An Interesting and Counterintuitive video about Cancer

 I found this an intriguing perspective on cancer. There are many interesting concepts explored in this video. 

(1) Systemic thinking about cancer | Miscellaneous | Heatlh & Medicine | Khan Academy - YouTube

Red Ginseng and Cancer

 

A new effect of red ginseng: suppression of lung cancer metastasis

Cancer, heat shock protein 90, and adaptation

I read about this quality of heat shock protein 90 a long time ago and was always puzzled by it because it challenged our conventional view of protein production control.  It means the capacity for adaptation does not require de novo mutations, that the potential for adaptation is often present but suppressed by hsp90, which can let this adaptive potential loose when conditions change or stress occurs. Fascinatingly, hsp90 also binds the key stress receptors, GCs and MRs, and their function requires a dissassociation from the two. So from single cell creatures to us, hsp90 has a strongly conserved evolutionary role, this being rather typical of most heat shock proteins.

Prions and chaperones: Outside the fold

Susan Lindquist has challenged conventional thinking on how misfolded proteins drive disease and may power evolution. But she still finds that criticism stings.

Starving Cancers

This news item is interesting because it represents a novel strategy to delay tumour progression but that strategy is also unlikely to eradicate the tumour.

Short fasting cycles work as well as chemotherapy in mice
Even fasting on its own effectively treated a majority of cancers tested in animals, including cancers from human cells.

It touches on the Warburg Effect. You can read the Wiki entry on this but it has some errors. Notably:

• Glycolysis is not just anaerobic, it can also be aerobic. Hence the claims by some that oxygen therapy should kill cancers is just plain wrong. As I said to a friend recently, if oxygen is the enemy of cancer then explain lung and brain cancer. Can't be done. 
• The collapse of mitochondrial function still remains a mystery. Any cell may contain hundreds of mitochondria so we can rule our mtDNA changes, the causal agents here must be humoral. One possible candidate is UCP proteins, these proteins uncouple mitochondrial respiration from producing ATP. Brown adipose tissue uses this property to generate heat in our bodies. So we have a situation where this is a specific class of normal cells with UCP being ubiquitous but not driving cancer. That may be irrelevant because to my knowledge in adulthood we do not produce new fat cells, only make existing fat cells fatter. So fat cells may be oncologically disabled. 

Why Does Fasting Have This Effect?

The Warburg Effect, which is surprisingly common if not pervasive in cancer cells, makes the cell entirely dependent on sugar. Caloric Restriction does very much lower the incidence of cancer but comes at a big cost. That being:

• Compromised fertility
• Potentially reduce immunological status. 
• Hypoglycemia
• In humans I suspect over the long term it damages cognition(Neurons are entirely dependent on sugar, astrocytes absorb sugar from the bloodstream, convert it to pyruvate, which is then excreted to the extra cellular space, where it is then picked up by neurons. 

Caloric Restriction is impractical and unnecessary. Short intermittent fasting can do provide many of the same benefits. It is my view that if you are concerned about cancer prevention then learning to fast is a good idea. Stop the cancer before it stops you because nearly all of us have nascent tumours. It is a probability game and intermittent fasting helps stack the odds in your favour by promoting cell death in pre-cancerous and cancerous cells.

Fasting can induce sugar loss but keep in mind that despite all the hype about the dangers of sugar we'd be dead without it. Our brains our critically dependent on sugar, whether it be from glucose, fructose, or carbs(reduced to sugar via our bodies), we need that sugar in our bodies, hence the large reserves stored in our liver and muscles as glycogen. It therefore becomes problematic that collapsing sugar levels is a key component in the anti-cancer effects of CR and fasting. In fact, without experiencing hypoglycemia, which knocks you to the floor and carries its own risks, including brain damage, I'm not sure how collapsing sugar intake can be beneficial in treating cancers. So .... .

A very notable effect found in Caloric Restriction studies is that very substantial decline in Insulin Growth Factor prodn. We are talking about multiple declines in concentration here, not just a dip but a big decline. Sugar levels play an important role in regulating insulin growth factor levels. Insulin growth factor, stimulated for release and production from the liver by Human Growth Hormone, is the key growth factor. This addresses the above quandary because reducing sugar levels will have an immediate impact on growth factor production. As there is an increasing view that cancers are being driven by cancer stem cells, and these cells are signalled by growth factors, and the recent trend towards identifying inhibitors of growth factor receptors in cancerous cells, this suggests that real benefit of fasting is not sugar restriction per se but rather its impact on growth factor production.

This study highlights an ongoing and mysterious problem with cancers treatments:

As with any potential cancer treatment, fasting has its limits. The growth of large tumor masses was reduced by multiple fasting and chemotherapy cycles, but cancer-free survival could not be achieved. Longo speculated that cells inside a large tumor may be protected in some way or that the variety of mutations in a large mass may make it more adaptable.

