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PubMed2004

O-methylated catechins from tea leaves inhibit multiple protein kinases in mast cells.

Tea contains a variety of bioactive compounds. In this study, we show that two O-methylated catechins, (-)-epigallocatechin-3-O-(3-O-methyl) gallate and (-)-epigallocatechin-3-O-(4-O-methyl) gallate, inhibit in vivo mast cell-dependent allergic reactions more potently than their nonmethylated form, (-)-epigallocatechin-3-O-gallate. Consistent with this, these O-methylated catechins inhibit IgE/Ag-induced activation of mouse mast cells: histamine release, leukotriene release, and cytokine production and secretion were all inhibited. As a molecular basis for the catechin-mediated inhibition of mast cell activation, Lyn, Syk, and Bruton's tyrosine kinase, the protein tyrosine kinases, known to be critical for early activation events, are shown to be inhibited by the O-methylated catechins. In vitro kinase assays using purified proteins show that the O-methylated catechins can directly inhibit the above protein tyrosine kinases. These catechins inhibit IgE/Ag-induced calcium response as well as the activation of downstream serine/threonine kinases such as Akt and c-Jun N-terminal kinase. These observations for the first time have revealed the molecular mechanisms of antiallergic effects of tea-derived catechins.

Animals↗
PubMed2004

Environmental and endogenous peroxisome proliferator-activated receptor gamma agonists induce bone marrow B cell growth arrest and apoptosis: interactions between mono(2-ethylhexyl)phthalate, 9-cis-retinoic acid, and 15-deoxy-Delta12,14-prostaglandin J2.

The common commercial use of phthalate esters has resulted in significant human exposure to these bioactive compounds. The facts that phthalate ester metabolites, like endogenous PGs, are peroxisome proliferator-activated receptor (PPAR) agonists, and that PPARgamma agonists induce lymphocyte apoptosis suggest that phthalate esters are immunosuppressants that could act together with PGs to modulate early B cell development. In this study we examined the effects of a metabolite of one environmental phthalate, mono(2-ethylhexyl)phthalate (MEHP), and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), on developing B cells. MEHP inhibited [(3)H]thymidine incorporation by primary murine bone marrow B cells and a nontransformed murine pro/pre-B cell line (BU-11). Cotreatment with a retinoid X receptor alpha ligand, 9-cis-retinoic acid, decreased [(3)H]thymidine incorporation synergistically, thereby implicating activation of a PPARgamma-retinoid X receptor alpha complex. These results were similar to those obtained with the natural PPARgamma ligand 15d-PGJ(2). At moderate MEHP concentrations (25 or 100 microM for primary pro-B cells and a pro/pre-B cell line, respectively), inhibition of [(3)H]thymidine incorporation resulted primarily from apoptosis induction, whereas at lower concentrations, the inhibition probably reflected growth arrest without apoptosis. Cotreatment of bone marrow B cells with 15d-PGJ(2) and MEHP significantly enhanced the inhibition of [(3)H]thymidine incorporation seen with MEHP alone, potentially mimicking exposure in the bone marrow microenvironment where PG concentrations are high. Finally, MEHP- and 15d-PGJ(2)-induced death does not result from a decrease in NF-kappaB activation. These data demonstrate that environmental phthalates can cooperate with an endogenous ligand, 15d-PGJ(2), to inhibit proliferation of and induce apoptosis in developing bone marrow B cells, potentially via PPARgamma activation.

Alitretinoin↗
PubMedDate not supplied

Cancer preventive role of selected dietary factors.

