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At least 1,009 records · Page 56Linked to original sources
PubMed2003

Immunosuppressive substances in Aspergillus fumigatus culture filtrate.

Invasive aspergillosis has become a serious problem in clinical practice, but the actual factor that confers virulence on the fungus has not been thoroughly elucidated. To identify and isolate the immunosuppressive substances produced by the fungus, the bioactivity of culture filtrates was assessed, and analyses of the culture filtrates were carried out. Culture filtrates from different strains of Aspergillus fumigatus were assessed for their effect on human polymorphonuclear leukocytes and murine macrophages. To assess their activities in vivo, their effect on the survival of mice infected by the fungus was also studied. Subsequently, the composition of the culture filtrates was analyzed by gas chromatography-mass spectrometry. The analyses revealed that the culture filtrates contained gliotoxin at concentrations of 3 to 4 microgram/ml, and some other unidentified compounds. The bioactivities of the culture filtrates were similar to those of gliotoxin. The fungal culture filtrate reduced the survival of infected mice, but the filtrate itself did not cause the death of mice. However, all the bioactivities could not be accounted for by gliotoxin itself. These results indicate that gliotoxin in the culture filtrates may be responsible for part of the immunosuppressive activity, but some other components produced by A. fumigatus contribute, in an additive or synergistic manner, to the virulence of the fungus.

Animals↗
PubMed2002

Steroid hormone receptors and dietary ligands: a selected review.

Members of the nuclear steroid hormone superfamily mediate essential physiological functions. Steroid hormone receptors (SHR) act directly on DNA, regulate the synthesis of their target genes and are usually activated by ligand binding. Both endogenous and exogenous compounds and their metabolites may act as activators of SHR and disruptors of endocrine, cellular and lipid homeostasis. The endogenous ligands are generally steroids such as 17beta-oestradiol, androgens, progesterone and pregnenolone. The exogenous compounds are usually delivered through the diet and include non-steroidal ligands. Examples of such ligands include isoflavanoids or phytooestrogens, and food contaminants such as exogenous oestrogens from hormone-treated cattle, pesticides, polychlorinated biphenyls and plasticisers. Certain drugs are also ligands; so nuclear receptors are also important drug targets for intervention in disease processes. The present review summarises recent reports on ligand-activated SHR that describe the selective regulation of a tightly-controlled cross-talking network involving exchange of ligands, and the control of major classes of cytochrome P450 (CYP) isoforms which metabolise many bioactive exogenous compounds. Many CYP have broad substrate activity and appear to be integrated into a coordinated metabolic pathway, such that whilst some receptors are ligand specific, other sensors may have a broader specificity and low ligand affinity to monitor aggregate levels of inducers. They can then trigger production of metabolising enzymes to defend against possible toxic nutrients and xenobiotic compounds. The influence of dietary intakes of nutrients and non-nutrients on the human oestrogen receptors (alpha and beta), the aryl hydrocarbon receptor, the pregnane X receptor, the constitutive androstane receptor, and the peroxisome proliferator-activated receptors (alpha and gamma), can be examined by utilising computer-generated molecular models of the ligand-receptor interaction, based on information generated from crystallographic data and sequence homology. In relation to experimental and observed data, molecular modelling can provide a scientifically sound perspective on the potential risk and benefits to human health from dietary exposure to hormone-mimicking chemicals, providing a useful tool in drug development and in a situation of considerable public concern.

Animals↗
PubMed2002

Identification of bioactive molecules by adipogenesis profiling of organic compounds.

An important step in the postgenomic drug discovery is the construction of high quality chemical libraries that generate bioactive molecules at high rates. Here we report a cell-based approach to composing a focused library of biologically active compounds. A collection of bioactive non-cytotoxic chemicals was identified from a divergent library through the effects on the insulin-induced adipogenesis of 3T3-L1 cells, one of the most drastic and sensitive morphological alterations in cultured mammalian cells. The resulting focused library amply contained unique compounds with a broad range of pharmacological effects, including glucose-uptake enhancement, cytokine inhibition, osteogenesis stimulation, and selective suppression of cancer cells. Adipogenesis profiling of organic compounds generates a focused chemical library for multiple biological effects that are seemingly unrelated to adipogenesis, just as genetic screens with the morphology of fly eyes identify oncogenes and neurodegenerative genes.

