Introdução: A acidemia 3-hidroxi-3-metilglutárica é causada pela deficiência da 3-hidroxi-3-metil-glutaril-CoA-liase, uma enzima do metabolismo da leucina, levando ao acúmulo, especialmente, do ácido 3-hidroxi-3-metilglutárico nos tecidos. Estudos sugerem que o estresse oxidativo pode contribuir para os danos neurológicos observados em algumas acidúrias orgânicas. Objetivo: Avaliar parâmetros de estresse oxidativo em pacientes com acidúria 3-hidroxi-3-metilglutárica antes e após o tratamento. Materiais e Métodos: Amostras de sangue e urina foram coletadas de pacientes no momento do diagnóstico e após tratamento com dieta com restrição de proteínas e suplementação de L-carnitina (100mg/kg/dia) e de controles. O TBA, um subproduto final da peroxidação lipídica, foi medido no plasma. A determinação do teor de carbonilas e de grupos sulfidrila, marcadores de dano oxidativo a proteínas, foi realizada no plasma. Para avaliar na urina a oxidação de proteínas, os níveis de di-tirosina foram medidos por autofluorescência. O ensaio da capacidade antioxidante urinária foi realizado utilizando um kit comercial. Os níveis de carnitina livre e isovalerilcarnitina foram analisados em amostras de sangue por espectrometria de massas em tandem usando o método de monitorização de reação múltipla (MRM). A concentração de proteínas foi determinada pelo método de biureto em amostras de plasma usando um kit comercial. Resultados e Discussão: Os resultados demonstraram um aumento significativo nos níveis de isovalerilcarnitina em sangue total, das concentrações plasmáticas de malondialdeído e urinárias de di-tirosina, além de uma redução significativa da capacidade antioxidante urinária e dos níveis sanguíneos de carnitina livre nos pacientes no momento do diagnóstico em relação aos controles. Verificou-se uma diminuição nas concentrações do malondialdeído plasmático e da di-tirosina na urina dos pacientes tratados, o que sugere um efeito de proteção do tratamento sobre a peroxidação de lípidos e do dano oxidativo a proteínas, bem como uma normalização dos níveis de L-carnitina durante o tratamento. Conclusões: Esses resultados permitem sugerir que o estresse oxidativo ocorre em pacientes com acidemia 3-hidroxi-3-metilglutárica e que o tratamento com a dieta restrita de proteína e suplementada com L-carnitina pode oferecer proteção contra o dano oxidativo a biomoléculas. / Introduction: The 3-hydroxy-3-methylglutaric acidemia is caused by the deficiency of 3-hydroxy-3-methyl-glutaryl-CoA lyase, an enzyme of leucine metabolism, leading to accumulation of 3-hydroxy-3-methylglutaric acid in tissues. Studies have suggested that oxidative stress may contribute to the neurological damage observed in some organic acidurias. Objective: Evaluate oxidative stress parameters in patients with 3-hydroxy-3-methylglutaric aciduria patiets before and after treatment. Materials and Methods: Blood and urine samples were collected from patients at diagnosis and after treatment with restricted protein diet and supplemented with L-carnitine (100mg/kg/dia) and from controls. TBA , an end subproduct of lipid peroxidation, was measured in plasma. Determination of carbonyl and sulphydryl content, biomarkers of oxidative damage to proteins, was done in plasma. To assess urine protein oxidation, levels of di-tyrosine were measured by autofluorescence. The assay of antioxidant urinary capacity was performed using a commercial kit. The levels of free carnitine and isovalerylcarnitine were analyzed in blood samples by tandem mass spectrometry using the method of multiple reaction monitoring (MRM). Protein content was determined by the biuret method for plasma samples using a commercial kit. Results and Discussion: The results demonstrated a significant increase of total blood isovalerylcarnitine, malondialdehyde plasma concentrations and di-tyrosine urinary levels and a significant reduction of the urinary antioxidant capacity and free-carnitine blood levels in pacients at diagnosis compared to controls. It was verified a decrease in plasma malondialdehyde concentrations and urinary di-tyrosine levels in treated patients, suggesting a protective effect of the treatment on lipid peroxidation and protein oxidative damage, as well as a normalization of L-carnitine levels during treatment. Conclusions: These results allow to suggest that oxidative stress occurs in 3-hydroxy-3-methyl-glutaryl-CoA lyase deficient patients and treatment with restricted protein diet and L-carnitine may offer protection against oxidative damage.

