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At least 1,189 records · Page 66Linked to original sources
PubMed2006

Arachidonate-derived dihomoprostaglandin production observed in endotoxin-stimulated macrophage-like cells.

Eicosanoids, including the prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids, epoxyeicosatetraenoic acids, and related compounds, are biosynthetic, bioactive mediators derived from arachidonic acid (AA), a 20:4(n-6) fatty acid. We have developed a comprehensive and sensitive mass spectral analysis to survey eicosanoid release from endotoxin-stimulated RAW 264.7 macrophage-like cells that is capable of detecting over 70 diverse eicosanoids and eicosanoid metabolites, should they be present. We now address the question: Are biologically significant eicosanoids being overlooked? Herein, we illustrate a general approach to diverse isotope metabolic profiling of labeled exogenous substrates using mass spectrometry (DIMPLES/MS), demonstrated for one substrate (AA) and its resultant products (eicosanoids). RAW cells were incubated in medium supplemented with deuterium-labeled AA. When the cells are stimulated, two sets of eicosanoids are produced, one from endogenous AA and the other from the supplemented (exogenous) deuterium-labeled form. This produces a signature mass spectral "doublet" pattern, allowing for a comprehensive and diverse eicosanoid search requiring no previous knowledge or assumptions as to what these species may be, in contrast to traditional methods. We report herein observing unexpected AA metabolites generated by the cells, some of which may constitute novel bioactive eicosanoids or eicosanoid inactivation metabolites, as well as demonstrating differing metabolic pathways for the generation of isomeric prostaglandins and potential peroxisome proliferator-activated receptor activators. Unexpectedly, we report observing a series of 1a, 1b-dihomologue prostaglandins, products of adrenic acid (22:4(n-6)), resulting from the two-carbon elongation of AA by the RAW cells.

Animals↗
PubMed1991

DNA adduct formation in liver following the administration of [3H]2-nitrofluorene to rats in vivo.

The formation of RNA and DNA adducts by the environmental pollutant 2-nitrofluorene (2-NF) has been investigated in rat liver in vivo. The adduct pattern was studied after trifluoroacetic acid hydrolysis of DNA or RNA, followed by analysis of the adducts by HPLC. This was also done by enzymatic hydrolysis of DNA, followed by 32P-postlabeling. Both after oral and i.v. administration of [3H]2-NF, one major adduct was found. This adduct did not co-migrate with one of the known adducts of 2-(acetyl)-aminofluorene, N-deoxyguanosin-8-yl-2-aminofluorene (dG-C8-AF), which could have been formed after nitroreduction of 2-NF. 32P-Postlabeling revealed that two minor adducts were also formed, one of which was dG-C8-AF. The observation that the major adduct was also formed after i.v. administration of 2-NF to bile duct-catheterized rats makes a role for the intestinal microflora in the formation of this adduct very unlikely. In vitro experiments with inhibitors of the enzyme epoxide hydrolase indicated that epoxidation of 2-NF may play a role in the microsomal bioactivation of this compound.

2-Acetylaminofluorene↗
PubMedDate not supplied

Perspectives on the use of the baboon in embryology and teratology research.

This paper summarizes the developmental stages of the baboon during the period of organ formation and provides comparative information for other primates, including the human. Special attention is directed to the early development of the nervous system, eye, ear and nose/palate. The similarity in development of these structures with humans indicates that the baboon is a suitable model for studies of normal and abnormal neurological development. Spontaneous prenatal loss rates in the baboon (2.4-11.2%) are slightly lower than those reported in rhesus and cynomologus monkeys. The baboon, in addition to the cynomologus monkey and macaque, has been used as a model in teratology research to assess the potential risk of thalidomide, sex steroids, Bendectin and rubella virus, as well as to study the pathogenesis of malformations associated with the corticosteroid triamcinolone acetonide. The rate of spontaneous malformations (<1%) in baboons, similar to that reported for other commonly used primates, supports their continued use as a teratological model. In this regard, a sample protocol is provided for the safety evaluation of biotechnology products using nonhuman primates, which are the most appropriate model for those compounds which are bioactive in species closely related to humans.

Abnormalities, Drug-Induced↗
PubMed2004

On the importance of exposure variability to the doses of volatile organic compounds.

