Can stress induced tinnitus xtc,how to wire an earring,tinnitus seit erk?ltung - Good Point

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Apoptosis, Free Radicals and Antioxidant Defense in Antitumor TherapyJulita Kulbacka1, Jolanta Saczko1, Agnieszka Chwilkowska1, Anna Choromanska1 and Nina Skolucka1[1] Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, , Poland1. While you are expected to lose about 100 hair strands every day, that number could significantly increase when you get stressed. Fundamentally, eating a natural diet rich in vitamins, mineral, omega-3 fatty acids, and other essential nutrients can serve as your first shield from stress.
Once in a while, it is not a bad idea to take a respite from all the hustle and bustle of your work life. Make it a habit to listen to good music, read inspirational books, or go for a full body massage, particularly scalp massage.
While the very word “exercise” conjures up feelings of exhaustion and muscle soreness, you just cannot dismiss the innumerable benefits that it brings to your health and emotional well-being. A hair product’s strong smell may indicate that it contains ingredients that can be harsh on your hair.
Though washing your hair regularly is a must, you don’t need to put shampoo on your hair as often. Kodjo is a home fitness enthusiast who believes the average person can get and stay in shape right in the comfort of their home.
This site is intended has hundreds of workout videos featuring superset workout routines as well as other standalone workout exercises designed to get you in the best shape of your life.
Watch your nutrition as well, it's a big part of the quest to getting in shape and developing a beach body.
As it says in the article, sleeping, exercise , taking a break, are the reasons I started losing my hair, I read in books that chopping an onion on you daily shampoo helps a lot, but the best thing is to visit your doctor. NATUREBOX HEALTHY DELICIOUS SNACKS NatureBox focuses on sourcing delicious, healthy snacks and sends them to you monthly. GYMBOSS INTERVAL TIMEREver since I discovered the power and effectiveness of interval training, I rarely conduct my workout routines without my Gymboss Interval Timer. The information on this Blog reflects my own opinions and is not a replacement for medical advice.
If you look out your window but cana€™t see the masts because they are obstructed by other buildings then the power density will be mainly absorbed by those buildings and too low to worry about. If the substation is immediately next to your home there is little in a practical sense you can do to reduce the magnetic fields. Unless the substation is immediately adjacent to your house the EMFa€™s from these small street substations fall to background levels within about 3 meters.
WI-FI and DECT phones are overwhelmingly the main contributors to household electro pollution with power densities far above any nearby mobile phone mast.
If your internet connection is by telephone you will need the Netgear DG834 model opposite. If your internet connection is via a cable connection you would need the Linksys wired modem opposite.
These alarms use the same technology as DECT cordless phones and will continuously pulsate microwave energy throughout the babya€™s room and beyond. Best to change your old cathode-ray monitors (the ones with the deep backs) to any type of flat screen monitor as these give of far less Electromagnetic fields than the old type which thankfully you cana€™t buy any more. In order to get your body back to its proper earth bound resonance you need to be sleeping earthed.A  Explanation of what is sleeping earthed and how you can do it is found on my website. Geobiology explores the relationship between life and the Eartha€™s physical and chemical environment.
The history of geobiology in this respect dates back to 1929 when a German aristocrat Baron Gustov Von Pohl, an eminent dowser, made the extraordinary claim that cancer was caused by a€?energy linesa€™ that ran under the beds of the people that had died from the disease. Underground Streams: a€?Water will flow through any underground passage, fracture of fissure. The dark square with flashing white lines is a photographic print of microwaves radiating in the space above an underground watercourse taken in total darkness.
Diagram depicts the flow of underground water and consequential chemical reactions within certain geological features that could be the origin of geopathic stress issues. The dipolar nature of water molecules can also be part of the origin of electromagnetic fields originating from ground contained water. The electromagnetic spectrum refers to the range of different types of Electromagnetic Radiation.a€?These are usually sorted by the frequency.
For visual explanation, NASA have a simple but useful diagram, and there is a far more detailed diagram available from thinkgeek (purchase required).
We believe that one of the main reasons that EMFs (particularly microwave frequencies) are potentially bioactive is due to the nature of the signal itself.
We have evolved with the natural levels of EMFs produced by both the sun and world around us. Power frequency (50Hz in the UK) is given off by any appliance or transmission of AC (alternating current) electrity. Childhood leukaemia has been internationally accepted as linked to powerfrequency exposure magnetic fields, with a wealth of literature finding increases in risk to this and other illnesses. It is well documented and generally accepted that over-exposure to ultraviolet rays can cause burning and skin cancer.
There are internationally accepted guidelines by the International Commission for Non-Ionising Radiation Protection (ICNIRP) that have been designed to limit both residential and occupational exposure to levels that are safely below those that can heat up tissue. However, recently there has been a number of studies showing very specific biological effects far lower than these levels (see our Studies list), and as yet there is no international guidance that has taken any of these studies into effect.
Powerfrequency electromagnetic fields are generated by any appliance running off AC (alternating current) power - anything plugged into a main power socket will generate them to some degree. At the moment, health effects primarily associated with powerfrequency EMFs are due to the magnetic component - these include, but are not limited to, Childhood Leukaemia, Adult Leukaemia, Amyotrophic Lateral Sclerosis, Miscarriage, and Clinical Depression. There is a fairly brief overview of health risks and evidence in the health concerns section of the electric power transmission article on Wikipedia. The last type of geopathic disturbance that I want to talk about before we have a look at man-made electromagnetic energies concerns the earth's natural geomagnetic field (the one that makes a compass needles pointA  north). The first geomagnetogram (G1) typically represents the values of the Earths normal geomagnetic field taken by me in a farmer's field near Poynings village not far from where I live. The second geomagnetogram (G2) was taken above a sprung mattress from a lady suffering from chronic fatigue syndrome and severe depression, and has a magnetic anomaly of 22,435.4 nT. The Cliff of Tears a€?It is important not to underestimate the value of the earth's natural geomagnetic field (DC Field) which interacts with our bodies in many positive waysA  This DC field rarely shows an anomaly above or below 2% of its normal strength which differs according to the latitude in which you live.
Unnatural Alterations in the Earth's Geomagnetic Field a€?A second and equally important influence on the sequence of mitosis is the role in which the normal earth's geomagnetic field (DC field) influences the formation and production of a healthy pregnancy. Health risks due to exposure to electromagnetic fields EMFa€™s in the home were first suggested in America by Wertheimer and Leeper, when they estimated the levels people were exposed to, using a€?wire codesa€™, and the local incidence of childhood leukaemia.
Stress sensitive hormones such as prolactin and thyroxide have been found to be elevated in people at work in high electromagnetic environments.A  Prolactin plays a key role in moderating parts of the neuro-immune system and may also be an important precipitator of auto immune diseases.
It has been scientifically proven for the first time, with a double blind study by means of an electrocardiogram, that the detrimental effects of a€?water veinsa€? and other geopathically disturbing phenomena can cause serious health problems to persons exposed to them. This presentation took place in March 2003 in the large auditorium of the Saint Johanns-hospital Landesklinjken SalzburgA  Germany. At locations where Geopathic stress zones are present, subsurface water plays a predominantrole, either as lakes, slowly moving underground water, or as water streams. Technical electromagnetic fields can also drastically affect the human body, as soon as certain field strengths are reached. The electromagnetic spectrum refers to the range of different types of Electromagnetic Radiation.These are usually sorted by the frequency.
