Physical Exercise and Stress
Health benefits of regular physical exercise are undebatable. Both resting and contracting skeletal muscles produce reactive oxygen and nitrogen species (ROS, RNS). Low physiological levels of ROS are generated in the muscles to maintain the normal tone and contractility, but the excessive generation of ROS promotes contractile dysfunction resulting in muscle weakness and fatigue. This is perhaps the reason why intense and prolonged exercise results in oxidative damage to both proteins and lipids in the contracting muscle fibers. The magnitude of exercise-mediated changes in superoxide dismutase (SOD) activity of skeletal muscle increases as a function of the intensity and duration of exercise. Adaption to exercise is the key to prolonged regulation of an oxidant / anti-oxidant “balance”. Here we have to distinguish several levels;
Physiological Role of Stress
The physiological role of ROS is associated with almost all of the body processes;
In the presence of metals such as iron or copper, H2O2 can form the reactive and toxic hydroxyl radical (HO•). Increasing evidence indicates that H2O2 is a particularly an intriguing candidate as an intracellular and intercellular signaling molecule because it is neutral and membrane permeable. Specifically, H2O2 can oxidize thiol (–SH) of cysteine residues and form a sulphenic acid (–SOH), which can get glutathionylated (–SSG), form a disulfide bond (–SS–) with adjacent thiols, or form a sulfenyl amide (–SN–) with amides. Each of these modifications modifies the activity of the target protein and thus its function in a signaling pathway. Phosphatases appear to be susceptible to regulation by ROS in this manner, as they possess a reactive cysteine moiety in their catalytic domain that can be reversibly oxidized, which inhibits their dephosphorylation activity. Specific examples of phosphatases known to be regulated in this manner are PTP1b, PTEN, and MAPK phosphatases.
Hydrogen peroxide (H2O2) production due to oxidative stress is also associated with apoptosis and melanogenesis in melanocytes.
Nutrition is one of the most important external factors for oxidative stress if not the most important. Food and drinks come in all combinations. Ingredients interact, react and deliver reactive parts into the body. Oxidants and anti-oxidant are just a few of it. The amount delivered through the digestive tracks all depend on diet, amount of product, a combination of particles, time and place of delivery and conditions under which it is delivered. There is more than one food regime. To name a few:
All food intake supposed to be climate controlled, which is no longer the case. This has positive and negative effects. New products in the wrong time of the year can deliver a negative instead of a positive physical reaction of the body.
Food regimes have a local, environmental, traditional or religious background. Going back in time there were times of lavishly overproduction or availability of food and times of limitation or not the availability of products. This periodical change strengthened the body and soul. Only recently it has been discovered that it also can make us stronger.
Fasting induces an increase in total leukocytes counts, eosinophils, and metamyelocytes in the blood profile, accompanied by a decrease in the basophils and monocytes, a typical “stress leukogram” produced in the animal body due to the increased endogenous production of cortisol from the adrenal glands during oxidative stress. The leukocytosis with neutrophilia associated with fasting may be a consequence of an inflammatory reaction, caused by the direct action of ammonia on the rumen wall. The monocytopenia may be a result of adaptation and defense mechanism undergoing in the body and leads to higher susceptibility to pathogens.
Nutritional stress causes adrenal gland hyperfunction and, thus, an increased release of catecholamines in the blood, with a simultaneous inhibition of the production of insulin in the pancreas. The process of glycogenolysis is observed in the first 24 hours of fasting. Thereafter, gluconeogenesis from amino acid precursors and lipolysis from glycerol, as well as from lactate through the Cori cycle, maintain a regular supply of glucose. Lactate gets transformed into pyruvate and participates in the gluconeogenesis along with the deaminated amino acids. The increased production of catecholamines (epinephrine and dopamine) owing to fasting results in peripheral vasoconstriction and redistribution in the blood which is expressed as erythrocytosis, leukocytosis, and neutrophilia
Unlike innate antioxidant defensive enzyme systems, nutritional antioxidants are non-enzymatic, meaning that they are not enzymes which catalyze redox reactions directly affecting pro-oxidant substrates. For the most part, they work by breaking oxidative chains, either by accepting (or donating) electrons, thereby eliminating the unpaired electron. They are inferior to the body’s natural enzymatic antioxidants because they cannot be activated selectively in response to the continually changing redox status of specific cellular compartments. Their activity is indiscriminate. Since ROS serve many important functions, neutralizing them is not always beneficial. Furthermore, by interfering with the normal signaling pathways that activate the body’s natural enzymatic defenses, in many cases, exogenous antioxidants can actually increase oxidative stress (OS).
