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At least 1,369 records · Page 76Linked to original sources
PubMed2000

Inhibitory effect of esculetin on oxidative damage induced by t-butyl hydroperoxide in rat liver.

Increasing evidence regarding free radical-generating agents and inflammatory processes suggests that accumulation of reactive oxygen species can cause hepatotoxicity. A short-chain analog of lipid hydroperoxide, t-butyl hydroperoxide (t-BHP), can be metabolized to free radical intermediates by cytochrome P-450 in hepatocytes, which in turn can initiate lipid peroxidation, affect cell integrity and result in cell injury. In this study, we used t-BHP to induce hepatotoxicity in vitro and in vivo and determined the antioxidative bioactivity of esculetin, a coumarin compound. Our investigations showed that pretreatment with esculetin (5-20 microg/ml) significantly decreased the leakage of lactate dehydrogenase (LDH) and alanine transaminase (ALT), and also decreased the formation of malondialdehyde (MDA) in primary cultured rat hepatocytes induced by a 30-min treatment with t-BHP. An in vivo study in rats showed that pretreatment with esculetin (i.p.) at concentrations of 0.5 and 5 mg/kg for 5 days before a single i.p. dose of t-BHP (0.1 mmol/kg) significantly lowered the serum levels of the hepatic enzyme markers (ALT and AST) and reduced oxidative stress in the liver. Histopathological evaluation of the rat livers revealed that esculetin reduced the incidence of liver lesions induced by t-BHP, including hepatocyte swelling, leukocyte infiltration, and necrosis. Based on the results described above, we speculate that esculetin may play a chemopreventive role via reducing oxidative stress in living systems.

Animals↗
PubMed1992

The covalent binding of acetaminophen to cellular nucleic acids as the result of the respiratory burst of neutrophils derived from the HL-60 cell line.

After being induced to differentiate into a neutrophilic type, cultures of the leukemic cell line HL-60 were able to cause the bioactivation and nucleic acid binding of acetaminophen upon stimulation of the respiratory burst. This phenomenon was found to simulate the same process as that previously shown with normal human granulocytes. Binding to both DNA and RNA of the cells was determined quantitatively by use of 14C-labeled acetaminophen congeners. Protein binding occurred to about the same extent as did RNA binding. Simultaneous labeling experiments with [ring-14C]- and [14C = O]acetaminophen further showed that the acetaminophen molecule was bound to DNA in an intact manner, while binding to RNA showed about a 50% excess binding of the acetaminophen ring relative to the carbonyl group. Experiments with certain inhibitors showed that catalase and azide ion strongly inhibited DNA binding, while superoxide dismutase had a slight stimulatory effect on binding. These results suggest a significant role for myeloperoxidase in the bioactivation process, which contrasts with the proposed bioactivation mechanism of certain arylamine compounds. A mechanism was proposed for acetaminophen binding to nucleic acids that requires the 1 e- oxidation of this substrate to its phenoxyl radical, although the production of the N-acetyl-p-benzoquinoneimine metabolite, which has been proposed to account for the extensive protein binding known to occur for acetaminophen, might also contribute to such binding. The potential genotoxicity of acetaminophen was considered in view of what might be a unique pathway which can metabolize this chemical to a nucleic acid-binding species.

Acetaminophen↗
PubMed2005

Synthesis of new, potent avermectin-like insecticidal agents.

4'-Modified avermectin derivatives were designed and synthesized. Some of the new synthetic compounds showed excellent in vivo bioactivity against cabbage larvae when compared to commercially available avermectin B1a. In this synthesis, uncommon thioglycosyl sugar donors, prepared from the hydrolysis of natural antibiotics, proved compatible with sugar-macrolide synthesis in the presence of N-iodosuccinimide (NIS) or I2 in N-methylpyrrolidone at room temperature.

Animals↗
PubMed2006

3D-QSAR study of sulfonamide inhibitors of human carbonic anhydrase II.

