Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--University OF MICHIGAN.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 129-137). Also available on the World Wide Web.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references. Also available on the World Wide Web.

FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O objetivo do presente trabalho foi investigar a existÃncia de variaÃÃo sazonal nos conteÃdos de carotenÃides provitamina A ( e caroteno) e vitamina E ( e tocoferol) em duas espÃcies de macroalgas marinhas vermelhas, Cryptonemia luxurians e C. crenulata. As algas foram coletadas mensalmente de janeiro a dezembro de 2007, durante as marÃs baixas na Praia do Pacheco, Caucaia, CearÃ. Em laboratÃrio as algas foram desidratadas em estufa a 40ÂC por 15 horas. O material desidratado foi triturado atà a obtenÃÃo de um pà fino e, em seguida, submetido aos procedimentos de extraÃÃo com metanol, saponificaÃÃo com hidrÃxido de potÃssio e partiÃÃo em n-hexano. Para a anÃlise simultÃnea de carotenÃides e tocoferÃis, por cromatografia lÃquida de alta eficiÃncia, uma coluna Waters Spherisorb-Hichrom S5 ODS-2 (4,6 x 250 mm) e fase mÃvel de MeOH: THF (95:5, v/v), com fluxo de 1,5 mL min -1 foram utilizadas, com detecÃÃo em 450 nm e 292 nm, respectivamente. Em ambas as espÃcies pertencentes ao gÃnero Cryptonemia foram detectados e caroteno ao longo dos meses de coleta. De uma maneira geral, as duas espÃcies apresentaram maiores teores de caroteno que caroteno. Apesar de as macroalgas analisadas pertencerem ao mesmo gÃnero, foi possÃvel verificar uma variaÃÃo nos teores de carotenÃides provitamina A ao longo do ano entre as espÃcies. C. luxurians pode ser eleita como melhor fonte de vitamina A que C. crenulata. Dentre os isÃmeros da vitamina E, tocoferol apresentou as maiores concentraÃÃes. C. luxurians exibiu os maiores teores de ambos os tocoferÃis. De acordo com os resultados obtidos no presente estudo, as macroalgas marinhas C. luxurians e C. crenulata desidratadas em estufa a 40ÂC por 15 horas possivelmente sÃo melhores fontes de vitamina E do que de vitamina A. Para avaliar o comportamento sazonal dos teores de  e caroteno e  e tocoferol, foi utilizada a anÃlise de agrupamentos. A partir dessa anÃlise constatou-se que os teores de tocoferÃis apresentaram variaÃÃo mais proeminente, tanto entre as estaÃÃes do ano como entre as espÃcies, quando comparados com os carotenÃides provitamina A, os quais demonstraram maior estabilidade nos teores por espÃcie e por estaÃÃo do ano. Entretanto, somente a partir de estudos posteriores serà possÃvel determinar quais fatores e sua influÃncia na variaÃÃo dos teores de carotenÃides provitamina A e vitamina E das espÃcies analisadas. / The objective of this research project was to investigate the existence of seasonal variation of both provitamin A carotenoids ( and carotene) and vitamin E ( and tocopherol) in two species of red marine macroalgae, Cryptonemia luxurians and C. crenulata. The alga samples were collected monthly from January to December of 2007, during the low tides of Pacheco Beach, Caucaia, CearÃ. The alga samples were dehydrated at 40ÂC for 15 h. The dried alga material was crushed into a fine powder and then submitted into the procedures of extraction with methanol, saponification with potassium hydroxide and partition with n-hexane. For simultaneous analyses of carotenoids and tocopherols the HPLC system consisted of a Waters Spherisorb-Hichrom S5 ODS-2 (4.6 x 250 mm) column and a mobile phase of MeOH: THF (95:5, v/v), delivered at 1.5 mL min -1 , with detection at 450 nm and 292 nm, respectively. In both species belonging to the genre Cryptonemia were detected  and carotene throughout all the sampling months. In general, both species contained larger concentrations of carotene than carotene. Despite the macroalgae analyzed belonged to the same genre, it was possible to verify a variation in the concentrations of provitamin A carotenoids throughout the year. C. luxurians was elected as a better source of vitamin A than C. crenulata. Among the isomers of vitamin E, tocopherol showed the higher concentrations. C. luxurians showed the highest levels of both tocopherols. According to these results, C. luxurians and C. crenulata oven-dried at 40ÂC for 15 h are possibly better sources of vitamin E than vitamin A. To verify the seasonal behavior of the concentrations of provitamin A carotenoids and vitamin E, grouping analysis was utilized. Based upon the results of this analysis it was established that tocopherol concentrations showed a more substantiated variation in the macroalgae within the seasons of the year as well as among the two species. On the other hand, the provitamin A carotenoids, exhibited more stable concentrations considering the species and the seasons. Nevertheless, only with subsequent studies it will be possible to determine the factors and its influence on the variation of provitamin A carotenoids and vitamin E contents of the analyzed species.

