Reproduction de : Thèse de doctorat : Qualité et sécurité des aliments : Toulouse, INPT : 2006. / Titre provenant de l'écran-titre. Bibliogr. 327 réf.

Our group previously reported that caveolin-1 (cav-1) was down-regulated by nitric oxide (NO) during cerebral ischemia and reperfusion (I/R). However, the role of cav-1 in regulating blood-brain barrier (BBB) permeability is unclear yet. This study aims to address whether the loss of cav-1 induced by NO production affects BBB permeability. Data showed that the expression of cav-1 in isolated cortical microvessels was down-regulated in ischemia-reperfused rat brains subjected to middle cerebral artery occlusion (MCAO). Treatment of NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, reserved cav-1 expression, inhibited matrix metalloproteinases (MMPs) activity and reduced the BBB permeability. Moreover, cav-1 knockdown remarkably increased MMPs activity in the culture medium of brain microvascular endothelial cells. Cav-1 deficiency mice displayed higher MMPs activity and BBB permeability than that of the wild-type mice. Interestingly, the effects of L-NAME on MMPs activity and BBB permeability were partly reversed in cav-1 deficiency mice. These results suggest that cav-1 plays important roles in regulating MMPs activity and BBB permeability in cerebral I/R injury. After completing the mechanism study, I investigated the potential drug candidate that targets cav-1 for protecting BBB and neuronal damage during cerebral I/R. Results showed that calycosin, an isoflavones from Astragali Radix, up-regulated the expression of cav-1 and inhibited MMPs activity, and decreased the BBB permeability in the MCAO ischemia-reperfused rat brains. I further investigated the neuroprotective effects of isoflavones of Astragali Radix, with in vitro oxygen glucose deprivation (OGD) model and in vivo cerebral ischemia-reperfusion models. In addition to calycosin and formononetin, two major isoflavones in Astragali Radix, daidzein was also included because it is a metabolite of formononetin after absorption. Results showed that all three isoflavones decreased infarction volume and neurological scores in MCAO rats and dose-dependently attenuated neuronal death induced by L-glutamate treatment and oxygen-glucose deprivation plus reoxygenation (OGD/RO). The neuroprotective effects were inhibited by estrogen receptors (ER) antagonist ICI 182,780. Interestingly, combine treatment of isoflavones displayed synergistic effects in both OGD/RO and L-glutamate induced neuronal injury models, as well as in MCAO cerebral ischemia-reperfusion rat brains. Mechanistically, estrogen receptor antagonist partly reduced the synergism in these models. PI3K/Akt activation was synergistically induced by treatment of those isoflavones simultaneously. In summary, cav-1 could be a potential therapeutic target for protecting the BBB in the treatment of cerebral I/R injury. Major findings in this thesis include: 1) Cav-1 plays an important role in maintaining BBB integrity through inhibition of MMPs activity. NO induced MMPs activities and BBB leakage are partially mediated by the down-regulation of cav-1 during cerebral I/R injury. 2) Calycosin treatment reserved cav-1 expression and reduced BBB permeability. 3) Isoflavones synergistically protected neurons against I/R-induced neuronal insults both in vitro and in vivo. The works provide a valuable step towards the clarification of the physiological and pathophysiological functions of cav-1, and a new clue for developing isoflavones as agents targeting cav-1 for the prevention or treatment of ischemic stroke. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy

Thesis (M.Phil.) - University of St Andrews, March 2007.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xiii, 154 p. : ill. Advisor: Steven J. Schwartz, Program in Nutrition (OSUN). Includes bibliographical references (p. 134-154).

Thesis (Ph.D.)--Georgetown University, 2008. / Includes bibliographical references.

