A Doença de Alzheimer é uma doença neurodegenerativa relacionada à idade, que se caracterizada pela perda progressiva da memória, pela incapacidade de realizar atividades do cotidiano e alterações de personalidade. Esta doença é caracterizada histopatologicamente pela presença de placas senis e dos emaranhados neurofibrilares e também pela perda sináptica e morte neuronal. Além disso, já está bem estabelecido que a neuroinflamação é uma característica proeminente do cérebro de pacientes com doença de Alzheimer, no qual respostas inflamatórias desempenham um papel significativo na progressão da doença. Infelizmente, os fármacos utilizados no tratamento desta doença são limitados a inibidores da acetilcolinesterase que não têm impacto na patogênese da doença. As estatinas, que pertencem à classe de drogas redutoras de colesterol, têm sido propostas como novos agentes úteis na terapia da doença de Alzheimer devido às suas propriedades neuroprotetoras e anti-inflamatórias. Neste estudo, avaliamos o efeito neuroprotetor da atorvastatina, um inibidor da HMG-CoA redutase contra a toxicidade induzida pelo peptídeo Aβ25-35 em culturas organotípicas de hipocampo de ratos. As culturas foram tratadas com 2,5 uM ou 5μM de atorvastatina e então expostas a 25μM do peptídeo Aβ25-35 durante 48h. Também foi investigado o envolvimento da via de sinalização PI3K, as respostas oxidativas, a ativação astroglial, e os níveis de sinaptofisina (marcador pré-sináptico) e de citocinas. O tratamento com atorvastatina impediu a lesão celular induzida pela exposição ao Aβ25-35, reduziu as respostas inflamatórias e oxidativa e aumentou o imunoconteúdo de sinaptofisina. Além disso, a atorvastatina preveniu significativamente a ativação da GSK-3β, a ativação astroglial e o aumento nos níveis de TNF-α e IL-6. Tomados em conjunto, estas observações sugerem que a atorvastatina pode proporcionar uma eficaz ação neuroprotetora contra a neurotoxicidade induzida pelo Aβ através da ativação da via de sinalização PI3K/AKT e atenuação das respostas oxidativas e neuroinflamatórias, podendo ser uma potencial terapia a ser usada na DA. / Alzheimer’s disease is an age-related neurodegenerative disorder characterized by progressive memory loss, inability to perform the activities of daily living and personality changes. AD is characterized histopathologically by the presence of senile plaques, neurofibrillary tangles, synapse loss and neuronal death. Moreover, it is now recognized that neuroinflammation is a proeminent feature of Alzheimer’s disease brain, with inflammatory responses playing a significant role in modulating disease progression. Unfortunately, drugs effective for this disease are limited to acetylcholinesterase inhibitors that do not impact disease pathogenesis. Statins, which belong to the class of cholesterol-reducing drugs, were proposed as novel agents useful in AD therapy due the neuroprotective and anti-inflammatory properties that they have. In this study, we evaluated the neuroprotective effect of atorvastatin, a HMG-CoA reductase inhibitor, against Aβ25-35 peptide induced toxicity in organotypic hippocampal slice cultures. The cultures were treated with 2.5μM or 5μM of atorvastatin and then exposed to 25μM of Aβ25-35 for 48h. We also investigated the involvement of PI3K signaling pathway, oxidative responses, astroglial activation, and synaptophysin (pre-synaptic marker) and cytokines levels on the atorvastatin protection against β-amyloid-induced toxicity. Atorvastatin treatment prevented the cell damage induced by the exposure to peptide Aβ25-35, reduced inflammatory and oxidative responses and increased the immunocontent of synaptophysin. In addition, atorvastatin significantly prevented the activation of GSK-3β, the astroglial activation and the β-amyloid-induced increase in TNF- and IL-6 levels. Taken together, these observations suggest that atorvastatin may provide an effective neuroprotective action against neurotoxicity induced by Aβ through the activation of the PI3K/AKT signaling pathway and attenuation of oxidative responses and neuroinflammation, and could be a potencial drug used on Alzheimer disease.

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Class of 2012 Abstract / Specific Aims: To evaluate the quality of evidence in the literature substantiating major drug-drug interactions of the HMG-CoA reductase inhibitors (statins) atorvastatin, lovastatin, and simvastatin with the azole anti-fungals fluconazole, itraconazole, and ketoconazole. Methods: In this descriptive retrospective analysis, a list of articles reporting on each drug-drug interaction was compiled from the online databases Medline and International Pharmaceutical Abstracts, and the drug compendia Micromedex and Facts & Comparisons. The studies included in this analysis were primary literature reports, written in English, and consisted of human subjects. All studies included were evaluated using a 5-point quality of evidence scale developed to assess drug-drug interactions (van Roon scale). This scale rates the study type from lowest to highest quality, from zero to four. Case reports were additionally analyzed using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. Main Results: Twenty-one studies met the selection criteria. There were three studies involving atorvastatin, four studies involving lovastatin, and fourteen studies involving simvastatin. The mean quality of evidence score on the van Roon scale was 2.0 + 0.77, where atorvastatin studies had a score of 2.3 + 1.15, lovastatin had a score of 2.25 + 0.95 and simvastatin had a score of 1.86 + 0.66. Seventy-one percent of the studies reviewed were case reports. Conclusions: The reports substantiating some drug-drug interactions may be of little and low quality evidence.