Certain botanical phenolic compounds appear to work indirectly. Rather than interrupt oxidative chains by directly reducing pro-oxidants, they appear to decrease OS through a variety of signaling pathways, some of which may result in upregulation of the body’s innate enzymatic antioxidants. This is true for the so-called “hormetic” botanicals including catechins, quercetin, and curcumin which are actually mild pro-oxidants, even though they indirectly decrease OS.
Assessment of Oxidative Stress
The concentration of different reductant-oxidant markers is considered an important parameter for assessing the prooxidant status in the body tissues. Several indicators of in vivo redox status are available, including the ratios of GSH to GSSG (glutathione(GSH)= is a tripeptide (γ-glutamylcysteinylglycine) / oxidized glutathione(GSSG), NADPH to, and NADH to, as well as the balance between reduced and oxidized thioredoxin. Out of these redox pairs, the GSH-to-GSSG ratio is thought to be one of most abundant redox buffer systems in mammalian species.
A decrease in this ratio indicates a relative shift from a reduced to an oxidized form of GSH, suggesting the presence of oxidative stress at the cellular or tissue level. In aging, an age-related shift from a redox balance to an oxidative profile is observed which results in a reduced ability to buffer ROS that is generated in both “normal” conditions and at times of challenge. Thus, a progressive shift in cellular redox status could potentially be one of the primary molecular mechanisms contributing to the aging process and accompanying functional declines.
Ascorbic acid has both antioxidant and prooxidant effects, depending upon the dose. Low electron potential and resonance stability of ascorbate and the ascorbyl radical have enabled ascorbic acid to enjoy the privilege as an antioxidant. In ascorbic acid alone treated rats, ascorbic acid has been found to act as a CYP (Cytochrome P ) inhibitor. Similar activity has also been observed for other antioxidants-quercetin and chitosan oligosaccharides, which may act as potential CYP inhibitors.
Specifically, Phase I genes of xenobiotic biotransformation, namely, CYP1A1, CYP2E1, and CYP2C29, have been previously reported to be downregulated in female rats in the presence of the antioxidant, resveratrol. The antioxidant and prooxidant role of ascorbic acid in low (30 and 100 mg/kg body weight) and high doses (1000 mg/kg body weight), respectively, have also been reported in case of ischemia-induced oxidative stress. Recently, the toxicity of ascorbic acid has also been attributed to its autooxidation. Ascorbic acid can be oxidized in the extracellular environment in the presence of metal ions to dehydroascorbic acid, which is transported into the cell through the glucose transporter (GLUT). Here it is reduced back to ascorbate. This movement of electrons changes the redox state of the cell influencing gene expression.
The in vivo prooxidant/antioxidant activity of beta-carotene and lycopene has also been found to depend on their interaction with biological membranes and the other co-anti-oxidant molecules like vitamin C or E. At higher oxygen tension, carotenoids tend to lose their effectiveness as antioxidants. In a turn around to this, the prooxidant effect of low levels of tocopherol is evident at low oxygen tension.
α-lipoic acid exerts a protective effect on the kidney of diabetic rats but a prooxidant effect in nondiabetic animals. The prooxidant effects have been attributed to dehydroxylipoic acid (DHLA), the reduced metabolite of α-lipoic acid owing to its ability to reduce iron, initiate reactive sulfur-containing radicals, and thus damage proteins such as alpha 1-antiproteinase and creatine kinase playing a role in renal homeostasis. An increase in α-lipoic acid and DHLA-induced mitochondrial and submitochondrial production in rat liver and NADPH-induced and expression of p47phox in the nondiabetic kidney has also been observed.
Use of ginseng and Eleutherococcus senticosus is thought to increase the body’s capacity to tolerate external stresses, leading to increased physical or mental performance. Although an extensive literature documenting adaptogenic effects in laboratory animal systems exists, results from human clinical studies are conflicting and variable. However, there is evidence that extracts of ginseng and Eleutherococcus sp. can have an immunostimulatory effect in humans, and this may contribute to the adaptogen or tonic effects of these plants. From laboratory studies, it has been suggested that the pharmacological target sites for these compounds involve the hypothalamus-pituitary-adrenal axis due to the observed effects upon serum levels of adrenocorticotropic hormone and corticosterone. However, it should also be noted that the overall effects of the ginsenosides can be complex due to their potential for multiple actions even within a single tissue. (see food congruence)
The flavonoids present in ginkgo extracts exist primarily as glycosylated derivatives of kaempferol and quercetin. These flavonoid glycosides have been shown to be effective free radical scavengers. It is believed that the collective action of these components leads to a reduction in damage and improved functioning of the blood vessels. Depending on the type and level of ROS and RNS, duration of exposure, antioxidant status of tissues, exposure to free radicals and their metabolites leads to different responses—increased proliferation, interrupted cell cycle, apoptosis, or necrosis.