Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis

Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans.     

Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal

Mitochondrial reactive oxygen species (ROS) are proposed to play a central role in aging and age-associated disorders, although direct in vivo evidence is lacking. We recently generated a mouse mutant with mutated inner mitochondrial membrane peptidase 2-like (Immp2l) gene, which impairs the signal peptide sequence processing of mitochondrial proteins cytochrome c1 and glycerol phosphate dehydrogenase 2. The mitochondria from mutant mice generate elevated levels of superoxide ion and cause impaired fertility in both sexes. Here, we design experiments to examine the effects of excessive mitochondrial ROS generation on health span. We show that Immp2l mutation increases oxidative stress in multiple organs such as the brain and the kidney, although expression of superoxide dismutases in these tissues of the mutants is also increased. The mutants show multiple aging-associated phenotypes, including wasting, sarcopenia, loss of subcutaneous fat, kyphosis, and ataxia, with female mutants showing earlier onset and more severe age-associated disorders than male mutants. The loss of body weight and fat was unrelated to food intake. Adipose-derived stromal cells (ADSC) from mutant mice showed impaired proliferation capability, formed significantly less and smaller colonies in colony formation assays, although they retained adipogenic differentiation capability in vitro. This functional impairment was accompanied by increased levels of oxidative stress. Our data showed that mitochondrial ROS is the driving force of accelerated aging and suggested that ROS damage to adult stem cells could be one of the mechanisms for age-associated disorders.     

Actions of "antioxidants" in the protection against atherosclerosis

This review addresses the role of oxidative processes in atherosclerosis and its resulting cardiovascular disease by focusing on the outcome of antioxidant interventions. Although there is unambiguous evidence for the presence of heightened oxidative stress and resulting damage in atherosclerosis, it remains to be established whether this represents a cause or a consequence of the disease. This critical question is complicated further by the increasing realization that oxidative processes, including those related to signaling, are part of normal cell function. Overall, the results from animal interventions suggest that antioxidants provide benefit neither generally nor consistently. Where benefit is observed, it appears to be achieved at least in part via modulation of biological processes such as increase in nitric oxide bioavailability and induction of protective enzymes such as heme oxygenase-1, rather than via inhibition of oxidative processes and lipid oxidation in the arterial wall. Exceptions to this may be situations of multiple/excessive stress, the relevance of which for humans is not clear. This interpretation is consistent with the overall disappointing outcome of antioxidant interventions in humans and can be rationalized by the spatial compartmentalization of cellular oxidative signaling and/or damage, complex roles of oxidant-producing enzymes, and the multifactorial nature of atherosclerosis.     

Oxidative stress in ALS: Key role in motor neuron injury and therapeutic target

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2–3 years of symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.     

Why do Neurons Enter the Cell Cycle?

Increasing evidence indicates that postmitotic, terminally differentiated neurons activate the cell cycle before death. The purpose of this cell cycle activation, however, remains elusive. In proliferating cells, cell cycle machinery is a major contributor to the DNA damage response, which is comprised of growth arrest. In quiescent cells such as terminally differentiated neurons, cell cycle-associated events may also be part of the DNA damage response. A link between DNA damage and repair, cell cycle regulation and cell death is becoming increasingly recognized for cycling cells but remains elusive for quiescent cells. Neurons are particularly susceptible to oxidative stress due to the high rate of oxidative metabolism in the brain and the low level of antioxidant enzymes compared to other somatic tissues. This is supported by fact that the intracellular end point of many neurotoxic stimuli is oxidative stress, which also represents a major cause of the neuropathology underlying a variety of neurodegenerative diseases. DNA is perhaps the major target of oxyradicals. Thus, oxidative stress may cause DNA damage, which is countered by a complex defense mechanism, the DNA damage response, which involves not only the elimination of DNA damage, but its coordination with other cellular processes such as cell-cycle progression, together directing to preserve genomic integrity. The function of such response is the removal of DNA damage by DNA repair pathways, or the elimination of damaged cells via apoptosis. The present review discusses the idea that the cell cycle machinery is a critical element of the DNA damage response not only in cycling, but also quiescent cells, and may bear the same function: to repair the damage or initiate apoptosis if the damage is too extensive to be repaired.     

Pioglitazone Improves Cognitive Function via Increasing Insulin Sensitivity and Strengthening Antioxidant Defense System in Fructose-Drinking Insulin Resistance Rats

Insulin resistance (IR) links Alzheimer’s disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.     