Clonal selection, somatic evolution, what a damned nuisance! It large tumours it may even be the case that the surviving cells are feeding off the debri from all those dead cells! Don't know. Alternatively, even in apoptosis, there is some degree of inflammation present and this may drive increased blood supply when large numbers of apoptotic cells are present as inflammation generally increases blood and nutrient flow to a given region. That is the primary purpose of inflammation, it "opens up" the blood vessels to allow in various immune cells, growth factors, and nutrients to enter into the damaged tissue. Don't friggin know!

The Dark Side of the Fish Oil component, DHA

This news release contains some very worrying information ...

"We found that mice developed deadly, late-stage colon cancer when given high doses of fish oil," she said. "More importantly, with the increased inflammation, it only took four weeks for the tumors to develop."


The results do not surprise me because I have long known that DHA can induce inflammation and in this study inflammation was very present in the gut tissue of the organisms. So for the last few years I have been warning people about the dangers of high fish oil intake, though I suspect most thought I was balmy for making such warnings. But hey, I actually read stuff! 


In relation to fish oil a large Australian study recently found no benefit for babes or mums who were taking DHA during pregnancy. No improvement in babe health and no reduction in post partum depression. What I don't understand is the empahsis on DHA, the emphasis should be on EPA because of its direct modulation of the prostaglandin pathways. 


I realise this is all very frustrating for health conscious people and can offer no easy solutions. The methodology I use to examine biomedical data is time and memory consuming, it takes a lot of work and a lot of memorisation. That is easy for me because I have time on my hands and a bloody good memory. For most people it simply is not possible to read the relevant literature and discern good health advice, especially in a world where there are so many "health experts" offering easy solutions! 

Do Neuroleptics Increase an Aberrant Neurodegenerative Autoimmune Response?

Long, 2250 words, difficult, give yourself a chance. My conclusion is that the current approach to treating schizophrenia could very well be inducing neurodegeneration through an autoimmune mediated pathology. I examine this from the perspective of heat shock proteins, autoimmunity, and neuroimmunology. This raises very serious questions about the current emphasis on "pre treating" so called "pre-psychotic" individuals.

This recent news item caught my interest because it relates to a set of immune cells that play a cardinal role in autoimmunity and cancer prevention. The news item addresses gamma delta T cells, a set of T cells that respond to one of the most abundantly expressed stress proteins in our body, heat shock protein 60. This protein is very strongly associated with autoimmunity. While autoimmunity is typically associated with pathology it plays a fundamental role in our health by eliminating dangerous cells that could become cancerous or induce the release inflammatory mediators that initiate tissue damage.

Blowing up Cancer Cells

Remarkably creative and clever approach to attacking cancer ...

In the zebra-fish study, Lapotko and his collaborators at Rice directed antibody-tagged gold nanoparticles into the implanted cancer cells. A short laser pulse overheated the surface of the nanoparticles and evaporated a very thin volume of the surrounding medium to create small vapor bubbles that expanded and collapsed within nanoseconds; this left cells undamaged but generated a strong optical scattering signal that was bright enough to detect a single cancer cell.

A second, stronger pulse generated larger nanobubbles that exploded (or, as the researchers called it, "mechanically ablated") the target cell without damaging surrounding tissue in the zebra fish. Scattering of the laser light by the second "killer" bubble confirmed the cellular destruction.

2- Enriched environment, stress, inhibits cancer?

In a previous post I mentioned the new research showing how an enriched environment can markedly impede the development of cancer. This research, the abstract of which is available here. (This research is concordant with research I earlier addressed, you can read it here.)The results of this current research indicate that a key variable is leptin. Leptin is a hormone released by fat cells(and other cells) that suppresses appetite. When writing up that previous post I was in a hurry so did not have time to think about it. As I driving over to a friend's place I had a petit epiphany, realising that there could very well be a linkage between the findings of this study and another post I put up on the same day that indicated regular coffee consumption is associated with cancer reduction. The typical assumption is that coffee confers this protection because it is extremely high in antioxidants, but together with the above research we can see another way in which coffee exerts its anti-cancer effects. There are some important lessons here, both in relation to the dangers of extrapolation when dealing with complex adaptive systems and the need to constantly re-evaluate our assumptions. I know, whilst thinking about this during the week I made some silly logical errors.

Cancer and Cellular Connections

Days of strange co-incidences. Today a friend in the USA sent me a fascinating little article from the Howard Hughes Medical Institute. Basically the story goes like this:

Cancer cells have very strong "pulling power", they tightly bind together. This has serious therapeutic implications which be latter addressed. What struck me as so odd about this research was just yesterday I read how immune cells also rely on pulling power to ensnare and devour dangerous cells.

Cancer, Diet, and Angiogenesis

Over the years there have been a multitude of reports on the anti-cancer properties of various foods. There is valuable truth in these reports and it does pay to adopt your diet so as to include a variety of these foods into your lifestyle. For example, it has long been known that a carotenoid found in tomatoes, lycopene, appears to confer protection against prostate cancer. Watermelon also contains good amounts of this carotenoid. However when eating tomatoes at least you really need to cook the tomatoes as this maximises the absorption of lycopene. This study highlights an unusual trend that is appearing in the data. As they state:

"The intake of isolated lycopene does not protect from the development of PCA."

