Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 222-247). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 222-247). Also available on the Internet.

Mitochondrial function declines with aging and obesity, and has been implicated in the development of many age-related diseases. Caloric restriction (CR) prevents aging and has been shown to induce mitochondrial biogenesis and improve mitochondrial function. These effects may involve increased activity of the \(NAD^+\)-dependent deacetylase SIRT1. Indeed, overexpression of SIRT1 reproduces many of the health benefits of CR including induction of mitochondrial biogenesis by deacetylation and activation of the transcriptional co-activator \(PGC-1\alpha\). Because mitochondria regulate cellular functions important for aging, including, cellular energy production, ROS generation, and apoptosis, determining why mitochondrial function declines with age will improve our understanding of the underlying forces that drive organismal aging. Resveratrol and other SIRT1 activators induce mitochondrial biogenesis and protect against metabolic decline, but whether SIRT1 mediates these benefits is still a matter of debate. To circumvent the developmental defects of germ-line SIRT1 knockouts, we have developed the first inducible system that permits whole-body deletion of SIRT1 in adult mice. Obese mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased \(NAD^+\) levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. Overexpression of SIRT1 in mice mimicked these effects, demonstrating that SIRT1 is sufficient and necessary for resveratrol to increase mitochondrial function in obese animals, and indicating a central role for SIRT1 in mediating the benefits of this molecule on muscle. Loss of SIRT1 or aging causes mitochondrial dysfunction and decreased expression of mitochondrial-encoded electron transport chain (ETC) components. This decrease in mitochondrial-encoded, but not nuclear-encoded ETC components in SIRT1 knockouts, which we have termed “genome asynchrony”, is independent of \(PGC-1\alpha\). Elevating \(NAD^+\) levels by treatment with the \(NAD^+\) precursor NMN prevented genome asynchrony and mitochondrial dysfunction in aged animals, similar to effects seen with CR. Together these data demonstrate that SIRT1 plays an essential role in preventing genome asynchrony, and that maintaining \(NAD^+\) levels and SIRT1 activity with age may prevent mitochondrial dysfunction. Since SIRT1 is required for NMN or resveratrol to improve mitochondrial function, compounds that activate SIRT1 or elevate \(NAD^+\) may help treat or prevent age-related diseases caused by mitochondrial dysfunction.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Thesis (doctoral)--Lund University, 1995. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1995. / Added t.p. with thesis statement inserted.

Thesis (Ph. D.)--State University of New York at Binghamton, Department of Biological Sciences, 2008.

Thesis (Ph.D.) - University of St Andrews, February 2010.

NAD+ has previously been shown to regulate TNF-α synthesis and TNF-α has been shown to regulate NAD+ homeostasis, thus providing a link between a pro-inflammatory response and redox status. Despite the well-established link between TNF-α and NAD+, the mechanism as to how NAD+ modulates TNF-α release is not fully understood. To achieve this, this link was investigated using THP-1 cell line-derived M1-like (pro-inflammatory) and M2-like (anti-inflammatory) macrophages using PMA and vitamin D3, respectively. NAD+ levels differed markedly between M1-like and M2-like macrophages, with M1-like having much higher basal levels. LPS increases NAD+ levels and TNF-α secretion in M1-like but not M2-like cells. In an effort to investigate the source of the NAD+ levels and the association with TNF-α release, three inhibitors (FK866, DPI and 1D-MT) were used. Following stimulation, NAD+ is produced partially via NADH oxidation and partially through NAD+ synthesis. Both DPI and FK866 reduced TNF-α secretion with DPI showing the largest effect. The two phenotypes showed differential profiles of NAD+ homeostasis gene expression compared with each other and with the progenitor THP-1 in both resting and activated states. While IDO expression was induced in both phenotypes, CD38 and NAMPT were upregulated in M1-like cells whereas CD157 was upregulated in M2-like cells. LPS induced M1-like cells to up-regulate CD38 and CD157 and down-regulate NAMPT unlike M2-like cells which up-regulated NAMPT and CD38 and down-regulated CD157. M1s increased glycolysis activity whereas conversely, decreased oxidative metabolism during LPS stimulation confirming previous findings showing that classical M1s are predominantly glycolytic. Collectively, these data suggest that the relationship between NAD+ levels and pro-/anti-inflammatory responses is complex and may be regulated via a combination of pathways. These findings open the possibility of pharmacological manipulation of NAD+ synthesis as a way of selectively modulating macrophage responses which may be beneficial for the development of therapeutics targeting inflammatory diseases.

This diploma thesis on "The situation of organic agriculture focusing on Žďársko" focuses on the current status of ecological farming in the selected region. The work is generally devoted to the history and development of ecological agriculture, its methods, legislation and regulation, environmental, agro-ecological and economic aspects. In the practical part the natural conditions are evaluated in district Žďár nad Sázavou. The selected organic farms are described further. The organic farms are approached by activities in animal and crop production and their economic situation. Nutrient balance were evaluated according to the data basic from choice organic farm as the indicator basic management agricultural enterprise.