3T3 Cells↗
PubMed2006

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts.

Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein was detected. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time- and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.

Anti-Infective Agents↗
PubMed1997

Genetically modified Escherichia coli for colorimetric detection of inorganic and organic Hg compounds.

A sensitive colorimetric bacterial system was developed for the detection of Hg(II) and organomercury compounds. The bioactive species, a recombinant Escherichia coli, produces proportionally elevated levels of the enzyme beta-galactosidase with increasing amounts of Hg. This is due to a reporter plasmid which carriers a Hg(II)-inducible promoter (mer promoter) from the Hg resistance transposon Tn501 regulating the transcription of a promoterless lacZ gene. Additionally, a pMB1 origin of replication without the natural RNA polymerase start site is fused downstream of the mer promoter leading to a Hg(II)-inducible plasmid replication, which results in an improved signal-to-noise ratio. To enhance the sensitivity of this cellular biosensor, the transport proteins for Hg(II) uptake are constitutively produced by a helper plasmid. To enable the detection of organically bound Hg, the Streptomyces lividans organomercurical lyase, an enzyme which catalyses the cleavage of C-Hg-bonds of organomercurial compounds, is also provided by the helper plasmid. Hg(II) and phenylmercuric acetate (PMA) concentrations as low as 5 x 10(-10) M (0.1 ppb) may be detected within a few minutes.

Biological Transport↗
PubMed2007

Effect of culture conditions on antifouling compound production of a sponge-associated fungus.

Microorganisms associated with invertebrate hosts have long been suggested to be a source for bioactive metabolites. In this study, we reported that a sponge-associated fungus, Letendraea helminthicola, produced two antifouling compounds: 3-methyl-N-(2-phenylethyl) butanamide and cyclo(D-Pro-D-Phe). To optimize the production of these antifouling compounds, we then examined the production of compounds under different culture conditions (temperature, salinity, pH, and carbon and nitrogen sources). This fungus grew well and produced more compounds at temperatures between 18 and 30 degrees C; the fungus grew well at 75 parts per thousand (ppt) salinity but produced the highest amount of antifouling compounds at 30 and 45 ppt. The optimal initial pH value for mycelial growth was 5.5 to 6.5, whereas the production of the antifouling compounds was maximized at pH 3.5 and 4.5. Glucose and xylose (as carbon sources) increased the production of antifouling compounds. Yeast extract and peptone (as nitrogen sources) maximized the production of mycelial biomass and antifouling compounds. Our results indicate that culture conditions greatly affect the production of bioactive compounds from mycelial fungal cultures as exemplified by strain L. helminthicola and that the conditions favorable for fungal growth may not be the best conditions for bioactive compound production.

Animals↗
PubMedDate not supplied

Chemoinformatics-based classification of prohibited substances employed for doping in sport.

Representative molecules from 10 classes of prohibited substances were taken from the World Anti-Doping Agency (WADA) list, augmented by molecules from corresponding activity classes found in the MDDR database. Together with some explicitly allowed compounds, these formed a set of 5245 molecules. Five types of fingerprints were calculated for these substances. The random forest classification method was used to predict membership of each prohibited class on the basis of each type of fingerprint, using 5-fold cross-validation. We also used a k-nearest neighbors (kNN) approach, which worked well for the smallest values of k. The most successful classifiers are based on Unity 2D fingerprints and give very similar Matthews correlation coefficients of 0.836 (kNN) and 0.829 (random forest). The kNN classifiers tend to give a higher recall of positives at the expense of lower precision. A naïve Bayesian classifier, however, lies much further toward the extreme of high recall and low precision. Our results suggest that it will be possible to produce a reliable and quantitative assignment of membership or otherwise of each class of prohibited substances. This should aid the fight against the use of bioactive novel compounds as doping agents, while also protecting athletes against unjust disqualification.