3D-QSAR models of Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarity Indices Analysis (CoMSIA) of 61 potent carbonic anhydrase II (CAII) sulfonamide inhibitors were performed using two methods. The conventional ligand-based 3D-QSAR studies were performed based on the lower energy conformations employing database alignment rule. The receptor-based 3D-QSAR models were also derived using bioactive conformations obtained by docking compounds to the active sites of CAII. The receptor-based model gave q(2) values of 0.623 and 0.562, r(2) values of 0.986 and 0.987 for CoMFA and CoMSIA, respectively, which were much better than those of ligand-based model (q(2) values of 0.532 and 0.466). The predictive ability of the models was validated using the test set of 10 compounds that were not included in the training set of 51 compounds. Results of CoMFA and CoMSIA suggested that heterocyclic sulfonamides are more active than aromatic sulfonamides, in the latter 1,3,5-triazole group substituting one hydrogen atom of the amido is favored and moderate groups in its 4- and 6-position are required. These results provided further understanding of the relationship between the structural features of CAII and its activities, which should be applicable to design and find new potential CAII inhibitors.

Carbonic Anhydrase II↗
PubMed2026

Insights into the mechanism of enhanced tetramethylpyrazine production in dehulled adlay fermented by Bacillus subtilis BJ3-2.

Tetramethylpyrazine (TTMP) is a vital bioactive alkaloid and characteristic flavor compound in fermented foods. Our previous study found that fermentation of adlay by Bacillus subtilis BJ3-2 efficiently accumulates TTMP, whereas the underlying high-yield mechanism remains unclear. This study investigated the fermentation characteristics, gene transcription and protein expression of B. subtilis BJ3-2 in dehulled adlay (BDA) and soybean (BSB), respectively, and elucidated the mechanism responsible for high-yield TTMP production. The results showed that glutamate, leucine and phenylalanine were major free amino acids in BDA. The TTMP yield in BDA at 48 h (6.11 mg/g dry weight) was 360-fold higher than that in BSB. Transcriptomic and proteomic analysis demonstrated that compared with the soybean substrate, dehulled adlay substrate significantly up-regulated the expression of alsSD and ilvBH genes and their encoding proteins in B. subtilis BJ3-2, which were involved in C5-branched dibasic acid metabolism, 2-oxocarboxylic acid metabolism, and valine, leucine and isoleucine biosynthesis. Meanwhile, acetoin degradation was inhibited by down-regulating acetoin dehydrogenase complex (acoABCL) in citrate cycle, glycolysis/gluconeogenesis and carbon metabolism. Additionally, nitrogen metabolism pathway was transcriptionally enhanced to guarantee sufficient ammonium supply. Notably, protein-protein interaction and molecular docking analyses revealed that acetohydroxyacid synthase (ilvBH) interacted tightly with α-acetolactate decarboxylase (alsD), potentially forming a metabolic channel for acetoin synthesis. In conclusion, the efficient synthesis of TTMP in BDA was primarily attributed to the high synthesis and low degradation of acetoin, and the moderate synthesis of ammonium/ammonia. This study provided a theoretical basis for the targeted and efficient biosynthesis of TTMP.

Bacillus subtilis↗
PubMed2004

Studies on structure-activity relationship of sphaeropsidins A-F, phytotoxins produced by Sphaeropsis sapinea f. sp. cupressi.

Six forms of sphaeropsidins (SA-SF), three- and tetra-cyclic unrearranged pimarane diterpenes produced by Sphaeropsis sapinea f. sp. cupressi, as well as eight derivatives obtained by chemical modification of SA-SC, were assayed for their bioactivity. The effect of each compound on plants which are host or non-host of the pathogen was investigated. Activity on some plant pathogenic fungi was also tested. Some structure-activity relationships have been identified for both phytotoxic and antifungal activity. It appears that the integrity of the tricyclic pimarane system, the preservation of the double bond C(8)-C(14), the tertiary hydroxyl group at C-9, the vinyl group at C-13, and the carboxylic group at C-10 as well as the integrity of the A-ring provide these molecules with non selective phytotoxic and antimycotic activity.