Einleitung: L-Carnitin spielt eine zentrale Rolle im Energiestoffwechsel. Da dieser in der Frühlaktation bei Hochleistungskühen besonders beansprucht und z.T. überlastet wird, ergibt sich die Frage, ob durch L-Carnitinsupplementation ein stabilerer Stoffwechsel und damit bessere Leistungen erreicht werden können. Zielstellung: Es wurde geprüft, ob bei Hochleistungskühen mit einer mittleren Milchleistung von 12000 kg/Jahr die orale Supplementation von L Carnitin im peripartalem Zeitraum bei zwei verschiedenen Applikationszeiträumen Stoffwechsel-, Leistungs- und Gesundheitsverbesserung erbringt. Versuchsanordnung: Aus einer Gesamtherde von 322 Kühen wurden 81 Tiere randomisiert auf vier Gruppen aufgeteilt. Zwei dieser Gruppen erhielten L-Carnitin (Supplementationsgruppen) und die anderen zwei Gruppen stellten die Kontrollgruppen (KG 1 n = 14/ KG 2 n = 11) dar. Von den supplementierten Gruppen erhielt Car. 1 (n = 26) von 3 Wochen (Wo.) ante partum (a.p.) bis zur Kalbung über das Futter täglich 5g L Carnitin (Carnipas®). Post partum bekamen die Tiere 1g L Carnitin von der Kalbung bis vier Wo. p.p. Parallel wurden einer zweiten supplementierten Gruppe, Car. 2 (n = 30), täglich 5g L Carnitin 3 Wochen a.p. bis zur Kalbung verabreicht. Klinische und Blutkontrollen erfolgten 28 Tage (d) a.p., drei d p.p, 28 d p.p. sowie 56 d p.p. Es wurden das Gesamtcarnitin (GC, n = 5), das freie Carnitin (FC, n = 5), Carnitinester (CE, n = 5), FFS, BHB, Bilirubin, Glucose, Cholesterol, Harnstoff, TTP, Albumin, CK, AST, Pi, Ca, Fe bei allen Tieren analysiert. Zusätzlich erfolgte die Erfassung der Laktationsleistung, der Milchinhaltsstoffe, der Rastzeit (RZ), der Zwischentragezeit (ZTZ) und der Morbidität. Ergebnisse: Das GC, FC und die CE besitzen in den supplementierten Gruppen Car 1 drei d p.p. höhere Konzentrationen als die Kontrollgruppen, die bei Car. 2 (p < 0,05) im GC und FC auch im weiteren Verlauf beobachtet wurden. Ein deutlicher Konzentrationsabfall aller L-Carnitinfraktionen vier Wo. p.p. wurde in den supplementierten Gruppen beobachtet. In den Kontrollgruppen stiegen sie zur gleichen Zeit nicht einheitlich an. Acht Wochen p.p. sanken die L-Carnitinkonzentrationen im Blut sowohl in den Kontrollgruppen, als auch in der supplementierten Gruppen weiter ab. In allen Gruppen stiegen drei d p.p. die FFS-Konzentrationen an (p < 0,05), das BHB auch in den supplementierten Gruppen, die Glucose- und Cholesterolkonzentration fielen ab (p < 0,05). Vier und 8 Wo. p.p. ließen sich ein Abfallen der FFS- (p < 0,05) und der BHB-Konzentrationen (p < 0,05) erkennen. Die Cholesterol- (p < 0,05) und verzögert auch die Glucosekonzentration stiegen an. Drei d p.p. stiegen die Bilirubinkonzentration (p < 0,05) und die AST-Aktivität (p < 0,05) an, dem ein ebensolcher Abfall (p < 0,05) folgte. Präpartal trat in der supplementierten Gruppen Car. 2 eine höhere Bilirubinkonzentration als in der Kontrollgruppe (p < 0,05) auf, was bei den AST-Aktivitäten zwischen den supplementierten Gruppen postpartal (p < 0,05) der Fall war. Drei d p.p waren niedrigere Konzentrationen des Proteins (p < 0,05), des Albumins (p < 0,05) in Car. 2 und in der Kontrollgruppe sowie des Harnstoffs (p < 0,05) in den Kontrollgruppen zu beobachten. Die CK-Aktivität nahm drei d p.p. zu (p < 0,05), um vier Wo. p.p. wieder abzufallen (p < 0,05). Gleichzeitig war einen Anstieg des Proteins (p < 0,05) und des Albumins in den Kontrollgruppen (p < 0,05), verzögert auch in den supplementierten Gruppen (p < 0,05), messbar. In allen Gruppen waren drei d p.p. niedrigere Ca- (p < 0,05), Fe- (p < 0,05) und Pi- Konzentrationen (p < 0,05) auffällig, die später wieder anstiegen. Im Verlauf war die Ca-Konzentration bei Car. 2 gegenüber der Kontrollgruppe höher (p < 0,05). Die Leistungsparameter differierten weder bei den Milchleistungs-, noch bei den Fruchtbarkeitskennzahlen gesichert. Bezüglich der Morbidität war auffällig, dass das GC und FC bei gesunden Kühen a.p. gegenüber den im Laktationsverlauf erkrankten gesichert höher war (p < 0,05). Schlussfolgerungen: Orale L Carnitinapplikation bei Kühen mit hohem Milchleistungsniveau erbrachte keine Stoffwechsel-, Leistungs- und Morbiditätsunterschiede gegenüber den Kontrollgruppen. Die Ergebnisse entsprechen aber der Hypothese einer gesteigerten ß-Oxidation durch die Carnitinsupplementation mit erhöhten BHB-Konzentrationen als Folge. Post partum gesunde Kühe hatten a.p. signifikant höhere L-Carnitinkonzentrationen als kranke.