The Cliff of Tears It is important not to underestimate the value of the earth's natural geomagnetic field (DC Field) which interacts with our bodies in many positive waysA  This DC field rarely shows an anomaly above or below 2% of its normal strength which differs according to the latitude in which you live. Body temperature and emotional state are closely related in humans, and stress-induced hyperthermia (SIH) in rodents has predictive validity for certain anxiolytic drugs. IntroductionTumor markers are measurable biochemicals that are associated with a malignancy. There are several factors involving your day-to-day experiences that can hold you susceptible to stress and eventually to hair loss. Observing healthier eating habits combats several diseases that can make you vulnerable to hair loss.
Doing any of these will not only let you feel revitalized; it will also lower the risk of suffering from stress-induced hair loss to a significant extent. Going for a jog, doing yoga or meditating once in a while,and even as simple as cleaning your house—as long as you’re able to move your body and sweat out—are already very effective stress busters. You may tend to ignore the importance of getting enough, well-rested sleep, but it brings a number of indispensable benefits on to your health.
Only buy products that are mild and that contain vitamin E, which is an important nutrient in growing a strong, beautiful hair. Say if you wash your hair twice or thrice a day, you can just put conditioner the succeeding time. These tips can provide you with an effective way to prevent the onset of premature hair loss. Mattressnextday stocks a LARGE assortment of beds and mattresses, probably the largest collection on-line today!
There is no more excuse for people who do not have a gym membership; all your workout can now be done at home, bootcamp style. In fact, nutrition is a critical part of the fitness equation and you cannot attain your goal of losing weight and getting fit without proper nutrition. Or if you are addicted to cordless phones by the low energy Eco + friendly types that only emit a signal when you are using them.A  Google Siemens Gigaset Low Radiation Phones. An example of this is a digital bedside alarm clock that only need 6 volts to operate but plugged into your 240 volt ring circuit. Click first on my a€?Studenta€™s Notesa€™ button and scroll to the end for pictures and explanation. The term was adopted many years ago by some German dowsers, a€?geobiologistsa€™ who specialised in surveying houses for both geopathic and electromagnetic stress using both dowsing and scientific instruments. To test his theory he persuaded the Mayor of the Bavarian town of Vilsbiburg to allow him to survey the town for such energies with his dowsing rod.
As it does so it produces its own electromagnetic field often high into microwave frequency. It has been known for a long time that when there is flowing water under a dwelling the inhabitants always feel more tired, are prone to premature aging and have a loss of vitality than those who sleep above neutral ground. As an extremely dialectic medium, water favours the formation of potential vortices, which immediately after their formation contract swiftly. Background levels of EMFs vary hugely depending on which part of the spectrum being looked for - natural light is an obvious example. Electrical wiring creates electric and magnetic powerfrequency fields throughout houses and other wired buildings, but these levels are usually very low unless there is a wiring fault.
Most areas of science can only deal in probabilities, and that becomes clearer as more scientific studies investigating health effects are produced. There is more disagreement about ill health effects from radiofrequency radiation, which is newer for most of the population, though a well-established 'microwave sickness' has been described.
As a result fortunes are spent on protective sun cream and information services as to prudent avoidance of such exposures. Molecules in the food are vibrated by high levels of microwave frequency Electromagnetic energy, causing it to heat up and subsequently cook.
This, coupled with misleading statements designed to imply that there is currently no published evidence showing a link from organisations such as WHO, are the primary reasons why this topic remains in such hotly-disputed contention.
ICNIRP have set guidelines for residential and occupational exposure to powerfrequency magnetic fields, based primarily on electric shock responses and induced currents, currently set at 100 microtesla (AµT) - equivalent to 1 Gauss. The evidence on these is mixed, but the link with Childhood Leukaemia is now considered to be pretty solid, with a doubling in risk at magnetic fields above 0.4 AµT (again far below the guidelines set by ICNIRP).
The bottom line is that nature neverA  intended us to sleep on such a disturbed site as shown in figure G2 which has been artificially produced by the bed being placed near to a radiator ( causing the high spike to the right of the graph)A  and the springs causing the rest of the disturbed site. As you can see the magnetic contours of this bed size area (6a€™x4a€™) are very gentle and slightly undulating showing an overall geomagnetic anomaly of 582 nT (nano Tesla). The sprung mattresses I have measured so far over the past two years have had magnetic anomalies between 4,000 and 61,000 nT. However there are instances in nature where abnormal magnetic anomalies exist usually due to a sudden change in mineralogy or geological structure over a short distance. It appears that the exposure of a dividing cell to an inhomogeneous DC magnetic field causes a physical force to be exerted on the chromosomes or on one of the other microscopic structures associated with mitosis, resulting in structural abnormalities in the chromosomes.
Since that time, international research has increased year by year, and the potential health risks have been identified as cancer (especially childhood leukaemia, probably the most studied illness because of the original findings), depression, suicide, miscarriage, some forms of dementia, respiratory and immune system problems. Research by scientists such as Ross Adey in the USA and Dr Cyril Smith here in Britain is moving the frontier of our understanding.
Hubank of Vienna: a€?Speaking at a conference in England paid tribute to a group of Austrian researches composed of medical doctors, physicists and biochemists.
There is clear indication that a combination of technical fields and Geopathic stress zones can multiply the effect and therefore become extremely harmful to all living beings. This test allows to assess the effect of anxiolytics on stress-induced hyperthermia and simultaneously measure the intrinsic effects of these drugs on core body temperature. They are either produced by tumor cells (tumor-derived) or by the body in response to tumor cells (tumor-associated). When left unheeded, stress could eventually give way to numerous physical and mental conditions. Shampooing your hair too often can make your hair brittle and prone to breakage, since it strips your hair off its natural oils and proteins. So you won’t ever need a wig, make sure you switch to a healthy lifestyle so as to avoid stress and its damaging effects on your hair and the rest of your body. The Mayor agreed and in January that year Baron Von Pohl accompanied by the Mayor and other officials measured numerous energy lines that ran through the streets and houses of the town.
This field will fluctuate depending on what is dissolved in it, how fast it is flowing or whether it is interacting with any other type of earth energy. While water running beneath a domestic dwelling should be avoided, a stream situated nearby and open to the sky will favourably discharge its negative energies harmlessly into the atmosphere. Taking its electric charge distribution in to account, turning a water molecule will result in a changed field composition.
