The Role of Oxidative Stress and Antioxidants in Liver Diseases

published_or_final_versio

Hepatic Mitochondrial Alterations and Increased Oxidative Stress in Nutritional Diabetes-Prone Psammomys obesus Model

Mitochondrial dysfunction is considered to be a pivotal component of insulin resistance and associated metabolic diseases. Psammomys obesus is a relevant model of nutritional diabetes since these adult animals exhibit a state of insulin resistance when fed a standard laboratory chow, hypercaloric for them as compared to their natural food. In this context, alterations in bioenergetics were studied. Using liver mitochondria isolated from these rats fed such a diet for 18 weeks, oxygen consumption rates, activities of respiratory complexes, and content in cytochromes were examined. Levels of malondialdehyde (MDA) and gluthatione (GSH) were measured in tissue homogenates. Diabetic Psammomys showed a serious liver deterioration (hepatic mass accretion, lipids accumulation), accompanied by an enhanced oxidative stress (MDA increased, GSH depleted). On the other hand, both ADP-dependent and uncoupled respirations greatly diminished below control values, and the respiratory flux to cytochrome oxydase was mildly lowered. Furthermore, an inhibition of complexes I and III together with an activation of complex II were found. With emergence of oxidative stress, possibly related to a defect in oxidative phosphorylation, some molecular adjustments could contribute to alleviate, at least in part, the deleterious outcomes of insulin resistance in this gerbil species

Hepatoprotective Effects of Chinese Medicinal Herbs: A Focus on Anti-Inflammatory and Anti-Oxidative Activities

published_or_final_versio

High Glucose, High Fatty Acid-Induced Toxicity, Oxidative and Metabolic Stress and Alterations in Cell Signalling In Pancreatic Rin-5f Cells: Attenuation by N-Acetylcysteine

Hyperglycaemia and hyperlipidaemia are the main causes of diabetes and obesity-associated complications. Increased oxidative stress, inflammatory responses and altered energy metabolism have been associated with hyperglycaemia and hyperlipidaemia. The concept of ‘glucolipotoxicity’ has arisen from the combination of the deleterious effects of the chronic elevation of levels of glucose and fatty acids on pancreatic β-cells’ function and/or survival. The synergistic effect of both nutrients exacerbates β-cells’ dysfunction over time and creates a vicious cycle of impaired insulin secretion and metabolic disturbances. Though numerous studies have been conducted in this field, the exact molecular mechanisms and causative factors still need to be established. The aim of the present work is to elucidate the molecular mechanisms of altered cell signalling, oxidative and metabolic stress, and inflammatory/antioxidant responses in the presence of high concentrations of glucose/fatty acids in a cell-culture system using an insulin-secreting pancreatic β- cell line (Rin-5F) and to study the effect of the antioxidant N-acetylcysteine (NAC) on β-cell toxicity. In our study, we investigated the molecular mechanism of cytotoxicity due to high glucose concentration (up to 25mM) and high saturated fatty acid concentration (up to 0.3mM palmitic acid) on Rin-5F cells. In this regard, initially, we investigated the effects of streptozotocin (STZ), a known β-cell toxin that is structurally related to glucose, to identify specific molecular and metabolic targets affected in pancreatic β-cells. Furthermore, we aim to elucidate the cytoprotective effects of NAC on β-cell toxicity induced by STZ/high glucose/high palmitic acid. Our results show that the cellular and molecular mechanisms of β-cell toxicity are mediated by increased oxidative stress, imbalance of redox homeostasis, disruption of mitochondrial bioenergetics and alterations in cell signalling. On the other hand, NAC treatment attenuates β-cell cytotoxicity, apoptosis and mitochondrial damage associated with oxidative stress. The use of an in-vitro cell-culture model in this study suggests the cellular and molecular mechanism(s) of β-cell toxicity without the involvement of multiple physiological factors that would be seen in vivo, which might contribute to the disease progression

Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

Biological consequences of Vanadium effects on formation of reactive oxygen species and lipid peroxidation

Lipid peroxidation (LPO), a process that affects human health, can be induced by exposure to vanadium salts and compounds. LPO is often exacerbated by oxidation stress, with some forms of vanadium providing protective effects. The LPO reaction involves the oxidation of the alkene bonds, primarily in polyunsaturated fatty acids, in a chain reaction to form radical and reactive oxygen species (ROS). LPO reactions typically affect cellular membranes through direct effects on membrane structure and function as well as impacting other cellular functions due to increases in ROS. Although LPO effects on mitochondrial function have been studied in detail, other cellular components and organelles are affected. Because vanadium salts and complexes can induce ROS formation both directly and indirectly, the study of LPO arising from increased ROS should include investigations of both processes. This is made more challenging by the range of vanadium species that exist under physiological conditions and the diverse effects of these species. Thus, complex vanadium chemistry requires speciation studies of vanadium to evaluate the direct and indirect effects of the various species that are present during vanadium exposure. Undoubtedly, speciation is important in assessing how vanadium exerts effects in biological systems and is likely the underlying cause for some of the beneficial effects reported in cancerous, diabetic, neurodegenerative conditions and other diseased tissues impacted by LPO processes. Speciation of vanadium, together with investigations of ROS and LPO, should be considered in future biological studies evaluating vanadium effects on the formation of ROS and on LPO in cells, tissues, and organisms as discussed in this review.info:eu-repo/semantics/publishedVersio