No description available.

Aging can be described as an extremely complex occurrence from which no organism can be excluded. Intrinsic and extrinsic aging make out the two components of skin aging and they differ on the macromolecular level while sharing specific molecular characteristics which include elevated levels of reactive oxygen species (ROS) and matrix metalloproteinase (MMP) while collagen synthesis decreases. The skin functions as a protective barrier against the harsh environment and is essential for regulating body temperature. The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-aging treatment includes the epidermal and dermal layers of the skin. Calendula oil and L-carnitine L-tartrate was utilised as the cosmeceutical actives as they can be classified as a mixed category of compounds/products that lie between cosmetics and drugs. Both show excellent properties which can prove valuable during anti-aging treatment, whether it is due to the scavenging of ROS (calendula oil), moisturising effects (calendula oil and L-carnitine L-tartrate) or the improvement of the skin turnover rate (L-carnitine L-tartrate). The Pheroid™ delivery system can enhance the absorption of a selection of active ingredients. The aim of this study was to determine whether the Pheroid™ delivery system will enhance the flux and/or delivery of the named actives to the target site by performing Franz cell diffusion studies over an 8 h period, followed by tape stripping experiments. The Pheroid™ results of the actives were compared to the results obtained when 1 00 % calendula oil was applied and the L-carnitine L-tartrate was dissolved in phosphate buffer solution (PBS), respectively. In the case of calendula oil only a qualitative gas chromatography mass spectrometry (GC/MS) method could be employed. No calendula oil was observed to permeate through the skin, but linoleic acid (marker compound) was present in the epidermis and dermis layers. Components in the Pheroid™ delivery system hampered the results as the marker compound identified is a fundamental component of the Pheroid™, making it difficult to determine whether or not the Pheroid™ delivery system enhanced calendula oil's penetration. The aqueous solubility and log D partition coefficient of L-carnitine L-tartrate was determined. Inspection of the log D value of -1.35 indicated that the compound is unfavourable to penetrate the skin, whereas the aqueous solubility of 16.63 mg/ml in PBS at a temperature of 32º C indicated favourable penetration. During the Franz cell diffusion and tape stripping studies it was determined by liquid chromatography mass spectrometry (LC/MS) that carnitine may be inherent to human skin. Pheroid™ enhanced the flux (average of 0.0361 µg/cm2.h, median of 0.0393 µg/cm2.h) of the L-carnitine L-tartrate when compared to PBS (average of 0.0180 µg/cm2.h, median of 0.0142 µg/cm2.h ) for the time interval of 2 -8 h. The PBS was more effective in delivering the active to the target site (0.270 µg/ml in the epidermis and 2.403 µg/ml in the dermis) than Pheroid™ (0.111 µg/ml and 1.641 µg/ml in the epidermis and dermis respectively). Confocal laser scanning microscopy (CLSM) confirmed the entrapment of L-carnitine L-tartrate in the Pheroid™ vesicle, while in the case of calendula oil it was impossible to differentiate between the oil and the Pheroid™ components. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

Aging can be described as an extremely complex occurrence from which no organism can be excluded. Intrinsic and extrinsic aging make out the two components of skin aging and they differ on the macromolecular level while sharing specific molecular characteristics which include elevated levels of reactive oxygen species (ROS) and matrix metalloproteinase (MMP) while collagen synthesis decreases. The skin functions as a protective barrier against the harsh environment and is essential for regulating body temperature. The stratum corneum (SC) is responsible for the main resistance to the penetration of most compounds; nevertheless the skin represents as an appropriate target for delivery. The target site for anti-aging treatment includes the epidermal and dermal layers of the skin. Calendula oil and L-carnitine L-tartrate was utilised as the cosmeceutical actives as they can be classified as a mixed category of compounds/products that lie between cosmetics and drugs. Both show excellent properties which can prove valuable during anti-aging treatment, whether it is due to the scavenging of ROS (calendula oil), moisturising effects (calendula oil and L-carnitine L-tartrate) or the improvement of the skin turnover rate (L-carnitine L-tartrate). The Pheroid™ delivery system can enhance the absorption of a selection of active ingredients. The aim of this study was to determine whether the Pheroid™ delivery system will enhance the flux and/or delivery of the named actives to the target site by performing Franz cell diffusion studies over an 8 h period, followed by tape stripping experiments. The Pheroid™ results of the actives were compared to the results obtained when 1 00 % calendula oil was applied and the L-carnitine L-tartrate was dissolved in phosphate buffer solution (PBS), respectively. In the case of calendula oil only a qualitative gas chromatography mass spectrometry (GC/MS) method could be employed. No calendula oil was observed to permeate through the skin, but linoleic acid (marker compound) was present in the epidermis and dermis layers. Components in the Pheroid™ delivery system hampered the results as the marker compound identified is a fundamental component of the Pheroid™, making it difficult to determine whether or not the Pheroid™ delivery system enhanced calendula oil's penetration. The