Antifungal Agents↗
PubMed2005

Developments in glucocorticoid therapy.

Recent evidence for a disease-modifying potential of low-dose glucocorticoids (GCs) in the treatment of rheumatoid arthritis has renewed the debate on the risk benefit ratio with this therapy. Two recent developments are described that might have a positive influence on these risk benefit ratios. One is the improvement in new GC compounds--designer GCs, alterations in bioactivity, and alterations in formulations. The other is a better understanding and management of the toxicity of GCs.

Animals↗
PubMed2002

Mechanisms of idiosyncratic drug reactions: the case of felbamate.

Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and often result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate. To date there exists no pre-clinical model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, we have studied the IDR associated with a model compound, felbamate. Our studies with felbamate are consistent with the theory that compounds which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In additon, our data suggest that under normal physiological conditions glutathione plays a protective role in preventing IDR during felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clinical studies with felbamate have been able to demonstrate an association between reactive metabolite formation and a clinically relevant toxicity; however, additional research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.

Aldehyde Dehydrogenase↗
PubMed1999

Effects of superovulation on endogenous LH secretion in cattle, and consequences for embryo production.

Stimulation of follicular growth during superovulation is achieved by the injection of FSH or compounds with high FSH-bioactivities. However, some LH-activity is required for follicle maturation. It is of relevance to evaluate, therefore, the effect of superovulatory treatments on endogenous LH secretion. Luteinizing hormone is secreted in discrete pulses, and the pattern of pulsatile LH secretion during superovulation is reviewed. Four of five published studies have shown that LH pulse frequency is significantly reduced by injection of eCG or FSH preparations. This suppression appears within 8 h of treatment Effects of superovulation on LH pulse amplitude are less consistent. The reasons for the decrease in pulse frequency have been investigated, and although the answer is not definitive, it would seem that increased follicular estradiol, acting perhaps in synergism with progesterone, may play a role. Changes in plasma progesterone concentrations are not related to changes in LH pulse frequency. What is the significance of decreased LH pulse frequency? We attempted to investigate this by inducing LH pulses during superovulation, but the result was a major reduction in ovulation rate. More research is required to determine if modification of endogenous LH secretion can improve superovulatory responses.

Animals↗
PubMed2000

Direct and translactational effect of arecoline alkaloid on the clocimum oil-modulated hepatic drug metabolizing enzymes in mice.

The present study assesses the potential of arecoline alkaloid, by direct exposure in lactating dams and translactational exposure in neonates, to modulate the efficacy of clocimum oil as a blocking agent in chemopreventive pathway. Clocimum oil (25 or 50 microl/dam/day) induced a significant increase in the hepatic levels of phase II glutathione S-transferase (GST) and acid-soluble sulfhydryl in lactating dams and suckling neonates while the elevated levels of hepatic phase I cytochrome b5 (Cyt. b5) and cytochrome P-450 (P450) were observed only in the dams. Arecoline (0.6 mg/dam/day) alone did not modulate the hepatic GST and sulfhydryl levels in either dams or pups, although significant induction was observed in the hepatic levels of Cyt. b5, P450 and malondialdehyde (MDA) in lactating dams and suckling neonates. Clocimum oil-modulated hepatic levels of phase II components were depressed whereas phase I enzymes and lipid peroxides levels were further elevated by clocimum oil-plus-arecoline treatment. The direct or translactationally augmented levels of bioactivated species of the administered compounds, via enhanced phase I oxidative catalysis and less efficient GST/GSH conjugational detoxication, may suggest the antagonistic influence of arecoline on chemopreventive efficacy of clocimum oil.

Animals↗
PubMed1997

Anticonvulsant properties of gamma-decanolactone in mice.