No description available.

For more than 80 years vitamin E has been in the focus of scientific research. Most of the progress concerning non-antioxidant functions, nevertheless, has only arisen from publications during the last decade.<br> Most recently, the metabolic pathway of vitamin E has been almost completely elucidated. Vitamin E is metabolized by truncation of its side chain. The initial step of an omega-hydroxylation is carried out by cytochromes P450 (CYPs). This was evidenced by the inhibition of the metabolism of alpha-tocopherol by ketoconozole, an inhibitor of CYP3A expression, whereas rifampicin, an inducer of CYP3A expression increased the metabolism of alpha-tocopherol. Although the degradation pathway is identical for all tocopherols and tocotrienols, there is a marked difference in the amount of the release of metabolites from the individual vitamin E forms in cell culture as well as in experimental animals and in humans. Recent findings not only proposed an CYP3A4-mediated degradation of vitamin E but also suggested an induction of the metabolizing enzymes by vitamin E itself.<br> In order to investigate how vitamin E is able to influence the expression of metabolizing enzymes like CYP3A4, a pregnane X receptor (PXR)-based reporter gene assay was chosen. PXR is a nuclear receptor which regulates the transcription of genes, e.g., CYP3A4, by binding to specific DNA response elements. And indeed, as shown here, vitamin E is able to influence the expression of CYP3A via PXR in an in vitro reporter gene assay. Tocotrienols showed the highest activity followed by delta- and alpha-tocopherol. An up-regulation of Cyp3a11 mRNA, the murine homolog of the human CYP3A4, could also be confirmed in an animal experiment. The PXR-mediated change in gene expression displayed the first evidence of a direct transcriptional activity of vitamin E. PXR regulates the expression of genes involved in xenobiotic detoxification, including oxidation, conjugation, and transport. CYP3A, e.g., is involved in the oxidative metabolism of numerous currently used drugs. This opens a discussion of possible side effects of vitamin E, but the extent to which supranutritional doses of vitamin E modulate these pathways in humans has yet to be determined. <br><br> Additionally, as there is arising evidence that vitamin E's essentiality is more likely to be based on gene regulation than on antioxidant functions, it appeared necessary to further investigate the ability of vitamin E to influence gene expression. Mice were divided in three groups with diets (i) deficient in alpha-tocopherol, (ii) adequate in alpha-tocopherol supply and (iii) with a supranutritional dosage of alpha-tocopherol. After three months, half of each group was supplemented via a gastric tube with a supranutritional dosage of gamma-tocotrienol per day for 7 days. Livers were analyzed for vitamin E content and liver RNA was prepared for hybridization using cDNA array and oligonucleotide array technology. A significant change in gene expression was observed by alpha-tocopherol but not by gamma-tocotrienol and only using the oligonucleotide array but not using the cDNA array. The latter effect is most probably due to the limited number of genes represented on a cDNA array, the lacking gamma-tocotrienol effect is obviously caused by a rapid degradation, which might prevent bioefficacy of gamma-tocotrienol.