Autophagy, Aging, ATP, and AMD

Over recent months I have being trying to deepen my understanding of autophagy. For a good overview of autophagy check out this site. The nutshell goes like this:

Autophagy is an intra cellular process whereby cellular contents are degraded and then either recycled or expelled from the cell. Autophagy is mediated by organelles called lysosomes, which have a high internal acidity of 4.5 so as to allow the degradation of many molecules and organelles such as mitochondria; the latter process being mediated via macroautophagy, the former through chaperone mediated autophagy.

Autophagy can induce cell death in cancer cell lines though exactly how this happens is not understood. This issue has been bugging me for some time now, I'll come back to it later.

Under most circumstances however autophagy is protective for many cell types and improving autophagy, particularly in the aging cell, is fundamental to preserving cellular health. Autophagy tends to decrease with age, probably concurrently with the increase in lipofuscin waste products in cells. Lipofuscin is undegraded waste products that accumulate in the lysosomes. Lipofuscin can occupy a very large intra cellular volume and will inhibit lysosomal function. This can create a vicious feedback cycle as more lipofuscin will acccumulate, eventually causing the lysosome to rupture and spill the contents into the cytoplasm. Lysosomes used to be known as "suicide vesicles" and with good reason, the degradative enzymes and a pH of 4.5 do a lot of damage in the cytoplasm, potentially killing the cell.

Why does autophagy decrease with age? Speculations:

To maintain an internal pH of 4.5 lysosomes have proton pumps which are ATP dependent. "ATP" is an acronym for a molecule the provides energy in various chemical reactions. It is produced predominantly by mitochondria. ATP levels tend to fall with age and strategies to promote ATP production are vital in maintaining cellular health. If lysosomes cannot maintain an appropriate pH then lipofuscin accumulation will be accelerated.

An aging cell requires more house keeping. Protein production is not as good as it used to be, thereby placing more work on lysosomes and the ubiquiotin - proteasome processes to degrade damaged or dangerous molecules. These two degradative pathways must also contend with the problems created by various irritants that have entered the cell. While these irritants may never actually kill a cell there is the potential for the disruption of any number of processes that could perturb cellular functions.

Nuclear DNA Damage. Again, essentially the aging cell is confronted with increased maintenance. More aberrant proteins are transcribed which requires more degradation by the ubiquitin - proteasome system.

Mitochondrial DNA damage. Mitochondria have DNA more typical of bacteria than mammals. It is single stranded and circular, encoding only 13 proteins, the other proteins required by mitochondria are provided by nuclear DNA. Mitochondrial DNA is much more susceptible to damage than nuclear DNA and lacks the repair enzyme capacity of nuclear DNA. This is unfortunate because mitochondria are the major source of all oxidants created in our cells. The consequent of this is reduced ATP production and all the downstream consequences that entails.

Before Autophagy There Must be ATP

While small amounts of ATP are produced in the cytoplasm it is the ATP production of mitochondria that can determine the health of a cell. Following the ideas of Lynn Marguilis, mitochondria appear to be ancient cells that took up residence in another cell type, thereby allowing a powerful symbiosis that underlies the increasingly complexity of cells through evolution. Various studies have indicated that targeting mitochondrial function could have considerable clinical value.

Professor Bruce Ames was so impressed with his results that he started a company, Juvenon, to market a product specifically aimed at "rejuvenating" mitochondria. The active components of this product are Alpha Lipoic Acid and Acetyl L Carnitine. For an overview of their research refer to this page where you can download various scientific articles. Alpha Lipoic Acid is a very powerful antioxidant that can "regenerate" vitamins C and E. Acetyl L Carnitine transports fatty acids into mitohondria, thereby providing the essential substrates for ATP production.

In the work of Ames et al there is a striking recovery of mitochondrial structure. The internal cristae are like those from the mitochondria of young cells. There are a number of issues here that baffle me. I find it hard to believe that mitochondria, with a genome encoding only 13 proteins, can initiate repair processes. Alternatively this recovery of structure may reflect a simple reiterative process of molecular dynamics that gives rise to the structure. Chaperones and heat shock proteins, typically providing a protective effect for cells, often play important roles in folding proteins and unfolding misfolded proteins. As many of these functions are ATP dependent, increased ATP availability will enhance the protective effects of chaperones and heat shock proteins.

As the principal mode of house keeping for lysosomes is chaperone mediated autophagy, an important chaperone here being HSC70, and the ATP dependent proton pump in lysosomes, improved ATP levels will enhance autophagic processes. This raises the question as to whether the improved mitochondrial structure arose because the increased "house keeping" activities removed various misfolded proteins and irritants thereby allowing mitochondrial structure to become more like that associated with healthy mitochondria. This suggests a complex interplay between mitochondrial and lysosomal functions. Aging and rejuvenation studies clearly indicate that mitochondrial and lysosomal functions are linchpins of health.