The connection between occupational exposure to volatile organic compounds (VOCs) and the resulting internal doses is complicated by variability in air levels from day to day and by nonlinear kinetics of metabolism. We investigated long-term liver doses of VOCs and their metabolites using a physiologically based toxicokinetic model, to which 10,000 random 8-h exposures were inputted. Three carcinogenic VOCs were studied (i.e., benzene, perchloroethylene, and acrylonitrile); these compounds are all bioactivated in the liver and represent a wide range of an important toxicokinetic parameter Vmax/QL x KM. For each VOC, simulations were performed using mean air concentrations (muX) between 0.0003 and 1 mg/l (which covers both linear and saturated metabolism) and using coefficients of variation of exposure (CVX) between 0.23 and 2.18 (which includes most occupational settings). Two long-term measures of internal dose were examined, i.e., the area under the liver concentration-time curve (AUCL) and the area under the metabolic rate-time curve (AURC). Interestingly, both AUCL and AURC were linear functions of cumulative exposure (CE, mg x h/l air) even when metabolism was saturated and CVX was large. Yet, at a given CE, both AUCL and AURC were affected by CVX, with the magnitude of the effect increasing with Vmax/QL x KM (i.e., perchloroethylene < benzene < acrylonitrile). Nonetheless, the effects of CVX were typically only a few percent and should be of little consequence unless a VOC has large values of Vmax/QL x KM, muX,and CVX. We conclude that CE should be a sufficient predictor of the dose of either the parent chemical (VOC) or its metabolite in the liver, even when metabolism is nonlinear. We also observed that AUCL and AURC were sensitive to changes in values of model parameters in the high-variability scenarios, suggesting that (when CVX is large) the population variability of AUCL and AURC can be quite large at a fixed CE.

Acrylonitrile↗
PubMed2006

Cyanobacterial peptides - nature's own combinatorial biosynthesis.

Cyanobacterial secondary metabolites have attracted increasing scientific interest due to bioactivity of many compounds in various test systems. Among the known structures, oligopeptides are often found with many congeners sharing conserved substructures, while being highly variable in others. A major part of known oligopeptides are of non-ribosomal origin and can be grouped into classes with conserved structural properties. Thus, the overall structural diversity of cyanobacterial oligopeptides only seemingly suggests an equally high diversity of biosynthetic pathways and respective genes. For each class of peptides, some of which have been found in all major branches of the cyanobacterial evolutionary tree, homologous synthetases and genes can be inferred. This implies that non-ribosomal peptide synthetase genes are a very ancient part of the cyanobacterial genome and presumably have evolved by recombination and duplication events to reach the present structural diversity of cyanobacterial oligopeptides. In addition, peptide synthetases would appear to be an essential part of the cyanobacterial evolution and physiology. The present review presents an overview of the biosynthesis of cyanobacterial peptides and corresponding gene clusters, the structural diversity of structural types and structural variations within peptide classes, and implications for the evolution and plasticity of biosynthetic genes and the potential function of cyanobacterial peptides.

Cyanobacteria↗
PubMed1984

Reactive metabolites from the bioactivation of toxic methylfurans.

An important mechanism of toxicity of furans involves the cytochrome P-450 monooxygenase-catalyzed bioactivation of the compound in situ directly within the target tissues to highly reactive electrophilic products. The unsaturated aldehydes acetylacrolein and methylbutenedial have been identified as the principal reactive intermediates of 2- and 3-methylfuran, respectively, that are produced and bound covalently to tissue macromolecules in hepatic and pulmonary microsomal systems in vitro.

Animals↗
PubMed2004

Anthocyanins and Human Health: An In Vitro Investigative Approach.

Anthocyanin pigments and associated flavonoids have demonstrated ability to protect against a myriad of human diseases, yet they have been notoriously difficult to study with regard to human health. Anthocyanins frequently interact with other phytochemicals to potentiate biological effects, thus contributions from individual components are difficult to decipher. The complex, multicomponent structure of compounds in a bioactive mixture and the degradation of flavonoids during harsh extraction procedures obscure the precise assignment of bioactivity to individual pigments. Extensive metabolic breakdown after ingestion complicates tracking of anthocyanins to assess absorption, bioavailability, and accumulation in various organs. Anthocyanin pigments and other flavonoids that are uniformly, predictably produced in rigorously controlled plant cell culture systems can be a great advantage for health and nutrition research because they are quickly, easily isolated, lack interferences found in whole fruits, can be elicited to provoke rapid and prolific accumulation, and are amenable to biolabeling so that metabolic fate can be investigated after ingestion.

Journal Article↗
PubMed2003

Antimycobacterial activity of prenylated xanthones from the fruits of Garcinia mangostana.