<br> Alpha-tocopherol changed the expression of various genes. The most striking observation was an up-regulation of genes, which code for proteins involved in synaptic transmitter release and calcium signal transduction. Synapsin, synaptotagmin, synaptophysin, synaptobrevin, RAB3A, complexin 1, Snap25, ionotropic glutamate receptors (alpha 2 and zeta 1) were shown to be up-regulated in the supranutritional group compared to the deficient group. The up-regulation of synaptic genes shown in this work are not only supported by the strong concentration of genes which all are involved in the process of vesicular transport of neurotransmitters, but were also confirmed by a recent publication. However, a confirmation by real time PCR in neuronal tissue like brain is now required to explain the effect of vitamin E on neurological functionality. The change in expression of genes coding for synaptic proteins by vitamin E is of principal interest thus far, since the only human disease directly originating from an inadequate vitamin E status is ataxia with isolated vitamin E deficiency. Therefore, with the results of this work, an explanation for the observed neurological symptoms associated with vitamin E deficiency can be presented for the first time. / Chemisch handelt es sich bei Vitamin E um acht lipophile Derivate des 6 Chromanols mit einer Seitenkette. Nach dem Sättigungsgrad der Seitenkette lassen sich die Derivate in die Tocopherole (gesättigte Seitenkette) und die Tocotrienole (ungesättigte Seitenkette mit drei Doppelbindungen) einteilen. Entsprechend der Methylierung des Chromanrings lassen sie sich in alpha-, beta-, gamma- und delta-Tocopherol, bzw. Tocotrienol unterscheiden. Davon besitzt alpha-Tocopherol, das gleichzeitig die im Plasma dominierende Form darstellt, die höchste biologische Aktivität. Aufnahme wie auch der Transport von Vitamin E im Körper sind vergleichsweise gut erforscht. Die Kenntnisse zu Metabolismus und Elimination waren jedoch bis vor kurzem sehr lückenhaft. Lange Zeit waren nur Vitamin E-Metabolite mit geöffnetem Chromanring, die sogenannten Simon-Metabolite Tocopheronsäure und Tocopheronolacton bekannt. Diese Metabolite können nur aus oxidativ gespaltenem Vitamin E entstehen und galten daher auch als Beweis für die antioxidative Wirkung von Vitamin E. Mit verbesserter Analytik wurde vor einigen Jahren gezeigt, dass die Simon-Metabolite größtenteils Isolierungsartefakte sind. Stattdessen wurden Metabolite mit intaktem Chromanring identifiziert. Tocopherole wie auch Tocotrienole werden im Körper durch eine Verkürzung der Seitenkette abgebaut. Die Endprodukte sind in jedem Fall CEHCs (Carboxyethyl Hydroxychromane). Die Seitenkettenverkürzung startet mit einer omega-Hydroxylierung gefolgt von 5 Schritten &#61472;beta-Oxidation. Die omega Hydroxylierung der Seitenkette durch Cytochrom P450 (CYP) Enzyme wurde indirekt bestätigt. CYP3A4 gilt dabei als eines der wahrscheinlichsten Enzyme im Abbau von Vitamin E, die Beteiligung weiterer CYPs wird jedoch gleichfalls angenommen. Auffällig ist, dass nicht alle Vitamin E-Formen in gleichem Ausmaß abgebaut werden. Die Ausscheidung von CEHCs aus alpha-Tocopherol ist, verglichen zu andern Vitamin E-Formen, in kultivierten Zellen wie auch in vivo sehr gering. Die Art der Seitenkettenverkürzung von Vitamin E spricht für einen Abbau über das Fremdstoff-metabolisierende System, welches auch eine Vielzahl von Medikamenten verstoffwechselt.<br> Im ersten Teil der vorliegenden Arbeit konnte mittels Reportergenassay in HepG2 Zellen gezeigt werden, dass Vitamin E einen nukleären Rezeptor, den Pregnan X Rezeptor (PXR), zu aktivieren und die Expression von PXR-regulierten Genen zu beeinflussen vermag. PXR reguliert eine Reihe von Genen für Fremdstoff-metabolisierende Enzyme wie z.B. Cytochrom P450 3A4 durch Bindung an sein responsives Element im Promotor der Zielgene. Die untersuchten Vitamin E-Formen unterschieden sich deutlich hinsichtlich ihrer PXR-Aktivierung. Die Tocotrienole zeigten die höchste PXR-Aktivierung - vergleichbar mit Rifampicin, einem bekannt guten PXR-Aktivator - gefolgt von delta / alpha- und gamma-Tocopherol. Im Tierversuch an Mäusen konnte die erhöhte