1 |
Total synthesis of methyl 8(S)-, 9(S)-, 11(S)- and 12(S)- hydroxyeicosatetraenoates & of oligosaccharides from Haemophilus influenzae type BWang, Zhi Yuan January 1987 (has links)
No description available.
|
2 |
Total synthesis of methyl 8(S)-, 9(S)-, 11(S)- and 12(S)- hydroxyeicosatetraenoates & of oligosaccharides from Haemophilus influenzae type B / Total syntheses of methyl 8(S)-, 9(S), 11(S)- and 12(S)- hydroxyeicosatetraenoates and of oligosaccharides from Haemophilus influenzae type B.Wang, Zhi Yuan January 1987 (has links)
A general approach to the asymmetric syntheses of HETEs in both enantiomeric forms was developed. The syntheses of 8(S)-, 9(S)-, 11(S)- and 12(S)-HETE methyl esters, starting from D-arabinose, were accomplished. / A practical approach to the solution synthesis of fragments from Haemophilus influenzae type b capsular polymer was established, which opens a route to the development of a new vaccine against meningitis. The major aspects of this approach, stereocontrolled glycosidation, selective protection and deprotection, and efficient phosphorylation were detailed. The normal solution syntheses of the mono-, di- and tetrasaccharides were accomplished. / A new class of spacer for the linkage of the oligosaccharide with a protein was introduced. The spacer and the spacer-linked tetrasaccharide were prepared.
|
3 |
Oral green tea catechin metabolites are incorporated into human skin and protect against UV radiation-induced cutaneous inflammation in association with reduced production of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid.Rhodes, L.E., Darby, G., Massey, Karen A., Clarke, K.A., Dew, T.P., Farrar, M.D., Bennett, S., Watson, R.E.B., Williamson, G., Nicolaou, Anna 09 1900 (has links)
No / Green tea catechins (GTC) reduce UV radiation (UVR)-induced inflammation in experimental models, but human studies are scarce and their cutaneous bioavailability and mechanism of photoprotection are unknown. We aimed to examine oral GTC cutaneous uptake, ability to protect human skin against erythema induced by a UVR dose range and impact on potent cyclo-oxygenase- and lipoxygenase-produced mediators of UVR inflammation, PGE2 and 12-hydroxyeicosatetraenoic acid (12-HETE), respectively. In an open oral intervention study, sixteen healthy human subjects (phototype I/II) were given low-dose GTC (540 mg) with vitamin C (50 mg) daily for 12 weeks. Pre- and post-supplementation, the buttock skin was exposed to UVR and the resultant erythema quantified. Skin blister fluid and biopsies were taken from the unexposed and the UVR-exposed skin 24 h after a pro-inflammatory UVR challenge (three minimal erythema doses). Urine, skin tissue and fluid were analysed for catechin content and skin fluid for PGE2 and 12-HETE by liquid chromatography coupled to tandem MS. A total of fourteen completing subjects were supplement compliant (twelve female, median 42·5 years, range 29–59 years). Benzoic acid levels were increased in skin fluid post-supplementation (P= 0·03), and methylated gallic acid and several intact catechins and hydroxyphenyl-valerolactones were detected in the skin tissue and fluid. AUC analysis for UVR erythema revealed reduced response post-GTC (P= 0·037). Pre-supplementation, PGE2 and 12-HETE were UVR induced (P= 0·003, 0·0001). After GTC, UVR-induced 12-HETE reduced from mean 64 (sd 42) to 41 (sd 32) pg/μl (P= 0·01), while PGE2 was unaltered. Thus, GTC intake results in the incorporation of catechin metabolites into human skin associated with abrogated UVR-induced 12-HETE; this may contribute to protection against sunburn inflammation and potentially longer-term UVR-mediated damage.
