New approaches and potential treatments for dry age-related macular degeneration

Emerging treatments for dry age-related macular degeneration (AMD) and geographi c atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS) formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.

Food lipids: their effects on quality and oxidative stability of animal tissues and emulsions

Lipolysis and oxidation of lipids in foods are the major biochemical and chemical processes that cause food quality deterioration, leading to the characteristic, unpalatable odour and flavour called rancidity. In addition to unpalatability, rancidity may give rise to toxic levels of certain compounds like aldehydes, hydroperoxides, epoxides and cholesterol oxidation products. In this PhD study chromatographic and spectroscopic techniques were employed to determine the degree of lipid oxidation in different animal products and its relationship with technological parameters like feeding fat sources, packaging, processing and storage conditions. To achieve this goal capillary gas chromatography (CGC) was employed not only to determine the fatty acids profile but also, after solid phase extraction, the amount of sterols (cholesterol and phytosterols) and cholesterol oxidation products (COPs). To determine hydroperoxides, primary products of oxidation and quantify secondary products UV/VIS absorbance spectroscopy was applied. Beef and pork meat in this study were analysed. In actual fact, lipid oxidation is a major deterioration reaction in meat, meat products and results in adverse changes in the colour, flavour, texture of meat and develops different compounds which should be a risk to human health as oxysterols. On beef and pork meat, a study of lipid fraction during storage was carried out to evaluate its shelf-life and some nutritional features life saturated/unsaturated fatty acids ratio and sterols content, in according to the interest that has been growing around functional food in the last years. The last part of this research was focused on the study of lipid oxidation in emulsions. In oil-in-water emulsions antioxidant activity of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) was evaluated. The rates of lipid oxidation of 1.0% stripped soybean oil-in-water emulsions with DOPC were followed by monitoring lipid hydroperoxide and hexanal as indicators of primary and secondary oxidation products and the droplet surface charge or zeta potential (ζ) of the emulsions with varying concentrations of DOPC were tested. This manuscript reports the main results obtained in the three activities briefly summarized as follows: 1. study on effects of feeding composition on the photoxidative stability of lipids from beef meat, evaluated during storage under commercial retail conditions; 2. evaluation of effects of diets and storage conditions on the oxidative stability of pork meat lipids; 3. study on oxidative behavior of DOPC in stripped soybean oil-in-water emulsions stabilized by nonionic surfactant.

Lipid quality and oxidative stability in food products from animal origin, as affected by breeding factor

Nowadays it is requested more investigations on alternative rearing systems that are able to improve poultry welfare and to warrant high-quality and safe meat products. This thesis work was focused on the evaluation of the oxidative stability of poultry meats, obtained with different rearing systems, diets (supplemented with bioactive compounds), and packaging conditions. The thesis work was divided into the following parts: - Evaluation of the effects of different rearing systems on the quality, fatty acid composition and oxidative stability of poultry thigh and breast meat belonging to different product categories (“rotisserie” and “cut-up” carcasses); - Evaluation of the effects of different rearing systems and packaging conditions on the shelf-life of poultry thigh meat stored at 4°C for 14 days, and the effects of feed supplementation with thymol (control diet and diet with 2 different concentration of thymol) and packaging conditions on lipid oxidation of poultry thigh meat shelf-life (stored at 4°C for 14 days). The oxidative stability of poultry meat was studied by means of the spectrophotometric determinations of peroxide value and thiobarbituric acid reactive substances. - Evaluation of anti-inflammatory effects of different flavonoids (thymol, luteolin, tangeretin, sulforaphane, polymethoxyflavones, curcumin derivates) to detect their biological activity in LPS-stimulated RAW 264.7 macrophage cells in vitro, in order to study more in depth their action mechanisms. It was evaluated the cell vitality (MTT assay), nitrite concentration and protein profile. The study was focused on the identification of potential dietary bioactive compounds in order to investigate their biological activity and possible synergic effects, and to develop new suitable strategies for long-term promotion of human health, in particular against cancer.