The decline in ATP production with age is probably occurring through the gradual loss of mitochondrial numbers and efficiency. (And, I just stumbled upon this, for a laugh, read it.) However, according to this article at least, under the right conditions it does seem possible that mitochondrial structure can be repaired. Note the chaperone and heat shock protein involvement in these processes and also the "spontaneous" macromolecule assembly that occurs.
The article addresses mitochondrial replication, an ongoing process in our cells.

The Retina as a Model of Autophagy and Aging

While enhancing cellular house keeping functions is essential to warding off damage and maintaining optimal cellular metabolism there remains the problem that lipofuscin accumulation is almost inevitable. These are chemical processes after all and there are always residues that are not excreted as digested products from lysosomes. lipofuscin accumulates, not only in lysosomes but also in other cellular regions including mitochondria, where it directly impacts on ATP production. Lysosomal degradation results in the expelling of the digested products for recycling. There is also evidence for some of these products being "packaged", transported to the cell surface, and expelled.

In one hypothesis, what I consider to be an exquisite process that gives me a moment's sympathy with Intelligent Design, it is put forward that lysosomes and\or the waste products are transported to the cell surface, excreted, absorbed by microglia, which then move to the capillary and dump the contents into the general circulation. As hard as I find that to believe recently I read a study addressing the contents of drusen, the waste products that builds up in the retina and beyond a certain level is a key marker for Age Related Macular Degeneration, is composed of molecules that are related to autophagic processes, including mitochondrial related proteins. That finding suggests that the waste products of lysosomal processes are being excreted. In relation to the retinal pigment epithelium the finding is not surprising because these are probably the cells that do the most degradation work of any cells in the body; at least in terms of constancy of demand.

That study raises the interesting question: why are the RPE cells expelling these materials into Bruch's Membrane, which lies between the RPE cells and the choroid, the blood supply? I hate to so obviously invoke intentionality but I trust you'll understand my point: Bruch's Membrane is a two way transport membrane, allowing nutrients to reach the RPE and waste products to be excreted into the bloodstream. In one study I read it was found that with age the permeability of Bruch's Membrane decreases by many orders of magnitude. In many perhaps most people over 50 there are some traces of drusen. In AMD drusen is all over place and where drusen is present the underlying photoreceptors cells are either suffering or dying; probably both.

A very interesting aspect of that study is the finding of mitochondrial related proteins. Such contents may have been expelled from the cell in vesicles. Mitochondria are degraded by a complicated process called macroautophagy. from what I can presently understand this process requires a lot of energy and makes big demands on a lysosome. Thus any strategy which can reduce the overall rate of mitochondrial turnover could have value in retinal and neural degenerative conditions. This may explain some experimental and clinical results suggesting improving mitochondrial function can impede disease progression.

With the decreasing permeability of Bruch's Membrane larger particles may effectively become trapped in the membrane. However all is not lost for this is where the little appreciated aspects of immune function come into play. There are various types of immune cells that carry what is called a "scavenger receptor". These cells move through tissues and do the extra-cellular equivalent of house keeping. Extra cellular debri is removed, dead or dying cells are absorbed and digested, cell health in the tissues is monitored through MHC class I receptors.

When the Peace Corps Come Marching In

At this point we need to enter into immunology. Here's the nutshell. Cytokines are a class of molecular messengers with far ranging effects, mostly immunological but that can get difficult ... . The types of immune cells that are engaged in the above functions are helped along by cytokines il4 and il10. These are typically perceived as anti-inflammatory cytokines. It appears to be the case that inflammation and house keeping don't go together(males may disagree). That makes sense, you don't vacuum the carpet when there's a burgler in the house.

In times of peace the immune system is cleaning up the area. This is a natural extension of an important process in limiting inflammation. As the inflammatory process progresses there must eventually be an elimination of inflammatory signals. This will involve the elimination of various proteins and lipids that signals danger and so invites an inflammatory response. For example, heat shock protein 60, expressed at very high levels, can and will drive inflammatory signals. The more quickly proteins like hsp 60 are removed from the extra cellular environment the more quickly inflammation will recede and then the repair processes can begin.

It is important to remember that "inflammation" is a word describing a series of processes. Unfortunately it is a loaded word. "Inflammation" can play important roles in initiating cellular repair, providing nutrients, and some so called "inflammatory mediators" are important in regulating neural transmission. (That's a whole fascinating other subject, the many relationships between the the nervous systems and the immune "system".) Take heed of Wittgenstein's Wisdom: "Words are posts on which we hang meanings".

In studies of Age Related Macular Degeneration there is are clear genetic linkages with immunological function and susceptibility to AMD. In particular, Complement Factor H, an inhibitor of complement function, is strongly implicated. The general trend suggests that a persistently elevated level of systemic inflammation is a considerable risk factor for AMD. Systemic inflammation is driven by two principal cytokines: tnf a and il1. A current model popular in immunology is the Th1 - Th2 paradigm. Th 1 is typically perceived as inflammatory and driven by by tnf a and il1, whereas Th 2 is driven by il4 and il10. Echinacea can cause a distinct shift towards the Th 2 type of function, and vitamin D also plays an important role here. Even omega 3's can be important as these fats will, over time, alter the production of prostaglandins, the downstream effect of this being to inhibit the production of il1 and tnfa.

