Ferroptosis is a recently characterized cell death pathway associated with the iron-dependent accumulation of lipid hydroperoxides in phospholipid bilayers. The origin of these hydroperoxides has been an ongoing topic of debate and many researchers argue for a lipoxygenase (LOX) enzyme-controlled mechanism of initiation, given their known role as dioxygenases of polyunsaturated fatty acids (PUFAs). In response to this, our lab investigated the induction and inhibition of ferroptosis in human embryonic kidney (HEK-293) cells transfected to overexpress the three most prevalent LOX isoforms, 5-LOX, p12-LOX, and 15-LOX-1. These studies did not support a role for LOX in the execution of ferroptosis; LOX inhibition was not associated with ferroptosis suppression and in fact, anti-ferroptotic activity was directly tied to purported LOX inhibitors’ ability to act as radical-trapping antioxidants (RTAs). We have investigated the effects of LOX inhibitors on ferroptosis in human fibrosarcoma (HT-1080) cells, the cell line in which ferroptosis was initially characterized, and mouse hippocampal neuronal (HT-22) cells, the cell line in which the closely related cell death modality oxytosis was characterized. In sum, our findings mirror those obtained in HEK-293 cells, and the effectiveness of an inhibitor is tied to its off-target RTA activity, not inhibition of LOX. Moreover, we observed suppression of ferroptosis via necrostatin-1 (Nec-1), a known receptor-interacting serine/threonine-protein kinase 1 (RIPK1) (and necroptosis) inhibitor. Herein, we show that Nec-1 is not an RTA and exerts its effects by a yet unknown mechanism which we investigate in a series of exploratory experiments. Conjugated fatty acids – particularly α-ESA – have recently been reported to induce ferroptosis by an unclear mechanism. Theorizing this phenomenon was tied to the autoxidation of α-ESA’s conjugated trienic unit, we aimed to investigate the kinetic and biological properties of natural α-ESA alongside a deuterated isotopologue. Herein, we report preliminary work to derive biologically relevant rate constants for addition and hydrogen-atom transfer (HAT) of α-ESA. Moreover, we report our progress towards the synthesis of a deuterated α-ESA which will facilitate future study alongside its natural counterpart.

The aim of this research was to investigate the phytochemistry of two species Sanicula europaea and Teucrium davaeanum which are traditionally used in treatment of wounds. Four compounds were isolated from the 80% methanolic extract of S. europaea; bis-(2-ethylhexyl) phthalate (1), palmitic acid (2), rosmarinic acid (3), saniculoside N (4). Compounds 1 and 2 were isolated for the first time from this species. The structure elucidation of the isolated compounds was on the basis of 1D, 2D NMR spectroscopy and mass spectrometry measurements. Two compounds were isolated from the crude glycosides extract of T.davaeanum; 6 is a phenylethanoid glycoside and 8 is an iridoid glycoside, from the data available these may be new compounds for which the names davaeanuside A and davaeanuside B are proposed respectively." The total polyphenol content of S. europaea L, T. davaeanum leaves-flowers and T. davaeanum stem were found to be 5.0, 1.20 and 0.65 mg per 100 mg dried plant material respectively. A study of the antioxidant activity of the 50 % ethanol extracts of S. europaea and T. davaeanum showed that on a mg/mg basis S. europaea and T. davaeanum have approximately 5%, 8 % antioxidant capacity of Trolox respectively. A study of the cytotoxic activity of davaeanuside A (6), iridoid glycoside (7), davaeanuside B (8) and saponin compound (10) isolated from the crude glycosides extract of T. davaeanum revealed that saponin compound (10) inhibited the growth of Hela cells by 50 % at 50 μg/ml, P< 0.001, but the other compounds did not show activities against the tested cell lines at 100 μg/ml. The results of this work provide some basis for the traditional use of these species in the treatment of wounds. / Ministry of high education in Libya