Oxidative damage to macromolecules in human Parkinson disease and the rotenone model

Parkinson disease (PD), the most common neurodegenerative movement disorder, is associated with selective degeneration of nigrostriatal dopamine neurons. Although the underlying mechanisms contributing to neurodegeneration in PD seem to be multifactorial, mitochondrial impairment and oxidative stress are widely considered to be central to many forms of the disease. Whether oxidative stress is a cause or a consequence of dopaminergic death, there is substantial evidence for oxidative stress both in human PD patients and in animal models of PD, especially using rotenone, a complex I inhibitor. There are many indices of oxidative stress, but this review covers the recent evidence for oxidative damage to nucleic acids, lipids, and proteins in both the brain and the peripheral tissues in human PD and in the rotenone model. Limitations of the existing literature and future perspectives are discussed. Understanding how each particular macromolecule is damaged by oxidative stress and the interplay of secondary damage to other biomolecules may help us design better targets for the treatment of PD.     

Histopathology findings in common marmosets (<Emphasis Type="Italic">Callithrix jacchus</Emphasis> Linnaeus, 1758) with chronic weight loss associated with bile tract obstruction by infestation with <Emphasis Type="Italic">Platynosomum</Emphasis> (Loos, 1907)

Chronic weight loss in marmosets is often associated with wasting marmoset syndrome (WMS), an important disease that occurs in callitrichid colonies around the world. Even though its etiology is very difficult to determine, particular variables, such as weight loss, diarrhea and alopecia, associated or not with infestation in the pancreatic ducts with Trichospirura leptossoma (Nematoda: Thelazioidea), seem to be linked with the syndrome. This study investigated the histopathology of the lungs, duodenum, liver, gallbladder, extrahepatic bile ducts and pancreatic ducts of six common marmosets (Callithrix jacchus) suffering from severe non-diarrheic weight loss. Three individuals died naturally and the other three were euthanized. Microscopic findings showed the presence of adult flukes (Platynosomum) in the liver. These flukes, which provoke common infection in cats, were also observed inside the gallbladder as well as in the intra and extrahepatic bile ducts in common marmosets. Portal fibrosis was observed in two animals, which developed chronic fibrosing hepatopathy (biliary pattern, grade 3). The disease progresses without diarrhea and without pancreatic lesions or infestation. With the progression, the animals presented with ascending cholangitis, cholestasis and portal fibrosis, sometimes culminating in secondary biliary cirrhosis. Therefore, this infirmity, associated with chronic weight loss in common marmosets, could be another etiological factor linked with WMS.     

Differential thiol oxidation of the signaling proteins Akt,PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle

Oxidative stress, caused by excess reactive oxygen species (ROS), has been hypothesized to cause or exacerbate skeletal muscle wasting in a number of diseases and chronic conditions. ROS, such as hydrogen peroxide, have the potential to affect signal transduction pathways such as the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3 K)/Akt pathway that regulates protein synthesis. Previous studies have found contradictory outcomes for the effect of ROS on the PI3K/Akt signaling pathway, where oxidative stress can either enhance or inhibit Akt phosphorylation. The apparent contradictions could reflect differences in experimental cell types or types of ROS treatments. We replicate both effects in myotubes of cultured skeletal muscle C2C12 cells, and show that increased oxidative stress can either inhibit or enhance Akt phosphorylation. This differential response could be explained: thiol oxidation of Akt, but not the phosphatases PTEN or PP2A, caused a decline in Akt phosphorylation; whereas the thiol oxidation of Akt, PTEN and PP2A increased Akt phosphorylation. These observations indicate that a more complete understanding of the effects of oxidative stress on a signal transduction pathway comes not only from identifying the proteins susceptible to thiol oxidation, but also their relative sensitivity to ROS.     

Oxidative stress caused by inactivation of glutathione peroxidase and adaptive responses

Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. When the cellular production of ROS exceeds the cell's antioxidant capacity, cellular macromolecules such as lipids, proteins and DNA can be damaged. Because of this, 'oxidative stress' is thought to contribute to aging and pathogenesis of a variety of human diseases. However, in the last 10-15 years, a considerable body of evidence has accumulated that ROS serve as subcellular messengers, and play a role in gene regulation and signal transduction pathways, which may be involved in defensive mechanisms against oxidative stress. This review focuses on oxidative stress caused by the inactivation of glutathione peroxidase (GPx), a major peroxide scavenging enzyme. GPx is inactivated by a variety of physiological substances, including nitric oxide and carbonyl compounds in vitro and in cell culture. Decreased GPx activity has also been reported in tissues where oxidative stress occurs in several pathological animal models. The accumulation of increased levels of peroxide resulting from inactivation of GPx may act as a second messenger and regulate expression of anti-apoptotic genes and the GPx itself to protect against cell damage. These findings suggest that GPx undergoes inactivation under various conditions such as nitroxidative stress and glycoxidative stress, and that these changes are a common feature of various types of oxidative stress which may be associated with the modification of redox regulation and cellular function.     

