Antioxidant Bibliography

• I surveyed several meta-analyses of the antioxidant vitamins A, C, and E — demonstrating a lack of benefit from supplementation, and in some cases positive harm. At first, this result surprised me. How can one explain it? After all, we know that vitamin-rich fruits, vegetables and herbs are good for us. Extracts from these anti-oxidant-rich foods have been shown to neutralize reactive oxygen species (ROS) in the lab. Hence, it must be the case that fruits, vegetables and herbs are good for us because of their antioxidant content – right? Wrong. As we all know, correlation does not always imply causation. And it turns out that fruits, vegetables and nuts may improve our resistance to oxidative damage for reasons other than their antioxidant content. A more likely reason is that these foods are rich in polyphenolic phytochemicals–such as bioflavanoids– that stimulate the cells in our bodies to turn on a transcription factor called Nrf2, which activates our "xenobiotic" defense system. This xenobiotic defense system or Antioxdiant Response Element turns on the production of a number of endogenous anti-oxidant enzymes–such as superoxide dismutase and glutathione peroxidase–that inactivate ROS species catalytically. That means that unlike the antioxidant chemicals in foods–which quickly get used up one-for-one when neutralizating oxidant molecules–the anti-oxidant enzymes turn over thousands of times, and are thus far more potent and sustainable defenses. In addition, these enzymes are produced in cells throughout the body, localized where they are needed most. In short, empowering our in-born antioxidant defense system is much more effective than supplementing with chemical antioxidants. But what is even more startling is that supplementing with endogenous antioxidants can actually suppress your body's endogenous ARE defense system. Startling, but not too surprising once you realize that the ARE system is homeostatically regulated. [Getting Stronger]
• Johns Hopkins study in which broccoli extract applied to the skin of nude mice prevented oxidative damage from UV light for a period of several days, even after it was washed off the skin. The absorbed sulforaphane could only act as an antioxidant for 30-60 minutes, at best a short-term effect. However, the induced upregulation of antioxidants in the skin protected the skin from UV for two days! To put it in chemistry terms: antioxidants are stoichiometric and used up quickly, whereas the endogenous antioxidant enzyme system is catalytic and long-lasting. [Getting Stronger]
• Mother Nature embedded the Nrf2 signaling pathways in us intentionally, because she didn't want us to get cancer. She cleverly invented a molecule (sulforaphane) which could both activate Nrf2 then be incorporated into one of Nrf2's greatest weapons (glutathione). [Lagakos]
• In humans under normal conditions, I believe pro- and anti-oxidants are balanced by our own endogenous processes. If we ingest something that produces a bit too much ROS, they'll be neutralized. If we ingest something that induces antioxidant processes, they'll be used if necessary and degraded if not. In other words, as long as you're not mega-dosing beta-carotene or smoking 2 packs a day, etc., then none of this should matter. [Lagakos]
• The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles. [NLM]
• Oxidative stress is a major contributor to chronic lung diseases. Antioxidants such as N-acetylcysteine (NAC) are broadly viewed as protective molecules that prevent the mutagenic effects of reactive oxygen species. Antioxidants may, however, increase the risk of some forms of cancer and accelerate lung cancer progression in murine models. Here, we investigated chronic NAC treatment in aging mice displaying lung oxidative stress and cell senescence due to inactivation of the transcription factor JunD, which is downregulated in diseased human lungs. NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants. [link] 
• "Some sort of oxidative stress is a necessary signal for cells to marshal their genetic response to physiological stress. If we block oxidative stress, we may make ourselves more vulnerable to infection. Seen in this light, it is quite conceivable that we are 'refractory' to large doses of dietary antioxidants because they interfere with our response to stress." He says: "I suggest that there is a trade-off between oxidative stress as a signalling pathway that musters our defences against infection, and oxidative stress as a cause of ageing. In effect, the diseases of old age are the price we pay for the way in which we are set up to handle infections and other forms of stress in our youth." "Infectious diseases cause a rise in oxidative stress, which is largely responsible for coordinating our genetic response to the infection. As we age, mitochondrial respiration also causes a rise in oxidative stress, which activates essentially the same genes through a common mechanism that involves transcription factors like NFkB. Unlike infections, however, ageing is not easily reversed: mitochondrial damage accumulated continuously. The stress response and inflammation therefore persist, and this creates a harsh environment for the expression of 'normal' genes. The expression of normal genes in an oxidized environment is the basis of their negative pleiotropic effects in old age." "As we have seen, antioxidants rarely cure diseases, let alone ageing. Of the many possible explanations for this - perhaps they are not potent enough, or do not get to the right place in the right amount at the right time - the most inherently believable is that free radicals are only part of the problem." Antioxidants "cannot halt mitochondrial leakage, and cells are refractory to overloading with antioxidants, lest they smother the powerful genetic response to injury." [CBS]
• Based on the evidence derived from the current study, we here propose an essential role for exercise-induced ROS formation in promoting insulin sensitivity in humans. This induction appears to involve the ROS-dependent transcriptional coactivators PGC1α and PGC1β, and the transcription factor PPARγ and their targets SOD1, SOD2, GPx1, and, to a reduced extent, CAT. Most importantly, these changes in gene expression and the increase in insulin sensitivity following physical exercise are almost completely abrogated by daily ingestion of the commonly used antioxidants vitamin C and vitamin E. Thus, antioxidant supplementation blocks many of the beneficial effects of exercise on metabolism. [PNAS]
• During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. [link]