As a general rule the studies suggest that our physiology, particularly with age, is too inclined to shift towards an inflammatory state. The possible explanations for this, while plausible, are long winded and tedious so I'll avoid that aspect.

Our evolution predisposed towards a balance of fat intakes that is out of kilter in modern diets. There is too much omega 6 to omega 3, the consequence being that while omega 3's inhibit potentially inflammatory prostaglandins, omega 6 fats do the exact opposite. At the immunological level this involves a shift towards higher expression of il1 and tnfa. Hence there have been some very surprising results in treating early AMD with omega 3 fats and other nutrients. There is already one supplement out there that appears to even reverse early AMD, while another recent study suggest that even in juvenile retinal degenerative conditions nutrient support can delay disease progression.

With age there is a general increase for more house keeping functions. This arises as cell damage occurs and DNA damage, at both the nuclear and mitochondrial sites, induces aberrant protein production that places additional loads on the ubiquitin proteasome degradation pathway.

With age people can lose the capacity to produce vitamin D from sunlight exposure. Recent epidemiological studies suggest widespread vitamin D deficency. This has all sorts of worrying implications for general health but of particular relevance here is that vitamin D is very important in moving the immune balance towards a less inflammatory state.

Thus studies indicating the protective effects of vitamin D and omega 3's might be converging on the general metabolic effect this has and how this impacts of autophagy and immunological extra cellular house keeping functions. What is interesting about the successful supplement regimes is the specific targets the researchers had in mind: antioxidant strategy, omega 3s'(mininum of two functions here: DHA is a substrate for NPD1, an important neuroprotectant, and EPA works at the prostaglandin level), and mitochondrial enhancement.

And to Wrap Up ... .

This brings us all the way back to what I mentioned earlier about the susceptibility of mitochondrial DNA to oxidative damage. Mitochondria absorb nutrients and eventually divide but as the DNA is damaged the new mitochondria are effectively aged. Fortunately genes aren't everything, ongoing studies indicate that the astute use of nutrients can impact on cellular functions at such fundamental levels so as to provide cells with protective functions that may increase their lifespan and function.

Inducing autophagy is not easy but obviously a desired goal. Rapamycin, an antibiotic of all things, induces autophagy. Nutrient deprivation, as in Caloric Restriction where autophagy has long been recognised as an important antiaging component of this strategy, can induce autophagy but it is very difficult to know just how much nutrient deprivation ... . It might just be amino acid deprivation, or the deprivation of fuel. Indeed, it is known that rapamycin induces autophagy by inhibiting the receptor mTOR, which is a nutrient receptor. Interesting concordance with Caloric Restriction dynamics there. This is how in the earlier study I cited on cancer cells killed by autophagy the process unfolded. Now there's another fascinating mystery, why does autophagy kill cancer cells but not other cells; though it can kill other cells sometimes ... . It's just too difficult. At present, just today I managed to dream up at least one plausible approach to that challenge. "Plausible" don't mean that much though!

My other specific goal in relation to this is to find strategies that address the exocytosis of waste products from cells concurrently with a distinct immunological shift to induce a heightened state of extra cellular house keeping. It probably can be done to some decent extent but will require lots of discipline. Don't have much of that and besides I need to keep reading.

Antioxidants - A Risk Benefit Profile

Antioxidants are all the rage these days. Paradoxically, while there are many in vitro studies demonstrating potential benefits from antioxidants, and many studies indicating their utility in various pathologies, there is scant evidence that antioxidant supplementation prolongs life.

I have concerns about the absorbing huge doses of antioxidants. Oxidation is an intrinsic and vital physiological process, filling up your body with antioxidants may sound like a good idea but how often have we been subjected to the latest nutrition craze only to find that it was nonsense? Far too many times, there needs to be much caution in the use of antioxidants. This recent study highlights that while antioxidants have considerable therapeutic promise, indiscriminate use of antioxidants can also lead to pathological processes.

One thing not mentioned in this study but is very important is the use of alpha tocopherol, typically and misleading referred to as Vitamin E. There are in fact a number of types of vitamin E and high consumption of alpha tocopherol can reduce the concentrations of gamma tocopherol and delta tocopherol, both of which are better variants than alpha tocopherol. . This may explain why some studies have found that high dosages of alpha tocopherol can increase mortality. The reason why most vitamin E supplements only contain alpha tocopherol is simple: it is the cheapest to manufacture. If you want a good source of vitamin E use wheatgerm. Note what the below study found in relation to wheatgerm:

Intriguingly, the combined treatment with wheat germ and vitamin C profoundly inhibited metastasis formation in various tumor models of different origin (Lewis lung carcinoma, B16 melanoma and human colon carcinoma xenografts [HCR25]) [61]. On the contrary, wheat germ had no toxicity on peripheral blood leukocytes (PBLs) at doses that affected tumor cells. The crude powder extract of fermented wheat germ inhibits nucleic acid ribose synthesis primarily through the non-oxidative steps of the pentose cycle [60]. Curiously, another quinone compound, carnosic acid quinone, like wheat germ, recovers potent antioxidant activity upon standing [62].