aqueous solubility and log D partition coefficient of L-carnitine L-tartrate was determined. Inspection of the log D value of -1.35 indicated that the compound is unfavourable to penetrate the skin, whereas the aqueous solubility of 16.63 mg/ml in PBS at a temperature of 32º C indicated favourable penetration. During the Franz cell diffusion and tape stripping studies it was determined by liquid chromatography mass spectrometry (LC/MS) that carnitine may be inherent to human skin. Pheroid™ enhanced the flux (average of 0.0361 µg/cm2.h, median of 0.0393 µg/cm2.h) of the L-carnitine L-tartrate when compared to PBS (average of 0.0180 µg/cm2.h, median of 0.0142 µg/cm2.h ) for the time interval of 2 -8 h. The PBS was more effective in delivering the active to the target site (0.270 µg/ml in the epidermis and 2.403 µg/ml in the dermis) than Pheroid™ (0.111 µg/ml and 1.641 µg/ml in the epidermis and dermis respectively). Confocal laser scanning microscopy (CLSM) confirmed the entrapment of L-carnitine L-tartrate in the Pheroid™ vesicle, while in the case of calendula oil it was impossible to differentiate between the oil and the Pheroid™ components. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

Introdução: A acidemia 3-hidroxi-3-metilglutárica é causada pela deficiência da 3-hidroxi-3-metil-glutaril-CoA-liase, uma enzima do metabolismo da leucina, levando ao acúmulo, especialmente, do ácido 3-hidroxi-3-metilglutárico nos tecidos. Estudos sugerem que o estresse oxidativo pode contribuir para os danos neurológicos observados em algumas acidúrias orgânicas. Objetivo: Avaliar parâmetros de estresse oxidativo em pacientes com acidúria 3-hidroxi-3-metilglutárica antes e após o tratamento. Materiais e Métodos: Amostras de sangue e urina foram coletadas de pacientes no momento do diagnóstico e após tratamento com dieta com restrição de proteínas e suplementação de L-carnitina (100mg/kg/dia) e de controles. O TBA, um subproduto final da peroxidação lipídica, foi medido no plasma. A determinação do teor de carbonilas e de grupos sulfidrila, marcadores de dano oxidativo a proteínas, foi realizada no plasma. Para avaliar na urina a oxidação de proteínas, os níveis de di-tirosina foram medidos por autofluorescência. O ensaio da capacidade antioxidante urinária foi realizado utilizando um kit comercial. Os níveis de carnitina livre e isovalerilcarnitina foram analisados em amostras de sangue por espectrometria de massas em tandem usando o método de monitorização de reação múltipla (MRM). A concentração de proteínas foi determinada pelo método de biureto em amostras de plasma usando um kit comercial. Resultados e Discussão: Os resultados demonstraram um aumento significativo nos níveis de isovalerilcarnitina em sangue total, das concentrações plasmáticas de malondialdeído e urinárias de di-tirosina, além de uma redução significativa da capacidade antioxidante urinária e dos níveis sanguíneos de carnitina livre nos pacientes no momento do diagnóstico em relação aos controles. Verificou-se uma diminuição nas concentrações do malondialdeído plasmático e da di-tirosina na urina dos pacientes tratados, o que sugere um efeito de proteção do tratamento sobre a peroxidação de lípidos e do dano oxidativo a proteínas, bem como uma normalização dos níveis de L-carnitina durante o tratamento. Conclusões: Esses resultados permitem sugerir que o estresse oxidativo ocorre em pacientes com acidemia 3-hidroxi-3-metilglutárica e que o tratamento com a dieta restrita de proteína e suplementada com L-carnitina pode oferecer proteção contra o dano oxidativo a biomoléculas. / Introduction: The 3-hydroxy-3-methylglutaric acidemia is caused by the deficiency of 3-hydroxy-3-methyl-glutaryl-CoA lyase, an enzyme of leucine metabolism, leading to accumulation of 3-hydroxy-3-methylglutaric acid in tissues. Studies have suggested that oxidative stress may contribute to the neurological damage observed in some organic acidurias. Objective: Evaluate oxidative stress parameters in patients with 3-hydroxy-3-methylglutaric aciduria patiets before and after treatment. Materials and Methods: Blood and urine samples were collected from patients at diagnosis and after treatment with restricted protein diet and supplemented with L-carnitine (100mg/kg/dia) and from controls. TBA , an end subproduct of lipid peroxidation, was measured in plasma. Determination of carbonyl and sulphydryl content, biomarkers of oxidative damage to proteins, was done in plasma. To assess urine protein oxidation, levels of di-tyrosine were measured by autofluorescence. The assay of antioxidant urinary capacity was performed using a commercial kit. The levels of free carnitine and isovalerylcarnitine were analyzed in blood samples by tandem mass spectrometry using the method of multiple reaction monitoring (MRM). Protein content was determined by the biuret method for plasma samples using a commercial kit. Results and Discussion: The results demonstrated a significant increase of total blood isovalerylcarnitine, malondialdehyde plasma concentrations and di-tyrosine urinary levels and a significant reduction of the urinary antioxidant capacity and free-carnitine blood levels in pacients at diagnosis compared to controls. It was verified a decrease in plasma malondialdehyde concentrations and urinary di-tyrosine levels in treated patients, suggesting a protective effect of the treatment on lipid peroxidation and protein oxidative damage, as well as a normalization of L-carnitine levels during treatment. Conclusions: These results allow to suggest that oxidative stress occurs in 3-hydroxy-3-methyl-glutaryl-CoA lyase deficient patients and treatment with restricted protein diet and L-carnitine may offer protection against oxidative damage.

