Docosahexaenoic acid (DHA, 22:6n-3) from fish oil, and butyrate, a short-chain fatty acid fiber-fermentation product, protect against colon tumorigenesis in part by coordinately inducing apoptosis. We have demonstrated that the combination of these two bioactive compounds demonstrates an enhanced ability to induce colonocyte apoptosis by potentiating mitochondrial lipid oxidation. In order to explore the potential involvement of intracellular Ca2+ in the pro-apoptotic effect of DHA and butyrate, young adult mouse colonocytes (YAMC) and human colonocytes (HCT-116: p53+/+ and p53- /-) were treated with DHA or linoleic acid (LA) for 72 h ± butyrate for the final 6, 12 or 24 h. Cytosolic and mitochondrial Ca2+ levels were measured using Fluo-4 and Rhod-2. In addition, IP3 pool, store-operated channel (SOC)-mediated changes and apoptosis were measured. DHA did not alter basal Ca2+ or apoptosis following 6 h butyrate cotreatment. In contrast, at 12 and 24 h, DHA and butyrate treated cultures exhibited a decrease in cytosolic Ca2+ and enhanced apoptosis compared to LA and butyrate. DHA and butyrate also increased the mitochondrial-to-cytosolic Ca2+ ratio at 6, 12 and 24 h. The accumulation of mitochondrial Ca2+ preceded the onset of apoptosis which increased only following 12 h of butyrate co-treatment. RU-360, a mitochondrial uniporter inhibitor, abrogated mitochondrial Ca2+ accumulation and also partially blocked apoptosis in DHA and butyrate co-treated cells. p53+/+ and p53-/- cells demonstrated similar data with respect to all parameters. Additionally, mitochondrial Ca2+ measurements were also made in rat primarycolonocyte- culture. Rats were fed semipurified diets containing either fish oil (a source of DHA) or corn oil (a source of LA), and colonic crypts were incubated in butyrate exvivo and mitochondrial Ca2+ was quantified. Crypts from rats fed fish oil incubated in butyrate exhibited an increase in the mitochondrial-to-cytosolic Ca2+ ratio compared to fish oil only. In summary, our results indicate for the first time that the combination of DHA and butyrate, compared to butyrate alone, further enhances apoptosis by additionally recruiting a p53-independent Ca2+-mediated intrinsic mitochondrial pathway. These data explain in part why fermentable fiber when combined with fish oil exhibits an enhanced ability to induce apoptosis and protect against colon tumorigenesis.

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Thesis (M.S.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains viii, 95 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Thesis (M.S.)--Marshall University, 2004. / Title from document title page. Document formatted into pages; contains vi, 45 p. Includes abstract. Includes bibliographical references (p. 42-45).

Thesis (MS)--Montana State University--Bozeman, 2010. / Typescript. Chairperson, Graduate Committee: Patrick G. Hatfield. Includes bibliographical references (leaves 41-48).

Several studies have shown that dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) are beneficial in neurodegenerative diseases, although the mechanism of action is not agreed upon. Because most neurodegenerative diseases have an inflammatory component, it is possible that docosahexaenoic acid (DHA) is anti-inflammatory in the brain as it is known to be in several non-neural tissues. Specialized pro-resolving mediators (SPM) are metabolized from DHA and are leading candidates to explain the anti-inflammatory effects of DHA. The goal of this work was to investigate the role and potential mechanisms of action of DHA in neuroinflammation. In our first approach, fat-1 transgenic mice had higher phospholipid and unesterified DHA levels in their hippocampi, and attenuated lipopolysaccharide (LPS)-induced neuroinflammation, compared to wildtype littermates. Feeding wildtype littermates n-3 PUFA mimicked hippocampal DHA levels and LPS-induced neuroinflammatory responses of fat-1 mice, indicating DHA is anti-neuroinflammatory whether derived from the diet or the activity of the fat-1 protein. In an attempt to further augment hippocampal DHA levels, feeding n-3 PUFA adequate mice an n-3 PUFA diet increased phospholipid but not unesterified DHA levels, and did not attenuate LPS-induced neuroinflammation, highlighting the potential importance of unesterified DHA. Directly infusing unesterified DHA into a cerebral ventricle throughout LPS-induced neuroinflammation mimicked several aspects of the attenuated neuroinflammatory response seen with our chronic dietary and transgenic models, as did infusing its 17S-hydroperoxy-DHA (17S-HpDHA) derivative, a precursor to SPM. The metabolism of DHA to SPM in the brain was found to be distinct from non-neural tissues, characterized by the presence of protectin D1 and maresin 1, and the absence of resolvin D1 or D2. Further, infusing 17S-HpDHA increased protectin D1 concurrent to attenuating neuroinflammation, suggesting protectin D1 is responsible for some of the anti-neuroinflammatory effects of DHA. In conclusion, DHA is anti-neuroinflammatory in a mouse model of neuroinflammation, in part, via its metabolism to SPM.