Note that last sentence, that the antioxidants in wheat germ "recover" their antioxidant activity. Now whether or not this happens in the body is another question but given that wheat germ is cheap and a valuable nutrient source why bother with all those expensive supplements?

This study also highlights that certain antioxidants, at high doses, can actually induce oxidation. Ever since that now famous study on beta carotene which found it increased the rate of lung cancer in smokers(as if that were possible!) I have harbored suspicions that beta carotene should not be added to multi vitamins. Smokers should definitely avoid beta carotene in vitamin pills and problem be careful about the intake from natural sources. As for non smokers, the data is equivocal. Beta carotene does not appear to be a causative factor for or against developing cancer.

Ascorbic acid, a variant of vitamin C, appears to be a double edged sword. At high doses it can stimulate the production reactive oxygen species, particularly in the presence of free iron, the latter often being present in inflammatory conditions. Mega dosing of vitamin C is a waste of money and can damage the gut. Once tissue saturation of vitamin C is achieved there is little point in swallowing vitamin C tablets because it will not pass the gut wall. Smokers should increase their intake of vitamin C has it has been shown to help preserve vitamin E levels. As with most antioxidants, it is generally better to consume these throughout the day because this will help maintain tissue levels through the course of the day, whereas consuming antioxidant rich foods or supplements at one time of the day will lead to depletion until topping up occurs at the next meal.

The flip side of megadosing for vitamin C is recent studies which found that intravenous injections of vitamin C may have therapeutic use in treating some cancers.

The below study can be downloaded at this site.

Reading
Article
The role of antioxidant supplement in immune system, neoplastic,
and neurodegenerative disorders: a point of view for an assessment
of the risk/benefit profile
Authors
Daria Brambilla1, Cesare Mancuso2, Mariagrazia Rita Scuderi1, Paolo Bosco3,
Giuseppina Cantarella1, Laurence Lempereur1, Giulia Di BenedettoLL0000001,
Salvatore Pezzino1 and Renato Bernardini*1
Journal
Nutrition Journal 2008, 7:29 doi:10.1186/1475-2891-7-29
Location
Life\Nutrition\
Date obtained
2/11/2008
Date Read
7/11/2008
Date to Review
Web Page
http://www.nutritionj.com/content/7/1/29
Keywords
Printed
Notes
Abstract
This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.

Inflammation, Cancer, Targets of Ginseng

A word of warning about using Ginseng:

If you are diabetic it is ill advised. Ginseng has a remarkable affect on the adrenal glands and this may impact on sugar regulation. Always consult your doctor before using Ginseng.

Ginseng is known to interfere with the actions of various pharmaceutical drugs.

Ginseng should not be used on a continual basis, it can induce adrenal exhaustion.


Article: Inflammation, Cancer, and Targets of Ginseng
Image:
Authors: Lorne J. Hofseth and Michael J. Wargovich
Journal: J. Nutr. 137: 183S–185S, 2007.
Location: Life\Nutrition\Title
Date obtained: 18/10/2008
Date Read: 21/10/2008
Date to Review:
Web Page:
Keywords:
Printed:
Notes:
Abstract
Chronic inflammation is associated with a high cancer risk. At the molecular level, free radicals and aldehydes, produced during chronic inflammation, can induce deleterious gene mutation and posttranslational modifications of key cancerrelated proteins. Other products of inflammation, including cytokines, growth factors, and transcription factors such as nuclear factor kB, control the expression of cancer genes (e.g., suppressor genes and oncogenes) and key inflammatory enzymes such as inducible nitric oxide synthase and cyclooxygenase-2. These enzymes in turn directly influence reactive oxygen species and eicosanoid levels. The procancerous outcome of chronic inflammation is increased DNA damage, increased DNA synthesis, cellular proliferation, disruption of DNA repair pathways and cellular milieu, inhibition of apoptosis, and promotion of angiogenesis and invasion. Chronic inflammation is also associated with immunosuppression, which is a risk factor for cancer. Current treatment strategies for reactive species overload diseases are frequently aimed at treating or preventing the cause of inflammation. Although these strategies have led to some progress in combating reactive species overload diseases and associated cancers, exposure often occurs again after eradication, treatment to eradicate the cause fails, or the treatment has long-term side effects. Therefore, the identification of molecules and pathways involved in chronic inflammation and cancer is critical to the design of agents that may help in preventing the progression of reactive species overload disease and cancer associated with disease progression. Here, we use ginseng as an example of an antiinflammatory molecule that targets many of the key players in the inflammation-to-cancer sequence. J. Nutr. 137: 183S–185S, 2007.