Orientador: Sonia Nair Bao / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-08T07:53:58Z (GMT). No. of bitstreams: 1 Cardoso_JulioRoquete_D.pdf: 2342812 bytes, checksum: 608836a3972af8e207e90ef5ae664a4a (MD5) Previous issue date: 2007 / Resumo: Este estudo foi proposto para avaliar se a exposição perinatal (gestacional e lactacional) ou crônica a isoflavonas em dieta contendo soja ou na forma de concentrados de isoflavonas pode comprometer a saúde reprodutiva de coelhos machos. No primeiro experimento, fêmeas foram alimentadas com dieta contendo soja ou dieta isenta de soja e alfafa, suplementada com 10 ou 20 mg/kg/dia de isoflavonas ao longo da gestação e lactação. O grupo controle foi mantido somente com a dieta isenta de soja e alfafa. Na desmama, foram avaliados o peso e a morfologia dos órgãos do aparelho reprodutor e os níveis séricos de testosterona de parte dos filhotes machos. O restante deles foi submetido à dieta controle desde a desmama até a fase adulta. Após a puberdade, os animais foram avaliados quanto ao comportamento sexual, qualidade do sêmen e morfologia dos órgãos reprodutivos. No segundo experimento, fêmeas foram alimentadas com as mesmas dietas empregadas no primeiro experimento, porém a suplementação com isoflavonas foi realizada com doses variando de 2,5 a 20 mg/kg/dia. As doses de isoflavonas foram selecionadas com base em estimativas da ingestão de isoflavonas a partir do consumo de alimentos derivados da soja. Após a desmama, os filhotes machos receberam a mesma dieta fornecida para suas respectivas mães até o fim do experimento. Foi avaliado nestes animais a idade à puberdade, qualidade do sêmen e o comportamento sexual, e, na 33ª semana de vida o peso e a morfologia dos órgãos reprodutivos. Os resultados deste estudo foram baseados em dados obtidos da avaliação de 100 machos num período de 3 anos. O número de espermatozóides esteve de acordo com os valores da literatura para coelhos da raça Nova Zelândia e não variou significativamente em relação ao grupo controle, embora o volume de sêmen tenha sido menor em coelhos expostos à alta dose de isoflavonas (20 mg/kg/dia). O peso dos órgãos reprodutivos não diferiu estatisticamente do grupo controle e não houve evidência de malformações genitais, alterações metaplásicas, ou qualquer outra alteração histopatológica correlacionada com os tratamentos. Nos jovens, a análise histológica dos testículos não revelou diferenças no desenvolvimento gonadal. Coelhos suplementados de forma crônica com 20 mg/kg/dia de isoflavonas apresentaram menor ingestão de alimentos e peso corporal na fase adulta. Este achado é economicamente importante na produção animal; todavia os animais alimentados com a dieta contendo soja apresentaram na 33ª semana de idade consumo de alimento e peso corporal maiores em 6 e 4% respectivamente do que os animais do grupo controle (P < 0,05). Apesar dos recentes alertas, os resultados deste estudo não suportam a hipótese de que a exposição à isoflavonas em doses compatíveis com o consumo de alimentos à base de soja possa comprometer a saúde reprodutiva masculina / Abstract: This study was proposed to determine if perinatal (that is gestation and lactation) or chronic exposure to isoflavones trough consumption of soy containing diet or semipurified soy isoflavones may disrupt male reproductive health of rabbits. In the first experiment, groups of dams were fed either soy containing diet or soy and alfafa free diet supplemented with soy isoflavones at levels of 10 and 20 mg/kg/day throughout gestation and lactation. The control group was kept on soy and alfafa free diet only. Reproductive organs weight and morphology and serum levels of testosterone of part of the male offspring were evaluated at weaning. Remaining males were subjected to the control diet from weaning to adulthood. Sexual behavior, semen quality and reproductive organs morphology were evaluated after puberty. In the second experiment, groups of dams were fed same diets employed in the experiment 1, but supplementation with isoflavones were performed with doses ranging from 2,5 to 20 mg/kg/day. Dose levels of isoflavones were selected on the basis of the reported estimative of isoflavones intake from the consumption of soy-based foods. After weaning, male offspring received the same diet, which was given to the respective mother. The age that males reached puberty, semen quality and sexual behavior were evaluated in these animals and at 33 weeks of age reproductive organs weight and morphology were analyzed. Results of this study were sustained by data from the evaluation of 100 males in a period of 3 years. Sperm counts was within literature values for New Zealand rabbits and did not vary significantly in relation to control