Einfluss von Resveratrol auf oxidative DNA-Schäden und Mutagenese in vivo

Oxidative DNA-Basenmodifikationen, wie 7,8-Dihydro-8-oxoguanin (8-oxoG), werden endogen in allen Zellen gebildet. Die beobachtbaren Spiegel ergeben sich aus dem Gleichgewicht zwischen der Bildung durch reaktive Sauerstoffspezies (ROS), sowie der gleichzeitigen Reparatur der DNA-Schäden. Durch ihr hohes mutagenes Potential, tragen oxidative DNA-Basenmodifikationen zur spontanen Mutationsrate bei. Der Ausfall wichtiger DNA-Reparaturmechanismen führt in Ogg1(-/-)Csb(-/-)-Knockout-Mäusen zu einem Anstieg von 8 oxoG und der spontanen Mutationsrate.rnIn dieser Arbeit sollte untersucht werden, ob die basalen Spiegel an oxidativen Basenmodifikationen und die spontanen Mutationsraten in vivo durch die orale Gabe von Resveratrol moduliert werden können. Resveratrol ist ein Pflanzeninhaltsstoff (u.a. aus Rotwein) mit einer Vielzahl von Wirkungen, der bereits in zahlreichen Studien ein chemopräventives Potential gezeigt hat und antioxidativ wirkt.rnAn verschiedenen Mausgenotypen wurden zum einen eine Kurzzeit-Behandlung (7 Tage mit 100 mg/kg per Gavage) und zum anderen eine Langzeit-Behandlung (3-9 Monate mit 0,04% ad libitum) mit Resveratrol durchgeführt. Die oxidativen DNA Schäden wurden in primären Maushepatozyten mit Hilfe einer modifizierten Alkalischen Elution, mit der bakteriellen Formamidopyrimidin-DNA Glykosylase als Sonde, bestimmt. Zur Analyse der Mutationsrate wurde der BigBlue® Mutationsassay mit anschließender Sequenzierung der Mutationen verwendet.rnDie Ergebnisse zeigen, dass die Kurzzeit- und die Langzeit-Behandlung mit Resveratrol die basalen Spiegel oxidativer DNA-Basenmodifikationen senken. Die Reduktion ist jeweils wesentlich ausgeprägter in den reparaturdefizienten Ogg1(-/-)Csb(-/-)-Mäusen zu erkennen. Auch die spontane Mutationsrate wird durch eine mehrmonatige Behandlung mit Resveratrol um ungefähr 20-30% reduziert.rnAnschließende mechanistische Untersuchungen zeigten, dass dieser Schutz wahrscheinlich auf einer Induktion der antioxidativen Schutzmechanismen begründet ist. So wurde gefunden, dass primäre Hepatozyten aus mit Resveratrol behandelten Mäusen wesentlich besser gegen exogen herbeigeführten oxidativen Stress geschützt sind, als Hepatozyten von unbehandelten Tieren. Ein weiterer Hinweis ist die Hochregulation der mRNA-Spiegel von verschiedenen antioxidativen Schutzenzymen, wie Superoxiddismutase 1 / 2, Hämoxygenase 1, Glutathionperoxidase 1, nach der Gabe von Resveratrol in Mäuselebern. Außerdem sind die oxidativen Markermutationen (GC->TA-Transversionen) stärker von der Reduktion der spontanen Mutationsrate betroffen, als andere Mutationen (z.B. GC->AT-Transitionen).rnDie Ergebnisse zeigen erstmalig, dass spontane Mutationen in vivo durch Fremdstoffe in der Nahrung reduziert werden können. Im Falle von Resveratrol wird diese Reduktion wahrscheinlich durch eine Stimulation der antioxidativen Schutzmechanismen ausgelöst.rn

In vivo and in vitro effects of antioxidant compounds and PPAR γ modulators on rainbow trout oxidative stress and lipid metabolism.

The aquafeed use of raw plant materials, as protein and lipid sources, has been considered and approved as a sustainable alternative to fish products (fish meal and oils) because the current trend to use high-lipid diets has been shown to induce undesirable increase in fat depots or further physiological alterations, such as induction of oxidative stress. In the aquaculture perspective, the addition of natural substances with antioxidant properties is an emerging strategy for protecting biological systems and foodstuffs from oxidative damage. Among natural substances, hydroxytyrosol (HT) and caffeic acid (CA) have attracted considerable attention as food antioxidant additives and modulators of physiological and molecular pathways involved in energy metabolism and adiposity. The aim of this study was to evaluate the effects of CA and HT on lipid metabolism and oxidative stress of rainbow trout (Oncorhynchus mykiss). In vitro results showed the potential anti-obesogenic effects of the compounds CA and HT on the adipose tissue of the rainbow trout. To support these data, in vitro assays performed (MTT, ORO, immunofluorescence) resulted in accordance among them; only results from proliferating cell nuclear antigen (PCNA) assay were not significant. In vivo results showed a possible anti-obesogenic effect of CA in liver and HT in adipose tissue. Regarding oxidative stress, we could hypothesize a possible anti-oxidant role of CA in liver.

