Mustafa Atalay

Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula

Edible berry anthocyanins possess a broad spectrum of therapeutic and anti-carcinogenic properties. Berries are rich in anthocyanins, compounds that provide pigmentation to fruits and serve as natural antioxidants. Anthocyanins repair and protect genomic DNA integrity. Earlier studies have shown that berry anthocyanins are beneficial in reducing age-associated oxidative stress, as well as in improving neuronal and cognitive brain function. Six berry extracts (wild blueberry, bilberry, cranberry, elderberry, raspberry seeds, and strawberry) were studied for antioxidant efficacy, cytotoxic potential, cellular uptake, and anti-angiogenic (the ability to reduce unwanted growth of blood vessels, which can lead to varicose veins and tumor formation) properties. We evaluated various combinations of edible berry extracts and developed a synergistic formula, OptiBerry IH141, which exhibited high ORAC (Oxygen-Radical Absorbing Capacity) value, low cytotoxicity, and superior anti-angiogenic properties compared to the other combinations tested. Anti-angiogenic approaches to treat cancer represent a priority area in vascular tumor biology. OptiBerry significantly inhibited both H2O2- and TNF-α-induced VEGF (Vascular Endothelial Growth Factor) expression by human keratinocytes. VEGF is a key regulator of tumor angiogenesis. Matrigel assay using human microvascular endothelial cells showed that OptiBerry impaired angiogenesis. In anin vivo model of angiogenesis, OptiBerry significantly inhibited basal MCP-1 and inducible NF-κB transcriptions. Endothelioma cells pretreated with OptiBerry showed a diminished ability to form hemangioma and markedly decreased tumor growth by more than 50%. In essence, these studies highlight the novel anti-angiogenic, antioxidant, and anti-carcinogenic potential of a novel anthocyanin-rich berry extract formula, OptiBerry.

Chemistry and biochemistry of lipid peroxidation products

Abstract Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as ‘second messengers’ of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed.

Oxygen Consumption and Usage During Physical Exercise: The Balance Between Oxidative Stress and ROS-Dependent Adaptive Signaling

The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein-protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling.

Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats

Silent information regulators are potent NAD(+)-dependent protein deacetylases, which have been shown to regulate gene silencing, muscle differentiation and DNA damage repair. Here, changes in the level and activity of sirtuin 1 (SIRT1) in response to exercise in groups of young and old rats were studied. There was an age-related increase in SIRT1 level, while exercise training significantly increased the relative activity of SIRT1. A strong inverse correlation was found between the nuclear activity of SIRT1 and the level of acetylated proteins. Exercise training induced SIRT1 activity due to the positive effect of exercise on the activity of nicotinamide phosphoribosyltransferase (NAMPT) and thereby the production of sirtuin-fueling NAD(+). Exercise training normalized the age-associated shift in redox balance, since exercised animals had significantly lower levels of carbonylated proteins, expression of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor. The age-associated increase in the level of SIRT6 was attenuated by exercise training. On the other hand, aging did not significantly increase the level of DNA damage, which was in line with the activity of 8-oxoguanine DNA glycosylase, while exercise training increased the level of this enzyme. Regular exercise decelerates the deleterious effects of the aging process via SIRT1-dependent pathways through the stimulation of NAD(+) biosynthesis by NAMPT.

Exercise Plays a Preventive Role Against Alzheimer's Disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder affecting the elderly population. It is predicted that the incidence of AD will be increased in the future making this disease one of the greatest medical, social, and economic challenges for individuals, families, and the health care system worldwide. The etiology of AD is multifactorial. It features increased oxidative state and deposition of amyloid plaques and neurofibrillary tangles of protein tau in the central cortex and limbic system of the brain. Here we provide an overview of the positive impacts of exercise on this challenging disease. Regular physical activity increases the endurance of cells and tissues to oxidative stress, vascularization, energy metabolism, and neurotrophin synthesis, all important in neurogenesis, memory improvement, and brain plasticity. Although extensive studies are required to understand the mechanism, it is clear that physical exercise is beneficial in the prevention of AD and other age-associated neurodegenerative disorders.

