SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Four new antifungal compounds, terezines A-D [1-4], have been isolated from liquid cultures of the coprophilous fungus Sporormiella teretispora by preparative tlc and hplc. The structures of these compounds were determined on the basis of nmr and ms data. The known fungal metabolite hyalopyrone [6] was also isolated from S. teretispora.
Bioactivity-guided fractionation of several bioactive extracts obtained from Cerrado and Atlantic Forest plant species led to the isolation of potent DNA-damaging piperidine 1-5 and guanidine alkaloids 6-9 from Cassia leptophylla and Pterogyne nitens respectively, two common Leguminosae from Atlantic Forest. By means of biotechnological approach on Maytenus aquifolium, a species from Cerrado, moderate DNA-damaging sesquiterpene pyridine alkaloid 10-11 was isolated. Bioassay-guided fractionation on Casearia sylvestris, a medicinal plant species found in Cerrado and Atlantic Forest, led to the isolation of clerodane diterpenes 12-13 which showed effect on DNA. In addition, we have reported several interesting potent antifungal iridoids: 1 beta-hydroxy-dihydrocornin (14), 1 alpha-hydroxy-dihydrocornin (15), alpha-gardiol (16), beta-gardiol (17), plumericin (18), isoplumericin (19), 11-O-trans-caffeoylteucrein (20); ester derivative: 2-methyl-4-hydroxy-butyl-caffeoate (21), amide N-[7-(3',4'-methylenedioxyphenyl)-2Z, 4Z-heptadienoyl] pyrrolidine (22) and triterpene viburgenin (23).
The evaluation of luminol-dependent chemiluminescence (CL) for determination of free radicals generated during the oxidative reactions of microsomal enzymes in microsomes and reconstituted systems has been studied. The results indicated that the CL not only depended on NADPH induction but also on intact cytochrome P-450 enzymes. The light emission signal was strongly scavenged by SOD with inhibition rate of 93%. A concentration of 24 mumol.L-1 cadmium acetate and 2.5 mumol.L-1 mercuric chloride also inhibited the signal significantly as compared with the control. The study of CL in detecting free radicals formed by biotransformation of 44 xenobiotics suggested that some of the compounds known as free radicals producing agents by bioactivation increased the light emission in cytochrome P-450 enzyme system, such as carbon tetrachloride, chloroform, tetrachloroethylene etc., the others forming toxic metabolites by biotransformation induced the CL in some cases, such as carbon disulfide, benzene, methyldursban, methylparathion etc. or decreased the light emission, such as parathion, aniline and polychlorinated byphenyls etc., and still others whose toxic effects have no relationship with their biotransformation had no influence or an inhibitory effect on the CL, such as aminopyrine, TOCP, and acrylamide. CL in the cytochrome P-450 enzyme system remained unchanged during the biotransformation of carcinogens such as diethylnitrosamine, dipropylnitrosamine and benzo(a)pyrene as compared with the control. However, 3-methylcholanthrene and dimethylnitrosamine had an enhancing effect on the CL, while 2-acetylaminofluorene and 2-aminoanthracene showed an inhibition to the signals.
In this study, we evaluate the biosafety and bioactivity (antioxidant potential) of a traditional water infusion (tea) of common sage (Salvia officinalis L.) in vivo in mice and rats by quantification of plasma transaminase activities and liver glutathione-S-transferase (GST) and glutathione reductase (GR) enzyme activities. The replacement of water by sage tea for 14 days in the diet of rodents did not affect the body weight and food consumption and did not induce liver toxicity. On the other hand, a significant increase of liver GST activity was observed in rats (24%) and mice (10%) of sage drinking groups. The antioxidant potential of sage tea drinking was also studied in vitro in a model using rat hepatocytes in primary culture. The replacement of drinking water with sage tea in the rats used as hepatocyte donors resulted in an improvement of the antioxidant status of rat hepatocytes in primary culture, namely a significant increase in GSH content and GST activity after 4 h of culture. When these hepatocyte cultures were exposed to 0.75 or 1 mM of tert-butyl hydroperoxide (t-BHP) for 1 h, some protection against lipid peroxidation and GSH depletion was conferred by sage tea drinking. However, the cell death induced by t-BHP as shown by lactate dehydrogenase (LDH) leakage was not different from that observed in cultures from control animals. This study indicates that the compounds present in this sage preparation contain interesting bioactivities, which improve the liver antioxidant potential.
