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At least 433 records · Page 24Linked to original sources
PubMed1997

Enhancing endogenous effects of natriuretic peptides: inhibitors of neutral endopeptidase (EC.3.4.24.11) and phosphodiesterase.

Because diuretic drugs remain the main treatment for disorders of sodium and water metabolism, the quest for improved diuretic and natriuretic agents continues in the hope of achieving fewer side effects and a more rational basis in pathophysiology. One aim has been to enhance endogenous diuretic and natriuretic activity by selective manipulation of atrial natriuretic peptide and related compounds. The first approach has been to inhibit degradation of these peptides using inhibitors of their main catabolic enzyme, neutral endopeptidase, and to offset any antagonistic effect of the renin-angiotensin system by combination with an angiotensin-converting enzyme inhibitor. The second and more recent approach has been to inhibit breakdown of the second messenger of atrial natriuretic peptide, cGMP, using phosphodiesterase inhibitors. As yet, neutral endopeptidase inhibition has not advanced successfully beyond animal experimentation and phosphodiesterase inhibition is still in its infancy. Both strategies suffer from the problem that, on the one hand, neutral endopeptidase metabolizes a variety of bioactive peptides, including endothelin, and it is not possible to develop inhibitors that will be selective for a given peptide; whereas, on the other hand, there are several phosphodiesterase isoforms metabolizing cGMP and cAMP, both second messengers for many different bioactive compounds, and selective inhibitors are still under development.

Animals↗
PubMed2004

Aspergillus fumigatus CY018, an endophytic fungus in Cynodon dactylon as a versatile producer of new and bioactive metabolites.

Aspergillus fumigatus CY018 was recognized as an endophytic fungus for the first time in the leaf of Cynodon dactylon. By bioassay-guided fractionation, the EtOAc extract of a solid-matrix steady culture of this fungus afforded two new metabolites, named asperfumoid (1) and asperfumin (2), together with six known bioactive compounds including monomethylsulochrin, fumigaclavine C, fumitremorgin C, physcion, helvolic acid and 5alpha,8alpha-epidioxy-ergosta-6,22-diene-3beta-ol as well as other four known compounds ergosta-4,22-diene-3beta-ol, ergosterol, cyclo(Ala-Leu) and cyclo(Ala-Ile). Through detailed spectroscopic analyses including HRESI-MS, homo- and hetero-nuclear correlation NMR experiments (HMQC, COSY, NOESY and HMBC), the structures of asperfumoid and asperfumin were established to be spiro-(3-hydroxyl-2,6-dimethoxyl-2,5-diene-4-cyclohexone-(1,3')-5'-methoxyl-7'-methyl-(1'H, 2'H, 4'H)-quinoline-2',4'-dione) and 5-hydroxyl-2-(6-hydroxyl-2-methoxyl-4-methylbenzoyl)-3,6-dimethoxyl-benzoic methyl ester, respectively. All of the 12 isolates were subjected to in vitro bioactive assays against three human pathogenic fungi Candida albicans, Tricophyton rubrum and Aspergillus niger. As a result, asperfumoid, fumigaclavine C, fumitremorgin C, physcion and helvolic acid were shown to inhibit C. albicans with MICs of 75.0, 31.5, 62.5, 125.0 and 31.5 microg/mL, respectively.

Antifungal Agents↗
PubMed2006

Medicinal mushrooms and cancer therapy: translating a traditional practice into Western medicine.

Modern medical practice relies heavily on the use of highly purified pharmaceutical compounds whose purity can be easily assessed and whose pharmaceutical activity and toxicity show clear structure-function relationships. In contrast, many herbal medicines contain mixtures of natural compounds that have not undergone detailed chemical analyses and whose mechanism of action is not known. Traditional folk medicine and ethno-pharmacology coupled to bioprospecting have been an important source of many anticancer agents as well as other medicines. With the current decline in the number of new molecular entities from the pharmaceutical industry, novel anticancer agents are being sought from traditional medicine. As the example of medicinal mushrooms demonstrates, however, translating traditional Eastern practices into acceptable evidence-based Western therapies is difficult. Different manufacturing standards, criteria of purity, and under-powered clinical trials make assessment of efficacy and toxicity by Western standards of clinical evidence difficult. Purified bioactive compounds derived from medicinal mushrooms are a potentially important new source of anticancer agents; their assimilation into Western drug discovery programs and clinical trials also provides a framework for the study and use of other traditional medicines.