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Isoflavones have antioxidant activities in vivo, however, their antioxidative potential against oxidative stress initiated by exercise was not explored. The first study investigated the effect of high-genistin isoflavone (HGI) supplementation on erythrocyte antioxidant enzymes and tissues' thiobarbituric reactive substances (TBARS) in acutely exercised one-year old rats. All tissue genistein concentrations increased after exercise. Ingestion of HGI seemingly enhanced running time to exhaustion, and maintained glutathione peroxidase (GPx) and catalase (CAT) activities decreased due to exercise. The second study investigated the dose effect of HGI supplementation. Genistein concentrations were significantly higher (P<0.05) in tissues of rats fed the 1045 PPM HGI diet than in rats fed 522 or 209 PPM HGI diets and increased the glutathione (GSH)/total glutathione (TGSH) ratio (P<0.03). Reductions of the in vivo MDA concentrations (P<0.05) were observed only in the plasma of rats fed 522 and 1045 PPM HGI diets compared to those fed 0 PPM (-1.08, -0.82, and 0.03 mM, respectively). Therefore, isoflavones at 522-1045 PPM HGI diet have antioxidative effects in rats. The last two studies investigated the effect of isoflavone supplementation on the modulation of erythrocyte antioxidant enzyme activities, glutathione homeostasis, and other oxidative biomolecules in healthy young men undergoing 80%VO2pk exercise. In Study 3 exercise at 80%VO2pk increased oxidative stress which was best demonstrated by increased superoxide dismutase (SOD) activity (16.5%), GSH/TGSH ratio, in vivo MDA (12.6%), plasma uric acid (4.9%) and ferric reducing/antioxidant ability (FRAP) ( 7.8%). Therefore, 30 minutes 80% VO2pk exercise induced oxidative stress in moderately active college men. In study 4, four-week HGI supplementation produced plasma genistein and daidzein concentrations of 499 and 415 ng/ml, which were significantly increased to 633 and 539 ng/ml by exercise (P=0.04 and P=0.05). Isoflavones significantly decreased in vivo pre-exercise plasma MDA (P<0.05), increased pre-exercise blood TGSH (P=0.01) and pre-exercise erythrocyte SOD activity (P=0.0006), and maintained the decreased activities of GPx due to exercise at pre-exercise levels. Results demonstrated that isoflavones had antioxidant activity in vivo under normal physiological conditions in healthy young men. They also maintaining GPx activity which was decreased due to exercise, however, isoflavones may not overcome all oxidative stress initiated by intense exercise. / Ph. D.

Capparis spinosa is a wild and cultivated bush, which grows mainly in the Mediterranean Basin. Unopened flower buds, called capers are used in the Mediterranean cuisine as flavoring for meat, vegetable and other foods. Several studies evaluated bioactive component and antioxidant activity of Capparis spinosa, increasing the market demand and the economic importance of capers. The aim of this work was to evaluate the contents of bioactive compounds in floral buds fermented in salt of C. spinosa collected from different areas of Pantelleria Island (Italy), testing the effect on healthy function as total antioxidant compounds. Hydrophilic extracts of C. spinosa from Pantelleria Island were characterized by high-performance liquid chromatography-electrospray ionization/mass spectrometry. Among 24 compounds were detected and quantified by HPLC-MS technique: several Kaempherol and Quercetin derivate were characterized, based on UV spectra and MSn fragmentation pattern. The antioxidative activity of caper hydrophilic extracts was assessed in a number of chemical assays (ORAC, DPPH and ABTS). In order to determine the genetic diversity within and among populations of Capparis spinosa from Pantelleria Island, AFLPs (Amplified Fragment Length Polymorphism) markers were employed. Moreover, in the present study, a commercial model of an Electronic Nose (EN), EOS835 (Sacmi), was preliminarily used to investigate the flavor profile of capers. The EN technique was comparated with a classical techniques gas chromatography-mass spectrometry (GC-MS) analysis, using Head Space Solid-Phase Microextraction (HS-SPME) as a solvent-free sample preparation