Traditional medicinal plants in various countries, particularly in India have been used for centuries for various ailments; however, there has been little scientific effort to validate these anecdotal uses mentioned in the literature. A number of these traditionally used plant extracts and various "Ayurvedic medicines" that are highly valued in Ayurveda, the traditional system of medicine in India for antiaging, memory-enhancing, nerve tonic, anxiolytic, anti-inflammatory and immunopotentiation, have been screened using National Institutes of Mental Health (NIMH) Synthetic Screening Program for scientific validation and the development of new leads of psychotherapeutic compounds using Radioligand Receptor Binding Assays (RRA). Crude methanolic extracts of plants are screened using approximately 40 different in vitro RRA (primarily from rat brain homogenates) and 6 enzyme assays including acetylcholine esterase, choline acetyltransferase, and monoamine oxidase (MAO), A and B. The total crude extracts of many of these plants showed potent selectivity to various receptors, especially gamma-Amino Butyric Acid (GABA(A)), N-Methyl-D-Aspartic Acid (NMDA), and MAO receptors, which are presumed to be involved in mental disorders. The focus was on plants showing the highest displacement of GABA, cholecystokinin (CCK), NMDA, MAO, and benzodiazopines. Bioassay guided fractionation of the most active extracts resulted in pure compounds which retained the original activity of the crude extract validating the folkloric use. A bioactivity-guided fractionation of Terminalia bellerica fruit extract led to the isolation of several pure compounds which retained the original activity of the crude extract for CCK and GABA receptors, with the exception of compound B3EA-6, which exhibited high affinity for Neurokinin receptor (Substance K approximately NK-1). The absolute structure of B3EA-6 has been established by x-ray crystallography.
The bark of Annona squamosa yielded three new mono-tetrahydrofuran (THF) ring acetogenins, each bearing two flanking hydroxyls and a carbonyl group at the C-9 position. These compounds were isolated using the brine shrimp lethality assay as a guide for the bioactivity-directed fractionation. (2,4-cis and trans)-Mosinone A (1) is a mixture of ketolactone compounds bearing a threo/trans/threo ring relationship and s double bond two methylene units away from the flanking hydroxyl. The other two new acetogenins differ in their stereochemistries around the THF ring; mosin B (2) has a threo/trans/erythro configuration across the ring, and mosin C (3) possesses a threo/cis/threo relative stereochemistry. Also found was annoreticuin-9-one (4), a known acetogenin that bears a threo/trans/threo ring configuration and a C-9 carbonyl and is new to this species. The structures were elucidated based on spectroscopic and chemical methods. Compounds 1-4 all showed selective cytotoxic activity against the human pancreatic tumor cell line, PACA-2, with potency 10-100 times that of Adriamycin.