Algorithms↗
PubMed1999

3-Formyl-1-butyl pyrophosphate A novel mycobacterial metabolite-activating human gammadelta T cells.

Most human blood gammadelta T cells react without major histocompatibility complex restriction to small phosphorylated nonpeptide antigens (phosphoantigens) that are abundantly produced by mycobacteria and several other microbial pathogens. Although isopentenyl pyrophosphate has been identified as a mycobacterial antigen for gammadelta T cells, the structure of several other stimulating compounds with bioactivities around 1000-fold higher than isopentenyl pyrophosphate remains to be elucidated. This paper describes the structural identification of 3-formyl-1-butyl-pyrophosphate as the core of several non-prenyl mycobacterial phosphoantigens bioactive at the nM range. Recognition of this molecule by gammadelta T cells is very selective and relies on its aldehyde and pyrophosphate groups. This novel pyrophosphorylated aldehyde most probably corresponds to a metabolic intermediate of the non-mevalonate pathway of prenyl phosphate biosynthesis in eubacteria and algae. The reactivity to 3-formyl-1-butyl-pyrophosphate supports the view that human gammadelta T cells are physiologically devoted to antimicrobial surveillance.

Antigens, Bacterial↗
PubMed2004

Natural inhibitors of carcinogenesis.

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4'-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structure-activity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The compounds (2 S)-abyssinone II, (2 S)-2',4'-dihydroxy-2"-(1-hydroxy-1-methylethyl)dihydrofuro[2,3- h]-flavanone, 3'-[gamma-hydroxymethyl-( E)-gamma-methylallyl]-2,4,2',4'-tetrahydroxychalcone 11'- O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.

Animals↗
PubMed2006

Distance based algorithms for small biomolecule classification and structural similarity search.

MOTIVATION: Structural similarity search among small molecules is a standard tool used in molecular classification and in-silico drug discovery. The effectiveness of this general approach depends on how well the following problems are addressed. The notion of similarity should be chosen for providing the highest level of discrimination of compounds wrt the bioactivity of interest. The data structure for performing search should be very efficient as the molecular databases of interest include several millions of compounds. RESULTS: In this paper we focus on the k-nearest-neighbor search method, which, until recently was not considered for small molecule classification. The few recent applications of k-nn to compound classification focus on selecting the most relevant set of chemical descriptors which are then compared under standard Minkowski distance L(p). Here we show how to computationally design the optimal weighted Minkowski distance wL(p) for maximizing the discrimination between active and inactive compounds wrt bioactivities of interest. We then show how to construct pruning based k-nn search data structures for any wL(p) distance that minimizes similarity search time. The accuracy achieved by our classifier is better than the alternative LDA and MLR approaches and is comparable to the ANN methods. In terms of running time, our classifier is considerably faster than the ANN approach especially when large data sets are used. Furthermore, our classifier quantifies the level of bioactivity rather than returning a binary decision and thus is more informative than the ANN approach.

Algorithms↗
PubMed1998

Research on potentially bioactive aza and thiaza polycyclic compounds containing a bridgehead nitrogen atom. Synthesis and antimicrobial activity of some pyrrolo[1,2,3-de]-1,4-benzothiazines, Part 2.

Acid catalyzed cyclization reactions of both 3-alkyl- and 3-aryl-substituted N-(2,2-dialkoxyethyl)-3,4-dihydro-2H-1,4-benzothiazines (2) lead to 2,3-dihydro-pyrrolo[1,2,3-de]-1,4-benzothiazines (3). The pyrrolobenzothiazine structure was deduced on the basis of 2D 1H NMR-NOESY experiments and fully determined by X-ray data. Compounds 3a-c showed poor antibacterial activity. However, the 3-phenyl-N-(2,2-dimethoxyethyl)-3,4-dihydro-2H-1,4-benzothiazine (2b') showed antifungal activity against Aspergillus niger 16-fold greater than miconazole.