Antioxidant -Rich Natural Products and Diabetes Mellitus

Book chapte

Examining the protective effects of sesamol on oxidative stress associated blood -brain barrier dysfunction in streptozotocin-induced diabetic rats

Many studies point to vascular dysfunction as an underlying cause for the increased incidence of cognitive dysfunction and risk for development of Alzheimer\u27s disease during diabetes. Vascular dysfunction is not an uncommon occurrence in patients with diabetes and microvascular dysfunction commonly leads to clinical complications such as blindness, peripheral neuropathy, and kidney failure. Microangiopathies of the retina, kidney, and peripheral nerves have been well-characterized; however, the effects of diabetes on blood-brain barrier (BBB) function have been understudied.;Pathophysiological changes defining microvascular dysfunction include basement membrane thickening, cytoskeleton rearrangement, and increased paracellular leakage. Increased paracellular leakage of the BBB suggests a functional break down of the tight junction. To investigate changes in functional integrity, we used three different sized vascular space markers [sucrose (342 Da), inulin (5000 Da), and evans blue (68,000 Da)] to measure time-dependant paracellular permeability changes. Our findings revealed that the smallest vascular space marker (sucrose) showed subtle region-specific permeability changes that may represent an altered neuronal microenvironment. Previously published clinical data coincides with these region-specific changes observed in the hippocampus, cortex and midbrain. Patients with diabetes have a higher incidence of midbrain-related lacunar infarcts and cognitive deficiencies can be correlated to areas like the hippocampus and cortex.;Sesamol, a natural antioxidant, has been shown to improve cognitive function in STZ-induced diabetic rats. Furthermore, microangiopathy studies show that oxidative stress plays a major role in microvascular dysfunction; therefore, we investigated if oxidative-stress contributed to BBB permeability. Rats were randomly divided into four treatment groups (CON- control; STZ- STZ-induced diabetes; CON+S- control+sesamol; STZ+S-STZ-induced diabetes+sesamol). Functional and structural BBB changes were measured by in situ brain perfusion with sucrose and tight junction expression was assessed by real time RT-PCR and western blot analyses. Oxidative stress markers were visualized by fluorescent confocal microscopy and assayed by spectrophotometric analyses. Results demonstrated that STZ+S rats showed increased tight junction protein expression and decreased permeability as compared to STZ treated rats. Furthermore, STZ+S treated rats show increased antioxidant enzyme activity and decreased markers of oxidative stress in the brain. In conclusion, this study showed that sesamol treatment enhanced antioxidant capacity of the diabetic brain and led to decreased perturbation of oxidative stress-induced changes in BBB structure and function.;Next, we investigated the antioxidant mechanism for sesamol and oxidative mechanisms that may contribute to enhanced BBB permeability. The chemical properties of sesamol permit passage through the BBB and suggest that Fenton-induced lipid peroxidation can be inhibited. The brain, possessing iron stores and high levels of polyunstaturated fatty acids, may be vulnerable to Fenton-induced lipid peroxidation under pro-oxidant conditions during diabetes. Spectrophotometric assays were used to assess ferrous iron levels, hydrogen peroxide production, and lipid peroxidation in the brain. Furthermore, oxidative stress influences vascular remodeling and aberrant neovascularization of blood-retinal barrier (BRB) during diabetes. Because the BRB and BBB possess a similar structure and function, we examined whether similar pathophysiological changes occurred in the brain and if sesamol treatment influenced pathological changes. Gel zymography and real time RT-PCR were used to assess these parameters. Sesamol treatment reduced lipid peroxidation and enhanced mitochondrial superoxide dismutase (SOD) activity. Sesamol-related lignans can upregulate lipolytic enzymes, thus, sesamol may have exert similar effects. Elevated PDGF transcription in the STZ group was attenuated in the STZ+S group. PDGF plays a role in tight junction rearrangement and neovascularization in diabetic retinopathy, thus demonstrating neovascularizing factors may influence BBB integrity. This study suggests that sesamol may be beneficial as an adjuvant therapy for minimizing lipid peroxidative damage during diabetes.;The present results suggest that oxidative stress is a key factor promoting BBB dysfunction during STZ-induced diabetes and that sesamol or sesamol-related compounds might be beneficial adjuvant therapies for minimizing oxidative damage to the cerebral endothelium. Understanding the oxidative mechanisms contributing to BBB permeability may elucidate novel pharmacological targets for maintaining BBB function and promoting neuron survival. To accomplish this, more studies are needed to understand the signaling pathways connecting BBB integrity and supporting cells (e.g. astrocytes, microglia, pericytes)