Cinnamoyl, p-coumaroyl, feruloyl, caffeoyl aloesin, and related compounds were isolated from Aloe species. The antiinflammatory and antioxidative activities of these compounds were examined based on the structure-activity relationship. It was suggested that the bioactivities may link to acyl ester groups in aloesin, together with those of aloesin-related compounds. However, investigations using the contact hypersensitivity response indicated a preventive effect of aloesin on the UV-B-induced immune suppression. Furthermore, aloesin inhibited tyrosine hydroxylase and dihydroxyphenylalanine (DOPA) oxidase activities of tyrosinase from normal human melanocyte cell lysates. These results show that aloesin prevents not only UV-B-induced immune suppression, but also could be a positive pigment-altering agent for cosmetic application. In preclinical study, aloe extract was investigated using phagocytosis and nitroblue tetrazolium chloride (NBT) reduction in adult bronchial asthma, and high molecular-weight materials, such as polysaccharide and glycoprotein fractions, were identified as active ingredients. The neutral polysaccharides, aloemannan and acemannan showed antitumor, antiinflammatory and immunosuppressive activities, and glycoprotein fractions with bradykinindegrading and cell proliferation-stimulating activities were identified from the nondialysate fraction of the gel part of Aloe species. Verectin fractionated from Aloe vera gel was examined biochemically and immunochemically, and verectin antibody was used in the appraisal of commercial Aloe vera gel products. It was reported that aloesin stimulates the proliferation of cultured human hepatoma SK-Hep 1 cells. Thus aloesin, related compounds, and high molecular-weight materials, such as aloemannan and verectin, may act in concert to exert therapeutic properties for wounds, burns and inflammation. The biodisposition of fluoresceinylisothiocyanate (FITC)--labeled aloemannan (FITC-AM) with the homogenate from some organs in mice was demonstrated, and FITC-AM was metabolized to a smaller molecule (MW 3000) by the large intestinal microflora in feces. The modified aloe polysaccharide (MW: 80000) with cellulase under restricted conditions, immunologically stimulated the recovery of UV-B-induced tissue in jury. Thus the modified polysaccharides of aloemannan, together with acemannan (MW: about 600000), are expected to participate in biological activity following oral administration. The effects of tanshinone VI, a diterpenoid isolated from Salvia miltiorrhiza, on the heart are reviewed. First, the effects on the posthypoxic recovery of contractile function of perfused rat hearts were examined. Hypoxia/reoxygenation induced a release of purine nucleosides and bases (ATP metabolites) and resulted in little recovery of contractile force of reoxygenated hearts. Pretreatment of the perfused heart with 42 nM tanshinone VI under hypoxic conditions attenuated the release of ATP metabolites during hypoxia/reoxygenation. Treatment with tanshinone VI enhanced the posthypoxic recovery of myocardial contractility. These results show that tanshinone VI may protect the heart against hypoxia/reoxygenation injury and improve the posthypoxic cardiac function. Second, the effects of tanshinone VI on in vitro myocardial remodeling were examined. Cardiomyocytes and cardiac fibroblasts were isolated from neonatal rat hearts, and simultaneously prepared insulin-like growth factor-1 (IGF-1) induced the hypertrophy of cardiomyocytes. IGF-1 increased the collagen synthesis of cardiac fibroblasts, that is, in vitro fibrosis. The hypertrophy of cardiomyocytes was attenuated in the presence of tanshinone VI in the culture medium. The fibrosis of cardiac fibroblasts was decreased by treatment with tanshinone VI. When tanshinone VI was added to cardiac fibroblast-conditioned medium, the medium-mediated hypertrophy of cardiomyocytes was also attenuated. These results show that tanshinone VI may attenuate in vitro cardiac remodeling. The series of studies has shown that tanshinone VI protects the myocardium against hypoxia/reoxygenation injury and attenuates progression of in vitro myocardial remodeling, suggesting that tanshinone VI is a possible agent for the treatment of cardiac disease with contractile failure.
The studies presented here were designed to elucidate the enzymes involved in the biotransformation of naturally occurring 1, 8-dihydroxyanthraquinones and to investigate whether biotransformation of 1,8-dihydroxyanthraquinones may represent a bioactivation pathway. We first studied the metabolism of emodin (1, 3,8-trihydroxy-6-methylanthraquinone), a compound present in pharmaceutical preparations. With rat liver microsomes, the formation of two emodin metabolites, omega-hydroxyemodin and 2-hydroxyemodin, was observed. The rates of formation of omega-hydroxyemodin were not different with microsomes from rats that had been pretreated with inducers for different cytochrome P450 enzymes. Thus, the formation of omega-hydroxyemodin seems to be catalyzed by several cytochrome P450 enzymes at low rates. The formation of 2-hydroxyemodin was increased in liver microsomes from 3-methylcholanthrene-pretreated rats and was inhibited by alpha-naphthoflavone, by an anti-rat cytochrome P450 1A1/2 antibody, and, to a lesser degree, by an anti-rat cytochrome P450 1A1 antibody. These data suggest the involvement of cytochrome P450 1A2 in the formation of this metabolite. However, other cytochrome P450 enzymes also seem to catalyze this reaction. The anthraquinone chrysophanol (1,8-dihydroxy-3-methylanthraquinone) is transformed, in a cytochrome P450-dependent oxidation, to aloe-emodin (1, 8-dihydroxy-3-hydroxymethylanthraquinone) as the major product formed. The mutagenicity of the parent dihydroxyanthraquinones and their metabolites was compared in the in vitro micronucleus test in mouse lymphoma L5178Y cells. 2-Hydroxyemodin induced much higher micronucleus frequencies, compared with emodin. omega-Hydroxyemodin induced lower micronucleus frequencies, compared with emodin. Aloe-emodin induced significantly higher micronucleus frequencies than did chrysophanol. These data indicate that the cytochrome P450-dependent biotransformation of emodin and chrysophanol may represent bioactivation pathways for these compounds.