The electric field is produced by stationary charges, and the magnetic field by moving charges (currents). The earth's magnetic fields are static fields, unlike man-made alternating current (AC), which has no natural counterpart. Unfortunately the studies are not always well done, and the flaws in any given study (showing an effect or otherwise) are often not reported. Precautionary levels which will protect us from illness have not been agreed on, as some countries wish the levels to be lower than others. If you stood in front of an operational microwave with no door your insides would slowly be cooked. The reason for these abnormally high magnetic abnormalities is a result of the bed springs intensifying the magnetic flux of these fields, made worse by the interaction of high magnetic fields around the bed and house from numerous electrical appliances, extension cables running under the bed and transformers placed near to the bed. One instance of this is in the USA, at a place called Gyngywamp, near Croton, Connecticut knownA  as 'The Cliff of Tears' where visitors to this site very frequently become depressed, gums start to bleed and nose bleeds occur.
Messages pass between the brain, nerves and organs and even from cell to cell by electro- magnetic signalling. In the course of several years research using classical medical methods they investigated about 1000 people for the effects of these geopathic interference zones. There were about 400 people present including numerous renowned specialists; physicians, physicists and geologists, in the all-German audience. Also, metal ions moved by water can induce small intensity broadband electromagnetic fields (EMF).
They are usually substances that are released into the circulation and then measured in the blood sample. Our hair is often among the parts in our body that get badly affected when stress takes its toll. So before you worry about going bald, it is important that you do something to prevent stress from devouring you. If you choose to follow the Kodjoworkout Program without consulting your physician, you are doing so at your own risk. Baron Von Pohla€™s energy lines were then compared with the towna€™s record of houses where people had died from cancer during the last ten years, which showed a remarkable coincidence. Dr WA?rst conducted experiments in several German towns, in the rooms of cancer patients and found unusual amounts of gamma radiation in the houses he surveyed using a Geiger a€“counter.
Interference with the earths natural energy field is particularly marked by the flow of these underground streams especially where two watercourses or other types of energy line cross.
If thus in a pipe a hydronamic flow vortex is produced, an electric and magnetic vortex and eddy current, are the result. Microwave frequency exposure is a relatively new phenomenon: 100 years ago the background radiation was millions of times lower than it is now, and it is as recent as the mobile phone boom (~1990's) that the modern, digitally pulsed signals have become ubiquitous in the Western world. Because of this, microwave ovens are stringently designed against leaks, and opening the door operates a safety mechanism which disables the oven, thus removing the risk to the operator. Within our evolutionary history our bodies own magnetic field has integrated with this magnetic field which is responsible for controlling amongst other things, circadian rhythms, mood changes and certain hormone production such as melatonin and serotonin. Our forefathers sleeping on straw or feathered mattresses in houses devoid of any electrical fields or microwave energy would not have experienced such geomagnetic disturbances. Much of the research in the past 35 years into EMF health effects has concentrated on magnetic fields because they are easier to measure and it was thought they were more likely to interact with our bodiesa€™ cells. When this is interfered with by outside EMFa€™s problems begin to emerge, as the systems that control and regulate our bodies are impaired. They found that the altered electrical and magnetic field above a geographical distressed zone changed the electrical impulses passing along the nerves of the body.
There are a few exceptions to this, such as tissue-bound receptors that must be measured in a biopsy from the solid tumor or proteins that are secreted into the urine. Well this surprised the establishment at the time, and knowing Vilsbiburg to have a high degree on cancer victims anywayA  he was asked to repeat the exercise in the City of Stetten which had a far lower incidence of cancer thus ironing out any chance factors. StA¤ngle, who had a very good reputation of locating water bearing fissures in crystalline rock with his dowsing rod developed a stintilisation counter more sensitive and accurate than a Geiger counter and carried out a scientific survey in the French town of Moulins where a local physician, Dr, J Prichard claimed that cancer victims in the town dwelt above geological faults. In a league table of radiation associated with biological damage, the outside line of a subterranean water course would be at the very top since it is found in association with many terminal and debilitating diseases. You can't see, feel or hear electromagnetic fields, apart from visible light, which is a part of the electromagnetic spectrum. Each static magnetic field bump or sink on geomagnetogram (G2) may speed up or slow down body fluids (blood and lymphatic) in exposed areas such as the brain, heart, lung, liver, legs etc. Most scientists believe that, although EMFa€™s do not directly cause the illness in most cases, at least, living in fields above 200 nT (nano Tesla) may make a person develop the cancer or other illness, when if they didn't live in this field level, their bodies would be able to repair themselves, or cope with the daily damage from other causes in a healthier way. This wrong or confused information resulted in the dysfunction of individual organs and also explained the high number of diseases.
Despite the fact that tumor markers are hardly ever specific enough to be used alone to diagnose cancer, they do have a number of clinical applications.
When there is too little serotonin, a person may likely suffer depression, migraines, panic attacks and other stress-related disorders like food intolerance and hair loss.
Whilst WA?rst and StA¤ngle thought that gamma radiation from fissures could be a significant cause of cancer, more recent studies suggest that this is unlikely as gamma radiation tends to whiz straight through the body rather than causing direct hits on DNA. Sleep time exposure to the same sharp variations of magnetic fields for years may induce some chronic health effect. Indeed, in the town nearby, doctors and nurses are familiar with this sudden onset of illness in visitors to this old Indian sacred site. They proved a weakening in the immune system, which interacts with the wrongly programmed nervous system in persons who had been exposed.


Using a randomized double blinded trial*, it has been scientifically shown that Geopathic stress zones do cause chronic stress and therefore can weaken the body's defence systems.
Finally, this stress, in combination with a possible suppression of certain functions of the immune system. They can be used to stage cancer, to indicate a prognosis, to monitor treatment, or in follow-up to watch for cancer recurrence. Harger, chairman of the city's medical scientific association, declared that all such a€?deadly earth currentsa€™ ran beneath the beds of all the 5,348 people who had died from cancer during the last 21 years. The culprit is thought to be the more pernicious alpha radiation from Radon which is found with high levels of gamma radiation.
The World Health Organization in a health criteria report recognizes interactions between variations in static magnetic fields in cellular tissues to include an induction of electrical potentials and magneto hydrodynamic effects in the circulatory systems and by direct stimulation of nerve and muscle cells even under extremely weak thresholds. The causation seems to be that within a few meters the geomagnetic DC field varies from 330 milligauss at an 80 degree dip to 700 milligauss at a 59 degree dip.
Confirmation of these experiments continue to appear and links have been, formed with the onset of cancer, Alzheimer's Disease, Chronic Fatigue Syndrome, Miscarriages, Multiple Sclerosis (MS) and other diseases of the central nervous system. Changes in some tumor markers have been sensitive enough to be used as targets in clinical trials.
Research in this field continues with an increasing number of sophisticated environmental measuring instruments coming on the market to aid the geobiologist in identifying causative factors to illness and disease. The very high electric fields associated with high voltage overhead power lines also cause air ionization, charging toxic aerosols so that they become even more dangerous. Tumor markers for diagnosis are used in combination with other clinical parameters such as biopsy and radiological findings.