Several studies have shown that dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) are beneficial in neurodegenerative diseases, although the mechanism of action is not agreed upon. Because most neurodegenerative diseases have an inflammatory component, it is possible that docosahexaenoic acid (DHA) is anti-inflammatory in the brain as it is known to be in several non-neural tissues. Specialized pro-resolving mediators (SPM) are metabolized from DHA and are leading candidates to explain the anti-inflammatory effects of DHA. The goal of this work was to investigate the role and potential mechanisms of action of DHA in neuroinflammation. In our first approach, fat-1 transgenic mice had higher phospholipid and unesterified DHA levels in their hippocampi, and attenuated lipopolysaccharide (LPS)-induced neuroinflammation, compared to wildtype littermates. Feeding wildtype littermates n-3 PUFA mimicked hippocampal DHA levels and LPS-induced neuroinflammatory responses of fat-1 mice, indicating DHA is anti-neuroinflammatory whether derived from the diet or the activity of the fat-1 protein. In an attempt to further augment hippocampal DHA levels, feeding n-3 PUFA adequate mice an n-3 PUFA diet increased phospholipid but not unesterified DHA levels, and did not attenuate LPS-induced neuroinflammation, highlighting the potential importance of unesterified DHA. Directly infusing unesterified DHA into a cerebral ventricle throughout LPS-induced neuroinflammation mimicked several aspects of the attenuated neuroinflammatory response seen with our chronic dietary and transgenic models, as did infusing its 17S-hydroperoxy-DHA (17S-HpDHA) derivative, a precursor to SPM. The metabolism of DHA to SPM in the brain was found to be distinct from non-neural tissues, characterized by the presence of protectin D1 and maresin 1, and the absence of resolvin D1 or D2. Further, infusing 17S-HpDHA increased protectin D1 concurrent to attenuating neuroinflammation, suggesting protectin D1 is responsible for some of the anti-neuroinflammatory effects of DHA. In conclusion, DHA is anti-neuroinflammatory in a mouse model of neuroinflammation, in part, via its metabolism to SPM.

Thesis (Ph.D.) -- Flinders University, School of Medicine, Dept. of Paediatrics and Child Health. / Typescript (bound). Includes bibliographical references (leaves 186-203). Also available online.

As much as 10% of the US population will experience at least one bout of depression within their lifetime. It has been reported that an increased time spent with major depressive disorder (MDD) results in a decreased volume in the hippocampus. This decreased volume is the result of apoptosis, or programmed cell death. In recent years it has become known that new neurons (neurogenesis) are continuously born in the hippocampus of humans. In fact, it now appears that antidepressant drug efficacy may be dependent on adult neurogenesis in the hippocampus. At least six epidemiological studies have shown an inverse correlation between seafood intake and prevalence of mood disorders (p [less than]0.05 or better). There is mounting evidence that this result is due to fish oils containing the long-chain, poly-unsaturated, omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Although extensive study has been undertaken using both of these omega-3s together, very little has been done to determine which fatty acid has the greater effect. Although previously thought to be readily interconvertible, there is mounting evidence that these two lipids are not treated equally in the body. EPA has produced greater cell proliferation over DHA in the B-lymphocyte cells, and DHA has even been known to cause a decrease at higher concentrations. Differences have also been reported in both molecular and behavioral outcomes. This research tested the hypothesis that EPA facilitates proliferation and survival of neuronal precursor cells to a greater extent than does DHA. Human neuronal precursor cells were grown in the presence of EPA, DHA, and varying ratios of EPA and DHA to determine their dose-response relationships. While there were no large effects on proliferation or differentiation, EPA, but not DHA, protected cells from iron-induced oxidative stress. This protection appears to be, at least in part, the result of altered p53 translocation in EPA-treated cells. Future work will be needed to determine the role of this molecular protection in the antidepressant activity of EPA. / A Dissertation submitted to the Department of Nutrition, Food and Exercise Sciences in partial fulfillment of the requirements for the degree of Master of Science. / July 16, 2009. / Includes bibliographical references. / Cathy Levenson, Professor Directing Theis; Jodee Dorsey, Committee Member; Michael Meredith, Committee Member.

Introduction: One potential new therapy for epilepsy involves the omega-3 polyunsaturated fatty acids (PUFAs), and more specifically docosahexaenoic acid (DHA).   Methods: The anticonvulsant properties of the n-3 PUFAs were assessed in a series of different experiments. Subjects received chronic dietary supplementation, sub-chronic and acute injections of either fish oil (chronic) or DHA (sub-chronic, acute). Animals were tested in the electrical afterdischarge thresholds (ADTs) model in the amygdale and the maximal pentylenetetrazol (PTZ) model.   Results: Chronic, sub-chronic, and acute administrations of n-3 PUFAs were anticonvulsant in both the electrical stimulation and maximal PTZ models. In chronic experiments, amygala ADTs increased following 3 months of fish oil administration. Fourteen days of DHA i.p. injections increased latencies to maximal PTZ seizures. Acute injection of DHA s.c. and i.v. increased unesterified serum DHA and seizure latency. Conclusions: The present research suggests that n-3 PUFAs, and more specifically DHA, have anticonvulsant effects in vivo.