The aim of this thesis is to contribute to the understanding of iron metabolism, as a factor associated with cardiometabolic risk, by undertaking secondary data analyses. The objectives were to identify gaps in existing knowledge in terms of populations studied and alternative iron markers, and to attempt to fill the gaps with additional analyses and interpretation. Serum ferritin was the most widely available measure of iron status but the role of serum transferrin and soluble transferrin receptor (sTfR) levels was considered where available. I have taken a life-course approach with analyses in childhood and adulthood, and have included both intermediate factors such as the metabolic syndrome (MetS), and disease diagnoses of diabetes and cardiovascular disease as outcomes. Chapter one presents a review of empirical research literature on the relationship between iron metabolism and cardiometabolic risk, concepts surrounding iron markers and the study outcomes. This chapter also describes the gaps in understanding the iron-cardiometabolic risk relationship, which are subsequently explored in chapters two to six. Chapter two explores the link between serum ferritin and transferrin and MetS in cross-sectional and prospective studies of 725 Spanish children and 567 Chilean adolescents. I found associations between both ends of the ferritin distribution and MetS or glucose metabolism markers in different paediatric populations. For instance, whereas in the Spanish children there was a decrease of 0.02 SD units in the change of MetS score over time for every SD unit increase in ferritin, in the Chilean male adolescents being in the highest tertile of ferritin (v. the lowest) was associated with an increase of 0.25 SD units of MetS score. Furthermore, sustained high ferritin levels at various time points and gradual increase of ferritin during childhood were associated with higher MetS score in adolescence. The third chapter describes the association between serum ferritin status and MetS in adults in two cross-sectional studies of Scottish populations (2,047 individuals from Shetland Islands and 8,563 subjects from the Scottish Health Surveys (SHeS) 1995- 1998). I also examined the overall association between ferritin, MetS and each MetS component in adults, by conducting a meta-analysis and investigating potential relevant sources of heterogeneity for the association. Interestingly, ferritin levels were positively associated with MetS in the Scottish populations, but the association was not independent of the effect of covariates, mainly body mass index (BMI) and transaminase levels [Men Odds ratio (OR) 95% confidence interval (CI) 1.43(0.83- 2.46); Postmenopausal women OR (95%CI) 1.09(0.62-1.90); Premenopausal women OR (95%CI) 1.02(0.42-2.46), P > 0.05]. The meta-analysis supported this finding by describing hepatic injury markers and BMI as the major attenuating factors of the ferritin-MetS association. Chapter four investigates the association between sTfR or ferritin, and MetS in 725 Croatian adults in a cross-sectional study. There was no evidence of an association between sTfR and MetS [Men OR (95%CI) 1.35(0.90-2.02); Postmenopausal women OR (95%CI) 0.73(0.47-1.15); Premenopausal women OR (95%CI) 0.87(0.66-1.17), P > 0.05]. In contrast serum ferritin, was positively and independently associated with MetS in men and postmenopausal women (P < 0.05) [Men OR (95%CI) 1.78(1.31- 2.42); Postmenopausal women OR (95%CI) 1.71(1.12-2.62); Premenopausal women OR (95%CI) 1.24(0.85-1.80)]. These contrasting results suggest that different iron markers reflect different physiological processes other than iron metabolism. Chapter five evaluates the longitudinal association between serum ferritin and several cardiometabolic disease outcomes (CMDs) in the nationally representative SHeS 1995 and 1998 (n = 6,497). I found an independent positive longitudinal association between ferritin and cerebrovascular disease (CEVD), which was strengthened by using higher cut-points for increased ferritin [higher v. lowest sextile fully adjusted Hazard ratio(HR) 95%CI 2.08 (1.09-3.94), P=0.024], and a not significant association with coronary heart disease (CHD) after adjustment for covariates. My analyses confirmed the widely established association with type 2 diabetes (T2D) [whole sample fully adjusted HR 95% CI 1.59(1.10-2.34), P=0.006], even with serum ferritin within the normal range. The above set of observations confirm ferritin as biomarker mainly related to the development of T2D and identifies the need to investigate the association between ferritin and CEVD in other populations. Chapter six investigates whether ferritin is associated with risk for cardiovascular complications among people with T2D using cross-sectional study designs in two populations with differing baseline cardiovascular risk (Spanish study SIDIAP n=38,617) and (Edinburgh Type 2 Diabetes Study (ET2DS) n= 821) with additional analysis of follow-up data for ET2DS. Interestingly, ferritin levels were negatively associated with prevalence of cardiovascular disease, mainly CHD, in people with T2D in both studies [ET2DS OR (95%CI): 0.80(0.67-0.96), P=0.020; SIDIAP study: 0.85(0.83-0.88), P < 0.001). Ferritin was also negatively associated with incident cardiovascular disease in ET2DS: HR 95% CI: 0.39(0.16-0.93), P=0.035. Therefore, the association between iron status and CMD risk in people with T2D appears to differ from that in general populations in which a positive association has been more commonly described. In conclusion, serum ferritin is associated with cardiometabolic risk in different ways in a variety of populations. Inconsistent associations for other iron markers suggest that iron biomarkers reflect factors other than iron homeostasis that influence cardiometabolic risk. The association between iron markers and MetS appears to differ between populations. This thesis illustrates the complex relationship between iron metabolism markers, MetS and CMD, and identifies the need for further research on the topic in order to extend knowledge about pathophysiology and the potential for measures of iron status as biomarkers for CMD.