To varying degrees the health consequences of staying above one of these geopathically stressed locations can be replicatedA  in our own homes by the choice of mattresses we use.A  The bottom line is, if you suspect your sleeping site is being disturbed by an unusually high magnetic anomaly then buy a bed that has a wooden base and place there upon a mattress that has no springs and make sure it is not placed near a radiator or other heavy metal object. In the 1930a€™s a French engineer Pierie Cody who lived in the sea-port of Le HavreA knew of local a€?cancer housesa€™ in the port where many people had died from cancer over the years. Although there are a multitude of tumor markers, very few of them have found their way into clinical practice because of their lack of specificity. This equipment known as the Genitron Felix - 3 detects ultra short and radio microwave frequencies with the ability to print them out on a [UKW- Spektrometer und Linienschreiber] This equipment is used in German universities and research institutes that confirms dowsable energy above subterranean water lines. Effects central nervous system and the brain in the ways which effect powerful hormonal mechanisms.
However, some of these non-specific markers have found a place in monitoring cancer treatment rather than in diagnosis.Tumor marker discovering is focuses currently much research and attention. After checking large numbers of these dwellings, Cody concluded that the air in these a€?Cancer Housesa€™ were ionized to an unusual degree.
Important areas to be aware of are bedrooms, especially where pillows are on beds, because EMFa€™s affect an area of the brain, called the pineal gland, which works to protect the body against illness overnight. Their final clinical usage is directed by approval from the Food and Drug Administration (FDA) and guidelines established by organizations such as the American Society of Clinical Oncology and the American Cancer Society.
From various other tests Cody concluded that the ionization radiation consisted of positively charged Alpha Particles. It is also a good idea to look at places like a favourite armchair, or in front of a computer or TV. The only known source of alpha particle emission in dwellings was from a radioactive gas called Radon. It is important that places like these where you are sitting or lying still for a longish period of time should have low EMFa€™s; cells tend to cope better with external fields if the person is moving around. In the current review we attempt to propose and bring closer some new “cancer markers” connected to oxidative stress and cell death. When you are sitting still and particular cells keep being interfered with by EMFa€™s, there is an increased risk that the damage may become unrepairable. In recent times, therapeutic approaches take advantages from determination of oxidative stress markers.
In this chapter we try to explain the beneficial application of oxidative stress and apoptotic markers for medical requirements [1].2. ApoptosisApoptosis is the process of programmed cell death which is very important when cells harmful for organism appear. It is worthwhile taking particular precautionary action with regard to childrena€™s living environments.
In this way organism destroys cells that endanger the homeostasis, are malign,, mutated, cells that ignore the signals of cell cycle regulation, lose the ability to undergo apoptosis, and cannot communicate with neighboring cells. In case of cancer process of programmed cell death is inhibited and tumor cells are allowed to tolerate apoptotic signals. Defective Apoptosis has been recognized as a fundamental factor in the development and progression of cancer. Restore of appropriately induce apoptosis may establish antitumor therapy based on o triggering selective death of cancer cell [2,3].Large varieties of different stimuli are able to initiate programmed cell death by apoptosis signaling pathways. Thus there is the extrinsic pathway that depends on triggering of death receptors expressed on the cell surface, the intrinsic pathway mediated by molecules released from the mitochondria and the third pathway activated by granzmes [4,5]. Regulation and inhibition of apoptosis in cancer treatmentThe cells homeostasis is regulated by different mechanism included proliferation, growth arrest, and apoptosis [7].
The disorder in the balance between cell growth and death often leads to the carcinogenesis.
The cells proliferation is regulated by cell cycle, which is an involved sequence of grow and cells replication [8]. It is now accepted that cancer is more accurately described as being the product of malfunctions within the regulation of the cell cycle, such that injured or mutated cells which are normally killed, are allowed to progress through the cell cycle, accumulating mutations.
One possibility is that multiple redox-active flavoproteins all contribute a small portion to the overall production of oxidants under normal conditions.Other enzymes capable of producing superoxide are xanthine oxidase, NADPH oxidases and cytochromes P450. The restrictive points lead to repair damage in cells or eliminated cells in different ways: necrosis, senescence (permanent arrest) or apoptosis [10-13].
Reactive oxygen species play important roles in cell signalling, a process termed redox signaling. Many genes and their proteins products play a dual role in the cell division and apoptosis including p53, pRb, Bcl-2 family.
Thus, to maintain proper cellular homeostasis, a balance must be struck between reactive oxygen production and consumption.
Subsequent stimulation these molecules may induce cell proliferation, cell cycle arrest or cell elimination [8]. The best studied cellular antioxidants are the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. The different result is dependent on different factors, which respectively inhibit or support apoptotic cell death.
Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin. In many types of cancer the mutation of gene responsible for check points are observed [14]. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.Oxidative stress contributes to tissue injury following irradiation and hyperoxia. Apoptosis play a central role in the pathogenesis of human disease especially in malignance while the factors controlling the apoptotic progression are suppressed, overexpressed or modified their function (mutation, phosphorylation, acetylation) [15,16].
It is suspected (though not proven) to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease, Alzheimer's disease, and Huntington's disease. Defects in its pathways be able to promote cancer cell survival and also confer resistance to antineoplastic drugs.
Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the vascular endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia.
In case of the intrinsic pathway several stimuli, including reactive oxygen species and other cytotoxic elements, lack of growth factors, kinase inhibitors initiate this pathway. Cytochrome c binds apoptotic protease activating factor-1(Apaf-1) using the energy provided by ATP and procaspase 9 is activated into its active form [18,19]. This event results in the activation of caspases 3 and 7 as the down-stream effector caspases.
The effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state. However, more severe oxidative stress can cause cell death and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.A particularly destructive aspect of oxidative stress is the production of reactive oxygen species, which include free radicals and peroxides.
This caspase cleaves and activates Bid, which releases cytochrome c from the mitochondria to activate the apoptosome, and apoptosis events. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage. Caspase-8 may bypass the mitochondria and induce apoptosis by directly activating caspase-3. Most of these oxygen-derived species are produced at a low level by normal aerobic metabolism and the damage they cause to cells is constantly repaired.
Granzymes are a different family of serine proteases and the granule protein, perforin, supports granzyme (A or B) release to the target cell cytosol and, on entry [21,22]. Granzyme B can operate by specific cleavage of Bid and induction of cytochrome c release, by activation of initiator caspase-10 or by direct activation of caspase-3 [23]. Lipid soluble and thus able to diffuse across membranes.a€?OH, hydroxyl radicalThree-electron reduction state, formed by Fenton reaction and decomposition of peroxynitrite.
In case of granzyme A caspase-independent cell death can occur via initiation of DNA cleavage. They are aspartate-specific cysteine proteases that are present in healthy cells as zymogens, which are usually activated by proteolytic cleave to form a fully functional active site [19]. Produced in the presence of oxygen by radical addition to double bonds or hydrogen abstraction.HOCl, hypochlorous acidFormed from H2O2 by myeloperoxidase. The group of initiator caspases (2, 8, 9 and 10) triggers cleaves inactive proenzymes of effector caspases. Effector caspases (3, 6 and 7) in turn cleave other protein substrates within the cell, to initiate irreversible events of the apoptotic process [18]. Will readily oxidize protein constituents, including thiol groups, amino groups and methionine.ONOO-, peroxynitriteFormed in a rapid reaction between a€?O2- and NOa€?. Important factors involved in the regulation of apoptosis are inhibitors of apoptosis proteins (IAPs) that can block caspase cascade, but only some of them directly interact with caspases [25]. Protonation forms peroxynitrous acid, which can undergo homolytic cleavage to form hydroxyl radical and nitrogen dioxide. Initiator caspases -8, -9 or -10 directly or by with the participation of specific protein trigger effector caspases -3, -6 or -7 which results in cell death.The ability of chemotherapeutic agents to initiate caspase activation appears to be a crucial element of drug efficacy. Consequently, defects in caspase activation often results in chemoresistance.The normal epithelial cells of gastrointestinal tract colonic epithelium strongly express caspases 1 [26], 3, 7, 8, and 9 [27].