Paracrine factors secreted by endothelial progenitor cells prevent oxidative stress-induced apoptosis of mature endothelial cells

Endothelial progenitor cells (EPC) play a fundamental role in tissue regeneration and vascular repair. Current research suggests that EPC are more resistant to oxidative stress as compared to differentiated endothelial cells. Here we hypothesized that EPC not only possess the ability to protect themselves against oxidative stress but also confer this protection upon differentiated endothelial cells by release of paracrine factors. To test this hypothesis, HUVEC incubated with conditioned medium obtained from early EPC cultures (EPC-CM) were exposed to H2O2 to assess the accumulation of intracellular ROS, extent of apoptosis and endothelial cell functionality. Under oxidative stress conditions HUVEC treated with EPC-CM exhibited substantially lower levels of intracellular oxidative stress (0.2+/-0.02 vs. 0.4+/-0.03 relative fluorescence units, p<0.05) compared to control medium. Moreover, the incubation with EPC-CM elevated the expression level of antioxidant enzymes in HUVEC (catalase: 2.6+/-0.4; copper/zinc superoxide dismutase (Cu/ZnSOD): 1.6+/-0.1; manganese superoxide dismutase (MnSOD): 1.4+/-0.1-fold increase compared to control, all p<0.05). Furthermore, EPC-CM had the distinct potential to reverse the functional impairment of HUVEC as measured by their capability to form tubular structures in vitro. Finally, incubation of HUVEC with EPC-CM resulted in a significant reduction of apoptosis (0.34+/-0.01 vs. 1.52+/-0.12 relative fluorescence units, p<0.01) accompanied by an increased expression ratio of the anti/pro-apoptotic factors Bcl-2/Bax to 2.9+/-0.7-fold (compared to control, p<0.05). Most importantly, neutralization of selected cytokines such as VEGF, HGF, IL-8 and MMP-9 did not significantly reverse the cyto-protective effect of EPC-CM (p>0.05), suggesting that soluble factors secreted by EPC, possibly via broad synergistic actions, exert strong cyto-protective properties on differentiated endothelium through modulation of intracellular antioxidant defensive mechanisms and pro-survival signals.

Embryonic exposure to corticosterone modifies the juvenile stress response, oxidative stress, and telomere length.

Early embryonic exposure to maternal glucocorticoids can broadly impact physiology and behaviour across phylogenetically diverse taxa. The transfer of maternal glucocorticoids to offspring may be an inevitable cost associated with poor environmental conditions, or serve as a maternal effect that alters offspring phenotype in preparation for a stressful environment. Regardless, maternal glucocorticoids are likely to have both costs and benefits that are paid and collected over different developmental time periods. We manipulated yolk corticosterone (cort) in domestic chickens (Gallus domesticus) to examine the potential impacts of embryonic exposure to maternal stress on the juvenile stress response and cellular ageing. Here, we report that juveniles exposed to experimentally increased cort in ovo had a protracted decline in cort during the recovery phase of the stress response. All birds, regardless of treatment group, shifted to oxidative stress during an acute stress response. In addition, embryonic exposure to cort resulted in higher levels of reactive oxygen metabolites and an over-representation of short telomeres compared with the control birds. In many species, individuals with higher levels of oxidative stress and shorter telomeres have the poorest survival prospects. Given this, long-term costs of glucocorticoid-induced phenotypes may include accelerated ageing and increased mortality.

Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" effect--a Chinese concept for a worldwide pandemic

Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.