No description available.

Thesis (Ph. D.)--Brigham Young University. Dept. of Physics and Astronomy, 2004. / Includes bibliographical references (p. 71-75).

Previous experiments have demonstrated that the hepatoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) involves synergism with iron. It has been postulated that it is storage iron that plays a role in toxic effects observed with TCDD poisoning. It was hypothesized that TCDD induction of the Ah gene locus in some way leads to mobilization of storage iron from the iron storage protein ferritin. Microsomal ferritin iron release was investigated in intact microsomes and in a reconstituted system. Evidence is presented which suggests that NADPH-cytochrome c (P450) reductase is capable of effecting the release of iron from flavin (FMN), and that at the same time, the reduced flavin thus generated is capable of effecting the release of iron from ferritin. While no direct evidence was obtained, the results do lend support to the hypothesis that TCDD toxicity could result from the mobilization of iron from ferritin by the TCDD induced microsomal electron transport system. / Thesis / Master of Science (MSc)

No description available.

Thesis (M.S.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains vi, 43 p. Vita. Includes abstract. Includes bibliographical references (p. 34-36).

Lic.-avh. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 2 uppsatser.

Thesis (Ph. D.)--University of Sydney, 2008. / Title from title screen (viewed 11 February 2009). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Discipline of Pathology, Faculty of Medicine. Includes bibliographical references. Also available in print form.

Thesis (Ph.D.(Physiology))--University of Pretoria, 2009. / Abstract in English. Includes bibliographical references.