Characterizing the biological effects of metabolic transformations (or biotransformation) is one of the key steps in developing safe and effective pharmaceuticals. Sulfate conjugation, one of the major phase II biotransformations, is the focus of this study. While this biotransformation typically facilitates excretion of metabolites by making the compounds more water soluble, sulfation may also lead to bioactivation, producing carcinogenic products. The end result, excretion or bioactivation, depends on the structural features of the sulfation sites, so obtaining the structure of the sulfated metabolites is critically important. We describe herein a very simple, high-throughput procedure for using mass spectrometry to identify the structure-and thus the biological fate-of sulfated metabolites. We have chemically synthesized and analyzed libraries of compounds representing all the biologically relevant types of sulfation products, and using the mass spectral data, the structural features present in these analytes can be reliably determined, with a 97% success rate. This work represents the first example of a high-throughput analysis that can identify the structure of sulfated metabolites and predict their biological effects.
Chimeras of the double chain bis-cystinyl hinge fragment 225-232/225'-232' of the human IgG1 and of peptides related to human little-gastrin were synthesized, whereby the fully bioactive gastrin sequences 2-17 and 5-17 were amide-bond-linked N- and N- or C-terminally, respectively, to the hinge peptide. All the dimeric constructs proved to be efficient immunogens; however, both the configuration of the constructs and the length of the haptenic gastrin molecule were found to drastically affect the specificity of the antibody response and, thus, the type of dominant immune epitope expressed. The different degree of accessibility of the gastrin chains in the dimers is similarly reflected by their binding affinities to gastrin receptors and their bioactivities in vivo. Molecular dynamics simulations of the chimeric compounds clearly revealed that the conformational space of the gastrin peptide chains 2-17 and 5-17 is strongly restricted upon linkage to the hinge peptide. Only in the gastrin-(2-17) construct does sufficient free conformational space seem to be retained, at least for one of the two gastrin chains, in order to allow folding into the bioactive structure. This also agrees with the observation that the dimeric gastrin-(2-17) behaves like a gastrin monomer in terms of receptor binding affinity and biopotency in vivo; but it could additionally explain why an antibody response of gastrin receptor-like specificity could only be induced with this construct. The experimental data may therefore suggest a high degree of parallelism between the mechanism of recognition of the gastrin peptides in the dimeric constructs as hormonal ligands by the gastrin receptors and as haptens by the immune competent cells.
Anorganic materials as glass ceramics with their main crystal phase apatite can be used as biomaterial for the bone substitute. An interior compound between bioglass-ceramics implants and the bone was showed in animal experiments. The apatite crystals in the bioglass-ceramics produce obviously the start point for this fusion process. The shear strength of the compound is on average the eightfold of highly compact Al2O3 ceramics. The bioactive glass ceramics could solve possibly the problems of implant loosening and defect bridging-over. Mechanical processable bioactive ceramics was developed and tested with regard to these employment spheres.