Translocation and potential neurological effects of fine and ultrafine particles a critical update

ABSTRACT: Particulate air pollution has been associated with respiratory and cardiovascular disease. Evidence for cardiovascular and neurodegenerative effects of ambient particles was reviewed as part of a workshop. The purpose of this critical update is to summarize the evidence presented for the mechanisms involved in the translocation of particles from the lung to other organs and to highlight the potential of particles to cause neurodegenerative effects.Fine and ultrafine particles, after deposition on the surfactant film at the air-liquid interface, are displaced by surface forces exerted on them by surfactant film and may then interact with primary target cells upon this displacement. Ultrafine and fine particles can then penetrate through the different tissue compartments of the lungs and eventually reach the capillaries and circulating cells or constituents, e.g. erythrocytes. These particles are then translocated by the circulation to other organs including the liver, the spleen, the kidneys, the heart and the brain, where they may be deposited. It remains to be shown by which mechanisms ultrafine particles penetrate through pulmonary tissue and enter capillaries. In addition to translocation of ultrafine particles through the tissue, fine and coarse particles may be phagocytized by macrophages and dendritic cells which may carry the particles to lymph nodes in the lung or to those closely associated with the lungs. There is the potential for neurodegenerative consequence of particle entry to the brain. Histological evidence of neurodegeneration has been reported in both canine and human brains exposed to high ambient PM levels, suggesting the potential for neurotoxic consequences of PM-CNS entry. PM mediated damage may be caused by the oxidative stress pathway. Thus, oxidative stress due to nutrition, age, genetics among others may increase the susceptibility for neurodegenerative diseases. The relationship between PM exposure and CNS degeneration can also be detected under controlled experimental conditions. Transgenic mice (Apo E -/-), known to have high base line levels of oxidative stress, were exposed by inhalation to well characterized, concentrated ambient air pollution. Morphometric analysis of the CNS indicated unequivocally that the brain is a critical target for PM exposure and implicated oxidative stress as a predisposing factor that links PM exposure and susceptibility to neurodegeneration.Together, these data present evidence for potential translocation of ambient particles on organs distant from the lung and the neurodegenerative consequences of exposure to air pollutants.

DESIGN AND SYNTHESIS OF NOVEL SYNTHETIC ANTIOXIDANTS FOR THE TREATMENT OF OXIDATIVE STRESS RELATED DISEASES

Free radicals play an important role in many physiological processes that occur in the human body such as cellular defense responses to infectious agents and a variety of cellular signaling pathways. While at low concentrations free radicals are involved in many significant metabolic reactions, high levels of free radicals can have deleterious effects on biomolecules like proteins, lipids, and DNA. Many physiological disorders such as diabetes, ageing, neurodegenerative diseases, and ischemia-reperfusion (I/R) injury are associated with oxidative stress.1 In particular, the deleterious effects caused by I/R injury developed during organ transplantation, cardiac infarct, and stroke have become the main cause of death in the United States and Europe.1,2 In this context, we synthesized and characterized a series of novel indole-amino acid conjugates as potential antioxidants for I/R injury. The synthesis of indole-phenol conjugate compounds is also discussed. Phenolic derivatives such as caffeic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), resveratrol, and its analogues are known for their significant antioxidative properties. A series of resveratrol analogues have been designed and synthesized as potential antioxidants. The radical scavenging mechanisms for potential antioxidants and assays for the in vitro evaluation of antioxidant activities are also discussed.

Oxidative Damage on RNA Nucleobases

Oxidatively damaged RNA has recently gathered more attention and has been closely related to different neurodegenerative diseases. The principles of oxidative stress and its influence on nucleic acids are reported. In contrast to DNA oxidative lesions of RNA have been scarcely described in the literature so far. These known stable RNA base modifications which arise under oxidative stress are reviewed here with regard to their biophysical properties and their potential mutagenicity. Furthermore the possible mechanisms of how cells deal with oxidized RNA are discussed. Posttranscriptional RNA modifications and the oxidation of RNA as an early event in several neurodegenerative diseases are not in the scope of this review.

Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

BACKGROUND Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.

Evaluation of oxidative damage and renal distal tubule cell stress response following exposure to lindane