Agaricales↗
PubMed2006

Nutridynamics--studying the dynamics of food components in products and in the consumer.

The concentrations and biological effects of nutrients, antinutrients and bioactive compounds, including microbes and their constituents, are affected by production and processing steps, the food matrix in which they reside, the way they are digested and metabolized in the human body, and whether or not and in what form they subsequently reach their target site. A new scientific concept, denoted here as 'nutridynamics', aims to unravel the dynamics of these processes by using a systematic approach to study how a food component is affected by the food matrix itself and what it does in the body. This holistic concept has potential synergy with the areas of food technology and nutrigenomics, and provides a link between food production and the mechanistic effects of bioactive ingredients.

Eating↗
PubMed2006

Modulatory effects of resveratrol, citroflavan-3-ol, and plant-derived extracts on oxidative stress in U937 cells.

Phytochemicals and plant extracts, present in fruit, vegetables, plants, herbs, and beverages, have been shown to have antioxidant potential that may modulate the etiology of certain chronic diseases. The objective of the present study was to determine the concentration of compound that inhibited cell growth by 50% (IC(50)) of a range of phytochemicals and plant extracts and to investigate their antioxidant and genoprotective effects under conditions of oxidative stress in U937 cells. Two phytochemicals-resveratrol and citroflavan-3-ol-and four plant extracts-grapeseed polyphenols, olive leaf extract, bearberry, and Echinacea purpurea-were examined. Viability was assessed by the fluorescein diacetate/ethidium bromide assay. The IC(50) was calculated. To examine their antioxidant and genoprotective effects, U937 cells were pretreated with the test compounds at levels below the IC(50) and then exposed to oxidants: 0.5 microM etoposide or 100 microM hydrogen peroxide (H(2)O(2)) or 400 microM tert-butylhydroperoxide (tBOOH). Cellular reduced glutathione levels were measured as an indicator of oxidative stress. DNA damage was assessed by the alkaline single-cell gel electrophoresis assay or comet assay. Resveratrol demonstrated the highest IC50 value of 13.7 microg/mL, with Echinacea the lowest at 9,400 microg/mL. Etoposide-induced oxidative stress was strongly reduced by olive leaf extract and bearberry. Grapeseed polyphenols and bearberry strongly protected against H2O2- and tBOOH-induced DNA damage. In conclusion, these results provide evidence that non-nutrient dietary constituents may act as significant bioactive compounds and that plant extracts, such as bearberry, grapeseed polyphenols, and olive leaf extract, strongly protect against oxidative stress.

Antioxidants↗
PubMed2006

Lipid phosphate phosphatase-2 activity regulates S-phase entry of the cell cycle in Rat2 fibroblasts.

Lipid phosphates are potent mediators of cell signaling and control processes including development, cell migration and division, blood vessel formation, wound repair, and tumor progression. Lipid phosphate phosphatases (LPPs) regulate the dephosphorylation of lipid phosphates, thus modulating their signals and producing new bioactive compounds both at the cell surface and in intracellular compartments. Knock-down of endogenous LPP2 in fibroblasts delayed cyclin A accumulation and entry into S-phase of the cell cycle. Conversely, overexpression of LPP2, but not a catalytically inactive mutant, caused premature S-phase entry, accompanied by premature cyclin A accumulation. At high passage, many LPP2 overexpressing cells arrested in G(2)/M and the rate of proliferation declined severely. This was accompanied by changes in proteins and lipids characteristic of senescence. Additionally, arrested LPP2 cells contained decreased lysophosphatidate concentrations and increased ceramide. These effects of LPP2 activity were not reproduced by overexpression or knock-down of LPP1 or LPP3. This work identifies a novel and specific role for LPP2 activity and bioactive lipids in regulating cell cycle progression.