Dietary behavior seems to be an important modifiable determinant for the risk of cancer. The evidences from several epidemiological studies suggest that higher intakes of fruits and vegetables have been associated with lower risk of cancer. Dietary phenolic and polyphenolic substances, terpenoids, dietary fibers, fish oils, some micronutrients present in foods of both plant and animal origin, and a reduction of caloric intake appear to inhibit the process of cancer development. Many dietary factors possess antioxidant and anti-inflammatory properties and cause induction of phase II enzymes like glutathione-S-transferases. It has been suggested that cruciferous vegetables play an important role in cancer prevention, and their chemopreventive effects are due to high glucosinolate content which under enzymatic hydrolysis produces bioactive compound isothiocyanates. Further, isothiocyanates of a wide variety of cruciferous vegetables are powerful inhibitors of carcinogenesis in experimental animal models. Several flavonoids present in fruits, tea, soya beans, etc. may be useful as cancer preventive agents. Similarly, ellagic acid, perillyl alcohol and resveratrol found in various fruits may have chemoprotective effect. Moreover, different vanilloids such as curcumin and gingerol have been shown to possess antioxidative properties. Nevertheless, in spite of several studies, still the effects of various ingredients are not clearly distinguished. In human, little convincing evidence has been established for the proposed protective effects of dietary constituents. It is an important future research goal to provide necessary evidences to support the chemopreventive role of different dietary factors, and also to clarify misunderstandings in this perplexing area.

Anticarcinogenic Agents↗
PubMed1985

Novel antitumor antibiotics, CI-940 (PD 114,720) and PD 114,721. Taxonomy, fermentation and biological activity.

The novel, broad-spectrum antitumor antibiotics, CI-940 (PD 114,720) and PD 114,721 are components of bioactive compounds produced by a novel actinomycete (ATCC 39366). The organism is unique in that whole cell analysis revealed LL-diaminopimelic acid and major amounts of arabinose. These new antibiotics exhibit potent antitumor activity in vitro and in vivo versus an array of tumors and possess strong antibacterial and antifungal activity. The above antibiotics are produced in 7,570-liter fermentors at yields of 5 approximately 8 micrograms/ml.

Actinomycetales↗
PubMed2000

Alpha-aminoadipyl-cysteinyl-valine synthetases in beta-lactam producing organisms. From Abraham's discoveries to novel concepts of non-ribosomal peptide synthesis.

The tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) was discovered by ARNSTEIN and MORRIS in Penicillium chrysogenum and ABRAHAM and coworkers in Acremonium chrysogenum. Other analogous tripeptides and tetrapeptides were later reported in these and other beta-lactam producing fungi and actinomycetes. The ACV tripeptide is synthesized by a large non-ribosomal peptide synthetase named ACV synthetase encoded by the 11 kb pchAB gene. This gene has been cloned from the DNA of four different filamentous fungi and two actinomycetes. Detailed analysis of the multifunctional ACV synthetases reveals that they consist of three repeated modules (initially named domains) involved in activation of the corresponding amino acids L-alpha-aminoadipic acid, L-cysteine and L-valine. Each module consists of functional domains for amino acid activation (A), condensation (C) and thiolation (T). In addition the last module of the ACV synthetase contains an epimerization domain (E) involved in conversion of the L-valine to its D-isomer when the tripeptide is still enzyme linked. There are seven epimerization motifs conserved in the third module of all ACV synthetases. In addition, there is an integrated thioesterase domain in the C-terminal region of the ACV synthetases that appears to be involved in the selective release of the tripeptide with the correct LLD configuration. The structure of the ACV synthetase is similar to that of other modular non-ribosomal peptide synthetases of bacterial and fungal origin. This molecular knowledge opens the way for engineering novel tripeptide synthetases that may result in new bioactive compounds.

Actinomycetales↗
PubMed2003

Himalomycin A and B: isolation and structure elucidation of new fridamycin type antibiotics from a marine Streptomyces isolate.

In our screening of marine Streptomycetes for bioactive compounds, in addition to the known metabolites rabelomycin (1), fridamycin D (2b), N-benzylacetamide and N-(2'-phenylethyl)acetamide, two new anthracycline antibiotics designated as himalomycin A (2c) and B (2d) were isolated from the culture broth of the marine Streptomyces sp. isolate B6921. The structure of the new antibiotics was determined by comparison of the NMR data with those of fridamycin D (2b) and by detailed interpretation of mass, 1D and 2D NMR spectra.