Introdução: A acidemia 3-hidroxi-3-metilglutárica é causada pela deficiência da 3-hidroxi-3-metil-glutaril-CoA-liase, uma enzima do metabolismo da leucina, levando ao acúmulo, especialmente, do ácido 3-hidroxi-3-metilglutárico nos tecidos. Estudos sugerem que o estresse oxidativo pode contribuir para os danos neurológicos observados em algumas acidúrias orgânicas. Objetivo: Avaliar parâmetros de estresse oxidativo em pacientes com acidúria 3-hidroxi-3-metilglutárica antes e após o tratamento. Materiais e Métodos: Amostras de sangue e urina foram coletadas de pacientes no momento do diagnóstico e após tratamento com dieta com restrição de proteínas e suplementação de L-carnitina (100mg/kg/dia) e de controles. O TBA, um subproduto final da peroxidação lipídica, foi medido no plasma. A determinação do teor de carbonilas e de grupos sulfidrila, marcadores de dano oxidativo a proteínas, foi realizada no plasma. Para avaliar na urina a oxidação de proteínas, os níveis de di-tirosina foram medidos por autofluorescência. O ensaio da capacidade antioxidante urinária foi realizado utilizando um kit comercial. Os níveis de carnitina livre e isovalerilcarnitina foram analisados em amostras de sangue por espectrometria de massas em tandem usando o método de monitorização de reação múltipla (MRM). A concentração de proteínas foi determinada pelo método de biureto em amostras de plasma usando um kit comercial. Resultados e Discussão: Os resultados demonstraram um aumento significativo nos níveis de isovalerilcarnitina em sangue total, das concentrações plasmáticas de malondialdeído e urinárias de di-tirosina, além de uma redução significativa da capacidade antioxidante urinária e dos níveis sanguíneos de carnitina livre nos pacientes no momento do diagnóstico em relação aos controles. Verificou-se uma diminuição nas concentrações do malondialdeído plasmático e da di-tirosina na urina dos pacientes tratados, o que sugere um efeito de proteção do tratamento sobre a peroxidação de lípidos e do dano oxidativo a proteínas, bem como uma normalização dos níveis de L-carnitina durante o tratamento. Conclusões: Esses resultados permitem sugerir que o estresse oxidativo ocorre em pacientes com acidemia 3-hidroxi-3-metilglutárica e que o tratamento com a dieta restrita de proteína e suplementada com L-carnitina pode oferecer proteção contra o dano oxidativo a biomoléculas. / Introduction: The 3-hydroxy-3-methylglutaric acidemia is caused by the deficiency of 3-hydroxy-3-methyl-glutaryl-CoA lyase, an enzyme of leucine metabolism, leading to accumulation of 3-hydroxy-3-methylglutaric acid in tissues. Studies have suggested that oxidative stress may contribute to the neurological damage observed in some organic acidurias. Objective: Evaluate oxidative stress parameters in patients with 3-hydroxy-3-methylglutaric aciduria patiets before and after treatment. Materials and Methods: Blood and urine samples were collected from patients at diagnosis and after treatment with restricted protein diet and supplemented with L-carnitine (100mg/kg/dia) and from controls. TBA , an end subproduct of lipid peroxidation, was measured in plasma. Determination of carbonyl and sulphydryl content, biomarkers of oxidative damage to proteins, was done in plasma. To assess urine protein oxidation, levels of di-tyrosine were measured by autofluorescence. The assay of antioxidant urinary capacity was performed using a commercial kit. The levels of free carnitine and isovalerylcarnitine were analyzed in blood samples by tandem mass spectrometry using the method of multiple reaction monitoring (MRM). Protein content was determined by the biuret method for plasma samples using a commercial kit. Results and Discussion: The results demonstrated a significant increase of total blood isovalerylcarnitine, malondialdehyde plasma concentrations and di-tyrosine urinary levels and a significant reduction of the urinary antioxidant capacity and free-carnitine blood levels in pacients at diagnosis compared to controls. It was verified a decrease in plasma malondialdehyde concentrations and urinary di-tyrosine levels in treated patients, suggesting a protective effect of the treatment on lipid peroxidation and protein oxidative damage, as well as a normalization of L-carnitine levels during treatment. Conclusions: These results allow to suggest that oxidative stress occurs in 3-hydroxy-3-methyl-glutaryl-CoA lyase deficient patients and treatment with restricted protein diet and L-carnitine may offer protection against oxidative damage.