Aerobic exercise and the lipid profile in type 1 diabetic men: a randomized controlled trial

PURPOSE Despite the potential importance of favorable changes in the lipid profile produced by aerobic exercise, training-induced lipid profile changes in atherosclerosis-prone type 1 diabetes mellitus (DM) have not heretofore been adequately addressed. METHODS We assessed the effect of a 12- to 16-wk aerobic exercise program on cardiorespiratory fitness and the lipid profile in young men with type 1 DM. Generally active men aged 20-40 yr with type 1 DM (N = 56) were randomized into training (N = 28) and control (untrained, N = 28) groups after baseline measurements. Training consisted of 30-60 min moderate-intensity running 3-5 times a week for 12-16 wk. RESULTS For the 42 men finishing the study, peak oxygen consumption (VO2 peak) increased significantly only in the trained group. Total and low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B decreased and the high-density lipoprotein (HDL)/apo A-I ratio increased in the trained group. HDL and apo A-I increased in both groups. The exercise program brought about improvements in the HDL/LDL and apo A-I/apo B ratios and apo B and triglyceride levels when comparing the relative (%) changes in the trained versus control group. In the trained group, men with HDL/LDL ratios below the group median at baseline showed even more favorable changes in their lipid profile than those with higher initial HDL/LDL ratios. Body mass index, percent body fat and hemoglobin A1c did not change during the training period in either group. CONCLUSIONS Endurance training improved the lipid profile in already physically active type 1 diabetic men, independently of effects on body composition or glycemic control. The most favorable changes were in patients with low baseline HDL/LDL ratios, likely the group with the greatest benefit to be gained by such changes.

Oxygen Sensing by Primary Cardiac Fibroblasts: A Key Role of p21Waf1/Cip1/Sdi1

Abstract— In mammalian organs under normoxic conditions, O2 concentration ranges from 12% to <0.5%, with O2 ≈14% in arterial blood and <10% in the myocardium. During mild hypoxia, myocardial O2 drops to ≈1% to 3% or lower. In response to chronic moderate hypoxia, cells adjust their normoxia set point such that reoxygenation-dependent relative elevation of Po2 results in perceived hyperoxia. We hypothesized that O2, even in marginal relative excess of the Po2 to which cardiac cells are adjusted, results in activation of specific signal transduction pathways that alter the phenotype and function of these cells. To test this hypothesis, cardiac fibroblasts (CFs) isolated from adult murine ventricle were cultured in 10% or 21% O2 (hyperoxia relative to the Po2 to which cells are adjusted in vivo) and were compared with those cultured in 3% O2 (mild hypoxia). Compared with cells cultured in 3% O2, cells that were cultured in 10% or 21% O2 demonstrated remarkable reversible G2/M arrest and a phenotype indicative of differentiation to myofibroblasts. These effects were independent of NADPH oxidase function. CFs exposed to high O2 exhibited higher levels of reactive oxygen species production. The molecular signature response to perceived hyperoxia included (1) induction of p21, cyclin D1, cyclin D2, cyclin G1, Fos-related antigen-2, and transforming growth factor-&bgr;1, (2) lowered telomerase activity, and (3) activation of transforming growth factor-&bgr;1 and p38 mitogen-activated protein kinase. CFs deficient in p21 were resistant to such O2 sensitivity. This study raises the vital broad-based issue of controlling ambient O2 during the culture of primary cells isolated from organs.