group, although semen volume has been lesser in rabbits exposed to high levels of isoflavones (20 mg/kg/dia). Reproductive organs weight did not differ statistically from the control, and there was no gross evidence of genital malformations, metaplastic changes, or any histopathologic alteration that was correlated with the treatments. In the young rabbits, histological analysis of the testes did not revel differences in gonadal development. Rabbits chronically supplemented with 20 mg/kg/day of soy isoflavones showed lesser food intake and body weight at adulthood. This find is economically important in animal production; however the animals fed soy containing diet showed food consumption and body weight 6 and 4%, respectively higher than animals of the control group at 33 weeks of age (P <0.05). In conclusion, despite recent alerts, results of this study did not support the hypothesis that isoflavones consumption at dietary levels may impair male reproductive health / Doutorado / Biologia Celular / Doutor em Biologia Celular e Estrutural

Soy based products are growing in popularity in food supplementation, and a larger population of the world is consuming soy on a regular basis. Soy contains phytoestrogens, plant based mimics of the hormone estrogen. Estrogen has many functions in humans, but one relatively unexplored function is its ability to regulate the levels of the hormone oxytocin (OT) and its receptor (OTR) in the brain. OT is a hormone traditionally known for its role in birth, but recently has been as a key regulator in many different behaviors. These behaviors that OT may affect include increased maternal behaviors, increased sexual behaviors, increased social interactions, increased trust, decreased anxiety, and increased potential for pair bonding. Key phytoestrogens found in soy are of the isoflavone family, and genistein and diadzein are the main two isoflavones that have been shown to exert physiologic effects when ingested by binding to estrogen receptors in the brain. The isoflavones can be estrogen agonists or estrogen antagonists, based on the preexisting, endogenous levels of estrogen in the individual. For men and postmenopausal women, it is believed that ingesting soy can cause an increase in production of OT and OTR, resulting in an increased in OT driven behaviors. For premenopausal women, there is a high endogenous level of estrogen present, so the ingested soy can cause a decrease in production of OT and OTR in the brain, resulting in a decrease in OT driven behaviors. While there is strong evidence to suggest that this may in fact occur in humans, more human based studies, rather than animal models, must be conducted to further verify and validate this hypothesis. An important area yet unexplored is the onset and duration of these OT driven behaviors. It is unclear if these are transient, or more long lasting effects, and future studies must be done to answer this question. This area of research is certainly more relevant as soy based diets are becoming more common; moving forward additional research is needed to determine the extent of oxytocin's ability to alter behaviors in individuals in a significant way.

Five soymilk quality-related characteristics were investigated as affected by different grinding, heating, extraction methods and varieties. The five characteristics are (1) protein and solid recovery, (2) trypsin inhibitor activity, (3) antioxidant compounds and antioxidant capacity, (4) soy odor, and (5) isoflavone content and profile. The two varieties were Prosoy and black soybeans. The results show that significant differences existed among the three grinding methods (ambient grinding, cold grinding, and hot grinding). Ambient grinding gave the best protein and solid recoveries. Hot grinding showed the best results for the other four parameters. Cold grinding gave the poorest performance, with the exception of the odor profile. The three heating methods (traditional stove cooking, one-phase UHT, two-phase UHT) also resulted in significant differences in the chemical compounds and properties of the soymilk. In many cases, the effects of heating methods were closely related to grinding methods and varieties. Our results clearly demonstrated that a UHT processor equipped with a vacuum chamber was a very efficient way to reduce or eliminate some undesirable soy odors, especially in conjunction with hot grinding. Our results also demonstrated that many complex reactions occurred during thermal treatment. Because of different seed characteristics, the two different varieties behaved differently during processing. For both varieties, extraction with okara washing water from last batch (Method #2) gave the highest solid and protein recoveries.

