Chromatographic purification of a methylene chloride extract of Formosan soft coral Sarcophyton crassocaule (collected in Green island) led to the isolation of two new (1S*, 3R*, 4R*, 7E, 11E, 14R*)-3, 4-epoxycembra-7, 11, 15-trien-1, 14-olide (1) and (1R*, 3E, 7E,11R*, 12S*, 14R*)-11, 12-epoxycembra-3, 7, 15-trien-1, 14-olide (2) isomeric diterpenoids , a known cyclic peroxide diterpenoid (1R*, 2S*, 3E, 7S*, 8R*, 11S*, 12Z)-8, 11-epidioxy-7-acetoxycembra-3, 12, 15-trien-1, 2-olide (3), as well as two known (24S)-24-methylcholestane-3b, 5a, 6b-triol (4) and 24x-methyl-cholestane -3b, 5a, 6b, 25-tetrol 25-monoacetate (5) steroids. Chromatographic fractionation of a methylene chloride extract of two Formosan soft corals Sarcophyton elegans (collected in Green island) led to the isolation of a known 24x-methylcholestane -3b, 5a, 6b, 25-tetrol 25-monoacetate (5) steroid, the methylene chloride extract of Sarcophyton trocheliophorum, on the other hand, afforded a known diterpenoid, (+)-isosarcophine (6). Purification of a methylene chloride extract of Octocorallia soft coral (unidentified) led to the isolation of two known steroids, cholesterol (7) and (22E, 24S)-24-methylcholesta-5, 22-dien-3b-ol (8). Compounds 1-7 exhibited cytotoxicity against P388 cancer cell line. Compounds 2 and 5 were active against HT-29 cancer cell line.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 70-81).

Reproduction de : Thèse de doctorat : Biologie cellulaire et moléculaire : Lyon 1 : 2004. / Titre provenant de l'écran titre. 256 réf. bibliogr.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 86-98).

Thesis (Ph. D.)--University of California, Riverside, 2009. / Includes abstract. Available via ProQuest Digital Dissertations. Title from first page of PDF file (viewed March 16, 2010). Includes bibliographical references. Also issued in print.

Thesis (Ph. D.)--University of Oregon, 2000. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 76-79). Also available for download via the World Wide Web; free to University of Oregon users.

Thesis (Ph. D.)--University of Oregon, 2002. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 101-112). Also available for download via the World Wide Web; free to University of Oregon users.

The fungus Cunninghamella elegans has in many studies shown to have abiotransformation similar to the metabolism of mammals. If the biotransformation isgeneral, it enables the production of metabolites by the fungus and the use asreference material. The purpose of the project were to examine whether themetabolic process of C. elegans is general, with respect to the formation ofglucosides, and can be applied to different classes of drugs. During the project, theanalyses were performed on a UPLC Q-TOF, run in both MSE and MSMS mode. Themobile phase used consisted of MeOH and 0.1 % formic acid in MQ water. Toincrease the concentration of possible glucosides, the samples were subjected to anacidic or alkaline SPE. Glucosides were detected in the fungal incubates of diclofenac,buprenorphine, norbuprenorphine and oxazepam. For diclofenac, besides twodifferent glucosides (diclofenac glucoside and hydroxylated diclofenac glucoside), ahydroxylated metabolite and a hydroxylated metabolite conjugated with sulfate werediscovered. In the samples containing buprenorphine, the phase I metabolitenorbuprenorphine was also encountered. Further, in the fungal incubates ofdexamethasone a defluorinated metabolite was identified, which is a metabolicpathway never before described for C. elegans.ISSN: 1650