High-performance centrifugal partition chromatography (HPCPC) for efficient isolation of diphlorethohydroxycarmalol (DPHC) and screening of its antioxidant activity in a zebrafish model

High-performance centrifugal partition chromatography (HPCPC) can be used for the rapid isolation of biologically active metabolites from natural sources. The present study investigates the one-step isolation of diphlorethohydroxycarmalol (DPHC), an algal polyphenol, from the brown seaweed Ishige okamurae by HPCPC and its protective effect against 2,2’-azobis dihydrochloride (AAPH) induced oxidative stress in zebrafish embryos. HPCPC was found to be efficient and effective for the isolation of DPHC from Ishige okamurae under optimized solvent conditions, yielding a high purity product. The present purification method helps overcome compound wasting and possible degradation, which cause a low yield in conventional column separations. Further, zebrafish embryos exposed to AAPH were compared with and without DPHC treatment, two days after fertilization for ROS generation, cell death, lipid peroxidation, survival rate, and heartbeat rates. These evaluations revealed that DPHC treatment significantly enhanced protection against oxidative stress in zebrafish embryos. HPCPC was, therefore, established as an efficient DPHC isolation method and could be used for separating other complex phlorotannins from seaweeds.     

Oxidative stress-induced DNA damage by particulate air pollution

Exposure to ambient air particulate matter (PM) is associated with pulmonary and cardiovascular diseases and cancer. The mechanisms of PM-induced health effects are believed to involve inflammation and oxidative stress. The oxidative stress mediated by PM may arise from direct generation of reactive oxygen species from the surface of particles, soluble compounds such as transition metals or organic compounds, altered function of mitochondria or NADPH-oxidase, and activation of inflammatory cells capable of generating ROS and reactive nitrogen species. Resulting oxidative DNA damage may be implicated in cancer risk and may serve as marker for oxidative stress relevant for other ailments caused by particulate air pollution. There is overwhelming evidence from animal experimental models, cell culture experiments, and cell free systems that exposure to diesel exhaust and diesel exhaust particles causes oxidative DNA damage. Similarly, various preparations of ambient air PM induce oxidative DNA damage in in vitro systems, whereas in vivo studies are scarce. Studies with various model/surrogate particle preparations, such as carbon black, suggest that the surface area is the most important determinant of effect for ultrafine particles (diameter less than 100 nm), whereas chemical composition may be more important for larger particles. The knowledge concerning mechanisms of action of PM has prompted the use of markers of oxidative stress and DNA damage for human biomonitoring in relation to ambient air. By means of personal monitoring and biomarkers a few studies have attempted to characterize individual exposure, explore mechanisms and identify significant sources to size fractions of ambient air PM with respect to relevant biological effects. In these studies guanine oxidation in DNA has been correlated with exposure to PM(2.5) and ultrafine particles outdoor and indoor. Oxidative stress-induced DNA damage appears to an important mechanism of action of urban particulate air pollution. Related biomarkers and personal monitoring may be useful tools for risk characterization.     

Does vitamin D protect against DNA damage?

Vitamin D is a secosteroid best known for its role in maintaining bone and muscle health. Adequate levels of vitamin D may also be beneficial in maintaining DNA integrity. This role of vitamin D can be divided into a primary function that prevents damage from DNA and a secondary function that regulates the growth rate of cells. The potential for vitamin D to reduce oxidative damage to DNA in a human has been suggested by clinical trial where vitamin D supplementation reduced 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage, in colorectal epithelial crypt cells. Studies in animal models and in different cell types have also shown marked reduction in oxidative stress damage and chromosomal aberrations, prevention of telomere shortening and inhibition of telomerase activity following treatment with vitamin D. The secondary function of vitamin D in preventing DNA damage includes regulation of the poly-ADP-ribose polymerase activity in the DNA damage response pathway involved in the detection of DNA lesions. It is also able to regulate the cell cycle to prevent the propagation of damaged DNA, and to regulate apoptosis to promote cell death. Vitamin D may contribute to prevention of human colorectal cancer, though there is little evidence to suggest that prevention of DNA damage mediates this effect, if real. Very limited human data mean that the intake of vitamin D required to minimise DNA damage remains uncertain.     

Oxidative and non-oxidative DNA damage and cardiovascular disease

Evidence for the association of DNA damage with cardiovascular disease has been obtained from in vitro cell culture models, experimental cardiovascular disease and analysis of samples obtained from humans with disease. There is general acceptance that several factors associated with the risk of developing cardiovascular disease cause oxidative damage to DNA in cell culture models with both nuclear and mitochondrial DNA as targets. Moreover, evidence obtained over the past 10 years points to a possible mechanistic role for DNA damage in experimental atherosclerosis culminating in recent studies challenging the assumption that DNA damage is merely a biomarker of the disease process. This kind of mechanistic insight provides a renewed impetus for further studies in this area.     