Anthracyclines↗
PubMed2004

Lightweight expanded clay aggregates (LECA), a new up-scaleable matrix for production of microfungal metabolites.

In order to compare the effects of different growth matrices on secondary metabolite production we compared 16 Penicillium species known to produce several families of bioactive compounds. The isolates were grown in rich complex media formulated as semisolid (agar), liquid (still), shake culture, and absorbed in Lightweight Expanded Clay Aggregates (LECA). Both the number of metabolites and their quantities were compared via a chemo-diversity index. The matrix had a profound effect on fungal growth and secondary metabolism in some of the investigated species. LECA was shown to be a powerful alternative for production of sporulation-associated metabolites, such as cyclopenins and viridicatins, for quick up-scaling from agar based media, and as an alternative for production of metabolites that are not induced under submerse conditions.

Agar↗
PubMed1999

Chemoprevention of urological cancer.

PURPOSE: Cancer is a major cause of mortality and morbidity throughout the world, and ranks as the second leading cause of death in the United States. Most cancers have a latent period of 10 to 20 years, which provides ample time for preventive measures. Transitional cell carcinoma of the bladder and adenocarcinoma of the prostate have protracted courses and may be ideal for chemopreventive strategies. We review the biochemistry and epidemiology of chemopreventive agents, and the laboratory and clinical studies of their role in urological cancer. MATERIALS AND METHODS: We performed a computerized MEDLINE search and manual bibliographical review of relevant peer reviewed studies and reports from 1966 to 1998. These reports were analyzed and scrutinized, and the important findings are summarized. RESULTS: Neoplastic lesions of the bladder and prostate are uniquely suited to the development and evaluation of chemopreventive agents. Epidemiological reports provide the strongest evidence of a protective role for dietary agents in cancer of the bladder, prostate and kidney. Observational and recent experimental trials support these findings in cases of adenocarcinoma of the prostate and transitional cell carcinoma of the bladder. There is strong evidence for a protective effect of vitamin A in bladder cancer. Superior protection has been reported with a combination of high doses of vitamins A, B6, C and E plus zinc. For prostate cancer strong evidence exists for a preventive effect of reduced fat intake, vitamin E, selenium and soy proteins. A lesser benefit is also suggested with intake of vitamins D and C. Evidence of chemoprevention against renal cell cancer is supported mainly by epidemiological studies, and animal studies indicate possible benefit of vitamin D supplementation. CONCLUSIONS: Although there is no incontrovertible proof, numerous studies implicate dietary and nutritional factors in the onset and progression of cancer of the bladder, prostate and kidney. It is possible that the preventive effect of dietary constituents may be in part from consumption with other nutrients and bioactive compounds in whole foods. Further research is needed before vitamins and other nutritional supplements can be advocated as standard therapy but the preponderance of evidence supports increased intake of vitamins A, B6, C, D and E, reduction of animal fat, and increased consumption of fruits and vegetables.

Animals↗
PubMed1994

[Pseudoreceptor modeling - a tool in the pharmacological screening process]

Pseudoreceptor Modeling, a new concept within the field of Computer-Aided Drug Design, allows the reconstruction of the three-dimensional structure of an unknown bioregulator based on the structures of its ligands (known bioactive compounds). It combines the present techniques but significantly extends their possibilities by the generation of an explicit receptor model. This model may subsequently be used for the qualitative prediction of the binding strength of novel drug molecules. The relevance of pseudoreceptor modeling for reducing and replacing animal models is given by the fact that the technique can be applied under circumstances where little or no information is available on the true biological receptor, a situation where up to date only in vivo techniques were promising. As a first technique, pseudoreceptor modeling allows the screening of potential drug molecules of an unknown bioregulator ex vivo.

Journal Article↗
PubMed2001

Bioactive anthocyanins detected in human urine after ingestion of blackcurrant juice.

