In recent years vitamin D has gained popularity in the media, on the internet, and throughout alternative treatment practitioners as a cheap and effective option to treat many diseases. Research showing that vitamin D receptors are present in virtually all cells of the body, and the increasing data demonstrating a relationship of vitamin D metabolites to chronic diseases, have led to widespread treatment of medical conditions with vitamin D supplementation. Chronic pain and inflammatory conditions are increasingly linked to vitamin D deficiency. The question posed in this review is whether there is significant, quality research to recommend vitamin D supplementation for patients with chronic pain conditions. Utilizing publications from PubMed for the review, various search terms were entered for vitamin D (vitamin D; vitamin D2; vitamin D3; 1,25-dihydroxyvitamin D3; 1,25-dihydroxycholecalciferol; 25 hydroxycholecalciferol; 25-hydroxyvitamin D; alfacalcidol; calcidiol; calcitriol; calcifediol; calciferol; ergocalciferal; cholecalciferol); and "pain." The search was continued from the last day of the Straub et. al. review, September 8th, 2008. The last search was conducted on December 5, 2012. The search protocol from Straub et. al was followed as well. Also, added to this search protocol were the terms: vitamin D receptor; VDR and "pain." These terms enabled a search for genetic links between vitamin D and pain. The search criteria resulted in nine relevant articles (from the original 1,069 studies) with varying treatment protocols in each article making any statistical representation impossible. Results on the effectiveness of vitamin D correlation with chronic pain were extremely variable, with most papers drawing the conclusion that more quality research needs to be implemented on the subject. Due to the variability and lack of quality randomized controlled trials, the current literature can only suggest a possible link between vitamin D levels and pain. Also, recent research into Vitamin D Receptors (VDR) has opened up a possible connection between VDR polymorphisms and pain. So, after a comprehensive review of vitamin D, Vitamin D Receptors, and pain, there is still not enough evidence to recommend supplementation to treat chronic pain conditions. However, enough evidence is available to recommend future high quality, randomized controlled trials to help determine the influence vitamin D and VDRs have on pain issues. / Oral Biology

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Vitamin D plays a vital role in modulating both innate and adaptive immune systems. Therefore, vitamin D deficiency has been associated with higher levels of autoimmune response and increased susceptibility to infections. CYP27B1 encodes a member of the cytochrome P450 superfamily of enzymes. It is instrumental in the conversion of circulating vitamin D (calcifediol) to active vitamin D (calcitriol). This is a crucial step for macrophages to express Cathelicidin Anti-microbial Peptide (CAMP), an anti-bacterial factor released during the immune response. Our recent study indicated that Crohn's disease (CD)-associated pathogen known as Mycobacterium avium paratuberculosis (MAP) decreases vitamin D activation in macrophages, thereby impeding cathelicidin production and MAP infection clearance. The mechanism by which MAP infection exerts these effects on the vitamin D metabolic axis remains elusive. In this study, we found that MAP infection interferes with vitamin D activation inside THP-1 macrophages by reducing levels of CYP27B1 and vitamin D receptor (VDR) gene expression via interaction with the TLR2-dependent p38/MAPK pathway. MAP infection exerts its effects in a time-dependent manner, with the maximal inhibition observed at 24 hours post-infection. We also demonstrated the necessity to have toll-like receptor 2 (TLR2) for MAP infection to influence CYP27B1 and CAMP expression, as TLR2 gene knockdown resulted in an average increase of 7.78±0.88 and 13.90±3.5 folds in their expression, respectively. MAP infection also clearly decreased the levels of p38 phosphorylation and showed dependency on the p38/MAPK pathway to influence the expression of CYP27B1, VDR, and CAMP which was evident by the average fold increase of 1.93±0.28, 1.86±0.27, and 6.34±0.51 in their expression, respectively, following p38 antagonism. Finally, we showed that calcitriol treatment, and p38/MAPK blockade reduce cellular oxidative stress and inflammatory markers in Caco-2 monolayers following macrophage-mediated MAP infection. In conclusion, this study characterized the primary mechanism by which MAP infection leads to diminished levels of active vitamin D and cathelicidin in CD patients, which may explain the exacerbated vitamin D deficiency state in these cases.