Death receptor (extrinsic) pathway of apoptosis and mitochondrial (intrinsic) pathway of apoptosis were investigated in SW480 and SW620 colon cancer cells.
The investigation study revealed that SW620 cell lines appeared more resistant to apoptosis induced by CH-11, cisplatin and ionizing radiation then SW480 and that Fas receptor and Apaf-1 was decreased in comparison to SW480 cells [28]. The protease activating factor Apaf-1, which was identified as the molecular core of the apoptosome executes mitochondria dependent apoptosis. The relevant levels of Apaf-1 are crucial in the inhibition of tumor progression and for preserving the sensitivity of cancer cells to apoptosis [30]. Allelic loss and subsequent absence of Apaf-1 expression in melanoma cells is associated with chemoresistance [32]. Treating melanoma cells with the methylation inhibitor 5-aza-29-deoxyctyidine increased Apaf-1 expression and chemosensitized melanoma cells [32]. In the other study Shinoura et al showed A-172 cells did not undergo apoptosis after p53 transduction, whereas U251 cells were markedly sensitive to p53-mediated apoptosis. A-172 cells showed higher endogenous expression of Bcl-X(L) than U251, and transduction of Bcl-X(L) repressed p53-mediated apoptosis in U251 cells, suggesting that high endogenous expression of Bcl-X(L) renders A-172 cells, at least in part, resistant to p53-mediated apoptosis. CD20 is a B-cell surface antigen that is an effective target for immunotherapy of B-cell malignancies using unmodified or radiolabeled murine monoclonal anti-CD20 antibodies.
This cell surface phosphoprotein is involved in cellular signaling events including proliferation, activation, differentiation, and apoptosis. They also observed upregulation of Raf-1 kinase inhibitor protein (RKIP) expression in non-ARL cell line. Immunotherapy with specific antibody could be applied alone or in combination with chemotherapy. In the Jurkat clone J16, CD95 stimulation as well as anti-cancer agents’ etoposide induces apoptosis.
Etoposide was also found to induce caspase-8 processing and apoptosis in a CD95-independent fashion because blocking of CD95 receptor function with a specific antibody does not inhibit etoposide-induced apoptosis [38].
2007 showed cancer cell lines transfected with chemokine-like factor CMTM8 submit to apoptosis. Caspase-dependent and independent mediated apoptosis, induced by CMTM8 overexpression, was facilitated by the mitochondria and inhibited by knockdown of Bad or overexpression of Bcl-xL [39].An apoptosis promotion involves signaling through members of the tumor necrosis factors (TNF).
On binding to their proper receptors, some members of the TNF family can initiate caspase activation, resulting in apoptosis. There was also observed that TNF can induce apoptosis in a limited number of tumor cell lines [40]. The effect of TNF induction with anticancer agent OK-432 on the survival rate of colorectal cancer patient was investigated. Patients in the TNF- producing group proved a better prognosis than those of the nonproducing group [41]. The role of p53 and Bcl-2 family in apoptosisOxidative stress oncogene activation and arrest of cell growth lead to activation of tumor suppressor gene p53, which activates apoptosis or senescence [42-44].
The p53 gene has been called “guardian of the genome”, due to crucial role in protecting the genome against the proliferation of mutated cells [45]. The gene p53 is a 53-kDa nuclear phospho-protein that binds to DNA to act as a transcription factor, and controls cell proliferation and DNA repair.
However tumor suppressor protein p53 is induced in response to stress such as DNA damage, oncogene activation and hypoxia. Under the influence of DNA damaging agents the level of p53 protein increased and stopped the cell cycle in order to repair or cell death [46].
DNA damage in the course of therapy cancer increases the expression of PARP and increases the amount of poly-ADP-ribose (PAR) in tumor cells, which positively correlates with the severity of the reaction of proapoptotic [48].
This fact supports that p53 plays an important role in the prevention of tumor development. The decisive function of p53 regulating the verdict of a cell to live or die makes it an attractive target for anticancer therapeutics [51]. Moreover, there are many conflicting studies and approaches which would be the main therapeutic strategy to cancer therapeutics.
Previous study was based on the idea that activation of p53 can induce apoptosis in the tumor. Other are based on the observation that cells with defective p53 are more sensitive to combinations of chemotherapeutic drugs [52].There are numerous investigations where the cells with defective p53 undergo apoptosis. The p53 protein can mediate apoptosis in response to DNA damage caused by chemotherapy but the inducing cell cycle arrest and favoring DNA repair might increase resistance by allowing cells to live after DNA has been damaged by chemotherapeutic treatment [53].
The decisive function of p53 regulating the verdict of a cell to live or die makes it an attractive target for anticancer therapeutics [50]. Other is based on the observation that cells with defective p53 are more sensitive to combinations of chemotherapeutic drugs [52]. It is common known that malignant cells undergoing apoptosis p-53 dependent or p-53 independent. However many examination conducted in recent years have resulted in the discovery of drugs which have been used successfully to treat patients with p53- defective tumors.
Additionally, radiation therapy is usually applied patients independent of their p53 status [54]. The crucial investigation supporting the significance of p53 in mediating DNA damage and induced apoptosis in cells derived from p53 knockout mice.
The authors showed that p53 is required for radiation-induced apoptosis in mouse thymocytes. Similar the fibroblast isolated from the same mice were also resistant to radiotherapy and chemotherapy with adriamycin [56]. Other scientific reports indicated that radiation of T cell lymphoma derived from the same mice with knockout p53 was able to its killing.
There are many studies in which the effect of p53 on the cellular response to chemotherapy and radiotherapy is controversial.
Some reports suggesting that p53 wild-type are more sensitive to many of anticancer drugs, but there are many investigation, which demonstrated that p53-defective are or not sensitive to chemotherapy.
Some examination designate that p53 is necessary for executor caspase 3 activation, suggesting that can play a decisive role in PDT- induced early apoptosis in malignant tissue [57]. Other study examined the outcome of photodynamic reaction with Photofrin (Ph-PDT) on clear human ovarian carcinoma OvBH-1 with “silent mutation” in the p53 gene.
