that of the bioactive glass was tested. Counts of bacteria suspended in a pure unbuffered saline solution served as controls. RESULTS: A significant drop in viable microorganisms was observed in suspensions of bioactive glass and bone powder compared to counterparts of pure bioactive glass. In contrast, neither the presence of hydroxylapatite powder nor the presence of decalcified bone in suspension caused any increase in bioactive glass killing efficacy on the microorganisms under investigation. Inert borosilicate glass showed no antibacterial effects per se or in combination with bone powder. CONCLUSION: The antimicrobial effect of a combined bioactive glass-ground bone powder suspension was an in vitro observation which should be confirmed using adequate in vivo models.

Aggregatibacter actinomycetemcomitans↗

PubMed1988

Benzo[a]pyrene: kinetics of in vitro bioactivation in relation to inhibition of viral interferon induction.

The kinetics of benzo[a]pyrene (BaP) bioactivation by rat liver S9 fraction was characterized on the basis of inhibition of influenza virus induction of interferon-alpha/beta (IFN-alpha/beta) in mammalian LLC-MK2 cell cultures. Both viral IFN induction and production phases were sensitive to the adverse effects of bioactivated BaP. The integral role of S9 for BaP bioactivation and the resultant inhibition of viral IFN induction was substantiated by dose-response relationships, time-dependency of effects, and reversibility of adverse reactivity. When preceded by the analog, benzo[e]pyrene (BeP), the inhibitive action of bioactivated BaP on IFN induction was abrogated. That the ability of exogenous IFN to confer antiviral cellular resistance was unaffected by bioactivated BaP indicates that neither requisite cellular protein nor enzyme syntheses were impaired. In cells pretreated with bioactivated BaP, influenza virus multiplication reached a level that was more than twofold higher than in normal cells which was a reflection of decreased IFN production. These findings further imply that neither virus inducer-cell interactions (attachment and penetration) nor requisite viral protein and RNA syntheses were affected appreciably. BaP was selectively cyto-antagonistic to critical inducer-processing phases of IFN induction. Of 32 different mammalian cell cultures tested for indigenous metabolizing enzyme-bioactivation of BaP, based on approximately equal to 50% resultant inhibition of IFN induction, only 37.5% were responsive.

Animals↗

PubMed1992

Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris.

The factors that initiate the inflammatory response in acne are not known. The presence of pro-inflammatory cytokines in acne comedones was therefore investigated. One hundred eight open comedones were collected from 18 untreated acne patients (10 male, 8 female). Each comedone was homogenized and centrifuged, and the supernatant was analyzed for bioactive and immunochemically detectable IL-1 alpha, IL-1 beta, and TNF alpha. Viable counts of propionibacteria, staphylococci, and Malassezia spp. were determined in the comedone pellet. Bioactive IL-1 alpha-like material was demonstrated in 76% of open comedones (range of 23-4765 pg IL-1 alpha-like bioactivity/mg of comedone material). In 58% of comedones, levels exceeded 100 pg/mg. There was no correlation between IL-1 alpha-like bioactivity and IL-1 alpha determined immunochemically. Bioactive IL-1 beta was not detected in any comedones. Twenty-four percent contained low levels of immunochemical IL-1 beta (range 12-103 pg IL-1 beta/mg comedone material). Bioactive TNF alpha was detected in three comedones with a further five comedones containing immunochemical TNF alpha (range of 61-820 pg TNF alpha/mg comedone material). The majority of open comedones (97%) contained microorganisms. There was, however, no significant correlation (Spearman's rank) between levels of any cytokine, in particular IL-1 alpha-like bioactivity, and numbers of microorganisms. Thus, bioactive IL-1 alpha-like material in the majority of open comedones may be concerned in the initiation of inflammation in acne following spongiosis or rupture of the pilosebaceous follicle wall.

Acne Vulgaris↗

PubMed2004

Detecting bioactive amyloid beta peptide species in Alzheimer's disease.

Amyloid beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of A beta that induces neurodegeneration in AD, defined here as bioactive A beta, is not clear. Preventing the formation of bioactive A beta or inactivating previously formed bioactive A beta should be a promising approach to treat AD. We have previously developed a cell-based assay for the detection of bioactive A beta species. The assay is based upon the correlation between the ability of an A beta sample to induce a unique form of cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] formazan exocytosis, and its ability to activate glia and induce neurotoxicity. Here, we show that this cell-based assay is not only useful for a cellular model of A beta amyloidogenesis but is also able to detect bioactive A beta species in a transgenic mouse model of AD, as well as in post-mortem cortex samples from AD patients. There is a good correlation between the extent of glia activation and the level of bioactive A beta species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive A beta species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD.

Age Factors↗

PubMed1984

Bioactive parathyroid hormone in canine progressive renal insufficiency.

Bioactive parathyroid hormone and hormonal actions were monitored as hyperparathyroidism evolved in a model of progressive canine renal failure. Circulating levels of bioactive and immunoreactive parathyroid hormone rose as renal insufficiency worsened, but elevations, especially in bioactivity, were most marked in the final stage of uremia. By gel filtration analysis, the major circulating bioactive moiety was similar to the major glandular form of parathyroid hormone, although a smaller-molecular-weight entity was seen in the final stage of renal failure. Renal phosphate threshold fell, urinary hydroxyproline corrected for glomerular filtration rose, and plasma 1,25-dihydroxyvitamin D fell but remained detectable, as renal function deteriorated. The results demonstrate a progressive rise in bioactive parathyroid hormone, show the appearance of a small-molecular-weight bioactive entity in severe renal disease, and correlate effects of the rising bioactive parathyroid hormone with changes in renal phosphate handling and with skeletal resorption.

Animals↗