Understanding how metabolites contribute to anaplerosis, antioxidant effects, and hormetic pathways during aging is fundamental to creating supplements and dietary habits that may decrease age-associated disease and decline, thus improving the quality of life in old age. In order to uncover metabolic pathways that delay aging, the effects of large sets of metabolites associated with mitochondrial function on lifespan were investigated. Malate, the tricarboxylic acid (TCA) cycle metabolite, increased lifespan and thermotolerance in C. elegans. Addition of fumarate and succinate also extended lifespan and all three metabolites activated nuclear translocation of the cytoprotective DAF-16/FOXO transcription factor and protected from paraquat-induced oxidative stress. The increased longevity provided by malate addition did not occur in fumarase (fum-1), glyoxylate shunt (gei-7), succinate dehydrogenase flavoprotein (sdha-2), or soluble fumarate reductaseF48E8.3 RNAi knockdown worms. Therefore, to increase lifespan, malate must be first converted to fumarate, then fumarate must be reduced to succinate by soluble fumarate reductase and the mitochondrial electron transport chain complex II. Lifespan extension induced by malate depended upon the longevity regulators DAF-16 and SIR-2.1. Malate supplementation did not extend the lifespan of long-lived eat-2 mutant worms, a model of dietary restriction. Malate and fumarate addition increased oxygen consumption, but decreased ATP levels and mitochondrial membrane potential suggesting a mild uncoupling of oxidative phosphorylation. Each of the twenty amino acids was individually supplemented to C. elegans and the effects on lifespan were determined. All amino acids except phenylalanine were found to extend lifespan at least to a small extent at one or more of the 3 concentrations tested with serine, histidine, and proline showing the largest effects. In most cases, amino acid supplementation did not extend lifespan in eat-2 worms, a model of dietary restriction or in daf-16, sir-2.1, rsks-1 (S6 kinase), or aak-2 (AMPK) longevity pathway mutants or in worms fed RNAi to skn-1, the C. elegans Nrf2 homolog. Serine and tryptophan addition further protected worms from Alzheimer’s amyloid-beta toxicity. Tryptophan and its catabolites nicotinic acid, picolinic acid, and NAD further induced a broad heat shock response. These results indicate that dietary amino acid imbalance and amino acid catabolism affect organismal longevity. The ketone body beta-hydroxybutyrate (βHB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of βHB supplementation on the lifespan of C. elegans. βHB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented βHB-mediated lifespan extension. βHB-mediated lifespan extension required the DAF-16/FOXO and SKN-1/Nrf longevity pathways, the sirtuin SIR-2.1, and the AMP kinase subunit AAK-2. βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated ΒHB dehydrogenase activity and increased oxygen consumption in the worms. RNAi knockdown of F55E10.6, a short chain dehydrogenase and SKN-1 target gene, prevented the increased lifespan and βHB dehydrogenase activity induced by βHB addition, suggesting that F55E10.6 functions as an inducible βHB dehydrogenase. Furthermore, βHB supplementation delayed Alzheimer's amyloid-beta toxicity and decreased Parkinson's alpha-synuclein aggregation. The results indicate that D-βHB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways. Aging is a progressive disease caused by the time dependent decline of an organism and is the primary risk factor for many human ailments, including heart disease, cancer, and Alzheimer’s disease. Uncovering metabolic pathways and metabolites that delay the onset of age-related decline was the primary drive of this investigation.

Alzheimer disease is characterized by the initial degeneration of a subset of cholinergic neurons. This pattern of degeneration can be triggered by overexpression of the amyloid precursor protein (APP) gene in humans. Interestingly, APP is widely expressed; it is therefore unclear why only certain cholinergic neurons are vulnerable to degeneration. We show that widespread expression of the human APP gene in the nematode Caenorhabditis elegans also induces age-dependent apoptotic degeneration of select cholinergic neurons. Identical results were obtained by overexpressing the orthologous worm gene apl-1. The pattern of neurodegeneration matched the cell-autonomous accumulation of APP protein in vulnerable neurons and could be activated cell-non-autonomously by distinct portions of APP. Vulnerability to APP accumulation and degeneration depended inversely on the level of ASK1/p38MAPK innate-immune signaling in cholinergic neurons. Lastly, we identify a compound P7C3 that blocks entrance to apoptosis caused by APP or immunodeficiency. Our results suggest that immunosenescence sculpts the cellular pattern of neurodegeneration by APP. / text