TABLE 1 Key players in the inflammation-to-cancer sequence1
The inflammatory player: Examples of mechanisms toward carcinogenesis
RONS, COX, and NOS Damage DNA, modify cancer protein, alter proliferation and
apoptosis (depending on concentration, microenvironment, and genetic background
of target cells), inactivate tumor suppressor pathways (e.g., pRb and p53).
NF-kB Activate proliferation and inhibit apoptosis by activating modulators of these
event: cytokines (e.g., TNF-a), growth factors, survival genes (e.g., Bcl-XL),
angiogenic factors (e.g., VEGF), inflammatory genes (e.g., COX and NOS). Recent
high profile studies indicate this molecule is a key molecular node in the
inflammation-to-cancer sequence (2).
TLRs Activate MAP kinase and NF-kB pathways.
Cytokines Activate or deactive many inflammation and cancer pathways (1). Example:
The proinflammatory cytokine, IL-6 can antagonize p53, inactivate pRb, and activate
survival genes (Bcl-2 and Bcl-XL); The antiinflammatory cytokine, IL-10, can inhibit
proliferation and ras signaling.
Growth factors Transforming growth factor-b, at high concentrations, activates
p21/p27-mediated growth arrest and smad- and p53-mediated apoptosis.
MMPs MMP-2 promotes proliferation by activation of the discoidin domain tyrosine
kinase receptor 2. MMPs also are immunomodulators and stimulate angiogenesis,
inhibit cell adhesion, and inhibit apoptosis.
PPARs PPAR-g ligands are mostly protective to the inflammation- to-cancer sequence.
They inhibit iNOS, COX-2, NF-kB, MMPs, and E2Fs; they activate p53, p27, and p21.
Kinase pathways p38 stimulates proliferation and inhibits apoptosis. An inhibitor of
MAP kinase signaling (CNI-1493) has shown promise in ameliorating Crohn disease
in humans (3).
p53 and pRb pathways Both pathways are inactivated in reactive species overload
diseases (4,5).

Studies indicate that ginseng has potential as a chemopreventive agent or adjuvant treatment. Some of the cancers shown to decrease significantly with ginseng use include cancersof the pharynx, stomach, liver, pancreas, and colon (22,23). Mechanisms include inhibition of DNA damage (24), induction of apoptosis (25), and inhibition of cell proliferation (26). It is also becoming increasingly clear that ginseng has potent effects on the inflammatory cascade and may inhibit the inflammationto- cancer sequence.
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Ginseng targets the inflammatory players There is evidence that ginseng has potent effects on key players in the inflammatory cascade (Fig. 1). For example, ginsan, a polysaccharide extracted from P. ginseng, showed inhibition of s, the p38 MAP kinase pathway, and NF-kB in vitro and inhibition of proinflammatory cytokines in vivo (27). The ginsenoside Rg3 was shown to inhibit phorbol ester–induced COX-2 and NF-kB induction (28). BST204, a fermented ginseng extract, can inhibit inducible NOS (iNOS) expression and subsequent nitric oxide production from lipopolysaccharidestimulated RAW264.7 murine macrophages.

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Ginseng can also inhibit other mediators of the inflammation- to-cancer sequence, such as matrix metalloproteases and kinase pathways (31).
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Project:

Antioxidants, Neurodegeneration, and Cancer

Research article. Interesting but lacking depth. Good balance on the issue of antioxidant supplementation.

The study can be downloaded here.