Genom detta arbete installerades en färdskrivaranläggning, Voyage Data Recorder, på sjöfartshögskolans fartyg Calmare Nyckel. Syftet med installationen var att skapa ett hjälpmedel till läraren då denne ska ge återkoppling på nautikerelevernas manöverövningar med fartyget. Arbetet utfördes i projektform under sista året på sjöingenjörsprogrammet samt bitvis under de tre efterföljande åren. Resultatet blev en anläggning som spelar in informationen från den bryggutrustning som bedömts vara central för att korrekt kunna återspegla en körning med fartyget, samt möjligheten att kunna återuppspela denna information. / Through this exam work, a Voyage Data Recorder was installed on the Kalmar Maritime Academy’s school ship Calmare Nyckel. The purpose of the installation was to create a tool for the teachers when they are giving feedback on the students’ manoeuvring exercises with the school ship. This work was made in project form during the last year of the marine engineer programme and partly during the following three years. The result was an installation that records the information from the bridge equipment that was judged to be central to be able to correctly mirror the manoeuvring of the ship, and the possibility to replay this information.

Alterações morfológicas no tecido ósseo têm sido descritas nos usuários de hipoglicemiantes orais da classe das tiazolidinedionas (TZDs). Hipotetiza-se que alguns genes relacionados com a osteogênese e osteoclastogênese podem ser influenciados pelo tratamento farmacológico, entretanto, o exato mecanismo ainda não está bem esclarecido. O objetivo do estudo foi avaliar o efeito da pioglitazona no remodelamento ósseo através de genes envolvidos na osteoclastogênese em indivíduos recentemente diagnosticados com DM2 e modelos animais, com a finalidade de identificar marcadores genéticos sensíveis de alterações ósseas. Foram convidados para participar do estudo 199 indivíduos (100 diabéticos e 99 normoglicêmicos), no ambulatório de dislipidemias do Instituto Dante Pazzanese de Cardiologia. Os indivíduos diabéticos foram tratados com pioglitazona (15, 30, 45, 45 mg/ dia/ via oral) por 16 semanas. Foram colhidas amostras de sangue, antes e após o tratamento para avaliações laboratoriais, extração de DNA genômico e de RNA total. Os polimorfismos e a expressão do mRNA nas células sanguíneas foram determinados pela PCR em tempo real através do sistema TaqMan®. Para o estudo em modelo animal após a indução da dieta hiperlipídica por 32 semanas, foram utilizados 12 camundongos machos da linhagem C57BL/J6, os quais foram divididos em três grupos: controle (n=4); diabéticos induzidos pela dieta hiperlipídica (DH, n=4) e diabéticos induzidos pela dieta hiperlipídica e tratados com pioglitazona 35mg/Kg/dia por 16 semanas (DHP, n=4). Para os grupos experimentais foram colhidos: amostras de sangue, para exames laboratoriais; fêmures, para a extração do RNA total; e tíbias, para determinação dos parâmetros histomorfométricos. Os pacientes DM2 apresentaram diminuição nas concentrações séricas de osteocalcina e na expressão de OPG e aumento na expressão de VDR em comparação ao grupo NG (p<0,05). A expressão de RANKL e IL6 foi maior entre as mulheres, enquanto que a expressão de PPARG foi maior entre os homens com DM2 em comparação ao grupo NG (p=0,032). Pacientes DM2 antes do tratamento apresentaram glicemia e expressão do mRNA de IL6 negativamente associados ao cálcio ionizado, enquanto que as transcrições de TNFA e VDR foram associadas positivamente e negativamente com bALP respectivamente (p<0,05). O tratamento com pioglitazona reduziu a glicemia de jejum, glicemia pós-prandial, insulina, HOMA-IR, triglicerídeos, VLDL-C, tALP e bALP e aumentou a HDL, tACP, TNF-&#945; e a transcrição de OPG (p<0,05). A glicemia basal associou-se positivamente com o cálcio ionizado. A expressão basal de OPG foi associado negativamente com tALP, enquanto que a expressão basal de TNFA foi associada positivamente com tALP e negativamente com tACP. A expressão basal IL6 foi associada positivamente com tALP, enquanto que a expressão basal de VDR foi associada negativamente com osteocalcina e positivamente com bALP em resposta ao tratamento (p<0,05). O polimorfismo RANK rs1805034 foi associado com redução na transcrição do gene RANK nos indivíduos DM2 e com o remodelamento ósseo após o tratamento com pioglitazona (p<0,05). O polimorfismo RANKL rs9525641 foi associado com aumento da transcrição gênica de RANKL nos indivíduos NG e DM2 e melhora da resposta farmacológica nos indivíduos DM2 tratados com pioglitazona (p<0,05). O polimorfismo rs3102735 do gene OPG foi associado com aumento da formação óssea nos indivíduos DM2 antes e após o tratamento (p<0,05). O genótipo CG do polimorfismo OPG rs2073618 foi associado com alteração da transcrição de OPG no grupo DM2 pré e pós-tratamento (p<0,05). O polimorfismo PPARG rs1801282 foi associado com menor risco para o desenvolvimento de diabetes (p<0,05). O polimorfismo PPARG rs2972162 foi associado com melhora da resistência insulínica nos indivíduos DM2 tratados com pioglitazona (p=0,017). O polimorfismo ESRI rs9340799 foi associado com redução da formação