Animals↗
PubMed2004

New PCR primers for the screening of NRPS and PKS-I systems in actinomycetes: detection and distribution of these biosynthetic gene sequences in major taxonomic groups.

Nonribosomal peptide synthetases (NRPS) and type I polyketide synthases (PKS-I) are biosynthetic systems involved in the synthesis of a large number of important biologically active compounds produced by microorganisms, among others by actinomycetes. In order to assess the occurrence of these biosynthetic systems in this metabolically active bacterial group, we designed new PCR primers targeted to specifically amplify NRPS and PKS-I gene sequences from actinomycetes. The sequence analysis of amplified products cloned from two model systems and used to validate these molecular tools has shown the extreme richness of NRPS or PKS-I-like sequences in the actinomycete genome. When these PCR primers were tested on a large collection of 210 reference strains encompassing all major families and genera in actinomycetes, we observed that the wide distribution of these genes in the well-known productive Streptomyces species is also extended to other minor lineages where in some cases very few bioactive compounds have been identified to date.

Actinobacteria↗
PubMed2003

[Development of drug delivery system based on a new administration route for targeting to the specific region in the liver].

Development of drug delivery systems to achieve site-specific delivery or prolonged retention in the circulation has attracted attention, because new types of drugs are expected to be created with advances in life science and biotechnology such as the Human Genome Project. We have tried to develop a new administration route for drug targeting to the liver, since drug administration by the intravenous and oral routes makes it difficult to achieve a local site of action in the liver. Although direct application to the liver surface should result in local drug distribution, drug absorption from the liver surface has not been reported in the literature. Therefore we analyzed the absorption mechanism of several organic anions and dextrans with different molecular weights as model drugs, after application to the rat liver surface in vivo, employing a cylindrical diffusion cell. Every compound appeared gradually in the plasma, followed by excretion into the bile and/or urine, indicating the possibility of drug absorption from the liver surface. A specific transport system might not be involved in the absorption process from the liver surface, because the effect of dose and transport inhibitors on the absorption was not recognized. In addition, molecular weight was found to be a determining factor in absorption from the liver surface. The targeting efficacy was considerably enhanced by application to the liver surface, as compared with intravenous administration. Moreover, we have identified important physicochemical and pharmaceutical factors determining the absorption rate of a drug from the liver surface for clinical use. Consequently, drug application to the liver surface could improve availability in the desired site of a new drug such as bioactive compounds and genomic medicines, by combination with appropriate chemical and pharmaceutical formulation modifications.

Animals↗
PubMed1991

Cloning and expression of cDNA for a human thromboxane A2 receptor.

Thromboxane A2 is a very unstable arachidonate metabolite, yet a potent stimulator of platelet aggregation and a constrictor of vascular and respiratory smooth muscles. It has been implicated as a mediator in diseases such as myocardial infarction, stroke and bronchial asthma. Using a stable analogue of this compound we recently purified the human platelet thromboxane A2 receptor to apparent homogeneity. Using an oligonucleotide probe corresponding to its partial amino-acid sequence, we have obtained a complementary DNA clone encoding this receptor from human placenta and a partial clone from cultured human megakaryocytic leukaemia cells. The placenta cDNA encodes a protein of 343 amino acids with seven putative transmembrane domains. The protein expressed in COS-7 cells binds drugs with affinities identical to those of the platelet receptor, and that in Xenopus oocytes opens Ca2(+)-activated Cl- channel on agonist stimulation. Northern blot analysis and nucleotide sequences of the two clones suggest that an identical species of the thromboxane A2 receptor is present in platelets and vascular tissues. This first report on the molecular structure of an eicosanoid receptor will promote the molecular pharmacology and pathophysiology of these bioactive compounds.

Amino Acid Sequence↗
PubMed1990

Uncouplers of oxidative phosphorylation.

Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound.

Acids↗
PubMed1994

Introduction of oxygen into the alkyl chain of N-decyl-dNM decreases lipophilicity and results in increased retention of glucose residues on N-linked oligosaccharides.

N-Alkylation of the alpha-glucosidase inhibitor 1-deoxynojirimycin (dNM) dramatically increases its inhibitory potency (Tan et al., J. Biol. Chem., 266, 14504-14510, 1991). However, the possibility of extending the alkyl chain to N-decyl-dNM is limited by an increase of detergent-like (amphiphilic) properties of long-chain alkylated dNM derivatives. Substitution of methylene groups in the N-decyl chain by oxygen reduced the amphiphilicity of N-decyl-dNM derivatives, while retaining their superior inhibitory properties. In intact HepG2 cells, the compound N-7-oxadecyl-dNM was found to result in the most pronounced retention of glucose residues on N-linked glycans. Permeabilization of the plasma membrane with the bacterial toxin Streptolysin O improves the inhibitory properties of the derivatives N-3,6,9-trioxadecyl-, N-7,10,13-trioxatetradecyl-, N-3-oxadecyl- and N-7-oxadecyl-dNM, but not those of dNM. These observations suggest differences in the mode of entry of the oxygen-substituted dNM derivatives in comparison with dNM. We observed that the dNM derivative N-3,6,9-trioxadecyl-dNM, devoid of inhibitory activity in intact cells, was inhibitory in Streptolysin O-permeabilized cells. Thus, the permeability barriers posed by plasma membrane and endoplasmic reticulum membrane are not equivalent. The use of a permeabilized cell system thus allows the elaboration of inhibitory principles for novel bioactive compounds where study of the isolated enzymes may not be possible, and where intact cells are not a suitable target due to permeability barriers.

1-Deoxynojirimycin↗
PubMed2005

Biological activity of selected tyrosine-containing 2,5-diketopiperazines.

The study investigates two cyclic dipeptides, cyclo(Tyr-Tyr) (cTT) and cyclo(Phe-Tyr) (cPT) with respect to their biological activity. Investigations using the whole-cell patch-clamp technique testing the effects of 100 microM cyclic dipeptide on ion channels, revealed reversible voltage-dependant blockade for cTT, while cPT exhibited irreversible time-dependant blockade of L-type calcium channels. The isolated retrogradely-perfused rat heart was used to determine the effects of 100 microM of either cTT or cPT on heart rate (HR), coronary flow rate (CFR), left ventricular systolic pressure (LVSP) and cardiac conduction speed. Results indicated opposing effects for the two compounds, where cTT increased HR and CF while cPT decreased HR, CF, LVSP as well as conduction speed. Other biological investigations included opioid binding and anti-neoplastic assays. Competitive binding curves, using tritiated DAMGO, revealed significant binding to micro-opioid receptors with IC50 values for cTT and cPT being 0.82 microM and 69.7 microM respectively. Anti-neoplastic activity was tested using three cultured cell lines: HT-29, MCF-7 and HeLa which were exposed to 2.5 mM cyclic dipeptide or 0.1 mM melphalan as a positive control. While cTT showed little activity against these lines, cPT resulted in as much as a 75.6% growth inhibition of MCF-7 cells, while also being active against HeLa (73.4% inhibition) and HT-29 (60.6%). The results indicate potential biological activity, showing a need for more investigation into tyrosine containing cyclic dipeptides and their analogues as potential bioactive compounds.

Algorithms↗
PubMed2006

Extracellular accumulation of bioactive substances; interleukin-1beta (IL-1beta) and plasminogen activator inhibitor-1 (PAI-1) in stored blood units and relation to bacterial contamination.