Submitted by Angela Maria de Oliveira (amolivei@uepg.br) on 2017-11-24T13:23:07Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Lidiane Pescke Pereira.pdf: 897636 bytes, checksum: 92549067a59b73ac61dbce09ee1c1ee0 (MD5) / Made available in DSpace on 2017-11-24T13:23:07Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Lidiane Pescke Pereira.pdf: 897636 bytes, checksum: 92549067a59b73ac61dbce09ee1c1ee0 (MD5) Previous issue date: 2017-09-20 / Com o aumento da produtividade e da demanda nutricional pela fêmea suína, o uso de moduladores L-carnitina, L-arginina, cromo, somatotropina e ractopamina tem sido uma alternativa para melhorar os índices produtivos. Entretanto, a variabilidade nas informações e a complexidade dos estudos envolvendo o tema exige uma abordagem mais sistêmica. Objetivou-se por meio desta meta-análise determinar o efeito do uso de moduladores nutricionais no desempenho reprodutivo e das leitegadas de porcas em gestação e lactação. A base de dados utilizada incluiu 83 artigos publicados entre os anos de 1989 e 2017, totalizando 22.608 porcas em 534 tratamentos. Critérios foram estabelecidos para a seleção dos artigos: uso de moduladores nutricionais: L-carnitina, L-arginina, cromo, somatotropina e ractopamina; conter as variáveis corporais e reprodutivas de porcas gestantes e lactantes. A meta-análise envolveu as análises de heterogeneidade, gráfica, correlação, variância e de resíduos. Não houve correlação (P>0,05) entre o uso de moduladores nutricionais e as variáveis corporais das porcas. No estudo de correlações verificou-se que a suplementação com L-carnitina, L-arginina e cromo aumentam (>0,450; P<0,05) o peso do leitão ao nascer e número de leitões nascidos vivos e o peso dos leitões ao nascer. Já o uso de somatotropina aumenta o número de leitões desmamados (0,985; P<0,01). Não houve diferença significativa (P>0,05) entre as médias dos grupos dos tratamentos com L-carnitina, cromo, e somatotropina para o consumo de ração e condição corporal das porcas. O uso de ractopamina aumentou em 3,41 % (P<0,05) a espessura de toucinho ao parto. A suplementação com L-carnitina e cromo aumentaram em 2,30 % e 4,73 % (P<0,05) o número de leitões nascidos vivos, respectivamente. O uso da L-carnitina, arginina e somatotropina proporcionaram, em média, leitões mais pesados ao nascer em relação ao controle (1,48 vs. 1,43kg; P<0,05). A administração da somatotropina aumentou em 9,01 % (P<0,05) o número de leitões desmamados em relação ao controle. Os estudos sobre o uso de moduladores nutricionais encontrados na literatura são pouco explorados quanto a condição corporal e nutricional, o que impossibilita conclusões sobre o uso adequado destes aditivos para ajustes nutricionais em porcas gestantes e lactantes. Entretanto, os moduladores nutricionais L-carnitina, L-arginina, cromo e somatotropina podem melhorar o desempenho produtivo das porcas e de suas leitegadas. / The increase in productivity and nutritional demand by sows, the use of modulators L-carnitine, L-arginine, chromium, somatotropin and ractopamine has been an alternative to improve the productive indexes. However, the variability in information and the complexity of studies involving the subject requires a more systemic approach. The objective of this meta-analysis was to determine the effect of the use of nutritional modulators on the reproductive performance and litter of sows in gestation and lactation. The database used included 83 articles published between 1989 and 2017, totaling 22,608 sows in 534 treatments. Criteria were established for the selection of articles: use of nutritional modulators: L-carnitine, L-arginine, chromium, somatotropin and ractopamine; contain the body and reproductive variables of pregnant and lactating sows. The meta-analysis involved analyzes of heterogeneity, graph, correlation, variance and residuals. Don´t were significant correlations (P>0.05) between the body variables of the sows and nutritional modulators and their use. In correlation study, the L-carnitine, L-arginine and chromium supplementation increases (>0.450; P<0.05) the birth piglets weight and liveborn number. Somatotropin administration increased the weaner piglets number (0.985; P<0.01). There were no significant difference (P>0.05) between the means of groups with L-carnitine, chromium, and somatotropin for feed intake and body condition of the sows. Ractopamine use increased in 3.41% (P<0.05) the backfat thickness at farrowing. Supplementation with L-carnitine and chromium increased in 2.30 % e 4.73 % (P<0.05) the alive piglets number, respectively. The use of L-carnitine, L-arginine and somatotropin provided heavier piglets at birth in relation to control groups (1.48 vs. 1.43kg; P<0.05). Somatotropin administration increased in 9.01% (P<0.05) the of weaned piglets number in relation to control group. Studies on the use of nutritional modulators found in the literature are poorly explored in body and nutritional condition terms, which makes it impossible to reach conclusions about the proper use of these additives for nutritional adjustments in pregnant and lactating sows. However, the nutritional modulators L-carnitine, L-arginine, chromium and somatotropin can improve the productive performance of sows and their litters.