Prenylated xanthones, isolated from the fruit hulls and the edible arils and seeds of Garcinia mangostana, were tested for their antituberculosis potential. Alpha- and beta-mangostins and garcinone B exhibited strong inhibitory effect against Mycobacterium tuberculosis with the minimum inhibitory concentration (MIC) value of 6.25 microg/ml. Tri- and tetra-oxygenated xanthones with di-C5 units or with a C5 and a modified C5 groups are essential for high activities. Substitution in the A and C rings has been shown to modify the bioactivity of the compounds.

Anti-Bacterial Agents↗
PubMed2003

Dietary phytoestrogens and bone health.

The role of soy phytoestrogens in preserving bone health has to date not been studied in large randomised controlled studies. These bioactive naturally occurring compounds are viewed as potential selective oestrogen receptor modulators based on their structural similarity to oestradiol, in vitro mechanisms of action and hormonal effects in human subjects. Much of the evidence for a role in bone health has stemmed from animal data, as most of the available human studies are of short duration and have used either bone biomarkers or bone mineral density as end point measures. However, recent data from a long-term study suggest these compounds have a bone conserving effect in menopausal women but to accurately examine the relative importance of these compounds for bone health in postmenopausal women an assessment of consumption on fracture rates will be critical.

Clinical Trials as Topic↗
PubMed2002

Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions.

Some carboxylic acid-containing drugs have been implicated in rare but serious adverse reactions. These compounds can be bioactivated via two distinct pathways: by UDP-glucuronosyltransferase-catalyzed conjugation with glucuronic acid, resulting in the formation of acyl glucuronides, or by acyl-CoA synthetase-catalyzed formation of acyl-CoA thioesters. This review compares the two types of potentially reactive metabolites with respect to their stability, protein-reactivity, target selectivity, and disposition in the liver, and summarizes the evidence which links acyl glucuronide and acyl-CoA thioester formation with downstream toxicologic effects. While with increasing drug concentration the acyl glucuronide pathway may prevail, CoA intermediates may be more reactive. Both metabolites are electrophilic species which can acylate target proteins if they escape inactivation by S-glutathione-thioester formation. A crucial factor is the up-concentration of acyl glucuronides in hepatocytes and the biliary tree, due to vectorial transport by conjugate export pumps, where they may selectively acylate canalicular membrane proteins. Furthermore, positional isomers, which are avidly formed by acyl migration, can glycate proteins in the liver and at more distal sites. In contrast, acyl-CoA esters may be more rapidly hydrolysed or further metabolized in hepatocytes, and their hepatobiliary transport has not been well explored. While there is accumulating evidence that acyl glucuronides can alter cellular function by various mechanisms, including haptenation of peptides, critical protein acylation or glycation, or direct stimulation of neutrophils and macrophages, the role of acyl-CoA intermediates is less clear. More work is needed to provide a causal link between protein-reactive acyl glucuronides and acyl-CoA thioesters and the rare and unpredictable idiosyncratic drug reactions in humans.

Acyl Coenzyme A↗
PubMed1994

Ustiloxins, antimitotic cyclic peptides from false smut balls on rice panicles caused by Ustilaginoidea virens.

Ustiloxins A (1a), B (1b), C (1c), D (1d) and E (1e), antimitotic peptides, have been isolated from the water extract of false smut balls caused on the panicles of rice plant by a fungus Ustilaginoidea virens. The structure of 1b was assigned from its spectral property and its amino acid analysis in relation to 1a whose structure was determined previously by a combination of X-ray crystallographic and amino acid analyses. Structures of 1c and 1d were elucidated by their spectroscopic data, specially based on their 1H and 13C NMR spectra. Bioactivities of these compounds against microtubule assembly as well as mammal, plant and fungal cells have been studied.

Amino Acid Sequence↗
PubMed2002

Mother nature's combinatorial libraries; their influence on the synthesis of drugs.

Natural products or secondary metabolites, whether from the microbial, plant or marine worlds, represent the results of evolutionary pressures to preserve and enhance the life of their producing organism. They have evolved into structurally and usually stereochemically complex compounds with specific bioactivities. They thus represent a diverse 'combinatorial library' that may have potential pharmaceutical use. In principle, the combination of this diverse library with the methods of combinatorial chemistry could lead to an unlimited supply of diverse and complex structures, and is recommended as a fruitful approach for future drug development. Examples of the application of combinatorial methods to nature's combinatorial library will be presented and discussed, with an emphasis on the antitumor, anti-infective and pain control disease areas.

Analgesics↗
PubMed2001

[Chemical constituents from the fruit of Rosa bella Rehd. et Wils].