Animals↗
PubMed2006

Impact of epimerization domains on the intermodular transfer of enzyme-bound intermediates in nonribosomal peptide synthesis.

Assembly of bioactive natural compounds through the action of nonribosomal peptide synthetases (NRPSs) relies on the specific interplay of modules and domains along these multiple mega-enzymes. As the C termini of several bacterial NRPSs often harbor epimerization (E) domains that generate D-amino acids, these seem to facilitate the ordered intermolecular enzymatic interaction and the directed transfer of intermediates. To elucidate this bifunctional role, E domains in recombinant bimodular proteins derived from the tyrocidine synthetase B were investigated. By utilizing sequent tryptic proteolysis and HPLC Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), we could directly interrogate and determine the formation of intermediates attached to the TycB(3)-PCP domain of wild-type TycB(2-3) and to the E domain exchange enzyme TycB(2-3)-ATCAT/E(tycA). In addition, the two proteins and a version of TycB(2-3) fused to the communication-mediating (COM) domain of TycA were applied in product formation assays with TycB(1) to corroborate E domain impact on intermodular NRPS interaction. Significant functional differences between the C-terminal aminoacyl- and peptidyl-E domains were observed in terms of in trans interaction and misinitiation. E domains originating from elongation modules (peptidyl-E domains) seem to be optimized for regulation of the progression of peptide bond formation, epimerization, and intermediate transfer to the downstream module, whereas E domains of initiation modules (aminoacyl-E domains) impair upstream condensation and cause misinitiation. The selection of E domains is therefore decisive for successful application in biocombinatorial engineering of nonribosomal peptides.

Binding Sites↗
PubMed2005

Retinoic acid signaling is required for proper morphogenesis of mammary gland.

Retinoic acid (RA), a bioactive chemical compound synthesized from dietary derived vitamin A, has been successfully used as a chemopreventive and chemotherapeutic agent through the regulation of cell proliferation, differentiation, and apoptosis acting via the retinoic acid receptors. Despite two decades of research on the function of retinoic acid, the physiological role of RA in mammary gland development is still not well characterized. In this report, we demonstrate that RA is required for proper morphogenesis of mouse mammary gland in a novel transgenic mouse model system. It was found that inhibition of RA signaling in vivo leads to excessive mammary ductal morphogenesis through upregulation of cyclin D1 and MMP-3 expression. Furthermore, we show that the transgene-induced excessive branching morphogenesis could be reversed by treatment with RA, demonstrating the direct physiological effect of RA signaling in vivo. In addition, we demonstrate that excessive branching morphogenesis in the transgenic mammary gland are cell-autonomous and do not require stromal signals within the transgenic mammary gland. Finally, we provide evidence suggesting that retinoic acid signaling is required for appropriate mammary gland differentiation. Collectively, our data indicate for the first time that retinoic acid signaling is required to maintain the homeostasis of mammary gland morphogenesis.

Animals↗
PubMed2003

Use of osmotic agents in microdialysis studies to improve the recovery of macromolecules.

The availability of microdialysis probes with higher molecular weight cutoff membranes has made it possible to measure larger molecular weight compounds like bioactive peptides and proteins. However, the higher molecular weight membrane cutoff allows for increased fluid loss from the probe, influencing both the physiology of the tissue compartment and analyte recovery. This study examined the ability of osmotic agents like bovine serum albumin (BSA) to offset the water loss from the microdialysis probe. In the presence of BSA, water loss from the microdialysis probe was minimized. Furthermore, addition of BSA to the perfusate produced significant increases in analyte recovery. Application of this technique to the measurement of bioactive macromolecules was examined using in vitro microdialysis of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1B). The results of the present study suggest osmotic agents like BSA can prevent fluid loss from the microdialysis probe and improve analyte recovery.