method. / Capparis spinosa es un arbusto silvestre y cultivado, que crece principalmente en la cuenca mediterránea. Cuando los botones de las flores aún no están abiertas reciben el nombre de alcaparras y se utilizan en la alimentación. Varios estudios han demostrado la presencia de un número de componentes bioactivos in C. spinosa y su actividad antioxidante, lo que ha provocado un aumento de su demanda y ha incrementado la importancia económica de las alcaparras. El propósito de este trabajo fue evaluar el contenido de compuestos bioactivos en el capullo de la flor de C. spinosa conservado en salmuera, procedente de diferentes zonas de la isla de Pantelleria (Italia). Los resultados se expresan como actividad antioxidante total. La actividad antioxidante de los extractos hidrófilos de alcaparra se evaluó mediante pruebas químicas (ORAC, DPPH, ABTS). Con el fin de determinar la diversidad genética dentro y entre poblaciones de C. Spinosa, se utilizaron marcadores moleculares del tipo AFLP (Amplified Fragment Length Polymorphism). Los extractos hidrófilos de C. spinosa se caracterizaron mediante cromatografía líquida de alta eficacia - ionización electrospray acoplada a espectrometría de masas. Se han identificado y cuantificado aproximadamente 24 compuestos con la técnica de HPLC-MS, y se han caracterizado varios derivados de kaempferol y quercetina, sobre la base de los espectros UV y con el modelo de fragmentación MSn. En el este estudio también se ha utilizado un modelo de nariz electrónica comercial (ES), EOS835 (Sacmi), para un estudio preliminar del perfil de aroma de las alcaparras. La técnica ES se ha comparado con una técnica de análisis clásicos tales como la cromatografía de gases acoplada a espectrometría de masas (GC-MS), utilizando como método de preparación de la muestra el espacio de cabeza de microextracción en fase sólida (HS-SPME) libre de disolventes. / Capparis spinosa és un arbust silvestre i conreat, que creix principalment a la conca mediterrània. Quan els botons de les flors encara no estan obertes reben el nom de tàperes i s'utilitzen en l'alimentació. Diversos estudis han demostrat la presència d'un nombre de components bioactius in C. spinosa i la seva activitat antioxidant, el que ha provocat un augment de la seva demanda i ha incrementat la importància econòmica de les tàperes. El propòsit d'aquest treball va ser avaluar el contingut de compostos bioactius en el capoll de la flor de C. spinosa conservat en salmorra, procedent de diferents zones de l'illa de Pantelleria (Itàlia). Els resultats s'expressen com a activitat antioxidant total. L'activitat antioxidant dels extractes hidròfils de tàperes es va avaluar mitjançant proves químiques (ORAC, DPPH, ABTS). Per tal de determinar la diversitat genètica dins i entre poblacions de C. Spinosa, es van utilitzar marcadors moleculars del tipus AFLP (Amplified Fragment Length Polymorphism). Els extractes hidròfils de C. spinosa es van caracteritzar mitjançant cromatografia líquida d'alta eficàcia - ionització electrospray acoblada a espectrometria de masses. S'han identificat i quantificat aproximadament 24 compostos amb la tècnica d'HPLC-MS, i s'han caracteritzat diversos derivats de kaempferol i quercetina, sobre la base dels espectres UV i amb el model de fragmentació MSN. Al aquest estudi també s'ha utilitzat un model de nas electrònic comercial (ES), EOS835 (Sacmi), per a un estudi preliminar del perfil d'aroma de les tàperes. La tècnica ÉS s'ha acoblat amb una tècnica d'anàlisi clàssics com ara la cromatografia de gasos acoblada a espectrometria de masses (GC-MS), utilitzant com a mètode de preparació de la mostra l'espai de cap de microextracció en fase sòlida (HS-SPME ) lliure de dissolvents. / Lo Bosco, F. (2017). Evaluation of antioxidant properties and assessment of genetic diversity of Capparis spinosa cultivated in Pantelleria Island [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/79872