As acidemias D-2-hidroxiglutárica e L-2-hidroxiglutárica são duas distintas desordens neurometabólicas bioquimicamente caracterizadas por níveis aumentados dos ácidos D-2-hidroxiglutárico e L-2-hidroxiglutárico em tecidos e fluidos biológicos, respectivamente. Pacientes acometidos pela acidemia D-2-hidroxiglutárica são classificados em duas variantes, a D-2-hidroxiglutárica do tipo I ou a D-2-hidroxiglutárica do tipo II. A acidemia D-2-hidroxiglutárica do tipo I é causada por uma mutação no gene da D-2-hidroxiglutarato desidrogenase enquanto que a acidemia D-2-hidroxiglutárica do tipo II é causada por uma mutação de ganho de função no gene da isocitrato desidrogenase II. A acidemia L-2-hidroxiglutárica é causada por uma mutação no gene da L-2-hidroxiglutarato desidrogenase. Considerando que a fisiopatologia destas doenças não está totalmente elucidada e que muitos estudos têm demonstrado o envolvimento do estresse oxidativo em erros inatos do metabolismo, este trabalho tem por objetivo principal investigar parâmetros de estresse oxidativo e nitrativo na urina de pacientes com acidemia L-2-hidroxiglutárica e o dano ao DNA in vitro causado pelos ácidos acumulados em ambas as patologias, as acidemias D-2-hidroxiglutárica e L-2-hidroxiglutárica, bem como o efeito protetor da L-carnitina sobre o dano. Dessa forma, verificou-se que as concentrações de 50 μM do ácido D-2-hidroxiglutárico e 30 μM do ácido L-2-hidroxiglutárico induzem dano ao DNA e que concentrações de 30 μM e 150 μM de L-carnitina reduzem significativamente in vitro o dano ao DNA, comparado aos controles. Além disso, foram analisadas amostras de urina dos pacientes com acidemia L-2-hidroxiglutárica. Observou-se aumento significativo de espécies de guanina oxidadas, um marcador bioquímico de dano oxidativo ao DNA, bem como um aumento significativo da excreção de di-tirosina, indicando que os pacientes tem dano a proteínas. Entretanto, não houve diferença significativa nos níveis de isoprostanos urinários e nos níveis de espécies reativas do nitrogênio. Esses resultados sugerem, pelo menos em parte, dano oxidativo a proteínas e ao DNA e ressaltam o potencial antioxidante da L-carnitina como um promissor adjuvante no tratamento de pacientes afetados pelas acidemias L-2-hidroxiglutárica ou D-2-hidroxiglutárica. / D-2-hydroxyglutaric and L-2-hydroxyglutaric acidurias are two distinct neurometabolic disorders biochemically characterized by increased levels of D-2-hydroxyglutaric and L-2-hydroxyglutaric acids in biological fluids and tissues, respectively. Patients affected by D-2-hydroxyglutaric aciduria are classified into two variants, D-2-hydroxyglutaric aciduria type I or D-2-hydroxyglutaric aciduria type II. D-2-hydroxyglutaric aciduria type I is caused by mutation of D-2-hydroxyglutarate dehydrogenase gene while D-2-hydroxyglutaric aciduria type II is caused by a gain of function mutation in isocitrate dehydrogenase 2 gene. L-2-hydroxyglutaric aciduria is caused by mutation in the L-2-hydroxyglutarate dehydrogenase gene. Considering that the pathophysiology of these diseases is not fully understood and that many studies have been shown the involvement of oxidative stress in inborn errors of metabolism, the main objective of this work was investigate oxidative and nitrative stress parameters in the urine of L-2-hydroxyglutaric aciduria patients and to investigate the in vitro DNA damage caused by the accumulated acids of D-2-hydroxyglutaric and L-2-hydroxyglutaric acidurias as well as the protective effect of L-carnitine on this damage. It has been found that concentrations of 50 μM of D-2-hydroxyglutaric acid and 30 μM of L-2-hydroxyglutaric acid induce DNA damage and concentrations of 30 μM and 150 μM of L-carnitine significantly reduced the in vitro DNA damage compared to controls. In addition, urine samples from L-2-hydroxyglutaric aciduria patients were analyzed. It was observed a significant increase of oxidized guanine species, an oxidative DNA damage biomarker as well as a significant increase of urinary di-tyrosine level, indicating protein oxidative damage in the patients. However, there was no significant difference in the levels of urinary isoprostanes and reactive nitrogen species. These results suggest, at least in part, proteins and DNA oxidative damage and highlight the L-carnitine antioxidant potential as a promising adjuvant in the treatment of patients affected by L-2-hydroxyglutaric or D-2-hydroxyglutaric aciduria.

