The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders.

>Magister Scientiae - MSc / Drought is a major stress that affects the productivity of plants across the globe. The consequences of drought are posed to continue reducing agricultural productivity as world climate changes. This makes it imperative to improve tolerance of staple food crops to drought. Under drought stress, reactive oxygen species (ROS) accumulate, which may lead to oxidative damage of DNA, proteins and lipids.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies because it is often diagnosed at a late disease stage and has a poor response rate to currently available treatments. Therefore, it is critical to develop new therapeutic approaches that will enhance the efficacy and reduce the toxicity of currently used therapies. Here we aimed to evaluate the therapeutic potential and mechanisms of action for piperlongumine (PL), an alkaloid from long pepper, in PDAC models. We postulated that PL causes PDAC cell death through oxidative stress and complements the therapeutic efficacy of chemotherapeutic agents in PDAC cells. First, we determined that PL is one of the most abundant alkaloids with antitumor properties in the long pepper plant. We also showed PL in combination with gemcitabine, a chemotherapy agent used to treat advanced pancreatic cancer, reduced tumor weight and volume compared to vehicle-control and individual treatments. Further, biochemical analysis, including RNA sequencing and immunohistochemistry, suggested that the antitumor activity of PL was associated with decreased cell proliferation, induction of cell cycle arrest, and oxidative stress-induced cell death. Moreover, we identified that c-Jun N-terminal kinase (JNK) inhibition blocks PL-induced cell death, translocation of Nrf2, and transcriptional activation of HMOX1 in PDAC. Finally, high-throughput drug and CRISPR screenings identified potential targets that could be used in combination with PL to treat PDAC cells. Collectively, our data suggests that cell cycle regulators in combination with PL might be an effective approach to combat pancreatic cancer. / NIH

The thioredoxin system is the major cellular reductant system present in the cell, whose role is to maintain cellular redox homeostasis. It does this in part, by regulating the activity of many other enzymes including ribonucleotide reductase, which is essential for DNA synthesis. It also acts as an antioxidant, reducing destructive reactive oxygen species. The thioredoxin system is comprised of thioredoxin (Trx) which reduces target protein disulfide bridges by thiol-disulfide exchange and thioredoxin reductase (TrxR) which reduces Trx back to its active state. Thioredoxin reductase is a common target for many cancer drugs including cisplatin and auranofin. Recently we have shown that the Florida red tide toxin, brevetoxin-2 (PbTx-2) can inhibit mammalian TrxR1. Brevetoxin-2 has α, β-unsaturated aldehyde moiety that was proposed to inhibit the enzyme by forming a Michael adduct. Several compounds which are similar to brevetoxin in size and functionality have a similar effect on TrxR. These compounds include antitumor and antibiotics such as manumycin A, geldanamycin, rifamycin SV and thiostrepton and toxins such as brevetoxin-3, nodularin and microcystin-LR. Manumycin A behaves as a typical TrxR1 inhibitor while other compounds screened activate the reduction of small disulfides such as DTNB (5,5’-dithiobis-(2-nitrobenzoic acid)). Mammalian thioredoxin reductase is a homodimer with two redox center viz. N-terminal dithiol buried in the enzyme and C-terminal selenosulfide located on the flexible C-terminal tail. Modification of the C-terminal tail of TrxR by these test compounds can expose N-terminal redox thiol that could reduce DTNB. The C-terminal Sec, a nucleophile can form a Michael adduct with α, β-unsaturated carbonyl moiety of test compounds. Together with point-specific mutant enzymes (C-terminal tail truncated, dead tail and Cys mutant) and enzyme assays that are specific/dependent on C-terminal Sec were used to decipher the site-specific interaction between these test compounds and TrxR. Inhibition of TrxR at the C-terminal redox center produces a pro-oxidant known as SecTRAP (Selenium Compromised Thioredoxin Reductase-derived Apoptotic Proteins), which uses NADPH to produce superoxide radical anion as observed with manumycin A. Since many cancer drugs target TrxR the present study has the potential to discover new cancer drugs.

Doctor Educationis / Maize (Zea mays L.) is grown globally as an important grain crop in South Africa, United States, China and Brazil and plays a major role in the worldwide economy. In South Africa, the grain is utilised for food consumption, livestock feed, for malting purposes and bioethanol production. Maize contains approximately 72% starch, 10% protein, 4% fat and supplying an energy density of 365 Kcal/100 g. The production of grain crops in South Africa is restricted by various factors such as abiotic and biotic stresses. The fungal genus Aspergillus is one of the most important biotic stresses affecting maize in the country. Aspergillus flavus can contaminate a wide range of agricultural commodities either in storage or field. Hydrogen sulfide appears to have a potential in the mechanism of resistance against pathogen attack by Aspergillus flavus. / 2023

>Magister Scientiae - MSc / Agricultural practices are significantly affected by drought. Drought is one of the most important plant stresses, causing several physiological, morphological, biochemical, and molecular changes in plants. Drought stress is of great challenge for crop growth, development and yield. Zea mays (maize) is one of the important crops worldwide due to the nutritional profile and other uses such as human consumption, manufacturing and animal feed. Under unfavorable conditions, plants produce high amounts of reactive oxygen species (ROS). Excessive formation of ROS is harmful for plant survival and can induce cell death. Defense mechanisms activated in response to drought in plants include antioxidant enzyme activity and proline accumulation. There is evidence of the use of nitric oxide (NO) donors and hydrogen peroxide (H2O2) at low concentrations to enhance the activity of antioxidant enzymes in stressed plants. Hence, the aim of the study is to examine the role of NO and H2O2 in regulation of antioxidant enzyme activity in maize subjected to water deficit. / 2023

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19751号 / 工博第4206号 / 新制||工||1649(附属図書館) / 32787 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 森 泰生, 教授 濵地 格, 教授 跡見 晴幸 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

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