Sepsis is a life threatening progression of a trauma or pathogen initiated systemic inflammatory response. Current treatment is supportive and depends mainly on antibiotics, fluids, and the careful administration of oxygen therapy. As sepsis progresses, it becomes a dysregulated inflammatory response, characterised by oxidative stress and excessive production of inflammatory cytokines, mitochondrial dysfunction and loss of antioxidant protection. Previous work on cells and animals has shown that novel antioxidants targeted to mitochondria may have a beneficial effect. To induce an inflammatory response and mitochondrial dysfunction, a human umbilical vein endothelial cell (HUVEC) in vitro mixed sepsis model with 0.2 μg/ml lipopolysaccharide (LPS) plus 20 μg/ml peptidoglycan (PepG) was used in the presence of a mitochondrially targeted vitamin E derivative, MitoVit E, and compared to the non-targeted vitamin E forms, Trolox and DL α-tocopherol acetate. Gene expression analysis was performed by quantitative polymerase chain reaction (qPCR) of the Toll-like receptor (TLR) 2 and 4 pathways from cells treated with the antioxidant +/- LPS/PepG for 4 h. Results showed that MitoVit E differentially regulated 11 genes compared to just four genes for the non-targeted forms of vitamin E. MitoVit E, Trolox and vitamin E were able to blunt IL-6 and IL-8 cytokine response in a dose-dependent manner. Inhibition of NFĸB gene and accessory protein expression was different for each antioxidant investigated along with effects on other inflammatory signalling proteins STAT 3 and MyD88. In addition, the antioxidants regulated radical production to similar extents, but had different effects on the reduced glutathione/oxidised glutathione, mitochondrial metabolic activity, mitochondrial membrane potential, oxygen consumption and mitochondrial number. In conclusion, MitoVit E showed encouraging effects in preventing dysregulation of the inflammatory response, maintaining mitochondrial membrane potential and radical production and normal cell function.

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Obesity is considered an underlying risk factor for metabolic disease including cardiovascular disease (CVD) and diabetes. The fractions containing flavonols from apple peel were evaluated for their antioxidant, anti-inflammatory, and hypolipidemic properties using in vitro and in vivo experimental model systems. The fractionated polyphenolics from apple peels showed a strong antioxidant property protecting against heat-induced oxidation of polyunsaturated fatty acids present in fish oil. Apple flavonols (AF), eicosapentaenoic acid (EPA) and the isoquercitrin-EPA ester (QE) significantly reduced serum triacylglycerols and elevated the high density lipoprotein (HDL)-cholesterol compared to the high fat control group. C-reactive protein and interleukin-6 were also reduced compared to the high fat control group and inflammation induced by lipopolysaccharides. Serum adiponectin and interferon-? concentrations were significantly altered by QE treatment. Overall, AF and QE exhibited anti-inflammatory and hypolipidemic effects under in vivo conditions. These beneficial physiological properties and mode of action of AF and QE need to be further investigated.

Although considered as a poison for long time, the importance of selenium as an essential trace element is now well recognized. In proteins, the redox active selenium moiety is incorportated as selenocysteine (Sec), the 21st amino acid. In mammals, selenium exerts its redox activities through several selenocysteine-containing enzymes, which include glutathione peroxidase (GPx), iodothyronine deiodinase (ID) and thioredoxin reductase (TrxR). Although these enzymes have Sec in their active sites, they catalyze completely different reactions and their substrate specificity and cofactor or co-substrate systems are significantly different. The most widely studied selenoenzyme GPx protects various organisms from oxidative stresses by catalyzing the reduction of hydroperoxides by using glutathione (GSH) as cofactor. The chemical aspects of the reduction of hydroperoxide by GPx have been extensively studied with the help of synthetic selenium and tellurium compounds. For example, 2-phenyl, 1, 2-benzoisoselenazol-3(2H)-one, commonly known as ebselen exhibits significant GPx activity by using GSH as cofactor. The anti-inflammatory, antiatherosclerotic and cytoprotective properties of ebselen have led to the design and synthesis of nex GPx mimics for potential therapeutic applications. In the first chapter, the importance of selenium in biochemistry in general and the function of selenoenzyme GPx and its synthetic mimics in particular are discussed. In the second chapter, the importance of ebselen as a GPx mimic and how thiol exchange reaction in the selenenyl sulfide intermediate deactivates its catalytic cycle and the possible ways to overcome thiol exchange reaction are described. The third chapter deals with the first synthetic chemical model that effectively mimics the unusual cyclization of sulfenic acid to a sulfenyl amide in protein Tyrosien Phosphatase 1B(PTP1B). PTP1B is a cysteine containing enzyme where the sulfenic acid (PTP1B-SOH) intermediate produced in response to its oxidation by H2O2 is rapidly converted into a sulfenyl amide species, in which sulfur atom of the catalytic cysteine is covalently bonded to the main chain nitrogen of an adjacent serine residue. This unusual protein modification in PTP1B has been proposed to protect the sulfur centre from irreversible oxidation to sulfinic acid and and sulfonic acids. In the fourth chapter, it is shown that not only the catalytic efficiency of ebselen but also its phosphatase like behavior is important for its antioxidant activity. Ebselen is regenerated from selenenic acid (R-SeOH) under a verity of conditions, which protects its selenium centre from irreversible oxidation and thus reduces its toxicity. The fifth chapter deals with spirodizaselenurane and Spirodiazatellurane. Although the chemistry of spirodioxyselenuranes and spirodiazasulfuranes has been studied extensively due to their interesting structural and stereochemical properties, there is no example of stable spirodiazaselenurane and its tellurium analogues. In the fifth chapter, the synthesis, structure and GPx-like activity of the spirodizzaselenurane and spirodiazatellurane are discussed. In summary, the synthetic sulfenic acids and seleneric acids undergo cyclization to their corresponding sulfenyl amides and selenenyl amides and thus protect their sulfur and selenium centers from irreversible inactivation. We have also observed that selenoxides and telluroxides with nearby amide moieties undergo cyclization to their corresponding cyclic spiro compounds. This unusual transformation of sulfenic acids has been recently discovered in PTP1B. As the redox regulation cycle of PTP1B and the catalytic cycle of GPx are similar we believe that GPx may involve a selenenyl amide intermediate in its catalytic cycle.