Expression von Cyp3a11, dem Homolog des humanen CYP3A4 in Abhängigkeit von der alpha-Tocopherol-Zufuhr bestätigt werden. Somit konnte erstmals gezeigt werden, dass Vitamin E die Expression von Genen direkt beeinflussen kann. Darüber hinaus unterstreicht diese Beobachtung die Möglichkeit einer Wechselwirkung von pharmakologischen Dosen Vitamin E mit dem Abbau von Medikamenten. Eine genregulatorische Funktion von Vitamin E ist auf den ersten Blick überraschend. Denn wenngleich Vitamin E vor über 80 Jahren als Fertilitätsfaktor bei Ratten entdeckt wurde, steht die erst später beschriebene antioxidative Eigenschaft von Vitamin E bis heute im Fokus der meisten Publikationen. Die molekularen Mechanismen der Essentialität von Vitamin E wurden dagegen wenig untersucht. Erst in den letzten Jahren finden Funktionen von Vitamin E Interesse, die über seine antioxidative Wirkung hinausgehen. Dabei konnte gezeigt werden, dass Vitamin E in vitro die Expression von Genen wie dem Scavenger Rezeptor CD36, dem Connective Tissue Growth Factor oder dem Peroxisomen-Proliferator aktivierten Rezeptor gamma beeinflussen kann.<br> Um weitere Zielgene von Vitamin E in vivo identifizieren zu können, wurden im zweiten Teil der vorliegenden Arbeit Mäuse in drei Fütterungsgruppen mit einer a) defizientem b) adäquatem sowie c) mit einer supranutritiven alpha Tocopherol-Versorgung über 3 Monate gefüttert. Zusätzlich erhielt die Hälfte der Tiere aus jeder Gruppe während der letzten Lebenswoche eine supranutritive Dosis gamma-Tocotrienol pro Tag. Aus den Lebern der Tiere wurde die RNA präpariert und die differentielle Genexpression mittels a) cDNA und b) Oligonukleotide enthaltenden GenChips analysiert.<br> Eine signifikante Änderung in der Genexpression zwischen den verschiedenen Fütterungsgruppen fand sich jedoch nur in den Analysen der Oligonukleotid GenChips. Dies kann auf die begrenzte Anzahl von Genen zurückzuführen sein, die auf den cDNA GenChips repräsentiert waren. Auch ein signifikanter Effekt von gamma-Tocotrienol auf die Genexpression konnte nicht beobachtet werden. Wahrscheinlich ist die hohe Ausscheidung von gamma-CEHC, dem Abbauprodukt von gamma-Tocotrienol, die im Urin der Tiere gemessen wurde und die damit womöglich verringerte Bioverfügbarkeit von gamma-Tocotrienol dafür verantwortlich.<br> Mit Hilfe der Oligonukleotid GenChips konnte jedoch ein signifikanter Effekt von alpha-Tocopherol auf die Expression einer Vielzahl von Genen beobachtet werden. Herausstechend war dabei die erhöhte Expression von für den vesikulären Transport essentiellen Genen, die für den synaptischen Signaltransfer benötigt werden. So wurden z.B. Synapsin, Synaptotagmin, Synaptophysin, Synaptobrevin, RAB3A, Complexin 1, Snap25, die ionotrophen Glutamat Rezeptoren alpha 2 und zeta 1 in Abhängigkeit von der alpha Tocopherol-Versorgung über die Diät erhöht exprimiert. Die Beobachtung, dass Vitamin E bei neurologischen Prozessen eine Rolle zu spielen scheint ist jedoch nicht neu. Bei Patienten mit einem Mangel an funktionellem alpha-Tocopherol-Transfer-Protein (alpha-TTP) kann es zu stark verringerten Plasmakonzentrationen an Vitamin E kommen, da alpha-TTP eine zentrale Rolle in der Aufnahme und Verteilung von Vitamin E im Körper einnimmt. An diesen Patienten können charakteristische Vitamin E-Mangelzustände beobachtet, die durch eine Reihe von neurologischen Störungen wie Ataxien, Hyporeflexie sowie eine verringerte propriozeptive und vibratorische Sensitivität gekennzeichnet sind. Mit den vorliegenden Ergebnissen kann nun erstmals eine mechanistische Erklärung für diese Symptome diskutiert werden. Eine Bestätigung der vorliegenden Ergebnisse via RT-PCR und Western Blot, z.B. in neuronalem Gewebe wie dem Gehirn, sowie anschließende funktionellen Untersuchungen ist daher dringend geboten.