The modification of this method by chemotherapeutic drug 2-methoxyestradiol leads to apoptotic pathway induction in these cells [59]. However, additional studies demonstrate that PDT can induce apoptosis in cancer cells by pathway independent of p53 [60].Differential cells sensitivity on chemo- and other anticancer therapy is probably dependent not only on p53 status but other genes and their products, which control cancer cells responding (c-Myc, protein kinase A, protein kinase C, cyclins). The big influence on anticancer therapy effectiveness is also individual dependent on type of cancer and their environment [61,62]. Recent studies have shown that important role in the effectiveness on anticancer therapy plays a modification by its phosphorylation [63]. One of approach, which leads to regulation of p53 function, depends on its post-translational modifications. It is common known that chemotherapy resulting in an increased stabilization of this protein [64,65]. The cells with phosphorylated p53 protein most often were observed in serine 392 and N-terminal and in serine 20 et C-terminal end observed in cells [66]. Recent investigation have shown that p53 phosphorylation et serine 15 and 20 was necessary to induce apoptosis in ovarian cancer cells after chemotherapy with cisplatin. The p53 protein is also change in lung cancer, but there was no strong correlation between changes in expression of this protein (both mutant and native) and course of disease [67,68]. There was, however, significant improvement in patients undergoing therapy combined, in which the course of exacerbation p53 protein expression [67]. It is known that phosphorylation area of p53 protein binding MDM2 inhibits degradation of p53, a C-terminal phosphorylation of Ser392 alters the cell cycle [69,70].
In addition the new examination have shown that stimulation or inhibition of tumor growth might be due to changes in proteins modify p53. The in vitro and in vivo studies demonstrate that Sir2 protein is involved in this procedure.
These proteins blocks apoptosis induced by “guardian of the genome” in response to stress, which may promote tumor growth The use of Sir2 inhibitors, that prevent p53 deacethylation along with its promoters allow the development of new anticancer strategy based on the maximization of action of this protein [71, 72]. It is obvious that only p53-tageted therapeutic strategy is not enough for the treatment of all type of malignant tissue. Ideally anticancer strategy will be therapy adapted to patients based on the p53 status, checkpoint proteins and gene controlling and oncogenic changes [73].Bcl-2 family is the other important proteins which near and with p53 take part in a decisive role in apoptosis [74]. The products of Bcl-2 gene family are divisible into two main groups: antiapoptotic Bcl-2, Bcl-Xl, and Bclw, and proapoptotic Bax, Bak, Bad, and Bim, which respectively inhibit or support the effecting of apoptotic cell death [76,77].
Thus families of proteins control mitochondrial stability by maintaining the balance between proapoptotic proteins that translocate to the mitochondria and antiapoptotic ones that exist in the mitochondrial membrane [76,77]. The Bcl-2 gene product is located in the membranes of the endoplasmic reticulum, nuclear envelope and the external membranes of the mitochondria [76]. The fact that key Bcl-2 family genes are p53 targets including pro- and antiapoptotic [80]. Bak and especially Bax were the groups induced by p53 mainly in response to stress [81,82].


Bax induced the mitochondrial pathway by outflow of apoptogenic proteins, such as cytochrome c. However, in different studies the involvement of Bax and p53 in different anticancer therapy mediated apoptosis was observed [83,84].Bax gene encoding the protein contains on the promotor sequence the binding location for p53. The requirement of Bax and Bak in p53 –activated apoptosis occurs to be cancer cell-type dependent. Moreover, p53 can also independently activate Bax present in the cytoplasm and this protein forms a homodimer and releases cytochrome c from the mitochondria [85]. Bax protein takes part in apoptotic response of the developing nervous system to irradiation and leads to sensitivity fibroblast cells with E1A-expressing to chemotherapy [86,87].
Additional studies showed that the level of Bax protein acts not crucial role in inducing apoptosis or growth arrest in other cancer cells.
In epithelial colon carcinoma undergoing apoptosis in response to radiotherapy, Bax did not appear to be main inductor of cell death [88,89]. The explanation of enigmatic function of Bax in apoptosis has recently been examined in the context of PUMA.
A fundamental balance between PUMA and p21 which controlled cell cycle determine growth arrest by senescence or death by apoptosis in cooperation with p53. This date was obtained from colorectal cancer cells where the growth arrest through of p21 is the normal rescue response to p53 expression in these cells. The defect of p21 induced in these cells apoptosis pathway, whereas PUMA is damage the apoptosis is prevented. Probably PUMA expression promotes mitochondrial translocation and multimineralization of Bax and in consequence inducing apoptosis.
The pro-apoptotic member of Bcl-2 protein Bid acts crucial function in connecting between the extrinsic and intrinsic apoptotic pathway. Activation of Bid involves cleavage of cytoplasmic Bid by activator caspase 8 and induces post-translational changes. This process leads to Bid translocation into the mitochondrial membrane and activates pro-apoptotic Bax and Bak proteins which initiate apoptosome formation.
Bid gene succumb p53 regulation in response to chemo- and radiotherapy in many type of cancer. Cellular sensitivity to chemotherapy with adriamycin or 5-fluoroacyl is dependent on wild-type p53 and Bid.
These results suggest that p53 can regulate the intrinsic and extrinsic pathway through Bid regulation [93]. Bcl-2 (Bcl-2 its self) residue in the outer mitochondrial membrane and mainly plays an anti-apoptotic function [94]. The Bcl-2 anti-apoptotic protein inhibits apoptosis in cancer cells and promotes cell survival. In many malignancies especially in hematologic the overexpression of Bcl-2 family was found. Recent studies showed that increasing levels of Bcl-2 and Bcl-XL have associated with a more aggressive malignant phenotype often connected with drug resistance to various type of chemotherapy not only in hematologic but also solid tumors [95,96]. As an example in primary prostate cancer, high Bcl-2 level is con were connected with high Gleason scores and an increase rate of cancer recurrence after radical prostatectomy. Also the high expression of BCL-XL in the NCI 60 cell line is strongly correlated with resistance to most chemotherapy agents.
There are many investigations determining the levels of expression of cell death inhibitors in various types of cancer.
These studies afford correlative evidence, but also are designed to search new possibilities of tumor destruction [52]. Many in vitro experiments confirm the preventing role of Bcl-2 in apoptosis activating in different type of cancer [97].This fact decides about therapeutic targets through inhibition of this protein and arrest malignance process [98]. Wild-type p53 can establish complex with Bcl-2 and Bcl-XL and suppress there anti-apoptotic function. However, in 50% of cancers the p53 gene is disrupted and losses its ability to bind to these proteins. Hence research is continuing on the use of synthetic inhibitors in preclinical and clinical study (Table 1.) [97].
The most of them determined the direction of future clinical development and are promising. The p53 and Bcl-2 pro-apoptotic protein are one of the many proteins that induce the intrinsic signaling pathway.
Previous and present studies yield new information about various factors which regulate apoptosis.
Protein plays the crucial role in regulatory cell development, cell cycle, cell growth and apoptosis.
The intracellular proteins are selective stabilized or eliminated by ubiquitin-depenedent pathways.