OBJECTIVE: To investigate the chemical constituents from the fruit of Rosa bella and its bioactivity. METHOD: The compounds were isolated from the methanol extract by column chromatography, then identified by 1H, 13C NMR and by comparison with authentic samples. The unorganized hoptoad heart was used for testing the contracting force of cardiac muscle and enzymology for measuring the bloody lipid of serum in rats. RESULT: Seven compounds were isolated and identified as pomolic acid, tiliroside, euscaphic acid, daucosterol, quercetin, oleanolic acid and beta-sitosterol, respectively. In the concentration of 0.4-1.0 mg.ml-1, the methanol extract had obvious cardiotonic effect. While at 400 mg.kg-1, there are no obvious effect to the TC, HDL-ac and TG of serum in rats. CONCLUSION: The isolated compounds may be the active components of this plant.

Animals↗
PubMed1989

Scanning electron microscopic study of cell attachment to biodegradable polymer implants.

The biodegradable polymers--polylactic acid (PLA) and polyglycolic acid (PGA)--are currently being studied as carriers for bioactive bone regeneration compounds. The inclusion of osteo-inductive substances in poly-(DL, lactide-co-glycolide) copolymer alloplastic implants has been shown to enhance the repair of osseous defects. The purpose of this study was to examine, by SEM, the attachment relationship of biodegradable polymer implants to cells and tissue matrix. Three groups of copolymer implants were studied: (1) plain 50:50 PLA-PGA copolymer, (2) PLA-PGA copolymer with hydroxyapatite (HA), and (3) PLA-PGA copolymer with autolyzed, antigen-extracted (AA) bone particles. Polymer discs were surgically implanted into the pectoralis muscles of rats. At seven, 14, and 21 days post-implantation, the baskets were removed and the contents prepared for SEM. Results showed that at one week, implants were coated primarily with red and white blood cells in a fibrinoid clot. Degradation of the polymers was evidenced by irregular enlarging of polymer surface pores. At two and three weeks, polymers became lobular and then fibrinoid as degradation progressed. Inflammatory cell and red blood cell adhesions were increasingly replaced by fibroblasts and collagen matrix deposition. As polymer degradation progressed, AA and HA particles were exposed; however, the lack of cell or tissue adhesion in these areas suggests that degradation may be more influenced by the fluid environment than by direct cell attachment. Furthermore, degradation may inhibit direct cell attachment.

Animals↗
PubMedDate not supplied

Low levels of hepatic cytochrome P-450 in Mexicans with uncomplicated cholelithiasis.

The multienzymatic complex known as cytochrome P-450 represents one of the most important hemoprotein families of the liver. It participates in the metabolism of steroids, fatty acids, prostaglandins and liposoluble vitamins, and also plays a role in the bioactivation of xenobiotic compounds (generates reactive metabolites which produce acute and chronic lesions in liver tissue). This is a report on the low concentrations of total microsomal P-450 (0.093 +/- SD = 0.069 nMoles/mg protein) found in liver biopsies of 19 mexican patients diagnosed as having biliary lithiasis, as compared to an anglosaxon population with the same liver pathology (0.415 +/- 0.105 nMoles/mg protein). These low values are in agreement with the observation of a high incidence in normal mexicans (91.7%) of poor nifedipine metabolizers. Our findings justify an analyses of hepatic RNAm and cDNA of mexican individuals according to ethnic background, diet and environmental contaminants.

Adult↗
PubMed1994

Synthesis and activity of new linear and cyclic peptide T derivatives.

Linear and head to tail cyclic hexapeptide analogs (Xaa-Thr-Thr-Asn-Tyr-Thr, Xaa = D-Asp or D-iso-Asp) of peptide T were prepared and tested for human monocyte chemotaxis. All new compounds showed significant bioactivity. In particular, the conformational restriction introduced into cyclo(-D-iso-Asp-Thr-Thr-Asn-Tyr-Thr-) was very suitable for CD4 receptor binding. The cyclic peptides also proved to be highly resistant to degradation by plasma or brain enzymes.

Amino Acid Sequence↗
PubMed2005

The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.

In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.

Adolescent↗
PubMed2006

[Research development of chemistry and bioactive activity of plant peptides].

As the technologies of separation, purification and determination develop rapidly, more and more peptide compounds, which have special bioactive and medical value, have been separated from natural plants, such as oligopeptides and cyclopeptides. The chemical structures and function of these plant peptides have been researched profoundly. This paper mainly reviews the composition, structure, bioactive function and medicine value of representative plant peptides in recent years, and can give some references about research and application of plant bioactive peptides.

Animals↗