Heat Shock Proteins in Diabetes and Wound Healing

The heat shock proteins (HSPs), originally identified as heat-inducible gene products, are a highly conserved family of proteins that respond to a wide variety of stress. Although HSPs are among the most abundant intracellular proteins, they are expressed at low levels under normal physiological conditions, and show marked induction in response to various stressors. HSPs function primarily as molecular chaperones, facilitating the folding of other cellular proteins, preventing protein aggregation, or targeting improperly folded proteins to specific pathways for degradation. By modulating inflammation, wound debris clearance, cell proliferation, migration and collagen synthesis, HSPs are essential for normal wound healing of the skin. In this review, our goal is to discuss the role and clinical implications of HSP with respect to skin wound healing and diabetes. The numerous defects in the function of HSPs associated with diabetes could contribute to the commonly observed complications and delayed wound healing in diabetics. Several physical, pharmacological and genetic approaches may be considered to address HSP-directed therapies both in the laboratory and in the clinics.

Anti-angiogenic property of edible berry in a model of hemangioma

Hemangiomas represent a powerful model to study in vivo angiogenesis. Monocyte chemotactic protein 1 (MCP‐1) is known to be responsible for recruiting macrophages to sites of infection or inflammation and facilitate angiogenesis. Recently we have demonstrated that edible berry extracts potently suppress inducible vascular endothelial growth factor expression and in vitro angiogenesis. Comparative analysis of several berry extracts led to the observation that wild blueberry and a berry mix were most effective. Our goal was to follow up on our findings with wild blueberry and the berry mix (OptiBerry). The present work rests on our current finding that these two berry powders significantly inhibit inducible MCP‐1 expression in endothelioma cells. Therefore, we sought to examine the effects of wild blueberry and berry mix in an in vivo model of experimental angiogenesis. Reporter studies showed that the berry powders significantly inhibited basal MCP‐1 transcription and inducible nuclear factor κB transcription. Endothelioma cells pre‐treated with berry powders showed diminished ability to form hemangioma. Histological analysis demonstrated markedly decreased infiltration of macrophages in hemangioma of treated mice compared to placebo‐treated controls. The current results provide the first in vivo evidence substantiating the anti‐angiogenic property of edible berries.

BLOOD GLUTATHIONE HOMEOSTASIS AS A DETERMINANT OF RESTING AND EXERCISE-INDUCED OXIDATIVE STRESS IN YOUNG MEN

Although the importance of glutathione in protection against oxidative stress is well recognized, the role of physiological levels of glutathione and other endogenous antioxidants in protecting against exercise-induced oxidative stress is less clear. We evaluated the role of glutathione and selected antioxidant enzymes as determinants of lipid peroxidation at rest and in response to exercise in men (n = 13-14) aged 20-30 years, who cycled for 40 min at 60% of their maximal oxygen consumption (VO2max). Levels of plasma thiobarbituric acid reactive substances (plasma TBARS) and blood oxidised glutathione (GSSG) increased by about 50% in response to exercise. Mean blood reduced glutathione (GSH) decreased by 13% with exercise. Of the measured red blood cell (RBC) antioxidant enzyme activities, only selenium-dependent glutathione peroxidase (Se-GPX) activity rose following exercise. In univariate regression analysis, plasma TBARS levels at rest predicted postexercise plasma TBARS and the exercise-induced change in total glutathione (TGSH). Blood GSSG levels at rest were strongly determinant of postexercise levels. Multiple regression analysis showed blood GSH to be a determinant of plasma TBARS at rest. The relative changes in TGSH were determinant of postexercise plasma TBARS. In summary, higher blood GSH and lower plasma TBARS at rest were associated with lower resting, and exercise-induced, lipid peroxidation. Subjects with a favourable blood glutathione redox status at rest maintained a more favourable redox status in response to exercise-induced oxidative stress. Changes in blood GSH and TGSH in response to exercise were closely associated with both resting and exercise-induced plasma lipid peroxidation. These results underscore the critical role of glutathione homeostasis in modulating exercise-induced oxidative stress and, conversely, the effect of oxidative stress at rest on exercise-induced changes in glutathione redox status.