Ubiquitin is a protein complex composed of the activating enzyme (E1), a coniugating enzyme (E2) and protein ligase (E3) [100-103]. This process plays a crucial role of many significant signaling pathways and important role in many cellular pathways including apoptosis. Many proteins which can regulate apoptotic pathways have been recognized as target substrates for ubiquitination [103]. The ubiquitin –proteosome protein damage can inhibit apoptosis by degradation proapoptotic controller. From this studies appear that proteosome inhibitors can apply as antitumor therapies through enhancing apoptosis [103]. Apoptosis regulatory molecules have been recognized as substrates and degraded in proteosome. The heat shock proteins can play an important role in recognition and degradation of damaged proteins by ubiquitination [107]. The heat shock proteins (HSPs) are a highly conserved class of proteins whose expression in increased in cells exposed to different kinds of stress. HSPs are a family which limit the consequences of damage and facilitate cellular recovery [108,109].
This results in dissociation of HSF (heat shock factor), then migrates to the nucleus, where it binds with HSE (heat shock rudiments) leading to HSP overexpression [110]. The basis for the classification on these proteins was their chaperone activity and molecular weight. HSPs can be divided into three subfamilies: large (HSP100, 90), intermediate HSP 70, 60 and 40) and small (sHSP less than 40 kDa).
In addition to many function the HSPs protein plays a crucial role in inhibition of apoptotic process. Anti-apoptotic role of sHSP proteins makes it encourages the development of tumor progression and metastasis. There are several reports according to which the use of antisense oligonucleotides directed against HSP27 can be basis of anti-cancer therapy.
The overexpression HSP27 is often finds in malignant cells for example in ovarian and breast cancer. Blocking apoptosis by the sHSP lead to interfere with some cytostatics and decrease the effectiveness of chemotherapy. HSP90 inhibits formation of an active apoptosome whereas HSP70 prevents the recruitment of procaspase-9 to the apoptosome complex [60].
HSP-mediated regulation of apoptosis through inhibition of major pro-apoptotic proteins is involved in this process [115,116].3. Enzymatic antioxidantsDefense against oxidative stress is provided by a system of antioxidants enzymes and non-enzymatic antioxidant substances capable of neutralizing free radicals and preventing an excess production of reactive oxidative species (ROS) [117]. The first line of cellular defense against oxidative stress enzymes are: the family of superoxide dismutases (SODs), glutathione peroxidases (GPXs), and catalase (CAT) enzymes.
They are the main free radical-scavenging enzymes which decomposing superoxide radicals and H2O2. It plays an important role in catalyzing the conjugation of reactive electrophilic agent to glutathione (GSH) [118].
SOD is an essential antioxidant enzyme that defends cells against potentially damaging superoxide radicals. These two compounds serve as the major redox couple within the cell, which determinant the total cellular antioxidant capacity [125, 126]. GPX1, which is localized in the cytoplasm and mitochondria in the liver, kidney, lung, and red blood cells, catalyzes the reduction of H2O2 and some organic peroxides [127].
GPX2, localized mainly in the liver and gastrointestinal tract, protects against lipid hydroperoxides.
GPX4, expressed in the testis, is capable of reducing phospholipid hydroperoxide, including lipid peroxides derived from cholesterol [128,129]. Catalase is an antioxidant enzyme which catalyzes the conversion of H2O2 to water and oxygen. It is concentrated mainly in peroxisomes [130].Persistent oxidative stress is a major initiator to progress cancer [119,121,131]. Reactive oxidative species (ROS) may cause irreparable damage, therein: base modification, DNA strand breaks, DNA-protein cross-links [132].
Following cellular damage initiated the deregulation of cell signaling pathways, tumor suppressors and an inhibition of apoptosis [121]. A variety of studies involving antioxidant enzyme levels and cancer development have been performed. Glutathione peroxidase activities have been found to be changeable, while catalase activity is generally lower in tumor cells than in healthy tissue [133-135].The changes in enzymatic antioxidants status [118], the level of lipid oxidation [136] and an increase of DNA breaks number in tumor cells and leukocytes of blood indicate the process of malignancy [137].
Oxidative DNA damage in blood and other tissues were detected in various types human carcinogenesis [118,138,139,140]. In smokers the role of GST is crucial in modulating susceptibility to smoking-related lung cancer, oral cancer and chronic obstructive pulmonary disease [118,142,143].
It is also observed that the GPx and SOD activities decrease in the group of cancer patients during cancer development [118,144]. They found no change in the malondialdehyde (MDA) level, which is consistent with the previous work in patients with oral cancer [117,145,146,147]. It was observed that SOD, GPx and GSH levels in the erythrocyte and plasma was significantly lower in cervical cancer patients, as well as Vitamin E, Vitamin C and GST level.
These results suggest possible use of antioxidant supplementation as prophylactic agents for prevention and treatment of this cancer [148].Carcinogenesis process is accompanied by weakening of the antioxidant enzyme system, but also by high expression ROS-generated enzymes [149]. The NADPH oxidases (Nox enzymes) share the capacity to transport electrons across the plasma membrane and to generate superoxide and other reactive oxygen species (ROS) [150,151]. The physiological functions of Nox enzymes include: cell differentiation, host defense, posttranlational processing of proteins, cellular signaling, and regulation of gene expression.
Those enzymes could also induce a wide range of pathological processes, including the process of carcinogenesis [150]. NOX1 homolog of the NADPH oxidase is highly expressed in the colon [152,153] and it might contribute to development of colon cancer through at least two mechanisms: ROS-dependent DNA damage and ROS-dependent enhancement of cell proliferation [150].
NOX4 homolog of the NADPH oxidase is suggested to promote cell growth in melanoma cells [153]. Drugs directly inhibiting the NADPH oxidases activation could successfully inhibit oxidative stress and inflammation caused by this enzymes [149]. Apocynin (4-hydroxy-3-methoxyacetophenone) is now used indiscriminately as a NOX4 [154] and as a NOX5 inhibitor [155].In some situations ROS are used in anticancer therapies.
Photodynamic therapy (PDT), a promising therapy for solid tumors, based on the photochemical reaction produces singlet oxygen and other forms of reactive oxygen, such as superoxide ion, hydrogen peroxide, hydroxyl radical [156-160].
Singlet oxygen and superoxide anion have been demonstrated to play a main role in the cytotoxic effects induced by PDT [164, 165].
SOD1 and SOD2 scavenged cells from singlet oxygen and significant extent the antitumor efficacy of PDT [156, 166, 167].
Combinations of SOD inhibitor with PDT might result in significant increase in the efficiency of anticancer treatment [154].
Overexpression of SOD2 suppresses apoptosis, negatively correlates with the sensitivity of tumor cells to radiation therapy and anticancer drugs [168, 169].
2-methoxyestradiol (2-MeOE2) was shown to selectively inhibit the activity of superoxide dismutases [170]. Products of the reaction catalyzed by this enzyme are CO and biliverdin which is rapidly converted to bilirubin. Biliverdin and bilirubin are potent antioxidants capable of scavenging peroxy radicals and inhibiting lipid peroxidation [174-176]. Induction of HO-1 protects against the cytotoxicity of oxidative stress, which seems to play a protective role against PDT-induced cell death [173, 177].Administration of HO-1 inhibitors might be an effective way to potentiate antitumor effectiveness of PDT. Zinc (II) propoporphyrin IX, and HO-1 inhibitor, markedly augmented PDT-mediated cytotoxicity towards colon adenocarcinoma C-26 and human ovarian carcinoma MDAH2774 cells [173]. Kocanova et al showed that treatment of HeLa (human cervix carcinoma cells) and T24 cells (human transitional cell carcinoma of the urinary bladder) with hypericin-PDT dramatically induced of HO-1 expression. This HO-1 stimulation is governed by the p38MAPK (p38 mitogen-activated protein kinase) and PI3K (phosphatidylinositol 3-kinase pathways).