Atherosclerosis, one of the major causative factors of cardiovascular diseases (CVD), is thought to be initiated by oxidative stress. Particular attention has been paid to the atherogenic effects of oxidative damage on low density lipoproteins (LDL). Current research shows that dietary antioxidant supplementation protects against oxidative stress, and therefore may present preventative measures and treatments for patients with diseases influenced by oxidative stress. Isoflavones found in soy, such as genistein and daidzein are reported to have potent antioxidant properties and have been shown to inhibit LDL oxidation in vitro. Although there is a strong base of data that supports the correlation between soy consumption, cholesterol reduction and cardiovascular protection, it remains to be elucidated whether it is the soy protein, the isoflavone, or a combination of both that confers benefits. This study investigated the effect of isoflavone supplementation on the following parameters: plasma genestein levels, oxidized LDL levels, plasma cholesterol, vitamin E, and C-reactive protein. Elevated serum cholesterol and C-reactive protein (CRP) have been identified as risk factors for cardiovascular disease. In a randomized, double-blind, placebo-controlled study, 150 mg/d isoflavone was supplemented for four weeks by 30 healthy, yet sedentary male subjects who underwent 30 minute exercise sessions at 80% VO2pk before and after a 28 day period of supplementation. The purpose of the exercise was to induce oxidative stress. The average plasma genistein and daidzein concentrations increased significantly after isoflavone supplementation from 0 ng/ml to 561.6 ± 39.3 and 466.3 ± 35.5 ng/ ml (SE) respectively (P < 0.0001), compared to 0 ng/ml in the placebo group throughout the study. There was no significant beneficial effect of isoflavone supplementation on oxidized LDL, plasma vitamin E concentrations, total cholesterol, LDL, HDL, or triglycerides. Isoflavone supplementation resulted in an average increase in CRP levels by 44% (P = 0.014), which was opposite from expectations. This study supports the theory that it may not be soy isoflavones alone that benefit lipid profiles, or offer protection from oxidative stress. / Master of Science

Han, Li. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 132-140). / Abstract and appendixes also in Chinese. / Chapter 1.1 --- BACKGROUND & SIGNIFICANCE OF THE STUDY --- p.1 / Chapter 1.2 --- STRUCTURE OF THE THESIS --- p.4 / Chapter 2.1 --- BPH --- p.6 / Chapter 2.1.1 --- PREVALENCE OF BPH --- p.6 / Chapter 2.1.2 --- IMPACT OF BPH SYMPTOMS ON PATIENTS --- p.9 / Chapter 2.1.2.1 --- CLINICAL SYMPTOMS OF BPH --- p.9 / Chapter 2.1.2.2 --- IMPACT OF CLINICAL SYMPTOMS ON QUALITY OF LIFE --- p.10 / Chapter 2.1.3 --- IMPACT OF BPH MEDICAL MANAGEMENT ON