As acidemias D-2-hidroxiglutárica e L-2-hidroxiglutárica são duas distintas desordens neurometabólicas bioquimicamente caracterizadas por níveis aumentados dos ácidos D-2-hidroxiglutárico e L-2-hidroxiglutárico em tecidos e fluidos biológicos, respectivamente. Pacientes acometidos pela acidemia D-2-hidroxiglutárica são classificados em duas variantes, a D-2-hidroxiglutárica do tipo I ou a D-2-hidroxiglutárica do tipo II. A acidemia D-2-hidroxiglutárica do tipo I é causada por uma mutação no gene da D-2-hidroxiglutarato desidrogenase enquanto que a acidemia D-2-hidroxiglutárica do tipo II é causada por uma mutação de ganho de função no gene da isocitrato desidrogenase II. A acidemia L-2-hidroxiglutárica é causada por uma mutação no gene da L-2-hidroxiglutarato desidrogenase. Considerando que a fisiopatologia destas doenças não está totalmente elucidada e que muitos estudos têm demonstrado o envolvimento do estresse oxidativo em erros inatos do metabolismo, este trabalho tem por objetivo principal investigar parâmetros de estresse oxidativo e nitrativo na urina de pacientes com acidemia L-2-hidroxiglutárica e o dano ao DNA in vitro causado pelos ácidos acumulados em ambas as patologias, as acidemias D-2-hidroxiglutárica e L-2-hidroxiglutárica, bem como o efeito protetor da L-carnitina sobre o dano. Dessa forma, verificou-se que as concentrações de 50 μM do ácido D-2-hidroxiglutárico e 30 μM do ácido L-2-hidroxiglutárico induzem dano ao DNA e que concentrações de 30 μM e 150 μM de L-carnitina reduzem significativamente in vitro o dano ao DNA, comparado aos controles. Além disso, foram analisadas amostras de urina dos pacientes com acidemia L-2-hidroxiglutárica. Observou-se aumento significativo de espécies de guanina oxidadas, um marcador bioquímico de dano oxidativo ao DNA, bem como um aumento significativo da excreção de di-tirosina, indicando que os pacientes tem dano a proteínas. Entretanto, não houve diferença significativa nos níveis de isoprostanos urinários e nos níveis de espécies reativas do nitrogênio. Esses resultados sugerem, pelo menos em parte, dano oxidativo a proteínas e ao DNA e ressaltam o potencial antioxidante da L-carnitina como um promissor adjuvante no tratamento de pacientes afetados pelas acidemias L-2-hidroxiglutárica ou D-2-hidroxiglutárica. / D-2-hydroxyglutaric and L-2-hydroxyglutaric acidurias are two distinct neurometabolic disorders biochemically characterized by increased levels of D-2-hydroxyglutaric and L-2-hydroxyglutaric acids in biological fluids and tissues, respectively. Patients affected by D-2-hydroxyglutaric aciduria are classified into two variants, D-2-hydroxyglutaric aciduria type I or D-2-hydroxyglutaric aciduria type II. D-2-hydroxyglutaric aciduria type I is caused by mutation of D-2-hydroxyglutarate dehydrogenase gene while D-2-hydroxyglutaric aciduria type II is caused by a gain of function mutation in isocitrate dehydrogenase 2 gene. L-2-hydroxyglutaric aciduria is caused by mutation in the L-2-hydroxyglutarate dehydrogenase gene. Considering that the pathophysiology of these diseases is not fully understood and that many studies have been shown the involvement of oxidative stress in inborn errors of metabolism, the main objective of this work was investigate oxidative and nitrative stress parameters in the urine of L-2-hydroxyglutaric aciduria patients and to investigate the in vitro DNA damage caused by the accumulated acids of D-2-hydroxyglutaric and L-2-hydroxyglutaric acidurias as well as the protective effect of L-carnitine on this damage. It has been found that concentrations of 50 μM of D-2-hydroxyglutaric acid and 30 μM of L-2-hydroxyglutaric acid induce DNA damage and concentrations of 30 μM and 150 μM of L-carnitine significantly reduced the in vitro DNA damage compared to controls. In addition, urine samples from L-2-hydroxyglutaric aciduria patients were analyzed. It was observed a significant increase of oxidized guanine species, an oxidative DNA damage biomarker as well as a significant increase of urinary di-tyrosine level, indicating protein oxidative damage in the patients. However, there was no significant difference in the levels of urinary isoprostanes and reactive nitrogen species. These results suggest, at least in part, proteins and DNA oxidative damage and highlight the L-carnitine antioxidant potential as a promising adjuvant in the treatment of patients affected by L-2-hydroxyglutaric or D-2-hydroxyglutaric aciduria.