Anthocyanins are a group of very efficient bioactive compounds that are widely distributed in plant food. Several fruits (blackcurrant, blackberry, red grape) and some vegetables (eggplant, onion, red radish) are rich sources of these natural pigments. Extracts of some of them are used as food colorants as well as components of pharmaceutical preparations and functional foods. Anthocyanins, through their ability to inhibit radical reactions, are considered to exert several protective effects in the human body. Until now there has been only a small amount of data available on their capability, in intact or metabolized form, to reach the systemic circulation of humans. The present study was designed to determine the potential bioavailability in humans of the most important anthocyanins of blackcurrants: delphinidine-3-glucoside, delphinidine-3-rutinoside, cyanidine-3-glucoside, and cyanidine-3-rutinoside. Urinary samples from 4 healthy volunteers (2 women and 2 men) were collected before (baseline) and over a period of 5 hours with intervals of 30 minutes after the ingestion of 200 mL of blackcurrant juice (containing 153 mg of anthocyanins). Using high-performance liquid chromatography (HPLC), it was possible to quantify the 4 main anthocyanins of blackcurrants, excreted unchanged in the urine (0.020-0.050% of the oral doses). We present data on the bioavailability in humans of blackcurrant anthocyanins, which are dietary antioxidants with possible biological effects.

Adult↗
PubMed2001

[Effect of severe multiple trauma complicated by acute lung injury on endothelial cell activity].

The pulmonary endothelium synthesizes many bioactive compounds and their activation or injury may cause release these substances into the blood. We determined the influence of trauma severity for endothelium activation/injury by measurement of specific endothelial cell markers--soluble E-selectin (sES) and von Willebrand factor antigen (vWF:Ag). Thirty six severely traumatized patients were stratified according to an Injury Severity Score (ISS). Group I--patients with ISS > or = 35, Group II--patients with ISS < 35. Eleven healthy volunteers served as controls. Serum sES and plasma vWF:Ag concentrations were measured and PaO2/FiO2 ratio, Lung Injury Score (LIS) and APACHE II ratio were calculated at the admission to IC, after 24 h and on 2, 3, 5, 7, 10th day. In all investigated time periods, we observed significant increase in serum sES concentration among patients from group I, in comparison to initial value and control. On day 3, serum sES concentration was significantly increased in group I, in comparison to group II. In the first seven days, plasma vWF:Ag concentration in patients with severe multiple trauma (ISS > or = 35) was significantly elevated, in comparison to group II and control. At the admission, significant correlation between plasma vWF:Ag and ISS was found (Rs = 0.568, p < 0.001). Significant correlation between plasma vWF:Ag and serum sES concentration was also observed (Rs = 0.501, p < 0.001). In conclusion, severe trauma patients manifest endothelial cell activation/injury. Plasma vWF:Ag concentration seems to be an important, early marker of trauma severity, while serum sE-selectin level may serve as prognostic factor in immediate postinjury period course.

APACHE↗
PubMed2002

Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells.

Indole-3-carbinol (I3C) is a bioactive compound present in Brassica vegetables that shows an antitumor activity in experimental animals and inhibits the growth of human cancer cells in vitro. In recent years, studies on prostate cancer (PCa) chemoprevention have been intensified, because there is a long latency for the development of clinical PCa, which makes the PCa a better target for chemoprevention. We have shown previously that I3C induces cell growth inhibition by G(1) cell cycle arrest and induces apoptosis in a dose- and time-dependent manner in PC-3 PCa cells; however, the mechanism(s) by which I3C induces apoptosis in PC-3 cells is still not clear. A cell survival pathway involving phosphatidylinositol 3'-kinase (PI3K) and Akt is known to play an important role in inhibiting apoptosis in response to growth factor signaling, which prompted us to investigate whether this pathway plays any role in I3C-induced apoptosis in PCa cells. Here we report that I3C inhibits the phosphorylation and subsequent activation of Akt kinase. In addition, I3C abrogated epidermal growth factor (EGF)-induced activation of Akt in PC-3 cells. Western blot analyses of EGF receptor showed that I3C down-regulates the EGF receptor levels and its autophosphorylation. This was also accompanied by the inhibition of EGF-induced phosphorylation of PI3K by I3C treatment. Furthermore, the known downstream modulators of the Akt/PI3K cell survival pathway, Bcl-x(L), and BAD proteins showed decreased expression after I3C treatment. From these results, we conclude that I3C-induced apoptosis is partly mediated by the inhibition of Akt activation, resulting in the alterations in the downstream regulatory molecules of Akt activation in PC-3 cells. However, further in-depth investigation is needed to establish a cause-and-effect relationship between Akt pathway and I3C effect.