Water extracts of garlic, deodorized garlic powder, and onions, but not leeks, were found to significantly (p < 0.05) reduce the in vitro formation of N-nitrosomorpholine (NMOR), a known liver carcinogen. Addition of increasing quantities (20, 40, and 80 mM) of S-allyl cysteine (SAC), a water-soluble compound in processed garlic, depressed NMOR formation by 16%, 27%, and 43%, respectively (p < 0.05). The ability of SAC to block NMOR formation decreased as the NaNO7 and morpholine concentrations increased. SAC and its non-allyl analog S-propyl cysteine effectively blocked NMOR formation. SAC and S-propyl cysteine were less effective than isomolar cysteine in reducing NMOR formation (p < 0.05). The oil-soluble sulfur compounds diallyl disulfide (DADS), dipropyl disulfide, and diallyl sulfide were ineffective inhibitors of NMOR generation (p > 0.05). SAC and DADS reduced the mutagenicity of NMOR in Salmonella typhimurium TA100 (p < 0.05). SAC at 70 mumol/plate reduced the number of histidine revertants per plate by 51% (p < 0.05), whereas DADS at 0.12 mumol/plate reduced mutant colony number by 76% (p < 0.05). SAC and DADS were more effective than isomolar cysteine in reducing NMOR mutagenicity (p < 0.05). The ability of sulfur compounds in garlic and onions to depress nitrosamine formation and bioactivation in these studies is consistent with epidemiologic evidence that higher intake of allium plants is associated with a reduction in the risks of some cancers.
The alcyonacean soft coral Sinularia flexibilis Quoy and Gaimard produces a number of bioactive complementary (secondary) metabolites. The ability of three of these diterpenes - flexibilide, sinulariolide and dihydroflexibilide - to elicit differential discriminatory feeding behavior in Gambusia affinis was assessed in a feeding deterrence study. Terpene-impregnated fish flakes were offered to fish trained to feed on such food, and their responses (acceptance, rejection, avoidance, or no response) were assessed as indicative of feeding deterrence. Food treated with sinulariolide (a compound previously determined to be non-bioactive) was generally accepted at a 1% concentration. It was avoided and rejected, however, at a concentration of 10%, a concentration level generally restricted to polyp-rich branchlets. This indicated negative olfactory and palatability cues, respectively. Flexibilide-treated flakes were accepted to some extent by the fish at the 1% concentration, but strongly avoided at the 10% concentration, indicating effective feeding deterrence via olfaction. Dihydroflexibilide-impregnated flakes were strongly rejected even at low concentrations (1%) after tasting, indicating a negative palatibility cue. They were strongly avoided or rejected at higher concentrations (10%), indicating a negative olfactory cue as well. This response at higher concentrations indicates that sinulariolide and flexibilide become effective at concentrations between 1% and 10%. Such concentrations may be found in the polypary (polyp-bearing portion) of the soft coral colonies. Dihydroflexibilide elicited the strongest negative palatability response from these test fish. The feeding deterrence characteristics of the compounds determined here represent the potentials of individual compounds to elicit differential feeding responses in organisms like Gambusia which are capable of discriminating between different but closely related complementary (secondary) metabolites.
A series of 2-alkyl-3-hydroxy-4-pyrone oxovanadium(IV) compounds has been synthesized, characterized, and tested for bioactivity as potential insulin-enhancing agents. The vanadyl complexes, bis(maltolato)oxovanadium(IV), BMOV, bis(ethylmaltolato)oxovanadium(IV), BEOV, and bis(isopropylmaltolato)oxovanadium(IV), BIOV, were compared against vanadyl sulfate for glucose-lowering ability, when administered i.p. to STZ-diabetic rats, at a one-time dose of 0.1 mmol kg(-1)body weight. Blood levels of vanadium were determined at regular intervals, to 72 h, following i.p. injection. All complexes tested exceeded vanadyl sulfate in glucose-lowering ability; this effect was not correlated, however, with blood vanadium levels. Analysis of the pharmacokinetics of the disappearance of [ethyl-1-(14)C]BEOV after an oral gavage dose (50 mg kg(-1), 0.144 mmol kg(-1), in a 10 mL kg(-1) volume of 1% CMC solution) indicated clearly that metal ion-ligand dissociation took place relatively soon after oral ingestion of the complex. Half-lives of fast phase uptake and slow phase disappearance for (14)C and V were calculated from a two-compartment model for whole blood, plasma, liver, kidney, bone, small intestine, and lung, ranging from 17 min ( t(1/2)alpha for (14)C, liver) to 30 days ( t(1/2)beta for V, bone). Curves of disappearance of plasma and whole blood (14)C and V diverged dramatically within the first hour after administration of the vanadium complex.