Lindane, or γ-hexachlorocyclohexane, is a chlorinated hydrocarbon pesticide that was banned from U.S. production in 1976, but until recently continued to be imported and applied for occupational and domestic purposes. Lindane is known to cause central nervous system (CNS), immune, cardiovascular, reproductive, liver, and kidney toxicity. The mechanism for which lindane interacts with the CNS has been elucidated, and involves antagonism of the γ-aminobutyric acid/benzodiazepine (GABAA/BZD) receptor. Antagonism of this receptor results in the inhibition of Cl- channel flux, with subsequent convulsions, seizures, and paralysis. This response makes lindane a desirable defense against arthropod pests in agriculture and the home. However, formulation and application of this compound can contribute to human toxicity. In conjunction with this exposure scenario, workers may be subject to both heat and physical stress that may increase their susceptibility to pesticide toxicity by altering their cellular stress response. The kidneys are responsible for maintaining osmotic homeostasis, and are exposed to agents that undergo urinary excretion. The mechanistic action of lindane on the kidneys is not well understood. Lindane, in other organ systems, has been shown to cause cellular damage by generation of free radicals and oxidative stress. Previous research in our laboratory has shown that lindane causes apoptosis in distal tubule cells, and delays renal stress response under hypertonic stress. Characterizing the mechanism of action of lindane under conditions of physiologic stress is necessary to understand the potential hazard cyclodiene pesticides and other organochlorine compounds pose to exposed individuals under baseline conditions, as well as under conditions of physiologic stress. We demonstrated that exposure to lindane results in oxidative damage and dysregulation of glutathione response in renal distal tubule (MDCK) cells. We showed that under conditions of hypertonic stress, lindane-induced oxidative stress resulted in early onset apoptosis and corresponding down-regulated expression of the anti-apoptotic protein, Bcl-xL. Thus, the interaction of lindane with renal peripheral benzodiazepine receptors (PBR) is associated with attenuation of cellular protective proteins, making the cell more susceptible to injury or death. ^

OXIDATIVE STRESS BASED STRATEGIES FOR ENHANCING THE EFFICACY OF HISTONE DEACETYLASE INHIBITORS (HDACi)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the earliest event observed starting at 12 h. Following this event, we observed increased levels of superoxide at 16 h, and ultimately caspase-3 activation. Pre-treatment with the antioxidant N-acetylcysteine (NAC) blocked ROS generation and reversed the loss of mitochondrial membrane potential for both combinations. Interestingly, DNA fragmentation and caspase-3 activity was only blocked by NAC in cells treated with vorinostat-adaphostin; but not with entinostat-adaphostin. These results suggest that different redox mechanisms are involved in the induction of ROS-mediated apoptosis. To further understand these events, we studied the role of the antioxidants glutathione (GSH) and thioredoxin (Trx). We found that the combination of entinostat-adaphostin induced acetylation of the antioxidant thioredoxin (Trx) and decreased intracellular levels of GSH. However, no effect on Trx activity was observed in either combination. In addition, pre-treatment with GSH ethyl ester, a soluble form of GSH, did not block DNA fragmentation. Together these results suggested that GSH and Trx are not major players in the induction of oxidative stress. Array data examining the expression of genes involved in oxidative stress demonstrated a differential regulation between cells treated with vorinostat-adaphostin and entinostat-adaphostin. Some of the genes differentially expressed between the combinations include aldehyde oxidase 1, glutathione peroxidase-5, -6, peroxiredoxin 6 and myeloperoxidase. Taken together, these experimental results indicate that the synergistic activity of two different HDACi with adaphostin is mediated by distinct redox mechanisms in ALL cells. Understanding the mechanism involved in these combinations will advance scientific knowledge of how the action of HDACi could be augmented in leukemia models. Moreover, this information could be used for the development of effective clinical trials combining HDACi with other anticancer agents.

The distribution of sulfur in oceanic crust with respect to oxidative diagenesis (Table 1)

A detailed geochemical-petrological examination of layer 2 basalts recovered during Leg 37 of the DSDP has revealed that the original distribution, form and abundance of igneous sulfide have been profoundly altered during low-grade oxidative diagenesis. The net result appears to have been a rather pervasive remobilization of igneous sulfide to form secondary pyrite accompanied by a bulk loss of sulfur equivalent to about 50-60% of the original igneous value, assuming initial saturation. It is suggested that during infiltration of seawater into the massive crystalline rock, igneous sulfide has experienced pervasive oxidation, under conditions of limited oxidation potential, to form a series of unstable, soluble sulfur species, primarily in the form of SO3[2-] and S2O3[2-]. Spontaneous decomposition of these intermediate compounds through disproportionation has resulted in partial reconstitution of the sulfur as secondary pyrite and the generation of SO4[2-] ion, which, due to its kinetic stability, has been lost from the basalt system and ultimately transferred to the ocean. This model not only satisfies the geochemical and petrological observations but also provides a suitable explanation for the highly variable delta34S values which characterize secondary sulfides in deep ocean floor basalts.