óssea nos indivíduos DM2 (p=0,038). Nos camundongos, após a indução da dieta hiperlipídica por 32 semanas, observou-se aumento do peso, da glicemia, do colesterol total, da expressão do mRNA de RANK, RANKL, IL6 e TNFA em fêmures e aumento de Tb.Sp e diminuição de BV/TV em comparação ao grupo controle (p<0,05). O tratamento com pioglitazona diminuiu a expressão de TNFA (p=0,028). As medidas histomorfométricas não alteraram-se após o tratamento (p>0,05). Os resultados sugerem que o estado hiperglicêmico e o tratamento influenciam os marcadores bioquímicos e moleculares. Os polimorfismos dos genes RANK, RANKL, OPG e ESRI parecem estar envolvidos no remodelamento ósseo independentemente da hiperglicemia e do tratamento e os polimorfismos do gene PPARG parecem estar envolvidos com menor risco para desenvolver diabetes e com a melhora da resistência insulínica em resposta ao tratamento com pioglitazona. / Morphological changes in bone tissue have been reported in users of oral hypoglycemic class of thiazolidinediones (TZDs). It is hypothesized that some genes related to osteogenesis and osteoclastogenesis may be influenced by pharmacological treatment, however, was not aware exact mechanism. The study aims was to evaluate pioglitazone effect on bone remodeling through genes involved in osteoclastogenesis in individuals newly diagnosed with DM2 and animal models, in order to identify sensibles genetics markers of bone alterations. Were invited to participate in study 199 patients (100 diabetics and 99 normoglycemic), in dyslipidemia ambulatory of Institute Dante Pazzanese of Cardiology. Diabetic subjects were treated with pioglitazone (15, 30, 45 or 45 mg /day/oral) for 16 weeks. Blood samples were collected before and after treatment for laboratory evaluations, extraction of genomic DNA and total RNA. Polymorphisms and mRNA expression in blood cells was determined by real time PCR using TaqMan® system. For study in animal model after 32 weeks of fat diet induction, was used 12 male mice C57BL/J6, which were divided into three groups: control (n=4); induced diabetic fat diet (DH, n=4) and induced diabetic fat diet and treated with pioglitazone 35mg/Kg/day for 16 weeks (DHP, n=4). For experimental groups were collected: blood samples for laboratory tests; femurs, for extraction of total RNA; and tibias, to determine histomorphometric parameters. DM2 patients showed decrease in serum osteocalcin and OPG expression and increased VDR expression compared to NG group (p<0.05). RANKL and IL6 expression were higher among women, whereas PPARG expression was higher among men with DM2 compared to NG group (p=0,032). DM2 patients before treatment showed blood glucose and IL6 mRNA expression negatively associated with ionized calcium, whereas TNFA and VDR transcription are positively and negatively associated with bALP respectively (p<0.05). Pioglitazone treatment reduced fasting glucose, postprandial glucose, insulin, HOMA-IR, triglycerides, VLDL-C, tALP and bALP and increased HDL, tACP, TNF-&#945; and OPG transcription (p<0.05). Basal blood glucose was positively associated with ionized calcium. Basal OPG expression was negatively associated with tALP, whereas basal TNFA expression was positively associated with tALP and negatively with tACP. Basal IL6 expression was positively associated with tALP, whereas basal VDR expression was negatively associated with osteocalcin and positively with bALP in response to treatment (p<0.05). RANK rs1805034 polymorphism was associated with RANK gene transcription reduction in subjects with DM2 and bone remodeling after treatment with pioglitazone (p<0.05). RANKL rs9525641 polymorphism was associated with increased RANKL gene transcription in NG and DM2 subjects and pharmacological response improvement in DM2 subjects treated with pioglitazone (p<0.05). OPG rs3102735polymorphism was associated with increased bone formation in DM2 subjects before and after treatment (p<0.05). CG genotype of OPG rs2073618 polymorphism was associated with OPG transcription change in DM2 group before and after treatment (p<0.05). PPARG rs1801282 polymorphism was associated with lower risk for diabetes development (p<0.05). PPARG rs2972162 polymorphism was associated with insulin resistance improvement in DM2 subjects treated with pioglitazone (p=0,017). ESRI rs9340799 polymorphism was associated with reduced bone formation in DM2 subjects (p=0,038). In mice, after 32 weeks of fat diet induction, was observed increase weight, blood glucose, total cholesterol and RANK, RANKL, IL6 and TNFA mRNA expression in femurs and Tb.Sp increase and BV/TV decrease compared to control group (p<0.05). Treatment with pioglitazone decrease TNFA (p=0,028). Histomorphometrics measurements not change after treatment (p>0.05). Results suggest that hyperglycemic state and treatment influence biochemical and molecular markers. RANK, RANKL, OPG and ESRI polymorphisms seens to be involved in bone remodeling regardless of hyperglycemia and treatment and PPARG gene polymorphisms seens to be associated with lower risk for diabetes development and with insulin resistance improvement in response to treatment with pioglitazone.