Abstract Multifunctional enzyme type 2 (MFE-2) catalyses the second and the third reactions in the eukaryotic peroxisomal β-oxidation cycle, which degrades fatty acids by removing a two-carbon unit per each cycle. In addition to the 2-enoyl-CoA hydratase 2 and (3R)-hydroxyacyl-CoA dehydrogenase activities, mammalian MFE-2 has also a sterol carrier protein type 2-like (SCP-2L) domain. In contrast, yeast MFE-2 has two (3R)-hydroxyacyl-CoA dehydrogenases, one 2-enoyl-CoA hydratase 2 and no SCP-2L domain. The physiological roles of yeast (3R)-hydroxyacyl-CoA dehydrogenases (A and B) were tested by inactivating them in turn by site-directed mutagenesis and testing the complementation of Saccharomyces cerevisiae fox-2 cells (devoid of endogenous MFE-2) with mutated variants of Sc MFE-2. Growth rates were lower for fox-2 cells expressing only a single functional domain than for those expressing the Sc MFE-2. Kinetic studies with purified Candida tropicalis MFE-2 and its mutated variants show that dehydrogenase A catalyzes the reaction more efficiently with the medium- and long-chain substrates than dehydrogenase B, which in turn is the only one active with the short chain fatty acids. The structural basis of the substrate specificity difference of these two dehydrogenases was solved by X-ray crystallography together with docking studies. Protein engineering was used to produce a stabile, homogenous recombinant protein of C. tropicalis dehydrogenases in one polypeptide. The heterodimeric structure contains the typical fold of the short-chain alcohol dehydrogenase/reductase (SDR) family. Docking studies suggest that dehydrogenase A binds medium chain-length substrates as bended, whereas short chain substrates are dislocated, because they do not reach the hydrophobic contacts needed for anchoring the substrate to the active site, but are instead attracted by L44. Dehydrogenase B has a more shallow binding pocket and thus locates the short chain-length substrates correctly for catalysis. Thus the data provide clues for structural basis of the different substrate specificities. The molecular basis of the patient mutations of MFE-2 (DBP deficiency) was studied using the recently solved crystal structures of rat (3R)-hydroxyacyl-CoA dehydrogenase, human 2-enoyl-CoA hydratase and SCP-2L. The predicted effect of the mutations on protein structure could in several cases be explained, and these data supported the conclusion that a genotype-phenotype correlation exists for DBP deficiency.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22145号 / 医博第4536号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 安達 泰治, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

During the process of domestication and selection reduction of genetic diversity of cultivated crops occurred. Currently the main interest of breeders is to transfer some of crop wild relatives’ genes to cultivated crops. Those genes of interest are related e.g. with desease and pest resistance or drought resistance. Hybridization of wild and cultivated species is prevented by reproductive isolation. The frequent phonomenon in hybrids is called nuclear-cytoplasmic incompatibility, which is manifested by reduced fertility, sterility or lethality. In this phenomenon occurs conflict between nuclear-encoded genes with genes encoded in the organellar genomes. The identified accD candidate gene responsible for nuclear-cytoplasmic incompatibility in pea is highly variable due to insertions and deletions. High variability of the accD gene was also confirmed in the genera Lathyrus and Vicia. Variability was observed in gene sequence lenghts caused by presence of indels and single nucleotide polymorphisms. In comparative analysis with other regions of cpDNA commonly used in phylogenetics, the region of the accD gene had the highest value of parsimonially informative sites. The phylogeny derived from the region of the accD gene corresponds to the phylogeny based on combined chloroplast markers, therefore the accD gene may be suitable for this type of analysis.

In February 2012, the FDA issued safety label changes and monitoring requirements for statin therapy. A risk of cognitive impairment was noted, although evidence was largely based on observational data, including case reports. In 2014, the National Lipid Association's safety task force found that evidence does not support cognitive decline as a classwide effect for statins. Some evidence has shown that statins may actually have beneficial effects on cognition. This article discusses management of statin therapy in patients with cardiovascular risk who may experience cognitive decline or have cognitive impairment, such as Alzheimer disease.

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This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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