N-oxide-containing compounds have been developed as prodrugs that are selectively bioactivated in the hypoxic cells in tumors. This selectivity is based on the net reduction of the N-oxide moiety in the absence of oxygen, in a one or two-electron process, by reductive enzymes. A wide range of N-oxides have been studied and some of them are currently in clinical use. This review covers the principal families of compounds under study and in clinical trials.
A series of 4-carboxychalcones 1 were prepared and coupled to 3,5-bis(phenylmethylene)-4-piperidone (2) giving rise to a novel series of N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones (3). Molecular simplification of the amides 3 led to the formation of the corresponding N-(3-aryl-1-oxo-2-propenyl)-3,5-bis(phenylmethylene)-4-piperidones (4). A cytotoxic evaluation of the compounds in series 1-4 utilized murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the compounds displayed significant toxicity; the IC(50) values of 54% of the enones were less than 10 microM when all four screens were considered and less than 1 microM for all members of series 3 in the P388 assay. Various correlations were established between the potencies of the compounds in series 1, 3 and 4 and the Hammett sigma, Hansch pi and molecular refractivity constants of the aryl substituents. Several torsion angles and interatomic distances of five representative compounds in series 3 and 4 were determined by X-ray crystallography, some of which contributed to the observed bioactivity. The marked cytotoxicity and lack of murine toxicity of most of the compounds described in this study, as well as their selective toxicity towards different tumour cell lines, revealed that development of the enones 2-4 as novel candidate antineoplastic agents should be pursued.
The agaricoglycerides are a new class of fungal secondary metabolites that constitute esters of chlorinated 4-hydroxy benzoic acid and glycerol. They are produced in cultures of the edible mushroom, Agaricus macrosporus, and several other basidiomycetes of the genera Agaricus, Hypholoma, Psathyrella and Stropharia. The main active principle, agaricoglyceride A, showed strong activities against neurolysin, a protease involved in the regulation of dynorphin and neurotensin metabolism (IC50 = 200 nM), and even exhibited moderate analgesic in vivo activities in an in vivo model. Agaricoglyceride monoacetates (IC50 = 50 nM) showed even stronger in vitro activities. Several further co-metabolites with weaker or lacking bioactivities were also obtained and characterized. Among those were further agaricoglyceride derivatives, as well as further chlorinated phenol derivatives such as the new compound, agaricic ester. The characteristics of the producer organisms, the isolation of bioactive metabolites from cultures of A. macrosporus, their biological activities, and preliminary results on their occurrence in basidiomycetes, are described.
Isoprostanes, are a novel group of prostaglandin-like compounds that are biosynthesised from esterified polyunsaturated fatty acid (PUFA) through a non-enzymatic free radical-catalysed reaction. Several of these compounds possess potent biological activity, as evidenced mainly through their pulmonary and renal vasoconstrictive effects, and have short half-lives. It has been shown that isoprostanes act as full or partial agonists through thromboxane receptors. Both human and experimental studies have indicated associations of isoprostanes and severe inflammatory conditions, ischemia-reperfusion, diabetes and atherosclerosis. Reports have shown that F2-isoprostanes are authentic biomarkers of lipid peroxidation and can be used as potential in vivo indicators of oxidant stress in various clinical conditions, as well as in evaluations of antioxidants or drugs for their free radical-scavenging properties. Higher levels of F2-isoprostanes have been found in the normal human pregnancy compared to non-pregnancy, but their physiological role has not been well studied so far. Since bioactive F2-isoprostanes are continuously formed in various tissues and large amounts of these potent compounds are found unmetabolised in their free acid form in the urine in normal basal conditions with a wide inter-individual variation, their role in the regulation of normal physiological functions could be of further biological interest, but has yet to be disclosed. Their potent biological activity has attracted great attention among scientists, since these compounds are found in humans and animals in both physiological and pathological conditions and can be used as reliable biomarkers of lipid peroxidation.