No description available.

Alterações morfológicas no tecido ósseo têm sido descritas nos usuários de hipoglicemiantes orais da classe das tiazolidinedionas (TZDs). Hipotetiza-se que alguns genes relacionados com a osteogênese e osteoclastogênese podem ser influenciados pelo tratamento farmacológico, entretanto, o exato mecanismo ainda não está bem esclarecido. O objetivo do estudo foi avaliar o efeito da pioglitazona no remodelamento ósseo através de genes envolvidos na osteoclastogênese em indivíduos recentemente diagnosticados com DM2 e modelos animais, com a finalidade de identificar marcadores genéticos sensíveis de alterações ósseas. Foram convidados para participar do estudo 199 indivíduos (100 diabéticos e 99 normoglicêmicos), no ambulatório de dislipidemias do Instituto Dante Pazzanese de Cardiologia. Os indivíduos diabéticos foram tratados com pioglitazona (15, 30, 45, 45 mg/ dia/ via oral) por 16 semanas. Foram colhidas amostras de sangue, antes e após o tratamento para avaliações laboratoriais, extração de DNA genômico e de RNA total. Os polimorfismos e a expressão do mRNA nas células sanguíneas foram determinados pela PCR em tempo real através do sistema TaqMan®. Para o estudo em modelo animal após a indução da dieta hiperlipídica por 32 semanas, foram utilizados 12 camundongos machos da linhagem C57BL/J6, os quais foram divididos em três grupos: controle (n=4); diabéticos induzidos pela dieta hiperlipídica (DH, n=4) e diabéticos induzidos pela dieta hiperlipídica e tratados com pioglitazona 35mg/Kg/dia por 16 semanas (DHP, n=4). Para os grupos experimentais foram colhidos: amostras de sangue, para exames laboratoriais; fêmures, para a extração do RNA total; e tíbias, para determinação dos parâmetros histomorfométricos. Os pacientes DM2 apresentaram diminuição nas concentrações séricas de osteocalcina e na expressão de OPG e aumento na expressão de VDR em comparação ao grupo NG (p<0,05). A expressão de RANKL e IL6 foi maior entre as mulheres, enquanto que a expressão de PPARG foi maior entre os homens com DM2 em comparação ao grupo NG (p=0,032). Pacientes DM2 antes do tratamento apresentaram glicemia e expressão do mRNA de IL6 negativamente associados ao cálcio ionizado, enquanto que as transcrições de TNFA e VDR foram associadas positivamente e negativamente com bALP respectivamente (p<0,05). O tratamento com pioglitazona reduziu a glicemia de jejum, glicemia pós-prandial, insulina, HOMA-IR, triglicerídeos, VLDL-C, tALP e bALP e aumentou a HDL, tACP, TNF-&#945; e a transcrição de OPG (p<0,05). A glicemia basal associou-se positivamente com o cálcio ionizado. A expressão basal de OPG foi associado negativamente com tALP, enquanto que a expressão basal de TNFA foi associada positivamente com tALP e negativamente com tACP. A expressão basal IL6 foi associada positivamente com tALP, enquanto que a expressão basal de VDR foi associada negativamente com osteocalcina e positivamente com bALP em resposta ao tratamento (p<0,05). O polimorfismo RANK rs1805034 foi associado com redução na transcrição do gene RANK nos indivíduos DM2 e com o remodelamento ósseo após o tratamento com pioglitazona (p<0,05). O polimorfismo RANKL rs9525641 foi associado com aumento da transcrição gênica de RANKL nos indivíduos NG e DM2 e melhora da resposta farmacológica nos indivíduos DM2 tratados com pioglitazona (p<0,05). O polimorfismo rs3102735 do gene OPG foi associado com aumento da formação óssea nos indivíduos DM2 antes e após o tratamento (p<0,05). O genótipo CG do polimorfismo OPG rs2073618 foi associado com alteração da transcrição de OPG no grupo DM2 pré e pós-tratamento (p<0,05). O polimorfismo PPARG rs1801282 foi associado com menor risco para o desenvolvimento de diabetes (p<0,05). O polimorfismo PPARG rs2972162 foi associado com melhora da resistência insulínica nos indivíduos DM2 tratados com pioglitazona (p=0,017). O polimorfismo ESRI rs9340799 foi associado com redução da formação óssea nos indivíduos DM2 (p=0,038). Nos camundongos, após a indução da dieta hiperlipídica por 32 semanas, observou-se aumento do peso, da glicemia, do colesterol total, da expressão do mRNA de RANK, RANKL, IL6 e TNFA em fêmures e aumento de Tb.Sp e diminuição de BV/TV em comparação ao grupo controle (p<0,05). O tratamento com pioglitazona diminuiu a expressão de TNFA (p=0,028). As medidas histomorfométricas não alteraram-se após o tratamento (p>0,05). Os resultados sugerem que o estado hiperglicêmico e o tratamento influenciam os marcadores bioquímicos e moleculares. Os polimorfismos dos genes RANK, RANKL, OPG