The plant Garcinia gardneriana (Planch. & Triana) Zappi, popularly known in Brazil as "bacupari" has traditionally been used for various types of inflammatory diseases and the evaluation of their chemical composition, mainly of leaves, has resulted in biflavonoids as major compounds. These phenolic compounds have shown anti-inflammatory activity validating the popular use of the plant. In this work was isolated from dried branches of Garcinia gardneriana the biflavonoids: morelloflavone, that is an naringenin covalently linked to luteolin, Gb-2a which is an naringenin linked to eriodictyol and Gb-2a- 7-O-glucose. These compounds have been previously evaluated in various activities such as anti-inflammatory and anti-antioxidants but there is no report of its activity as enzymatic inhibitors. However, the monomers that form it, have been evaluated in the inhibition of aromatase and antidepressant activity with positive outcome, which commonly are used MAO-A inhibitors. In the isolation process were also founded terpenoid compounds as lupeol and friedelin The isolated and purified biflavonoids were used to evaluate enzyme inhibition "in vitro" in monoamine oxidases (MAO-A MAO-B) and aromatase. The compounds showed a positive response even of IC50 5,47 μM and 1,35 μM for MAO-A inhibition of and aromatase enzyme respectively; discovering a way for a new proposal to link both enzymes for treatment of hormone-dependent cancers and anxiety and depression disorders. / La planta Garcinia gardneriana (Planch. & Triana) Zappi, popularmente conocida en Brasil como "bacupari" ha sido tradicionalmente usada para varios tipos de enfermedades inflamatorias y la evaluación de su composición química, principalmente de las hojas, ha resultado en biflavonoides como compuestos mayoritarios. Estos compuestos fenólicos han demostrado actividad anti-inflamatória validando el uso popular de la planta. En este trabajo se asilaron a partir de tallos secos de la Garcinia gardneriana los biflavonoides: moreloflavona, que consiste en una naringenina unida covalentemente a luteolina, Gb-2a que es un compuesto que consiste en una naringenina unida a un eriodictyol y Gb-2a-7-O-glucose. Estos compuestos ya han sido previamente evaluados en diversas actividades como anti inflamatorios y anti antioxidantes pero no se tiene reporte de su actividad como inhibidores enzimáticos. Sin embargo, los monomeros que los conforman han sido evaluados en la inhibición de la aromatasa y con resultados positivos como en la actividad antidepresiva, para la cual comúnmente son usados los inibidores de MAO-A. En el proceso de aislamiento también fueron encontrados compuestos terpenoides como lupeol y friedelina. Los biflavonoides aislados y purificados se usaron para evaluar la inhibición enzimática “in vitro” en monoaminooxidasas (MAO-A, MAO-B) y aromatasa. Los compuestos presentaron una respuesta positiva calculada con IC50 de hasta 5,47 μM y 1,35 μM para la inhibición de las enzimas MAO-A y aromatasa respectivamente, abriendo el camino a una nueva propuesta de relacionar estas dos enzimas para tratamiento de cánceres hormonodependientes y transtornos de ansiedad y depresión.

Monoamine oxidase (E.C.I.4.3.4) (MAO) oxidatively deaminates the biogenic amines normally present in the organism. The activities of the neurons utilizing these amines i.e. noradrenaline, dopamine and serotonin, are supposed to be involved in the pathogenesis of various psychiatric diseases. It is speculated that the MAO activity is changed as well as the monoaminergic activity in some psychiatric disorders. In the present thesis the MAO activity has been studied in brain tissue and in platelets in some psychiatric disorders. The result was as follows: MAO activities in different parts of the human brain seem to be highly intercorrelated in each individual. The brain MAO activity is also weakly correlated both to the concentration of 5-HT and of 5-HIAA, which may indicate that the MAO activity reflects the serotoninergic turnover in the brain. The MAO activity in brains from 15 suicides was compared to a control material of 20 individuals without known mental disorders, and it was found to be lower in the suicides in all 13 analysed brain parts. As eight of the patients had been chronic alcoholics, they were excluded and the remaining seven non-alcoholic suicides were tested as regards MAO activity by analysis of variance and still found to have significantly lower MAO activity than the controls. The eight chronic alcoholics in the suicide series had the most significantly (p<0.005) reduction of the MAO activity as compared to the control group. Rats were given chronic treatments with ethanol, either by 10 °/o ethanol as the only water supply or by exposition to ethanol vapor twice a day. In neither of these cases was the brain MAO activity changed as compared to control rats. The result supports the hypothesis that the low MAO activity found in alcoholic suicides most likely is related to a constitutional factor and not to a direct effect of the ethanol intake. Platelet MAO activity was found to be significantly reduced in human alcoholics as compared to matched controls. If samples were drawn from the alcoholic patients during their abstinence phase, there could be seen a transitory rise in the platelet MAO activity. This increased activity had its maximum after two weeks, and after four weeks the MAO activity had returned to the initial, low level. No difference as regards MAO activity, neither in brain tissue nor in platelets, could be registered when chronic schizophrenics were compared to matched controls. Reduced brain MAO activity was found in a group of patients diagnosed as cycloid psychoses when comparing the activity to controls or to the schizophrenic patients. The platelet MAO activity was also found to be lower in cycloid psychoses than in a group of unipolar affective psychoses, who repeatedly have been found not to differ from normals. These findings suggest that low MAO activities in brain and platelets reflect a phychic constitution in the individual making him more vulnerable for suicidal behaviour, ethanol abuse or cycloid psychosis. / digitalisering@umu.se

No description available.