Macromolecular Substances↗
PubMed2006

Bioactivity of extracts and isolated compounds from Vitex polygama (Verbenaceae) and Siphoneugena densiflora (Myrtaceae) against Spodoptera frugiperda (Lepidoptera: Noctuidae).

The effects of crude extracts, fractions and isolated compounds from Vitex polygama Cham. and Siphoneugena densiflora Berg were evaluated on the development of Spodoptera frugiperda JE Smith, a destructive insect pest of corn and several other crops. The extracts and fractions were incorporated into an artificial diet at 1 mg g(-1) and offered to the insect during its larval stage. Length and viability of larval and pupal stages as well as pupal weight were assessed. Isolated compounds were tested through superficial contamination of the diet at 0.1 mg g(-1). Weight and viability of ten-day-old larvae were determined. Methanolic and hydroalcoholic S. densiflora extracts caused 100% larval mortality, while leaf and fruit hydroalcoholic extracts from V. polygama were the most active. Among the isolated compounds, flavonoids presented the best insecticidal results, and tannins the best larval growth inhibition.

Animals↗
PubMed2004

Peptide and amino acid glycation: new insights into the Maillard reaction.

Nonenzymatic glycation of proteins, peptides and other macromolecules (the Maillard reaction) has been implicated in a number of pathologies, most clearly in diabetes mellitus. but also in the normal processes of aging and neurodegenerative amyloid diseases such as Alzheimer's. In the early stage, glycation results in the formation of Amadori-modified proteins. In the later stages, advanced glycation end products (AGE) are irreversibly formed from Amadori products leading to the formation of reactive intermediates, crosslinking of proteins, and the formation of brown and fluorescent polymeric materials. Although, the glycation of structural proteins has been attributed a key role in the complications of diabetes, recent attention has been devoted to the physiological significance of glycated peptide hormones. This review focuses on the physico-chemical properties of the Amadori compounds of bioactive peptides of endogenous and exogenous origin, such as Leu-enkephalin and morphiceptin, investigated under different conditions as well as on novel pathways in the Maillard reaction observed from investigating intramolecular events in ester-linked glycopeptides.

Amino Acids↗
PubMed2002

Synthesis of plumbagin derivatives and their inhibitory activities against Ehrlich ascites carcinoma in vivo and Leishmania donovani Promastigotes in vitro.

Plumbagin, a plant-derived bioactive naphthoquinonoid compound, was converted to a hydroquinonoid derivative, which was studied for its tumour-inhibitory and antileishmanial activities for the first time. A similar chemical transformation was undertaken on an analogous dimeric compound, diospyrin, and its bioassay results were compared with those of the plumbagin derivative. Synthesis of the derivative of plumbagin did not result in a marked enhancement of the tumour-inhibitory activity, whereas the improvement was obvious in the case of diospyrin vis à vis its hydroquinonoid analogue. The conversion of diospyrin to the hydroquinonoid compound also led to a substantial increase in the antileishmanial activity, while a similar conversion of plumbagin failed to do so.

Animals↗
PubMed2001

Bioactive four-membered heterocyclic compounds: the anti --> syn interconversion in dithietane-1,3-dioxide.

The anti-dithietane-1,3-dioxide --> syn-dithietane-1,3-dioxide isomerization reaction has been theoretically studied on the frame of MO theory both in the gas phase and in solution. In the gas phase the anti (II(a)) <--> syn (II(s)) equilibrium is slightly displaced to the anti isomer formation. The syn concentration ([Syn]) is ca. 36% in the gas phase, whereas in low polarity solvent, such as carbon tetrachloride, [Syn] is ca. 63%. In medium-high polarity solvents like acetonitrile and dimethyl-sulfoxide the [ anti]/[ syn ] ratio is ca. 0.37.

Acetonitriles↗