e ESRI parecem estar envolvidos no remodelamento ósseo independentemente da hiperglicemia e do tratamento e os polimorfismos do gene PPARG parecem estar envolvidos com menor risco para desenvolver diabetes e com a melhora da resistência insulínica em resposta ao tratamento com pioglitazona. / Morphological changes in bone tissue have been reported in users of oral hypoglycemic class of thiazolidinediones (TZDs). It is hypothesized that some genes related to osteogenesis and osteoclastogenesis may be influenced by pharmacological treatment, however, was not aware exact mechanism. The study aims was to evaluate pioglitazone effect on bone remodeling through genes involved in osteoclastogenesis in individuals newly diagnosed with DM2 and animal models, in order to identify sensibles genetics markers of bone alterations. Were invited to participate in study 199 patients (100 diabetics and 99 normoglycemic), in dyslipidemia ambulatory of Institute Dante Pazzanese of Cardiology. Diabetic subjects were treated with pioglitazone (15, 30, 45 or 45 mg /day/oral) for 16 weeks. Blood samples were collected before and after treatment for laboratory evaluations, extraction of genomic DNA and total RNA. Polymorphisms and mRNA expression in blood cells was determined by real time PCR using TaqMan® system. For study in animal model after 32 weeks of fat diet induction, was used 12 male mice C57BL/J6, which were divided into three groups: control (n=4); induced diabetic fat diet (DH, n=4) and induced diabetic fat diet and treated with pioglitazone 35mg/Kg/day for 16 weeks (DHP, n=4). For experimental groups were collected: blood samples for laboratory tests; femurs, for extraction of total RNA; and tibias, to determine histomorphometric parameters. DM2 patients showed decrease in serum osteocalcin and OPG expression and increased VDR expression compared to NG group (p<0.05). RANKL and IL6 expression were higher among women, whereas PPARG expression was higher among men with DM2 compared to NG group (p=0,032). DM2 patients before treatment showed blood glucose and IL6 mRNA expression negatively associated with ionized calcium, whereas TNFA and VDR transcription are positively and negatively associated with bALP respectively (p<0.05). Pioglitazone treatment reduced fasting glucose, postprandial glucose, insulin, HOMA-IR, triglycerides, VLDL-C, tALP and bALP and increased HDL, tACP, TNF-&#945; and OPG transcription (p<0.05). Basal blood glucose was positively associated with ionized calcium. Basal OPG expression was negatively associated with tALP, whereas basal TNFA expression was positively associated with tALP and negatively with tACP. Basal IL6 expression was positively associated with tALP, whereas basal VDR expression was negatively associated with osteocalcin and positively with bALP in response to treatment (p<0.05). RANK rs1805034 polymorphism was associated with RANK gene transcription reduction in subjects with DM2 and bone remodeling after treatment with pioglitazone (p<0.05). RANKL rs9525641 polymorphism was associated with increased RANKL gene transcription in NG and DM2 subjects and pharmacological response improvement in DM2 subjects treated with pioglitazone (p<0.05). OPG rs3102735polymorphism was associated with increased bone formation in DM2 subjects before and after treatment (p<0.05). CG genotype of OPG rs2073618 polymorphism was associated with OPG transcription change in DM2 group before and after treatment (p<0.05). PPARG rs1801282 polymorphism was associated with lower risk for diabetes development (p<0.05). PPARG rs2972162 polymorphism was associated with insulin resistance improvement in DM2 subjects treated with pioglitazone (p=0,017). ESRI rs9340799 polymorphism was associated with reduced bone formation in DM2 subjects (p=0,038). In mice, after 32 weeks of fat diet induction, was observed increase weight, blood glucose, total cholesterol and RANK, RANKL, IL6 and TNFA mRNA expression in femurs and Tb.Sp increase and BV/TV decrease compared to control group (p<0.05). Treatment with pioglitazone decrease TNFA (p=0,028). Histomorphometrics measurements not change after treatment (p>0.05). Results suggest that hyperglycemic state and treatment influence biochemical and molecular markers. RANK, RANKL, OPG and ESRI polymorphisms seens to be involved in bone remodeling regardless of hyperglycemia and treatment and PPARG gene polymorphisms seens to be associated with lower risk for diabetes development and with insulin resistance improvement in response to treatment with pioglitazone.