Bacterial contamination of blood and its cellular components remains an unresolved problem in transfusion medicine and is considered to be the most common microbiological cause of transfusion associated morbidity and mortality. The present work was designed to explore the levels of two bioactive compounds interleukin-1 beta (IL-1beta) and plasminogen activator inhibitor-1 (PAI-1) in stored blood units and their relation to bacterial contamination of these units. This study was conducted on 112 blood units obtained from blood bank of Mansoura University Children Hospital. Sequential blood samples were obtained both immediately at donation and after 10 days for measurement of IL-1beta and PAI-1 and for bacterial culture by BACTEC 9050 system. There was statistically significant increase in both IL-1 beta and PAI-1 (P = 0.0001) after 10 days of blood units storage. Bacteriological culture revealed no growth in 68% and positive growth in 32% of blood units. The commonest isolated organism was Staphylococcus aureus (15%) followed by Staphylococcus epidermedis (13%) then Yersinia sp. and Enterobacter sp. (2%) for each. From the present study we could conclude that stored blood units contain platelets and WBCs derived bioactive substances PAI-1 and IL-1beta which increase with the duration of blood storage. Furthermore, the extended duration of storage carries the danger of blood contamination by bacteria. Automated blood culture system seems to be helpful in identification of bacterial contamination of blood units. We recommend fresh blood transfusion as early as possible and the practice of Leucofiltration to avoid blood transfusion complications.

Adult↗
PubMed2005

Probabilistic neural network multiple classifier system for predicting the genotoxicity of quinolone and quinoline derivatives.

Quinolone and quinoline are known to be liver carcinogens in rodents, and a number of their derivatives have been shown to exhibit mutagenicity in the Ames test, using Salmonella typhimurium strain TA 100 in the presence of S9. Both the carcinogenicity and the mutagenicity of quinolone and quinoline derivatives, as determined by SAS, can be attributed to their genotoxicity potential. This potential, which is measured by genotoxicity tests, is a good indication of carcinogenicity and mutagenicity because compounds that are positive in these tests have the potential to be human carcinogens and/or mutagens. In this study, a collection of quinolone and quinoline derivatives' carcinogenicity is determined by qualitatively predicting their genotoxicity potential with predictive PNN (probabilistic neural network) classification models. In addition, a multiple classifier system is also developed to improve the predictability of genotoxicity. Superior results are seen with the multiple classifier system over the individual PNN classification models. With the multiple classifier system, 89.4% of the quinolone derivatives were predicted correctly, and higher predictability is seen with the quinoline derivatives at 92.2% correct. The multiple classifier system not only is able to accurately predict the genotoxicity but also provides an insight about the main determinants of genotoxicity of the quinolone and quinoline derivatives. Thus, the PNN multiple classifier system generated in this study is a beneficial contributor toward predictive toxicology in the design of less carcinogenic bioactive compounds.

Animals↗
PubMed2001

Nonribosomal peptide synthetase genes occur in most cyanobacterial genera as evidenced by their distribution in axenic strains of the PCC.

Previous studies largely carried out with environmental samples or axenic and non-axenic cultures suggested that cyanobacteria may be a rich source of hitherto unexplored bioactive compounds. This has been confirmed in the present study by a screening of 146 axenic strains from the Pasteur Culture Collection (PCC) of cyanobacteria. Use of degenerate PCR primers, designed on the basis of conserved sequence motifs in the aminoacyl-adenylation domain of peptide synthetases, revealed the presence of the corresponding genes in the majority (75.3%) of the strains examined. Among unicellular cyanobacteria, only Chamaesiphon sp. strain PCC 6605, two strains of Gloeocapsa and most Microcystis isolates (22 out of 24) contained these genes; no amplicons were detected for any members of the genera Cyanothece, Gloeobacter and Gloeothece and the genetically diverse representatives of Synechococcus and Synechocystis. By contrast, eight out of ten pleurocapsalean members, 16 out of 25 oscillatorian strains, and all but two of the 63 filamentous heterocystous cyanobacteria tested gave positive amplification results. This information will be highly valuable for further exploring the corresponding cyanobacterial peptides and for elucidating the bioactivity of such non-ribosomally synthesized molecules.

Cyanobacteria↗
PubMed2003

Natural products with anti-HIV activity from marine organisms.