Background: Folate and cobalamin are essential cofactors for homocysteine (HCY) metabolism. Hyperhomocysteinemia, a multifactorial condition, may reflect B vitamin deficiency and is associated with increased risk of cardiovascular disease, thrombosis, and neurodegenerative and chronic gastrointestinal diseases in humans. Hyperhomocysteinemia has been reported in Greyhounds with suspected chronic enteropathy. Objectives: To evaluate the frequencies of and the association between hypofolatemia and hyperhomocysteinemia in Greyhounds. Animals: Data and serum samples from 559 Greyhounds. Methods: Nested case-control study. The frequency of hypofolatemia in Greyhounds was determined by a laboratory database search. The relationship between hyperhomocysteinemia (measured by gas chromatography-mass spectrometry) and hypocobalaminemia and hypofolatemia was evaluated, and its frequency compared between healthy Greyhounds and Greyhounds with thrombosis or chronic diarrhea. Results: Hypofolatemia was identified in 172 of 423 (41%) Greyhounds and was more common in hypo- than in normocobalaminemic dogs (49% vs. 35%; P = .0064). Hyperhomocysteinemia was detected in 53 of 78 (68%) of Greyhounds, being more common in hypo- than in normofolatemic dogs (88% vs. 59%; P = .0175). All healthy Greyhounds, 21 of 30 (70%) of dogs with chronic diarrhea and 6 of 8 (75%) of those with thrombosis, were hyperhomocysteinemic. Serum HCY concentrations were inversely correlated with serum folate concentration (q = -0.28; P = .0386) and were positively associated with serum albumin concentration (q = 0.66; P = .0022). Conclusions and Clinical Relevance: Hyperhomocysteinemia occurs frequently in the Greyhound population. Its association with hypofolatemia suggests decreased intracellular availability of B vitamins, but the functional implications warrant further investigation. Hyperhomocysteinemia in Greyhounds potentially may serve as a spontaneous canine model to further investigate hyperhomocysteinemia in humans.

Hypertension and nutrition: Fat-soluble vitamins A, D and E Weber J1 , Vlcek J1 , Suarez-Varella MM2 1 Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Czech Republic 2 Department of Preventive Medicine and Public Health, Faculty of Pharmacy, University of Valencia, Spain Arterial hypertension (AH) is a disease affecting population globally, and thus considered as a problem of public health and socioeconomic. Studies are trying to identify the connection between diet and the prevalence of arterial hypertension. Objective of the study was to determine possible association between an occurrence of AH and fat-soluble vitamins A, D and E intake. The nested, case-control population study investigation was grounded on database from the Spanish Hortega study, and performed on a random sample of 1,514 people (50.3 % women, 49.7 % men). From this sample we selected those aged ≥ 40 years old and untreated for hypertension and divided them into two groups: non-hypertensive (n = 429; 63.6 %) (controls), and newly diagnosed AH (n = 246; 36.4 %) (cases). Biochemical and anthropometric measurements, data on dietary intakes, education, socioeconomic status, place of residence, health habits, comorbidities, consumption of alcohol and tobacco were used for our...