Article:
The role of antioxidant supplement in immune system, neoplastic, and
neurodegenerative disorders: a point of view for an assessment of the
risk/benefit profile
Authors:
Daria Brambilla, Cesare Mancuso,Mariagrazia Rita Scuderi,Paolo Bosco,Giuseppina Cantarella, Laurence Lempereur, Giulia Di Benedetto, Salvatore Pezzino, Renato Bernardini,
Journal: Nutrition Journal 2008, 7:29 doi:10.1186/1475-2891-7-29
Location: Life\Nutrition\title
Date obtained: 3/10/2008
Date Read: 19/10/2008
Date to Review:
Web Page:
Printed:
Notes:
Abstract
This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
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However, several clinical studies demonstrated that not only malnutrition, but also the excess of certain nutrients (e.g. iron, alphatocopherol, beta-carotene, ascorbic acid) may set into motion oxidation phenomena and, therefore, cell injury [8,9]. Thus, it is of relevance that prior to considering introducing antioxidant therapy into mainstream medicine, significant advances in basic cell biology, pharmacology and clinical bioanalysis will be required.
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Heme oxygenase is a microsomal enzyme which metabolizes heme into ferrous iron, carbon monoxide and biliverdin (BV); the latter is then reduced by BVR into bilirubin (BR), a molecule endowed with strong antioxidant and antinitrosative activities [11-14]. Interestingly, all these protective factors act in a concerted way, enhancing the antioxidant defense system of the cell. When the balance between ROS/RNS and antioxidants turns in favor of the former, oxidative/nitrosative stress occurs.
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Extracellularly generated ROS can diffuse through anion channels into the cytoplasm; the resulting variation in the cell redox state leads to modulation of an array of transcription factors (eg. NF-kB, AP-1), protein kinases (e.g. AKT, JNK, p38), and receptor activated MAP kinases involved in apoptosis [17, 24,25,26]
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However, not only immune cell produce ROS necessary for the microbicidal activity, but they are also sensitive to external ROS, due to their high polyunsaturated fatty acids (PUFA) content. Immune cells are atypical, as compared with other somatic cells, in that they contain high levels of antioxidant vitamins, presumably providing protection against lipid peroxidation and immunosuppression, both of which are well known risks posed by high PUFA content [38].
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Intriguingly, the combined treatment with wheat germ and vitamin C profoundly inhibited metastasis formation in various tumor models of different origin (Lewis lung carcinoma, B16 melanoma and human colon carcinoma xenografts [HCR25]) [61].
61. Hidvégi M, Ráso E, Tömösközi-Farkas R, Paku S, Lapis K, Szende B: Effect of Avemar
and Avemar + vitamin C on tumor growth and metastasis in experimental animals.
Anticancer Res 1998, 18(4A): 2353-2358.
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Heme oxygenase-1, the inducible isoform of HO, is a key protein in the cell stress response and its up-regulation is a common event during pro-inflammatory conditions [11,69-72]. Recent work clearly demonstrated that regulatory T cells overexpress HO-1 and release CO under pro-oxidant conditions. Carbon monoxide may inhibit the proliferation of effector T cells, thus reducing the immune response and prevent autoimmunity and/or graft reaction [73,74]. Dietary antioxidants, in particular polyphenols, has been shown to increase HO-1 expression in different in vitro systems [3,75,76] and the potential use of this natural substances to regulate immune response should be carefully addressed.
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Other studies report that combination of vitamin A and other antioxidants, significantly increases mortality related to neoplastic diseases. [91]. According to these studies, selenium would be the only element displaying beneficial effects, as it has been shown that it reduces total cancer incidence, an apparently sex-related effect, as it is predominant among males, rather than in females [89].
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Due to their scarce bioavailability, only a negligible amount of polyphenols reaches brain tissue and the concentrations achieved are much lower than those efficacious in vitro [3]. As far as NSAIDs, ad hoc designed clinical trials with a large number of patients, clearly demonstrated that these drugs do not have any significant effect in slowing cognitive decline in patients suffering from mild-to-moderate AD [120,121].
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It is noteworthy to underlie that as for all drugs, antioxidants may give important side effects if not correctly used or in combination with other drugs. Vitamin A, E and â-carotene for instance, have been shown to have pro-oxidant effects at higher doses or under certain conditions [39].
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Vitamin C May Inhibit Chemotherapy

For some time there has been a controversy regarding the use of antioxidants during chemotherapy. Concerns have been raised because antioxidants protects cells against stress and so taking large doses during chemo may impede the effectiveness of chemotherapy.

This study appears to bear that out. What they found is that vitamin C, both in vitro and in a mouse model, allowed the tumour cells to survive by protecting the mitochondria. That makes a great deal of sense because mitochondria are a "gateway" for death signals and anything that preserves mitochondrial function typically helps keep the cell alive.

Sounds simple but isn't, there is also the possibility that in some cancers activating certain functions of mitochondria, in particular the release of pro-apoptotic factors, can activate cell death pathways. Additionally some studies have found that high doses of intravenous vitamin C can be effective in killing cancer cells. What a dilemma, take antioxidants to try and prevent healthy cells from chemotherapy damage and run the risk of helping the cancer cells to survive.

Ironically part of the problem here lies in the singular tense word "cancer". Even cancer originating in the same body tissue of the same person may be a different type of cancer. Because of this, strategies to target cancer are never going to constitute a single magic bullet, we will always have to tailor the strategy to the specific type of cell present in the tumour. So in some instances antioxidants may not present a problem because in some cancers the mitochondria are disabled or poorly functioning. In other cancers improving mitochondrial function may induce death signals like APAF1, BAX, BAD. Even then it can become complicated because some cancers have high expression of the small heat shock protein, hsp27. This protein can bind these death signals so preventing cell death.

Just to confuse the picture there is clinical evidence that the intravenous administration of vitamin C can kill cancer cells. The reasons behind this are unclear but it is known that high doses of vitamin C, particularly in the presence of free iron, can drive oxidative processes via Haber-Weiss and Fenton reactions, thereby inducing cell death. To achieve such high doses though intravenous injection is required because the body will not absorb large amounts of vitamin C orally. Hence all those people taking large doses of oral vitamin C are wasting their money. For a look at the use of intravenous vitamin C read of this article. A short comment in the Canadian Medical Journal puts forward the case for using intravenous vitamin C in cancer therapy.

It is never going to be easy! So when you see all those internet advertisements proclaiming a universal cure for cancer don't go there. It simply isn't true, each type of cancer requires a different strategy. That is why the success in cancer treatments is not uniform. Great strides have been made in treating some cancers while other types, for example brain tumours, virtually no progress has been made in 20 years. In all this remember what Mencken once wrote:

"For every human problem, there is a neat, simple solution; and it is
always wrong"