Lactones have been proven to be bioactive. We have shown that compounds present in the essential oil from Aeollanthus suaveolens, used as an anticonvulsant in the Brazilian Amazon, has sedative properties. This paper reports on the evaluation of the systemic administration of gamma-decanolactone, structurally related to lactones present in the essential oil of A. suaveolens, on mice experimental models useful for detecting psychopharmacological activity. The results show that gamma-decanolactone has dose-dependent marked effects on the central nervous system, including hypnotic, anticonvulsant and hypothermic activity. The effects of gamma-decanolactone revealed by this evaluation point to the validity of exploring lactones as sources of new anticonvulsant agents.

Animals↗
PubMed2001

Blessings of the grape.

Numerous epidemiological studies have shown an inverse correlation between moderate consumption of alcoholic drinks and the risk of coronary heart disease. Wine, especially red wine, may be more favorable in this respect than beer or spirits because of its high content of flavonoids. These polyphenols originate from the skins, seeds, and vine stems of the grapes while some are formed during the process of vinification. In nature they exhibit a wide range of biological effects as antioxidants, antimicrobials, and modulators of various enzyme systems. Potential beneficial effects for humans have been demonstrated in experimental studies and include influences on the oxidation of LDL-cholesterol, on platelet aggregation, and on prostaglandin and nitric oxide metabolism. However, most of these studies concern semi in vivo experiments and research in animal models; data from human intervention trials are scarce. Furthermore, little is known about the absorption, bioavailability, and bioactivity of most of these compounds because of difficulties in reliable quantification in biological fluids. Until these issues are well addressed, and despite the enthusiasm and faith of many believers, evidence-based medicine justifies a critical attitude towards the application of these compounds outside the context of scientific research. Yet, there is no need to deny their potential, nor should we close our eyes to the blessings of the grape.

Journal Article↗
PubMed2002

Antioxidant activity of extracts obtained from residues of different oilseeds.

Residues of the oil-extracting process of oilseeds contain bioactive substances such as phenolic compounds, which could be used as natural antioxidants for the protection of fats and oils against oxidative deterioration. Thus, the extraction of such constituents from residual material can be considered to contribute to the added value of these residues, which could justify their isolation. In the present work the fat-free residues of eight different oilseeds whose oils are usable for nutritional applications, and also as renewable resources, were extracted with 70% methanol, 70% acetone, water, and ethyl acetate/water, respectively. The resulting extracts were investigated regarding their content of total phenolic compounds by the Folin-Ciocalteau assay, sinapine, flavanoids, and the UV-absorption spectra. Further, the antioxidant activity of the extracts was characterized by the DPPH method, the beta-carotene-linoleic acid assay, and ESR investigations. The fat-free residues of the different oilseeds contained considerable amounts of extractable substances. The yields decreased with decreasing polarity of the solvent in the order water, 70% methanol, 70% acetone, and ethyl acetate. The ratio of total phenolic compounds to the extractable compounds ranged from 3 to 19%. There was no significant correlation between the amount of total extractable compounds and the total phenolic compounds (p < 0.001). All extracts showed remarkable antioxidant activities determined with the different methods. The effects depended strongly on the solvent used for the extraction as well as on the extracted residue. A correlation between the methods used for the characterization of the antioxidant activity and the composition of the residues could not be shown.

Acetates↗
PubMed2003

Antifeedant and insecticide properties of a limonoid from Melia azedarach (Meliaceae) with potential use for pest management.

In the course of screening for novel naturally occurring insecticides from plants, the activity of the fruit extract of the Argentinian Melia azedarach L. (Meliaceae) and its recently described limonoid meliartenin were investigated. The antifeedant activity of the fruit extract was tested on a variety of herbivore and granivorous insects through choice tests. Sixteen of 17 species belonging to three orders consume significantly less food when treated with the extract. The bioactivity of the isolated active compound meliartenin and its interchangeable isomer 12-hydroxiamoorastatin (1) was further studied. In choice tests, compound 1 inhibited feeding of Epilachna paenulata Germ. (Coleoptera, Coccinellidae) larvae, with an ED(50) value of 0.80 microg/cm(2), comparable to that of azadirachtin (2) and lower than that of toosendanin (3) (0.72 and 3.69 microg/cm(2), respectively), both compounds used for comparison purposes. In no-choice tests, E. paenulata larvae reared on food treated with 1 or 2 ate less, gained less weight, and suffered greater mortality rates than control larvae. The activity of compound 1 was comparable to that of 2, with LD(50) values of 0.76 and 1.24 microg/cm(2), respectively, at 96 h. Shorter LT(50) values were recorded for 1 at 4 and 1 microg/cm(2) in comparison with 2. Thus, M. azedarach fruit extract and its active principle have interesting potential for use in pest control programs.