|
4 |
Perturbations of arachidonic acid metabolism in the metabolic syndromeTsai, I-Jung January 2009 (has links)
[Truncated abstract] Arachidonic acid is oxidised in vivo by non-enzymatic (free radical) or enzymatic pathways (cyclooxygenase, lipoxygenase, and cytochrome P450) to form a range of biologically active eicosanoids. Specifically, arachidonic acid is metabolised by cytochrome P450 -hydroxylase to produce vasoactive 20-hydroxyeicosatetraenoic acid (20-HETE), and by 5-lipoxygenase to produce proinflammatory leukotriene B4 (LTB4), which can further be metabolised by -hydroxylase to from 20-OH-LTB4 and 20-COOH-LTB4. F2-Isoprostanes (F2-IsoPs) are produced through free radical attack on arachidonic acid and have been recognised as the most reliable markers of lipid peroxidation in vivo. The metabolic syndrome (MetS) is characterised by abdominal obesity, hypertension, insulin resistance, glucose intolerance, and dyslipidemia. It is associated with low-grade inflammation and oxidative stress and an increased risk of developing cardiovascular diseases. Dietary weight loss is strongly recommended for the management of the MetS and can potentially minimise the risk of cardiovascular diseases and diabetes in individuals with the MetS. Little is known regarding the role of these arachidonic acid metabolites in the MetS and the effect of weight loss on their metabolism. Chapter three comprised of three in vitro studies aimed to examine 20-HETE synthesis in human blood cells. 20-HETE acts as a second messenger for vasoconstrictor actions of angiotensin II (Ang II) and endothelin-1 (ET-1) in renal and mesenteric beds. Human neutrophils and platelets are integral to the inflammatory process. ... Production of LTB4 and 20-OH-LTB4 was significantly lower compared with controls (P<0.005) and remained so after adjustment for neutrophil count (P<0.05).The weight loss intervention resulted in a 4.6kg reduction in body weight and a 6.6cm decrease in waist circumference and a significant increase in LTB4 and 20-OH- LTB4 in the weight loss group. Chapter Five continued to investigate the role of other arachidonic acid metabolites, 20-HETE and F2-IsoPs in the MetS and the effect of weight loss. In the case-control study (Human study 1), plasma and urinary 20-HETE and F2-IsoPs were significantly elevated in the MetS group, but no significant difference was found in stimulated-neutrophil 20-HETE. A significant gender x group interaction was observed in that women with the MetS had higher urinary 20-HETE and F2-IsoPs compared to controls (P<0.0001). In a randomised controlled trial (Human study 2), relative to the weight- maintenance group, a 4.6 kg loss in weight resulted in a 2 mmHg fall in blood pressure but did not alter the production of 20-HETE or F2-IsoPs. No significant differences were shown in 20-HETE released from stimulated-neutrophils before and after weight loss. 20-HETE and oxidative stress may be important mediators of cardiovascular disease risk in the MetS. Although a 4% reduction in body weight reduced BP, there were no changes in plasma or urinary 20-HETE or F2-IsoPs. In summary, in vitro studies show that human neutrophils and platelets can produce 20-HETE in response to Ang II and ET-1, and human studies demonstrate that the presence of MetS has a significant impact on arachidonic acid metabolism and effective weight loss can restore leukocyte synthesis of LTB4.
|
5 |
Úloha metabolitů kyseliny arachidonové v regulaci krevního tlaku u experimentálních modelů ANGII-dependentní formy hypertenze / The role of arachidonic acid metabolites in regulation of blood pressure in experimental models of angiotensin II- dependent hypertensionJíchová, Šárka January 2020 (has links)
Introduction: Two major product groups originate from the arachidonic acid metabolic pathway of cytochromes P450: epoxyeicosatrienoic acid (EETs) and 19 and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE). These metabolites play an important role in the regulation of blood pressure, inflammatory responses, regulation of sodium excretion and other crucial physiological processes. Hypothesis: Our studies were based on the hypothesis that abnormalities in the production and function of these cytochrome P450 metabolites significantly contribute to the pathophysiology of hypertension development, in particular in the angiotensin II-dependent models. Objective: To investigate if the increased bioavailability of the above-mentioned metabolites in the kidney tissue will result in blood pressure reduction in the ANG II - dependent rat model of hypertension. Methods: The two methods to increase the concentration of EETs was chosen. In the first part of the study, we administered a soluble epoxide hydrolase inhibitor cAUCB [cis-4- [4- (3-adamantan-1-yl- ureido) cyclohexyloxy] benzoic acid, at a dose of 26 mg.l-1 administered in drinking water], an enzyme responsible for inactivation of biologically active forms of EETs. In the second series of the experiments we applied a synthetic EET analogue, called...