Orientador: Paulo Mazzafera / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-13T02:41:43Z (GMT). No. of bitstreams: 1 Bottcher_Alexandra_M.pdf: 1074089 bytes, checksum: 5190092093a682d1c16cfe9c85d37e3f (MD5) Previous issue date: 2009 / Resumo: A ferritina é uma proteína que armazena átomos de ferro (Fe) em uma forma não tóxica, controlando o nível desse metal nas células. Em humanos, a ferritina também é capaz de se ligar ao alumínio (Al), evitando sua toxicidade. Como o cafeeiro consegue crescer adequadamente em solos ácidos, com níveis elevados de Al, e células em suspensão tratadas com esse mesmo metal têm expressão aumentada de genes que codificam para ferritina, há a possibilidade dessa proteína se complexar ao Al também em plantas. Na indução da síntese da ferritina em suspensões celulares de Coffea arabica cv. Mundo Novo com 300 e 1.200 µmol/L de sulfato ferroso observou-se um aumento de 8,9 e 18,2 vezes, respectivamente, do RNAm CaFer1 da ferritina, em relação ao controle. Já o tratamento com 5 mmol/L de sulfato de alumínio-potássio resultou na diminuição de 4,57 vezes na expressão desse gene, em relação ao controle. Para Coffea arabica cv. Icatu, todos os tratamentos resultaram na queda da expressão de CaFer1, sendo que essa diminuição foi de 29,0 e 6,3 vezes para as células tratadas com 300 e 1.200 µmol/L de sulfato ferroso, respectivamente, e de 98,0 vezes para o tratamento com 5 mmol/L de sulfato de alumínio-potássio, em relação ao controle. Esses mesmos tratamentos não induziram, em ambas as cultivares, expressão diferencial significativa de outro gene da ferritina analisado, o CaFer2. Os resultados do Western Blot mostraram certa concordância com esses resultados. Assim como em outras plantas, a ferritina de células em suspensão de cafeeiro responde à presença do Fe, entretanto, devido ao não acúmulo dessa proteína nas células submetidas ao tratamento com 5 mmol/L de sulfato de alumínio-potássio, provavelmente, a ferritina não esteja envolvida na complexação desse metal no cafeeiro ou a concentração utilizada foi elevada, o que pode ter causado danos nos ácidos nucléicos ou impedido a transcrição normal dos genes. Nas análises in silico utilizando CaFer1 e CaFer2 de C. arabica e os genes da ferritina de C. canephora e C. racemosa, observaram-se alta similaridade entre CaFer1 e a ferritina de C. canephora e entre CaFer2 e a ferritina de C. racemosa. Por fim, os ensaios com as enzimas antioxidantes superóxido dismutase (SOD), catalase (CAT), glutationa S-transferase (GST), glutationa redutase (GR) e guaiacol peroxidase (GPOX) revelaram que as culturas celulares de Mundo Novo foram mais responsivas aos tratamentos aplicados, exceto em relação à GST, que foi a enzima que apresentou atividade mais acentuada para Icatu. Além disso, observou-se que a resposta enzimática foi dose dependente e que as duas cultivares utilizaram vias distintas para defesa celular contra espécies ativas de oxigênio. / Abstract: Ferritin is a protein capable to store iron (Fe) atoms in a nontoxic form, controlling the level of this metal in the cells. In humans, ferritin is able to accommodate aluminium (Al) atoms, avoiding its toxicity. Considering that Coffea arabica plants are able to grow well in acidic soils with high Al and suspension cells treated with this same metal showed high ferritin gene expression, it is possible that this protein is also able to complex Al atoms in planta. The induction of ferritin synthesis in suspension cells of C. arabica cv. Mundo Novo with 300 and 1.200 µmol/L of ferrous sulphate revealed an increase of 8,9 and 18,2 times, respectively, of transcripts of ferritin gene CaFer1, as compared with the control. The treatment with 5 mmol/L of aluminium-potassium sulphate resulted in the reduction of 4,57 times the expression of this gene, as compared with the control. In cells from the Icatu cultivar all treatments resulted in reduction of the expression of CaFer1. This decrease was about 29,0 and 6,3 times in cells treated with 300 and 1.200 µmol/L of ferrous sulphate, respectively, and 98,02 times in the treatment with 5 mmol/L of aluminium-potassium sulphate, as compared with the control. For both varieties, these same treatments did not result in significant differential expression of the other ferritin gene analyzed, CaFer2. Western Blots data were in agreement with this observation. Therefore, ferritin expression in suspension cells of Coffea plants responds to Fe, as shown for other plants, however, on account of the no accumulation of ferritin in both cultivars treated with 5 mmol/L of aluminium-potassium sulphate, possibly this protein is not involved with Al complexation in C. arabica plants or the level of Al used was sufficiently high to provoke damages in the nucleic acids or to impair the normal transcription of the genes. An in silico analysis carried out with CaFer1 and CaFer2 from C. arabica and with ferritin genes of the Coffea canephora and Coffea racemosa revealed high similarity between CaFer1 and C. canephora ferritin, and CaFer2 with C. racemosa ferritin. Finally, assays of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR), and guaiacol peroxidase (GPOX) revealed that cell cultures of the Mundo Novo variety are more responsive to the treatments with the metals, except for GST, wich was the only enzyme with higher activity in cells from the Icatu cultivar. Furthermore, it was observed that enzymatic response was dose dependent and that Mundo Novo and Icatu used distinct mechanisms to protect cells against reactive oxygen species. / Mestrado / Mestre em Biologia Vegetal