Promotion of oxidative lipid membrane damage by amyloid beta proteins

Senile plaques in the cerebral parenchyma are a pathognomonic feature of Alzheimer's disease (AD) and are mainly composed of aggregated fibrillar amyloid beta (Abeta) proteins. The plaques are associated with neuronal degeneration, lipid membrane abnormalities, and chemical evidence of oxidative stress. The view that Abeta proteins cause these pathological changes has been challenged by suggestions that they have a protective function or that they are merely byproducts of the pathological process. This investigation was conducted to determine whether Abeta proteins promote or inhibit oxidative damage to lipid membranes. Using a mass spectrometric assay of oxidative lipid damage, the 42-residue form of Abeta (Abeta42) was found to accelerate the oxidative lipid damage caused by physiological concentrations of ascorbate and submicromolar concentrations of copper(II) ion. Under these conditions, Abeta42 was aggregated, but nonfibrillar. Ascorbate and copper produced H(2)O(2), but Abeta42 reduced H(2)O(2) concentrations, and its ability to accelerate oxidative damage was not affected by catalase. Lipids could be oxidized by H(2)O(2) and copper(II) in the absence of ascorbate, but only at significantly higher concentrations, and Abeta42 inhibited this reaction. These results indicate that the ability of Abeta42 to promote oxidative damage is more potent and more likely to be manifest in vivo than its ability to inhibit oxidative damage. In conjunction with prior results demonstrating that oxidatively damaged membranes cause Abeta42 to misfold and form fibrils, these results suggest a specific chemical mechanism linking Abeta42-promoted oxidative lipid damage to amyloid fibril formation.     

The potential role of mitochondrial dysfunction in seizure-associated cell death in the hippocampus and epileptogenesis

Epilepsy is considered one of the most common neurological disorders worldwide. The burst firing neurons associated with prolonged epileptic discharges could lead to a large number of changes with events of cascades at the cellular level. From its role as the cellular powerhouse, mitochondria also play a crucial role in the mechanisms of cell death. Emerging evidence has shown that prolonged seizures may result in mitochondrial dysfunction and increase of oxidative and nitrosative stress in the hippocampus that precede neuronal cell death and cause subsequent epileptogenesis. The selective dysfunction of mitochondrial respiratory chain Complex I has been suggested to be a biochemical hallmark of seizure-induced neuronal cell death and epileptogenesis. Therefore, protection of mitochondria from bioenergetic failure and oxidative stress in the hippocampus may open a new vista to the development of effective neuroprotective strategies against seizure-induced brain damage and to the design of novel treatment perspectives against therapy-resistant forms of epilepsy.     

Coronary atherosclerosis and somatic mutations: an overview of the contributive factors for oxidative DNA damage

Coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. Genetic research on CAD has traditionally focused on investigation aimed at identifying disease-susceptibility genes. Recent evidence suggests that somatically acquired DNA mutations may also contribute significantly to the pathogenesis of the disease, underlining the similarity between atherosclerotic and carcinogenic processes. The generation of oxidative stress has been emphasized as an important cause of DNA damage in atherosclerosis. This review highlights some of the major atherogenic risk factors as likely mediators in the oxidative modification of DNA. It also examines the hypothesis that an increase in oxidative stress may derive from "oxidatively" damaged mitochondria. Accordingly, further research in this field should be given high priority, since increased somatic DNA damage could be an important pathogenic factor and an additional prognostic predictor, as well as a potential target for therapeutic strategies in coronary artery disease.     

Fibrillin-1 Mutations Causing Weill-Marchesani Syndrome and Acromicric and Geleophysic Dysplasias Disrupt Heparan Sulfate Interactions

The extracellular glycoprotein fibrillin-1 forms microfibrils that act as the template for elastic fibers. Most mutations in fibrillin-1 cause Marfan syndrome with severe cardiovascular and ocular symptoms, and tall stature. This is in contrast to mutations within a heparin-binding TB domain (TB5), which is downstream of the arg-gly-asp cell adhesion domain, which can cause Weill-Marchesani syndrome (WMS) or Acromicric (AD) and Geleophysic Dysplasias (GD). WMS is characterized by short limbs, joint stiffness and ocular defects, whilst fibrillin-1 AD and GD have severe short stature, joint defects and thickened skin. We previously showed that TB5 binds heparin. Here, we show that the corresponding region of fibrillin-2 binds heparin very poorly, highlighting a novel functional difference between the two isoforms. This finding enabled us to map heparin/heparan sulfate binding to two sites on fibrillin-1 TB5 using a mutagenesis approach. Once these sites were mapped, we were able to investigate whether disease-causing mutations in this domain disrupt binding to HS. We show that a WMS deletion mutant, and five AD and GD point mutants all have disrupted heparin binding to TB5. These data provide insights into the biology of fibrillins and the pathologies of WMS, AD and GD.