PATIENTS --- p.11 / Chapter 2.1.3.1 --- MEDICAL MANAGEMENT OF BPH --- p.11 / Chapter 2.1.3.2 --- SIDE EFFECTS OF PHARMACOLOGICAL AND SURGICAL THERAPIES --- p.15 / Chapter 2.1.4 --- USE OF COMPLEMENTARY AND ALTERNATIVE THERAPY AMONG BPH PATIENTS --- p.19 / Chapter 2.1.4.1 --- PREVALENCE --- p.19 / Chapter 2.1.4.2 --- REASONS FOR TURNING TO CAM --- p.20 / Chapter 2.2 --- ISOFLAVONES --- p.43 / Chapter 2.2.1 --- ISOFLAVONES FUNCTION --- p.43 / Chapter 2.2.1.1 --- STRUCTURE --- p.43 / Chapter 2.2.1.2 --- FOOD SOURCES --- p.45 / Chapter 2.2.2 --- APPLICATION OF ISOFLAVONES IN BPH --- p.46 / Chapter 2.2.2.1 --- DOCUMENTED MECHANISM OF BPH --- p.46 / Chapter 2.2.2.2 --- STUDIES IN VITRO --- p.47 / Chapter 2.2.2.3 --- STUDIES IN VIVO --- p.48 / Chapter 2.2.2.4 --- EPIDEMIOLOGIC EVIDENCE --- p.49 / Chapter 2.3. --- RESEARCH GAP IN HUMAN STUDY --- p.50 / Chapter 3.1 --- STUDY DESIGN --- p.51 / Chapter 3.2 --- AIM --- p.51 / Chapter 3.3 --- STUDY POPULATION --- p.52 / Chapter 3.3.1 --- INCLUSION CRITERIA --- p.52 / Chapter 3.3.2 --- EXCLUSION CRITERIA --- p.52 / Chapter 3.3.3 --- SAMPLE SIZE ESTIMATION --- p.53 / Chapter 3.4 --- RANDOMIZATION --- p.54 / Chapter 3.4.1 --- GENERATION THE RANDOM ALLOCATION SEQUENCE AND DETAILS OF RESTRICTION OF RANDOMIZATION --- p.54 / Chapter 3.4.2 --- IMPLEMENTATION OF RANDOMIZATION --- p.54 / Chapter 3.5 --- BLINDING --- p.55 / Chapter 3.5.1 --- WHO WERE BLINDED --- p.55 / Chapter 3.6 --- INTERVENTION --- p.55 / Chapter 3.6.1 --- STUDY MEDICATIONS AND DOSAGE --- p.55 / Chapter 3.6.2 --- STUDY REGIMEN --- p.56 / Chapter 3.7 --- DATA COLLECTION --- p.56 / Chapter 3.8 --- OUTCOME MEASUREMENTS --- p.58 / Chapter 3.8.1 --- PRIMARY OUTCOME --- p.58 / Chapter 3.8.1.1 --- UROFLOWMETRY： PEAK URINE FLOW RATE (QMAX) --- p.58 / Chapter 3.8.2 --- SECONDARY OUTCOMES --- p.59 / Chapter 3.8.2.1 --- BLADDER SCAN： POST-VOIDING RESIDUAL VOLUME (PVR) --- p.59 / Chapter 3.8.2.2 --- SYMPTOMS SCORE (IPSS) --- p.60 / Chapter 3.8.2.3 --- QUALIFY OF LIFE --- p.61 / Chapter 3.8.2.4 --- SERUM PSA LEVEL --- p.62 / Chapter 3.8.2.5 --- URINALYSIS TEST --- p.62 / Chapter 3.8.3 --- AE/SAE --- p.63 / Chapter 3.8.3.1 --- SELF REPORTED AE/SAE --- p.63 / Chapter 3.8.3.2 --- SEXUAL HORMONE LEVEL --- p.64 / Chapter 3.8.3.3 --- SEXUAL RELATED QUALITY OF LIFE --- p.64 / Chapter 3.9 --- STATISTICAL ANALYSIS --- p.65 / Chapter 3.9.1 --- DESCRIPTIVE ANALYSIS --- p.65 / Chapter 3.9.2 --- COMPARATIVE ANALYSIS --- p.65 / Chapter 4.1 --- PARTICIPANTS FLOW --- p.67 / Chapter 4.2 --- DEMOGRAPHICS --- p.69 / Chapter 4.3 --- BASELINE CHARACTERISTICS COMPARISON --- p.70 / Chapter 4.3.1 --- IPSS --- p.72 / Chapter 4.3.2 --- QMAX AND PRV --- p.73 / Chapter 4.3.3 --- QUALITY OF LIFE --- p.73 / Chapter 4.3.4 --- SERUM PSA LEVEL --- p.74 / Chapter 4.4 --- EFFICACY OUTCOMES --- p.74 / Chapter 4.4.1 --- QMAX AND