Animals↗
PubMed2006

Factors affecting the contents of iridoid oleuropein in olive leaves (Olea europaea L.).

In this study, for the first time, the impact of the genetic factor on the contents of oleuropein in olive leaves was not only evaluated but the influence exerted by the color/age of leaves (green, green-yellowish, and yellow) and the collecting period (spring or autumn) was also evaluated. A repetitive high-resolution gas chromatographic quantitation method and an accurate high-performance liquid chromatographic method were developed. These analytical methods gave results showing a highly linear relationship. Samples of olive leaves were taken from seven major Italian olive cultivars, such as Dritta, Leccino, Caroleo, Coratina, Castiglionese, Nebbio, and Grossa di Cassano. Such a vegetal raw material could actually be exploited for recovering oleuropein, considered to be a high-added value molecule. This could be converted into hydrxytyrosol, a compound known to possess strong bioactive properties. Olive leaves showed considerable contents of oleuropein, which with some cultivars were even higher with respect to those present in the corresponding olive fruits (reported in the literature). The amounts of oleuropein in the collected leaves were markedly modified by the color/age and genetic factors, whereas meaningless variations were ascribable to the quantitation method and the collecting period factors. Various chemometrics, applied to the obtained analytical data, appeared to be effective in discriminating the samples on the basis of the above-examined experimental factors, thus confirming how these should be taken into account in future industrial recovery of oleuropein from olive leaves.

Analysis of Variance↗
PubMed1995

Peptide mimetics of thyrotropin-releasing hormone based on a cyclohexane framework: design, synthesis, and cognition-enhancing properties.

The design and synthesis of peptide mimetics of thyrotropin-releasing hormone (TRH) in which the peptide backbone is entirely replaced by a cyclohexane framework are described. The cis-1,3,5-trisubstituted ring was expected to permit key pharmacophoric groups to adopt conformations consistent with proposed bioactive conformations of the peptide. Compounds were synthesized by a stereoselective synthesis starting from L-glutamic acid. In a behavioral model of cognition in which TRH is active, the mimetics are potent, active compounds, exhibiting oral activity. One analog (26, (1S,3R,5(2S),5S)-5-[[5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-methyl]-5- [(1H-imidazol-5-yl)methyl]cyclohexaneacetamide) was radiolabeled for binding studies and evaluated in other binding assays and pharmacological tests. Competition binding of 26 vs [3H]MeTRH to rat brain slices suggests a two-site model for ligand binding with IC50's of 1 microM and 3 mM. Direct binding of [3H]-26 shows a biphasic curve with IC50's of 80 and 49 microM, respectively. Further studies would be needed to establish a link between the novel binding site(s) and the behavioral activity of 26 and TRH analogs.

Amino Acid Sequence↗
PubMed2006

New cannabidiol derivatives: synthesis, binding to cannabinoid receptor, and evaluation of their antiinflammatory activity.

Cannabidiol (CBD) and cannabidiol dimethyl hephtyl (CBD-DMH) were hydrogenated to give four different epimers. The new derivatives were evaluated for their ability to modulate the production of reactive oxygen intermediates (ROI), nitric oxide (NO), and tumor necrosis factor (TNF-alpha) by murine macrophages, and for their binding to the cannabinoid receptor (CB(1)). Surprisingly, we found that these derivatives exhibit good binding to CB(1). In addition hydrogenated CBD and CBD-DMH demonstrate bioactivities different from their original compounds.

Animals↗