|
6 |
Identifizierung, molekulare Eigenschaften und Regulation einer renalen 20-Hydroxyeicosatetraensäure-SynthaseSchmidt, Cosima 12 January 2009 (has links)
Cytochrom P450 (CYP)-Enzyme hydroxylieren und epoxydieren Arachidonsäure (AA) zu bioaktiven Metaboliten wie 20-Hydroxyeicosatetraensäure (20-HETE) und Epoxyeicosatriensäuren (EETs). Diese CYP-abhängigen Eicosanoide fungieren als Mediatoren bei der Regulation der Gefäß-, Nieren- und Herzfunktion. Hauptziel der vorliegenden Arbeit war es, die Identität der 20-HETE bildenden CYP-Isoformen in der Mausniere aufzuklären. Ein weiterer Schwerpunkt war die Bestimmung von Veränderungen im Metabolismus CYP-abhängiger Eicosanoide in Tiermodellen des akuten Nieren- und Herzversagens. Zur Identifizierung der 20-HETE bildenden CYP-Isoform wurde die Substrat- und Wirkungsspezifität von Cyp4a10, Cyp4a12a, Cyp4a12b und Cyp4a14, sowie ihre geschlechts- und stammspezifische Expression charakterisiert. Die Ergebnisse dieser Arbeit zeigen, dass Cyp4a12a die 20-HETE Synthase der Mausniere ist. Cyp4a12a wird durch Androgene induziert und seine Expressionshöhe ist für geschlechts- und stammspezifische Unterschiede in der 20-HETE Bildung verantwortlich. Im Rattenmodell des Ischämie/Reperfusions (I/R)-induzierten Nierenschadens wird eine 20-HETE Freisetzung durch I/R induziert. Wir konnten zeigen, dass der I/R-Schaden durch Hemmung der 20-HETE Bildung signifikant reduziert wird. Im Rattenmodell der Herzinsuffizienz (SHHF) ist das Herzversagen mit einer Variante des EPHX2 Gens assoziiert. EPHX2 kodiert für die lösliche Epoxidhydrolase (sEH), die den Abbau von EETs katalysiert. Wir konnten zeigen, dass die Genvariation zu signifikant höheren sEH-Aktivitäten im Herzen (3-fachen) und in der Niere (30-fachen) führt, im Vergleich zu Rattenstämmen, die keine Herzinsuffizienz entwickeln. Die vorliegende Arbeit unterstreicht die pathophysiologische Bedeutung von Veränderungen im Metabolismus von 20-HETE und EETs. Daher erscheint es vielversprechend, den CYP-Eicosanoid Stoffwechsel als neuen Angriffspunkt für die pharmakologische Behandlung kardiovaskulärer Erkrankungen zu erschließen. / Cytochrome P450 (CYP) enzymes hydroxylate and epoxidize arachidonic acid (AA) to bioactive metabolites such as 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs). These CYP-dependent eicosanoids serve as mediators in the regulation of vascular, renal and cardiac function. The main objective of the present study was to identify the 20-HETE producing CYP isoforms in the mouse kidney. Another focus was to determine changes in the metabolism of CYP-dependent eicosanoids in animal models of acute renal and heart failure. To identify the 20-HETE producing CYP-isoform the substrate and reaction specificity of Cyp4a10, Cyp4a12a, Cyp4a12b and Cyp4a14, as well as their sex- and strain-specific expression were characterized. The present study shows that Cyp4a12a is the predominant AA hydroxylase in the mouse kidney. Cyp4a12a is induced by androgens and its expression determines the sex and strain-specific differences in 20-HETE generation. In a rat model of renal ischemia/reperfusion (I/R) injury, I/R triggered the release of 20-HETE and we were able to ameliorate renal injury by pharmacological inhibition of 20-HETE production. In a rat model of heart failure (spontaneously hypertensive heart failure rats, SHHF) the heart failure phenotype is associated with a variant of the EPHX2 gene. EPHX2 is coding for the soluble epoxide hydrolase (sEH) which catalyze the degradation of EETs. We found that the gene variation leads to significantly higher sEH activities in the heart (3-fold) and in the kidney (30-fold) compared to rat strains not prone to the development of heart failure. The present study emphasizes the pathophysiological relevance of changes in the biosynthesis and degradation of 20-HETE and EETs. Therefore, it appears promising to develop the CYP-eicosanoid pathway as a novel clinical target for the treatment of cardiovascular diseases.
|
Page generated in 0.0953 seconds