Flavin adenine dinucleotide (FAD) is a coenzyme that participates in the redox process of flavoenzymes. Attempts to characterize the catalytic pathways of these enzymes have relied in part on the use of FAD chemical models. The efforts described in this dissertation focus on the chemical model approach to investigate the mechanism of the monoamine oxidase (MAO) catalyzed oxidation of the cyclic tertiary allylamine 1-methyl-4-(2-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (TMMP), which is a close analog of the parkinsonian-inducing designer drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MAO-B catalyzes the conversion of MPTP and its derivatives into active neurotoxins in the brain that subsequently mediate neurogenerative processes that mimic the events leading to idiopathic Parkinson\'s disease. Monoamine oxidase inhibitors are currently used to treat early stages of Parkinson\'s disease. Two FAD chemical models are examined in this project: 5-ethyl-3-methyllumiflavinium perchlorate (5Et3MLF+ClO4-) and 3-methyllumiflavin (3MLF). The flavinium salt 5Et3MLF+ClO4- is an activated form of 3MLF. These FAD chemical models have been used to examine the MAO catalyzed oxidation. MAO-B is expressed in the brain and is known to be involved in the conversion of TMMP into the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MMP+). MAO-B is responsible for the alpha-carbon oxidation of TMMP to yield 1-methyl-4-(2-methylpyrrol-2-yl)-2,3-dihydropyridinium (DHP+), which then undergoes a second 2-electron oxidation to MMP+. Previous findings demonstrated that 3MLF and 5Et3MLF+ClO4- promoted the oxidation reaction of primary and secondary amines but not tertiary amines. However, the cyclic tertiary allylamine TMMP has not been examined experimentally. Therefore, the alpha-carbon oxidation of TMMP in the presence of the FAD chemical models is reported in this dissertation. The effect of dioxygen and water on the activity of these FAD models is also investigated. / Ph. D.

<p>This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. </p><p>Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheritance of hearing disability in the Swedish family. Mutation screening of α-tectorin, a gene residing within the DFNA12 region revealed a mutation of a conserved amino acid (Cys to Ser), that segregated with the disease. The identification of the mutation added support to the involvement of α-tectorin in hearing disabilities. In contrast, no mutations were identified in two candidate genes at the DFNA2 locus, that were reported to cause hearing loss in other families. It is possible that the DFNA2 locus contains a third, not yet identified, hearing loss gene. </p><p>Monoamine oxidase A (MAOA) and B (MAOB) catalyze the degradation of certain neurotransmitters in the central nervous system and are associated with specific behavioral and neuropsychiatric human traits. Activity levels of both monoamine oxidases (MAO) are highly variable among humans and are determined by unknown genetic factors. This study investigated the relationship of different MAO alleles with MAO mRNA levels and enzyme activity in human brain. Several novel DNA polymorphisms were identified in a group of Swedish individuals. Haplotypes containing several closely located MAOA polymorphisms were assessed in Asian, African, and Caucasian populations. The haplotype distribution and diversity pattern found among the three populations supported the occurrence of a bottleneck during the dispersion of modem humans from Africa. </p><p>Allelic association studies conducted on postmortem human brain samples, revealed the association between a SNP in the MAOB intron 13, and different levels of both MAO enzyme activities. This suggested that this SNP is in linkage disequilibrium with at least one novel functional DNA polymorphism that controls MAO enzyme activities in human brain. The identification of functional polymorphisms regulating the activity of these enzymes will help to elucidate the involvement of MAO in human behavior and neuropsychiatric conditions. </p>