Non-enzymatic antioxidantsAmong the non-enzymatic antioxidants can be distinguished based compounds, both endogenous (glutathione, melatonin, estrogen, albumin) and exogenous (carotenoids, vitamin C, vitamin E, flavonoids), which must be delivered to the body with food because the body is not able to produce them himself. Carotenoids are natural antioxidants present in the chloroplasts and chromatopfores, giving the plants the color yellow, red and orange, visible especially in autumn. Their function is to stabilize the lipid peroxide radicals as well as provide protection against damage from sunlight by absorbing energy or redirecting it to other processes in the cell.
Vitamin A is fat-soluble antioxidant.Some studies have shown that supplementation with high doses of ?-carotene or carotenoid in smokers, as well as in laboratory animals exposed to tobacco smoke increases the risk of lung cancer [179-181]. A study have shown that administering both vitamin A and vitamin C to the cell culture of human breast cancer cells was three times more effective than the administration of these vitamins separately [184].
?-carotene it normally functions as an antioxidant, at high concentration it exhibits prooxidant effects especially at high oxygen tension [185, 186].
Carotenoids diets have demonstrated some anticarcinogenic activity in animal experiments [187-190].Ascorbic acid (vitamin C) is antioxidant that works in aqueous environments of the body. Humans cannot synthesize vitamin C, it must be provided exogenously in the diet and transported intracellularly. Vitamin C has important roles in vascular and connective tissue integrity, leukocyte function, and defense against microorganisms. Vitamin C is considered as a most powerful ROS scavenger because of its ability to donate electrons in a number of non-enzymatic and enzymatic reactions.
Some authors demonstrated ability to neutralize free radicals produced by exposure to light to compounds of lower toxicity [191,192]. Vitamin C plays an important role in the detoxification of substances such as tobacco smoke, ozone and nitrogen dioxide [193]. Ascorbic acid reduces tocopheryl radical formed by the reaction of vitamin E with lipid radicals, protects membranes against oxidation, and prevents lipid peroxidation and affect the regeneration of vitamin E [194,195].The data reported here suggest that the dose of vitamin C supplement used may induce additional defenses against oxidative damage, through an increase in lymphocyte SOD and CAT activity [196]. Low serum levels of Vitamin C in high risk population may contribute to the increased risk of chronic gastritis or gastric metaplasia, which are both precancerous lesions [201]. Vitamin C has proven to be beneficial as a factor in preventing cancer of the lungs, larynx, mouth, esophagus, stomach, colon, rectum, pancreas, bladder, cervix, endometrium, breast, and malignant brain tumor. Vitamin C is effective in the defense against oxidative stress-induced damage [203].?-tocopherol Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation[204]. The most active form of vitamin E in humans is ?-tocopherol and there is considered as a major antioxidant in biomembranes.
It has been noticed that in colorectal cancer patients the incidence decrease vitamin E [205-207] and the intake of Vitamin E [200 IU] reduced the incidence of colorectal cancer by triggered apoptosis of cancer cells [208]. Colorectal carcinogenesis may be reflected by greater elevation of MDA and decrease level of vitamin E and vitamin C in the serum [209]. Other study reported negative results for Vitamin E in combination with Vitamin C and beta carotene to prevent colorectal cancer adenoma [210, 211]. Since Vitamin C regenerates Vitamin E, it has been proposed that addition of Vitamin E hinders the protective effect of Vitamin C against oxidative damage.Flavonoids are polyphenolic compounds that are ubiquitous in nature. Over 4,000 flavonoids have been identified, many of which occur in fruits, vegetables and beverages (tea, coffee, beer, wine and citrus fruits, grapes, soy products).
The flavonoids have been reported to have antiviral, anti-allergic, anti-inflammatory, and antitumor and antioxidant activities.
Protective effect, preventing lipid peroxidation, is also responsible for maintaining the appropriate level of glutathione in the cells. For the flavonoids and their derivatives with the strongest antioxidant potential include: delfinina, epicatechin, kaempferol, quercetin, luteolin. Quercetin, the most abundant dietary flavonol, is a potent antioxidant because it has all structural features for free radical scavenging activity. At high experimental concentrations that would not exist in vivo, the antioxidant abilities of flavonoids in vitro may be stronger than those of vitamin C and E, depending on concentrations tested [212].
Epidemiological studies have shown that regular consumption of fruits and vegetables is associated with reduced risk of chronic diseases such as cancer and cardiovascular disease [213,214]. It has been reported that fresh apples have potent antioxidant activity inhibit the growth of colon and liver cancer cells in vitro [215]. Apples are commonly consumed and are the major contributors of phytochemicals in human diets.
Some studies have demonstrated that whole apple extracts prevent mammary cancer in rat models in a dose-dependent manner at doses comparable to human consumption of one, three, and six apples a day. The inhibitory effect of black tea polyphenols on aromatase activities has been investigated.
Black tea polyphenols, TF-1, TF-2, and TF-3, significantly inhibited rat ovarian and human placental aromatase activities. In in vivo models, these black tea polyphenols also inhibited the proliferation in MCF-7 cells [217].Glutathione (GSH) is the most important non-enzymatic cytosolic antioxidant. This tripeptide is produced by the body from three amino acids: cysteine, glutamic acid and glycine [218].
In addition to neutralize free radicals, glutathione is responsible for maintaining the antioxidant activity of other antioxidants, stabilizing its reduced form.
One of the basic functions of glutathione is to maintain the sulfhydryl groups of proteins in the reduced state and inhibition of oxidation by hydrogen peroxide [191, 193, 219]. Glutathione together with glutathione peroxidase (GSH-Px) reduces hydrogen peroxide H2O2 and lipid peroxides, which is accompanied by the formation of glutathione disulfide, which is reduced by NADPH in a reaction catalyzed by glutathione reductase [220].
Equally effective could lead hydroxyl radical HO, the most dangerous of free radicals to form water. Preliminary results indicate glutathione changes the level of reactive oxygen species in isolated cells grown in a laboratory, which may reduce cancer development [221, 222]. Others study demonstrates that in colorectal carcinoma patients, a very highly significant decrease in total plasma thiols and intracellular glutathione [224]. The antioxidant properties of selenoproteins help prevent cellular damage from free radicals.
Many studies confirm that selenium reduces the risk of all cancers especially cancer of the liver, prostate, colorectal and lung cancer [225, 226]. The results showed that Selenium could significantly inhibit tumor growth as well as extend the median survival time of tumor-bearing mice [227].
Selenium deficiency is associated with an increased risk of cancer and cancer death [229, 230]. Non-enzymatic antioxidants are relatively ineffective in comparison with the action of antioxidant enzymes.



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