High feed ingredient prices have increased the use of by-products containing a high proportion of polyunsaturated fatty acids (PUFA) in pig and chicken feeds. This can increase the oxidation of other feed nutrients as well as causing oxidative stress in animals. Two studies were conducted to evaluate the effects of a dietary antioxidant blend (AOX, ethoxyquin and propyl gallate) in pigs and broiler chickens fed a diet high in oxidants. The objective of the first study was to evaluate the antioxidant blend on growth performance, meat quality, liver function, oxidative status, carcass characteristics, meat quality, and fatty acid profile in pigs. Crossbred barrows (n = 100, 10.91 ± 0.65 kg, 36 ± 2 d of age, Landrace × Duroc) were allotted to 5 treatments based on body weight (BW, 5 replicate pens per treatment, 4 pigs per pen). Treatments included: 1) HO: high oxidant diet containing 5% oxidized soy oil and 10% PUFA source (containing docosahexaenoic acid, DHA, 3.7% of diet); 2) VE: the HO diet with 11 IU/kg of added vitamin E; 3) AOX: the HO diet with AOX (135 mg/kg); 4) VE+AOX: the HO diet with both vitamin E and AOX; and 5) SC: a standard corn-soy control diet. The trial lasted for 118 d; on d 83, the HO diet pigs were switched to the SC diet because the animals were displaying very poor health. Compared with SC pigs, HO pigs had decreased average daily gain (ADG) and average daily feed intake (ADFI) from d 26 to 82 (P < 0.05). However, after switching the HO pigs to the SC diet, the VE treatment became the most stressed treatment with the poorest performance from d 83 to 118 (P < 0.05). The AOX restored pig performance to a level similar to pigs fed the SC diet (P > 0.05) with greater gain to feed ratio (G:F) for the entire period (P < 0.05). The AOX added treatments also attenuated the enlarged liver symptoms and reduced markers of liver stress including total bilirubin and aspartate transaminase, thiobarbituric acid reactive substances (TBARS) and carbonyl concentrations. In addition, the AOX addition in the high oxidant diet restored the lighter carcass weight, less back fat, less lean body mass and smaller loin eye area, decreased dressing percentage and intensive lipofuscin deposition induced by the high oxidant diet. However, the traits of loin muscle redness and belly firmness were not fully corrected by AOX. The second study was to investigate the antioxidant blend and vitamin E on growth performance, oxidative status, meat quality, fatty acid profile, liver function and inflammatory response in broiler chickens. Cobb 500 male broilers (n = 1200, 44.7 ± 0.8 g, d 0) were randomly distributed into 60 floor pens across 6 treatments with 10 replicate pens of 20 chicks each. Treatments included: 1) HO: high oxidant diet with vitamin E at 10 IU/kg, 3% oxidized oil, 3% PUFA source; 2) VE: the HO diet with vitamin E at 200 IU/kg; 3) AOX: the HO diet with AOX at 135 mg/kg, 4) VE+AOX: the HO diet with both vitamin E at 200 IU/kg and AOX at 135 mg/kg, 5) SC: standard control, a corn soy diet with vitamin E at 10 IU/kg, 3% non-oxidized soybean oil, no PUFA source, and 6) PC: positive control, the SC diet with AOX at 135 mg/kg. Compared to the SC birds, the PUFA added treatments (HO, VE, AOX, VE+AOX) groups had greater body weight, ADG and ADFI from d 0 through d 21 (P < 0.05). However, the growth of birds fed the VE treatment fell behind that of other treatments (P < 0.05) during the last 21 d of the trial. Compared to the HO birds, the AOX birds had lower TBARS and greater uric acid concentrations in the plasma, greater gene expression of superoxide dismutase and less drip loss, suggesting enhanced systematic antioxidant capability. In addition, dietary addition of AOX or AOX plus VE moderately improved liver function and reduced inflammation in fat tissue to a level similar to control groups. In both studies, the AOX supplement was effective in preserving PUFA, especially DHA deposition in the back fat of pigs and abdominal fat of chickens. These results suggest that feeding the high oxidant diet caused a series of changes in growth performance, liver function, oxidative status, carcass characteristics and meat quality in pigs, and AOX addition attenuated many of these. The supplementation of AOX also showed some effects on reducing oxidative stress in chickens. However, the effects were not as profound as the pig study. / Ph. D.