Introdução: Uma elevada prevalência de deficiência de vitamina D (DVD) em crianças tem sido observada em todo o mundo, mas poucos são os estudos com relação ao estado nutricional da vitamina D (VD) em lactentes saudáveis. A principal causa da deficiência em crianças saudáveis é o aleitamento materno sem suplementação e a falta ou insuficiência de exposição solar. Objetivos: Determinar as concentrações séricas de VD e verificar sua associação com concentrações de paratormônio (PTH), fosfatase alcalina (FA), cálcio (Ca), fósforo (P) e albumina e uso da suplementação de VD em lactentes saudáveis com idades entre >= 6 e <= 24 meses atendidos em duas Unidades Básicas de Saúde do município de Ribeirão Preto, SP, Brasil. Métodos: Estudo transversal, observacional e analítico em que foram determinadas as concentrações séricas de 25 (OH)D, PTH, FA, Ca, P e albumina de 155 lactentes saudáveis. Informações sobre exposição solar, aspectos sociodemográficos das mães e características clínico-nutricionais dos lactentes foram obtidas por entrevistas com os responsáveis dos lactentes. Concentrações séricas de 25(OH)D maiores que 20ng/ml foram consideradas adequadas, entre 12 a 20ng/ml insuficientes e < 12ng/ml deficientes. Resultados: Dez lactentes (6,5%, Intervalo de Confiança 95% 3,5-11,4) apresentaram insuficiência de VD e nenhum apresentou DVD. Nenhuma alteração nas concentrações séricas de P, Ca e albumina foram detectadas. Apenas um lactente apresentou aumento nas concentrações séricas de PTH e 35,5% dos lactentes apresentaram FA elevada, porém nenhum apresentou DVD ou insuficiência de VD. Não foram encontradas associações entre as concentrações séricas de 25(OH)D e as de FA, Ca e albumina. Houve associação entre concentrações séricas de 25(OH)D e PTH mesmo após ajuste para sexo, idade e Índice de Massa Corporal; também foi observada associação entre concentrações séricas de 25(OH)D e P apenas após o ajuste pelas covariáveis. Não foram verificadas associações entre insuficiência de VD, exposição solar e suplementação de VD. Conclusões: Uma baixa prevalência de concentrações insuficientes de 25(OH)D foi observada. Não foram encontradas associações entre as concentrações séricas de 25(OH)D e PTH, FA, Ca, P e albumina. Da mesma forma, não foram encontradas associações entre de concentrações séricas de 25(OH)D, exposição solar e suplementação de VD. / Introduction: A high prevalence of vitamin D deficiency (VDD) in children has been observed worldwide, but there are few studies on the nutritional status of vitamin D (VD) in healthy infants. The main cause of deficiency in healthy children is breastfeeding without supplementation and lack or insufficiency of sun exposure. Objective: To determine serum concentrations of VD and verify its association with parathyroid hormone (PTH) levels and use of VD supplementation in healthy infants aged >= 6 to <= 24 months attended at two Basic Health Units in Ribeirão Preto city, São Paulo, Brazil. Methods: A cross-sectional, observational and analytical study was performed in which were determined serum concentrations of 25 (OH) D, PTH, alkaline phosphatase (AP), calcium (Ca), phosphorus (P) and albumin of 155 healthy infants. Information of sun exposure, sociodemographic aspects of mothers and clinical and nutritional characteristics of infants were obtained through interviews with responsible for infants. Serum concentrations of 25(OH)D greater than 20ng / ml were considered adequate, between 12 to 20ng / ml insufficient and <12ng/ml, deficient. Results: Ten infants (6.5%, 95% Confidence Interval 3.5-11.4) presented VD insufficiency and none presented DVD. Only one infant had an increase in PTH serum concentrations and 35.5% of infants had high AP but none presented DVD or VD insufficiency. No changes in serum P, Ca and albumin concentrations were detected. No associations were found between serum concentrations of 25 (OH) D and AP, Ca and albumin. There was an association between serum concentrations of 25(OH)D and PTH even after adjusting for sex, age and body mass index; an association between serum concentrations of 25(OH)D and P was observed only after adjustment for covariates. There were no associations between VD insufficiency, sun exposure and VD supplementation. Conclusions: A low prevalence of insufficient concentrations of 25 (OH)D was observed. No associations were found between serum concentrations of 25 (OH)D and PTH, FA, Ca, P and albumin. Likewise, no associations were found between serum concentrations of 25 (OH)D, sun exposure and VD supplementation.