Apoptosis↗
PubMed2001

Isolation, purification and partial chemical characterization of a lethal factor from common indian toad (Bufo melanostictus, Schneider) skin extract.

Indian toad (Bufo melanostictus, Schneider) skin extract (TSE) is pharmacologically potent and probably contains several bioactive compounds [Das et. al., Indian J Pharmacol, 28 (1996) 72]. A lethal factor was isolated and purified by neutral alumina column chromatography followed by HPLC. Spectroscopic (UV, IR, FAB-MASS) study indicated that the lethal factor (TSE-LF) was a 254 Da long chain compound with carbonyl, hydroxyl and ester as functional groups. LD50 of TSE-LF was found to be 3.5 mg/kg (iv). Biological study showed that TSE-LF possesses hypotensive, cardiotoxic, neurotoxic activity and produced death by apnoea in experimental animal. Cyproheptadine antagonised TSE-LF induced contraction of isolated smooth muscle indicating involvement of histamine/serotonin receptors. TSE-LF induced neurotoxic action on chick biventer cervices was mediated through Ca2+ ion.

Animals↗
PubMedDate not supplied

Determination of St. John's wort components in dietary supplements and functional foods by liquid chromatography.

St. John's wort (Hypericum perforatum L.) preparations, a top-selling botanical dietary supplement used primarily as an antidepressant, has recently been used as an ingredient in some food products sold as functional foods. A rapid extraction technique followed by a liquid chromatographic (LC) method was developed to determine 4 characteristic bioactive compounds (pseudohypericin, hypericin, hyperforin, and adhyperforin) from St. John's wort in dietary supplements and functional foods to which it was added. Solid samples, including dried leaf/flower mixture, dietary supplement capsules, tea bags, puff and snack bar, were extracted with methanol by sonication. Noncarbonated, fruit-flavored drinks were centrifuged and mixed with methanol. Compounds were then determined by isocratic, reversed-phase LC with UV detection at 2 wavelengths and further identified or confirmed by photodiode array spectra and LC/mass spectrometry. Within-laboratory method variations (% RSD) were satisfactory. Very low amounts, if any, of the 4 components were found in drink and puff samples, and none was found in the snack bar. The methods developed provide a useful means for the determination of St. John's wort components in dietary supplements and functional foods.

Algorithms↗
PubMed2002

Plant antimutagens and their mixtures in inhibition of genotoxic effects of xenobiotics and aging processes.

The antimutagenic effect of the bioactive compounds from fruits of Morus alba L. (MA), Punica granatum L. (PG), Diospyros kaki L. (DK), Cydonia oblonga Mill. (CO) and roots of Glycyrrhiza glabra (GG) were investigated. The antimutagenic effects of compounds separately as well as their action in complex mixtures were studied on mutations induced by genotoxicants (X-rays, N-methylnitrosourea, cyclophosphamide, NaF) and aging in bone marrow cell chromosomes from mice and rats. When tested separately and in a complex mixture, the plant products showed an ability to decrease the frequency of chromosome aberrations. The antimutagenic properties of the complex mixtures were considerably greater than those of the separate components. More antimutagenic activity of the mixture was revealed when mutagenesis was the result of X-rays and the natural aging processes.

Aging↗
PubMed2003

Phytosphingosine induces apoptotic cell death via caspase 8 activation and Bax translocation in human cancer cells.