In order to combat the human immunodeficiency virus (HIV), diverse strategies have been developed to research on compounds which can be developed as therapeutic agents. Screening of natural products derived from numerous species has afforded metabolites with significant antiviral activity against the HIV. The marine environment representing approximately half of the global biodiversity offers an enormous resource for novel compounds. Currently more than 150 natural products with promising levels of anti-HIV activity have been isolated following bioassay guided protocols from aqueous or organic extracts of marine organisms. Some of the most characteristic marinemetabolites that have exhibited significant anti-HIV activity on different biochemical assays designed for chemotherapeutic strategies are: Cyanovirin-N, a protein from a blue green alga; various sulfated polysaccharides extracted from seaweeds (i.e. Nothogenia fastigiata, Aghardhiella tenera); the peptides tachyplesin and polyphemusin, which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus; sponge metabolites such as avarol, avarone, ilimaquinone and several phloroglucinols; and a number of metabolites from marine fungi such as equisetin, phomasetin and integric acid. Considering that number of unique metabolites that have been isolated from a small extent of the ocean's biological and chemical diversity, the oceans represent a virtually untapped resource for the discovery of novel bioactive compounds.

Animals↗
PubMed2002

Antioxidant and antiproliferative activities of common fruits.

Consumption of fruits and vegetables has been associated with reduced risk of chronic diseases such as cardiovascular disease and cancer. Phytochemicals, especially phenolics, in fruits and vegetables are suggested to be the major bioactive compounds for the health benefits. However, the phenolic contents and their antioxidant activities in fruits and vegetables were underestimated in the literature, because bound phenolics were not included. This study was designed to investigate the profiles of total phenolics, including both soluble free and bound forms in common fruits, by applying solvent extraction, base digestion, and solid-phase extraction methods. Cranberry had the highest total phenolic content, followed by apple, red grape, strawberry, pineapple, banana, peach, lemon, orange, pear, and grapefruit. Total antioxidant activity was measured using the TOSC assay. Cranberry had the highest total antioxidant activity (177.0 +/- 4.3 micromol of vitamin C equiv/g of fruit), followed by apple, red grape, strawberry, peach, lemon, pear, banana, orange, grapefruit, and pineapple. Antiproliferation activities were also studied in vitro using HepG(2) human liver-cancer cells, and cranberry showed the highest inhibitory effect with an EC(50) of 14.5 +/- 0.5 mg/mL, followed by lemon, apple, strawberry, red grape, banana, grapefruit, and peach. A bioactivity index (BI) for dietary cancer prevention is proposed to provide a new alternative biomarker for future epidemiological studies in dietary cancer prevention and health promotion.

Ananas↗
PubMed2006

Diverse biomodulatory effects of glucomannan from Candida utilis.

Using four experimental model systems, it was demonstrated that glucomannan (GM) isolated from the cell wall of the industrial yeast Candida utilis revealed a broad range of protective activities. This effect depended on the nature and mode of action of the counteracting genotoxic compound as well as on the experimental model system used. In the Saccharomyces bioprotectivity assay, GM increased resistance towards ofloxacin-induced toxicity in the wild type and recombination repair-deficient yeast strains significantly enhancing survival of the cells. In the chromosomal aberration assay, GM exerted anticlastogenic effect against maleic hydrazide induced clastogenicity in Vicia faba L. In the DNA-topology assay, GM protected plasmid DNA from the breaks induced by Fe(2+) ions, but enhanced damage induced by bleomycin and hydrogen peroxide. In the cell-revitalization assay, it enhanced cytotoxic/cytostatic effect of teniposide applied to mouse leukemia cells. Thus, depending on the experimental model, GM acted as antimutagen, anticlastogen, DNA breaks inhibitor or inducer, and as cytotoxic/cytostatic effect enhancer. Several possible mechanisms of bioprotective action underlying the observed activities are suggested including iron chelation and free radical scavenging. The results imply that GM is a polysaccharide with marked biological activities and suggest its potential biomedical application, especially in combination with other bioactive compounds.

Animals↗