Submitted by FERNANDA DA SILVA VON PORSTER (fdsvporster@univates.br) on 2016-08-31T19:30:52Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) 2015NathaliaGrave.pdf: 1012668 bytes, checksum: 34206baa81b06129beaa75c62787bbc4 (MD5) / Approved for entry into archive by Ana Paula Lisboa Monteiro (monteiro@univates.br) on 2016-09-05T19:29:54Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) 2015NathaliaGrave.pdf: 1012668 bytes, checksum: 34206baa81b06129beaa75c62787bbc4 (MD5) / Made available in DSpace on 2016-09-05T19:29:54Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) 2015NathaliaGrave.pdf: 1012668 bytes, checksum: 34206baa81b06129beaa75c62787bbc4 (MD5) Previous issue date: 2016-08 / Introdução: Muitos estudos tem relacionado a deficiência de vitamina D com o risco para as doenças crônicas, principalmente obesidade e dislipidemia. A vitamina D age através da ligação ao receptor de vitamina D (VDR), o qual forma heterodímeros com o receptor do retinoide X gama (RXRG). O gene GC codifica a proteína de ligação da vitamina D (DBP), a qual é responsável pelo transporte da vitamina D na corrente sanguínea. Considerando que a genética desempenha um papel importante na etiologia destas doenças, poucos estudos analisam a associação de variantes em genes da rota da vitamina D com parâmetros antropométricos e bioquímicos relacionados a estes desfechos. Objetivo: Investigar a associação entre polimorfismos de genes relacionados à rota da vitamina D, rs2228570 (gene VDR), rs2134095 (gene RXRG), rs7041 (gene GC), e parâmetros antropométricos e bioquímicos em uma amostra de adultos. Métodos: Medidas antropométricas e bioquímicas foram avaliadas em 542 indivíduos adultos de ambos os gêneros em uma amostra de base populacional. O DNA genômico foi extraído a partir de amostra de sangue e os polimorfismos foram genotipados pela reação em cadeia da polimerase (PCR) através de discriminação alélica TaqMan (Applied Biosystems, Foster City, CA). As comparações dos desfechos entre os genótipos foram feitas usando ANOVA, Kruskal-Wallis, qui-quadrado de Pearson ou teste exato de Fisher, e as interações gene-gene foram avaliadas usando modelo linear geral. Resultados: Não identificamos nenhum efeito principal dos polimorfismos nos parâmetros avaliados. No entanto, ao analisarmos as interações gene-gene, detectamos uma interação significativa entre os genes RXRG e GC sobre os níveis de colesterol LDL. Conclusões: Nossos achados evidenciaram uma interação significativa entre polimorfismos de dois genes da rota da vitamina D, rs2134095 (RXRG) e rs7041 (GC) sobre os níveis de colesterol LDL, corroborando os achados da literatura que tem consistentemente relacionado a vitamina D com o perfil lipídico. / Introduction: Many studies have related vitamin D deficiency with the risk for chronic diseases, especially obesity and dyslipidemia. Vitamin D acts by binding to the vitamin D receptor (VDR), which form heterodimers with the retinoid X receptor gamma (RXRG). The GC gene encoding the binding protein Vitamin D (BPD), which is responsible for the vitamin D transport in the bloodstream. Considering that genetics play a significant role in the etiology of these diseases, few studies have analyzed the association of variants in genes of vitamin D route anthropometric and biochemical parameters related to these outcomes. Objective: To investigate the association between gene polymorphisms related to vitamin D route, rs2228570 (VDR gene), rs2134095 (RXRG gene), rs7041 (GC gene), and anthropometric and biochemical parameters in a sample of adults. Methods: anthropometric and biochemical measures were assessed in 542 adults of both genders in a population-based sample. Genomic DNA was extracted from blood sample and polymorphisms were genotyped by polymerase chain reaction (PCR) using the TaqMan allelic discrimination (Applied Biosystems, Foster City, CA). Comparisons of outcomes between genotypes were performed using ANOVA, Kruskal-Wallis test, chi-square test or Fisher's exact test, and gene-gene interactions were assessed using general linear model. Results: We have not identified any major effect of polymorphisms in the evaluated parameters. However, when we analyze the gene-gene interactions, we detected a significant interaction between RXRG and GC genes on LDL cholesterol levels. Conclusions: Our findings showed a significant interaction between polymorphisms in two genes of vitamin D route, rs2134095 (RXRG) and rs7041 (GC) on the levels of LDL cholesterol, corroborating literature findings that have consistently related to vitamin D with the profile lipid.