PURPOSE: Sphingolipid metabolites, such as sphingosine and ceramide, are highly bioactive compounds and are involved in diverse cell processes, including cell-cell interaction, cell proliferation, differentiation, and apoptosis. However, the physiological roles of phytosphingosine are poorly understood. In this study, we report that phytosphingosine can potently induce apoptotic cell death in human cancer cells via caspase activation and caspase-independent cytochrome c release. EXPERIMENTAL DESIGN: Phytosphingosine-induced apoptosis was determined by Hoechst 33258 staining, flow cytometric analysis, and DNA fragmentation assay. Involvement of caspases was determined by immunoblot analysis and cell death detection assays after treatment with synthetic inhibitor z-Val-Ala-Asp-fluoromethyl ketone, z-DEVD-fmk, or z-IETD-fmk. Death receptor (DR) dependency was analyzed by examining expression of DRs (Fas, DR4, DR5, TNFR1, and R2), and interaction of Fas-associated death domain and caspase 8. Involvement of the mitochondria pathway was examined by monitoring of the mitochondria membrane potential, cytochrome c release, and Bax translocation. RESULTS: Phytosphingosine-treated cells displayed several features of apoptosis, including increase of sub-G(1) population, DNA fragmentation, and poly(ADP-ribose) polymerase cleavage. We observed that phytosphingosine cause activation of caspase 8 in a DR-independent fashion. Phytosphingosine also induced activation of caspase 9 and 3, loss of mitochondrial membrane potential, and the cytochrome c release from mitochondria. However, we failed to detect Bid cleavage. Moreover, caspase 8 inhibitor z-IETD-fmk did not affect phytosphingosine-induced cytochrome c release and caspase 9 activation, suggesting that phytosphingosine-induced cytochrome c release is caused by caspase 8-independent manner. Phytosphingosine induced mitochondrial translocation of Bax from the cytosol without changes in the protein levels of Bcl-2, Bcl-xL, and Bax. In addition, Bcl-2/Bax interaction was diminished after addition of phytosphingosine. CONCLUSION: These findings indicate that phytosphingosine induces apoptotic cell death in human cancer cells by direct activation of caspase 8, and by mitochondrial translocation of Bax and subsequent release of cytochrome c into cytoplasm, providing a potential mechanism for the anticancer activity of phytosphingosine.

Apoptosis↗
PubMed2001

[Studies on chemical constituents of Stellera chamejasma L].

OBJECTIVE: Isolate and identify the bioactive compounds from the root of Stellera chamejasma. METHOD: The compounds were extracted with solvents, isolated by column chromatography and identified by spectroscopic methods. RESULT: Seven compounds were isolated and identified as umbelliferone(1); daphnoretin (2); 2,6-dimethoxyl p-benzoquinone(3); (-)-eudesmin(4); (+)-matairesinol(5); lirioresinol B(6) and daucosterol(7). CONCLUSION: Compounds 3, 4 and 5 were isolated from the plant for the first time.

Furans↗
PubMed2003

Omega-3 fatty acids and non-communicable diseases.

OBJECTIVE: To review the relation between dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA) and non-communicable diseases. METHOD: Data were collected from scientific journals and conference publications, MEDLINE (1979 - 2002) and current content which included 68 prospective, cross-sectional, case control and dietary-intervention studies. Scientific paper selections were based on the association between omega-3 PUFA and non-communicable diseases. RESULTS: omega-3 PUFA has beneficial effects on increasing heart rate variability, decreasing the risk of stroke, reducing both systolic and diastolic blood pressure, insulin resistance and glucose metabolism. Long chain omega-3 PUFA has anti-cancer and anti-inflammatory activities. omega-3 PUFA has also been reported to have a beneficial effect on attention-deficit/hyperactivity disorder and schizophrenia, and may be effective in managing depression in adults. CONCLUSIONS: Results from epidemiological and dietary intervention studies have shown that omega-3 PUFA represent powerfully a class of bioactive compounds and that dietary intake of omega-3 PUFA plays a critical role in human health in relation to non-communicable diseases.

Diabetes Mellitus↗