This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheritance of hearing disability in the Swedish family. Mutation screening of α-tectorin, a gene residing within the DFNA12 region revealed a mutation of a conserved amino acid (Cys to Ser), that segregated with the disease. The identification of the mutation added support to the involvement of α-tectorin in hearing disabilities. In contrast, no mutations were identified in two candidate genes at the DFNA2 locus, that were reported to cause hearing loss in other families. It is possible that the DFNA2 locus contains a third, not yet identified, hearing loss gene. Monoamine oxidase A (MAOA) and B (MAOB) catalyze the degradation of certain neurotransmitters in the central nervous system and are associated with specific behavioral and neuropsychiatric human traits. Activity levels of both monoamine oxidases (MAO) are highly variable among humans and are determined by unknown genetic factors. This study investigated the relationship of different MAO alleles with MAO mRNA levels and enzyme activity in human brain. Several novel DNA polymorphisms were identified in a group of Swedish individuals. Haplotypes containing several closely located MAOA polymorphisms were assessed in Asian, African, and Caucasian populations. The haplotype distribution and diversity pattern found among the three populations supported the occurrence of a bottleneck during the dispersion of modem humans from Africa. Allelic association studies conducted on postmortem human brain samples, revealed the association between a SNP in the MAOB intron 13, and different levels of both MAO enzyme activities. This suggested that this SNP is in linkage disequilibrium with at least one novel functional DNA polymorphism that controls MAO enzyme activities in human brain. The identification of functional polymorphisms regulating the activity of these enzymes will help to elucidate the involvement of MAO in human behavior and neuropsychiatric conditions.

This thesis investigated (1) social status and shaming experiences in relation to aggressive behaviour and depression, and (2) gene-environment interactions between two genetic polymorphisms related to the serotonergic system – MAOA-VNTR and 5HTTLPR – and experiences of maltreatment in relation to delinquent behaviour and depression among adolescents. The four included studies are based on questionnaire data from the Survey of Adolescent Life in Vestmanland 2006 (SALVe-2006). A total of 5396 students in 9th (15-16 years old) grade of elementary school and 2nd (17-18 years old) grade of high school comprised the target population. The students in 2nd grade of high school also provided a saliva sample for gene extraction. There were strong associations between shaming experiences and both aggressive behaviour and depression. In addition, individuals who reported many shaming experiences and had either low or high social status had increased risks of physical aggression or depression, whereas medium social status seemed to have a protective effect. Gene-environment interactions were found between experiences of maltreatment and the MAOA-VNTR in relation to delinquent behaviour. Moreover, the direction of the gene-environment interaction differed depending on sex: boys with the short (S) variant of the MAOA-VNTR, in contrast to girls with the long (LL) variant, had the highest risk of delinquency in combination with maltreatment. Gene-environment interactions were also found between experiences of maltreatment and the 5HTTLPR in relation to depression among girls. The girls that were homozygous for the S allele (SS) had the highest risk of depression in combination with maltreatment. Among boys however, no gene-environment interaction was found between the 5HTTLPR and maltreatment in relation to depression. In conclusion, it is important to consider both genetic effects, and psychosocial factors such as social status, shaming experiences, and experiences of maltreatment when investigating different aspects of health and behaviour among adolescents.

The brain is a major target site in acute cyanide intoxication, as indicated by several symptoms and signs. Cyanide inhibits the enzyme cytochrome oxidase. This inhibition causes impaired oxygen utilization in all cells affected, severe metabolic acidosis and inhibited production of energy. In this thesis, some neurotoxic effects of cyanide, in particular, the effects on dopaminergic pathways were studied. In a previous study, decreased levels of striatal dopamine and HVA were found after severe cyanide intoxication (5-20 mg/kg i.p.). However, increased striatal dopamine were found in rats showing convulsions after infusion of low doses of cyanide (0.9 mg/kg i.v.), at the optimal dose rate (the dose rate that gives the treshold dose). Increased striatal dopamine synthesis was observed in rats after cyanide treatment and in vitro. Furthermore, in rat, as well as in pig striatal tissue, cyanide dose- dependently increased the oxidative deamination of 5-HT (MAO-A) and DA (MAO-A and -B) but not that of PEA (MAO-B). Thus cyanide affects both the synthesis and metabolism of dopamine. In rats, sodium cyanide (2.0 mg/kg, i.p.) decreased the striatal dopamine Dj- and D2-receptor binding 1 hour after injection. Increased extracellular levels of striatal dopamine and homovanillic acid were also shown after cyanide (2.0 mg/kg; i.p.). DOPAC and 5-HIAA were slightly decreased. This indicates an increased release or an extracellular leakage of dopamine due to neuronal damage caused by cyanide. Thus the effects of cyanide on dopamine Dj- and D2~receptors could in part be due to cyanide-induced release of dopamine. Because of reported changes in intracellular calcium in cyanide-treated animals, the effects of cyanide on inositol phospholipid breakdown was studied. Cyanide seemed not to affect the inositol phospholipid breakdown in vitro. The effects of cyanide on the synthesis and metabolism of brain GAB A were also examined. A decreased activity of both GAD and GAB A-T were found in the rat brain tissue. The reduced activity of GAB A-T, but not that of GAD returned to the control value after adding PLP in the incubation media. The cyanide-produced reduction of GABA levels will increase the susceptibility to convulsions, and could partly be due to GAD inhibition. In conclusion, cyanide affects the central nervous system in a complex manner. Some effects are probably direct. The main part, however, appears to be secondary, e.g. hypoxia, seizures, changes in calcium levels or transmitter release produced by cyanide. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 7 uppsatser</p> / digitalisering@umu

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

No description available.