PVR --- p.74 / Chapter 4.4.1.1 --- QMAX --- p.74 / Chapter 4.4.1.2 --- PVR --- p.75 / Chapter 4.4.2 --- IPSS --- p.79 / Chapter 4.4.2.1 --- TOTAL IPSS --- p.79 / Chapter 4.4.2.2 --- IPSS SUB SCORE 1_ INCOMPLETE EMPTYING --- p.79 / Chapter 4.4.2.3 --- IPSS SUB SCORE 2_ FREQUENCY --- p.80 / Chapter 4.4.2.4 --- IPSS SUB SCORE 3_INTERMITTENCY --- p.81 / Chapter 4.4.2.5 --- IPSS SUB SCORE 4_ URGENCY --- p.82 / Chapter 4.4.2.6 --- IPSS SUB SCORE 5_ WEAK STREAM --- p.82 / Chapter 4.4.2.7 --- IPSS SUB SCORE 6_ STRAINING --- p.83 / Chapter 4.4.2.8 --- IPSS SUB SCORE 7_ NOCTURIA --- p.84 / Chapter 4.4.3 --- QOL --- p.90 / Chapter 4.4.3.1 --- QOL IN IPSS Q8_QOL_URINATION --- p.90 / Chapter 4.4.3.2 --- QOL IN SF-36 --- p.91 / Chapter 4.4.3.2.1 --- PHYSICAL FUNCTIONING --- p.91 / Chapter 4.4.3.2.2 --- ROLE-PHYSICAL --- p.92 / Chapter 4.4.3.2.3 --- BODY PAIN --- p.92 / Chapter 4.4.3.2.4 --- GENERAL HEALTH --- p.93 / Chapter 4.4.3.2.5 --- VITALITY --- p.94 / Chapter 4.4.3.2.6 --- SOCIAL FUNCTIONING --- p.95 / Chapter 4.4.3.2.7 --- ROLE-EMOTIONAL --- p.95 / Chapter 4.4.3.2.8 --- MENTAL HEALTH --- p.96 / Chapter 4.4.4 --- SERUM PSA LEVEL --- p.103 / Chapter 4.4.5 --- SUBGROUP ANALYSIS --- p.106 / Chapter 4.4.6 --- SELF-PREFERENCE EFFECT ANALYSIS --- p.107 / Chapter 4.4.7 --- DIARY ANALYSIS --- p.109 / Chapter 4.5 --- ADVERSE EVENTS --- p.113 / Chapter 4.5.1 --- SELF-REPORTED AE/SAE --- p.113 / Chapter 4.5.2 --- SEXUAL HORMONE LEVEL --- p.114 / Chapter 4.5.3 --- SEXUAL RELATED QUALITY OF LIFE --- p.114 / Chapter 4.5.3.1 --- SEXUAL LIFE UNSATISFACTORY --- p.114 / Chapter 4.5.3.2 --- LIBIDO DECREASE --- p.115 / Chapter 5.1 --- PRINCIPAL FINDINGS --- p.116 / Chapter 5.1.1 --- EFFICACY --- p.116 / Chapter 5.1.2 --- SAFETY --- p.117 / Chapter 5.2 --- STRENGH AND LIMITATIOINS --- p.117 / Chapter 5.2.1 --- STRENGTH --- p.117 / Chapter 5.2.1.1 --- BLINDING IS EFFECTIVE --- p.117 / Chapter 5.2.1.2 --- COMPLIANCE IS GOOD --- p.118 / Chapter 5.2.1.3 --- LONG TREATMENT PERIOD --- p.119 / Chapter 5.2.1.4 --- STUDY OUTCOMES INCLUDE BOTH OBJECTIVE OUTCOMES AND SUBJECTIVE OUTCOMES --- p.121 / Chapter 5.2.2 --- LIMITATIONS --- p.121 / Chapter 5.2.2.1 --- INSUFFICIENT SAMPLE SIZE --- p.122 / Chapter 5.2.2.2 --- POSSIBLY LOW DOSE --- p.122 / Chapter 5.2.2.3 --- LACK OF BASELINE DATA ON QUALITY OF SEXUAL LIFE --- p.123 / Chapter 5.2.2.4 --- "LACK OF DATA ON LIFESTY FACTORES INCLUDING DIETARY HABIT, PHYSICAL ACTIVITY, SMOKING STATUS AND ACOHOL CONSUMPTION" --- p.123 / Chapter 5.3 --- INTERPRETATIONS OF THE RESUTLS --- p.124 / Chapter 5.3.1 --- TWO POSIVE RESULTS IN EMPTYING FUNCTION AND QUALITY OF LIFE --- p.124 / Chapter 5.3.2 --- ONE NEGATIVE RESULT IN PEAK URINARY FLOW RATE --- p.127 / Chapter 5.3.3 --- QUALITY OF SEXUAL LIFE --- p.129 / Chapter 6.1 --- CONCLUSIONS --- p.130 / Chapter 6.2 --- IMPLICATIONS --- p.131