1a,25-Dihydroxyvitamin D3 (1a,25(OH)2D3) is a major functional metabolic form of vitamin D. 1a,25(OH)2D3 has drawn increasing attention due to its functions in addition to maintaining calcium phosphate homeostasis. It directly regulates mineralization by osteoblasts, matrix production and remodeling by chondrocytes, and contraction of cardiomyocytes. 1a,25(OH)2D3 and its analogues have shown beneficial effects in treating multiple sclerosis, diabetes and various types of cancer. In order to maximize the pharmaceutical potential of 1a,25(OH)2D3, a better understanding its cell signaling pathway is necessary. 1a,25(OH)2D3 regulates osteoblasts through both classical nuclear vitamin D receptor (nVDR) mediated genomic effects and plasma membrane receptor-mediated rapid responses. The identity of the plasma membrane receptor for 1a,25(OH)2D3 is controversial. Protein disulfide isomerase associated 3 (Pdia3) has been hypothesized as one of the putative plasma membrane receptors for 1a,25(OH)2D3. The overall goal of this thesis was to understand the general role and the molecular mechanism of Pdia3 in 1a,25(OH)2D3-initiated rapid responses, and to determine the role of Pdia3 and its dependent signaling in osteoblast biology. The results show that Pdia3 is required for membrane-mediated responses of 1a,25(OH)2D3. Moreover, both Pdia3 and nVDR are critical components of the plasma membrane receptor complex for 1a,25(OH)2D3. Finally, Pdia3 and signaling via Pdia3 regulate osteoblast differentiation and mineralization. Taken together, this study demonstrates the role of Pdia3 in rapid responses to 1a,25(OH)2D3 and osteoblast biology, reveals the unexpected complexity of the 1a,25(OH)2D3 plasma receptor complex and opens the new target, Pdia3, for pharmaceutical application and tissue engineering.

Submitted by Haroudo Xavier Filho (haroudo.xavierfo@ufpe.br) on 2016-03-22T18:32:27Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Neyla Alves_Versão digital.pdf: 1629049 bytes, checksum: aa72b7e3881142a178e5534aa4064d95 (MD5) / Made available in DSpace on 2016-03-22T18:32:27Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Neyla Alves_Versão digital.pdf: 1629049 bytes, checksum: aa72b7e3881142a178e5534aa4064d95 (MD5) Previous issue date: 2015-03-02 / CAPES / CNPq / HIV/aids (Vírus da Imunodeficiência Humana/aids) é considerado uma pandemia, envolvendo mais de 70 milhões de infecções e 35 milhões de mortes desde o primeiro relato na década de 80. O HIV tipo 1 (HIV-1) infecta principalmente linfócitos T CD4+ e linhagens de macrófagos, tendo sua patogenicidade definida pela depleção de LT CD4+. Além disso, a condição de infecção por HIV-1 é bastante complexa e dependente de diversos fatores relacionados à variabilidade dos indivíduos no que diz respeito à suscetibilidade à infecção e à progressão para a aids, sendo observada a ativação imunológica generalizada. Envolvida na modulação das respostas imunes inata e adaptativa encontra-se a vitamina D, que desempenha papel no metabolismo mineral e apresenta efeito pleiotrópico no crescimento e diferenciação celulares. Seus efeitos imunológicos são dados a partir da ligação com o receptor de vitamina D (VDR) de diversas células, regulando a liberação de citocinas, a função e proliferação de linfócitos T e a produção de peptídeos antimicrobianos como a catelicidina. O VDR atua modulando a ação dessa vitamina induzindo a resposta imune local e variações genéticas presentes no gene codificador do VDR podem levar à diminuição de sua atividade e, consequentemente, ao prejuízo para o papel da vitamina D. Nos indivíduos infectados pelo HIV, os níveis de deficiência dessa vitamina são altos e fatores como raça, insuficiência renal, pouca exposição à luz ultravioleta e exposição as drogas anti-HIV, como o Efavirenz, estão associados a essa deficiência, respectivamente, sendo determinantes para a susceptibilidade à infecção pelo HIV e a predição da progressão da doença. Sendo assim, neste trabalho foram estudados seis polimorfismos de base única (SNPs) (rs3890733, rs476048, rs1540339, rs2248098, rs2228570 e rs11568820) presentes no gene do receptor de vitamina D (VDR) e sua influência na resposta dos pacientes à Terapia Antirretroviral (TARV). Foram recrutados 107 pacientes acompanhados e tratados no Hospital Dia do Instituto de Medicina Integral Professor Fernando Figueira (IMIP), subdivididos em quatro grupos: I- Sucesso Terapêutico, II- Falha Terapêutica, III- Sucesso Imunológico, IV- Falha Imunológica, e analisadas variáveis clínicas e epidemiológicas, como gênero, idade, peso e etnia. Não foram observadas associações estatísticas nas análises isoladas entre os polimorfismos dos genes do VDR com a falha virológica ou a resposta imunológica. Porém, nas análises multivariadas, o genótipo C/C do rs1540339 mostrou-se associado com o gênero no sucesso virológico (OR=0,08, p=0,04). Em adição, a análise envolvendo peso, etnia e gênero e o rs3890733 mostrou associação com a resposta imunológica para os genótipos C/C e T/T no modelo sobredominante (OR=0,21, p=0,024). Os resultados indicam a importância do receptor de vitamina D em infecções por HIV-1 e poderão contribuir para o entendimento da variabilidade das respostas dos pacientes à TARV. / HIV/aids (Human Immunodeficiency Virus/aids) is considered a pandemic, involving more than 70 million infections and 35 million deaths since the first report in the 80’s. HIV type 1 (HIV-1) infects mainly T lymphocytes CD4 + and macrophage lineages, and their pathogenicity is defined by the depletion of CD4 +. Furthermore, the condition of HIV- 1 infection is very complex and dependent on many factors related to the individual variability, regarding the susceptibility to infection and progression to AIDS, generalized immune activation being observed. Involved in the modulation of innate and adaptive immune responses is vitamin D, which plays a role in mineral metabolism and has pleiotropic effects on cell growth and differentiation. Their immune effects are data from binding to the vitamin D receptor (VDR) in various cells, regulating the release of cytokines, the function and proliferation of T lymphocytes and the production of antimicrobial peptides as cathelicidin. The VDR acts modulating the action of vitamin D by inducing local immune responses and genetic variations present in the VDR encoding gene can lead to reduction of its activity and consequently, disfunction in the role of vitamin D. In HIV-infected individuals, this vitamin deficiency levels are high and factors such as race, kidney failure, lower exposure to ultraviolet light and exposure to anti- HIV drugs, such as Efavirenz, are associated with this deficiency, being determinants on the susceptibility to HIV infection as well as prediction of disease progression. Therefore, in this work we studied six single nucleotide polymorphisms (SNPs) (rs3890733, rs476048, rs1540339, rs2248098, rs2228570 and rs11568820) present in the D vitamin receptor gene (VDR) and its influence on patients’ response to Antiretroviral Therapy (ART). We recruited 107 patients followed from the Hospital Day Integrative Medicine Institute Professor Fernando Figueira (IMIP), subdivided into four groups: I. Therapeutic Success, II. Therapeutic Failure, III. Immune Success, IV. Immune Failure, and analyzed clinical and epidemiological variables, such as gender, age, weight and ethnicity. No statistically significant associations were observed in the isolated analyzes between polymorphisms of the VDR gene with therapeutic failure or immune response. However, in multivariate analyzes, the rs1540339 C/C genotype was associated with gender in therapeutic success (OR = 0.08, p = 0.04). In addition, analysis involving weight, ethnicity and gender and the rs3890733 showed association with the immune response to the C/C genotype and T/T in overdominant model (OR = 0.21, p = 0.024). The results indicate the importance of vitamin D receptor in HIV- 1 infections and may contribute to the understanding of variability of patient’s various responses to ART.