heart disease & cancer

Heart Disease & Cancer

These diseases kill more people than all others combined (except for dying “naturally” of organ failure due to old age)

~ 247 heart disease deaths / 100,000 people / year (USA - 2001)*

~ 195 cancer deaths / 100,000 / year (USA - 2001)*

~ 87 iatrogenic deaths / 100,000 / year (USA – 2004)

~ 60 stroke deaths / 100,000 / year (USA - 2001)*

~ 25 diabetes deaths / 100,000 / year (USA - 2001)*

~ 10 firearms deaths / 100,000 / year (USA – 2001)*

*(statistics from Kaiser Family Foundation)

- Kind of sad that in the USA death due to medical mistakes (iatrogenic) is the third biggest killer!

Coronary Artery Disease & Cancer

Because there are many common lifestyle-associated risks for both CAD and Cancer, these two diseases are discussed together (more or less)

A very important question to ask is why would anyone suspect that these two diseases could be related to diet (and lifestyle) at all

We all know that “cholesterol causes heart disease” and that “smoking causes heart disease and lung cancer” but these common associations may not be that simple…

If smoking was such an important component of risk for heart disease and lung cancer one would expect Japan to have far more heart disease and lung cancer than USA, Scotland or France, not so much less.

Atherosclerosis (CAD) is actually an inflammatory disease that is greatly affected by life-style issues. Research from different countries on the incidence of death due to heart disease in combination with various lifestyle factors illustrates this very nicely. For example, smoking cigarettes is strongly associated with risk for heart disease in the USA where nearly 40% of men smoke. In Japan, where about 70% of men smoke (1.75 x more smokers), there are almost 35% FEWER deaths (per 100,000) than in the USA. One might expect that with more smokers, there would be more heart disease but that is not the case.

Somewhat similar results are observed when you compare France to the USA, although the incidence of smoking is almost the same in the two countries. Two major differences, however, are in fat consumption and cholesterol levels in serum. Paradoxically, cholesterol levels are much higher in France, as is saturated fat consumption. While USA (only) studies correlate cholesterol and fat levels with heart disease deaths due to heart disease are much lower in France (indicating no real correlation between disease and cholesterol or fat consumption. Some have called this a paradox. When the dietary and activity habits of people who live in these countries are taken into consideration however, then the apparent differences in heart disease (deaths) become understandable.

Consumption of fruits and vegetables as well as fish is much higher in France (and Japan) than in the USA. In addition, the amount of physical activity performed by the French and Japanese also is so much greater than that performed by Americans. These lifestyle differences can explain the large differences in heart disease among these countries; especially when you consider that heart disease (atherosclerosis) is predominantly a disease of chronic inflammation and not a disease of disordered lipids

Again, with so many more smokers, one would expect China to have so much more disease than Germany - although the lower-risk lipid profile may be part of why there is less heart disease deaths..

For a variety of cancers both diet & exercise contribute to a significant percentage of risk.

Even when looking at the major smoking-associated cancers, diet still is a major component of risk

Smokers appear to be very different people than non-smokers in terms of overall dietary habits: maybe that has something to do with the “smoking” risk...

And American smokers seem to be even worse than the Scots…

For atherosclerosis, foam-cell production is the primary causal mechanism for initiating the deposition of plaque; note how 48 hours of no smoking or C + E supplements alter foam-cell production in cell culture experiments with smokers’ blood.

Some Summary Conclusions of Epidemiology Data

The diet and lifestyle of smokers are very different from non-smokers

High incidence of elevated serum cholesterol does not necessarily lead to a high incidence of heart disease

Foam cell production in active smokers can be drastically reduced

High incidence of smoking does not necessarily lead to a high incidence of lung cancer

Various cancers have an attributable risk due to low vegetable consumption and low physical activity of anywhere from 30% to 50% (and quite possibly much more)

To understand these complex relationships we really need to understand the mechanisms of the diseases

We’ll start off with CAD

Atherosclerosis is actually an inflammatory disease of the coronary blood vessels

Smooth muscle cells, vascular endothelial cells, monocytes, and platelets are the major cells involved in the atherosclerotic process with oxidized lipoproteins and other oxidized lipids also being intimately involved.

The activation of proinflammatory and prohypertrophy signaling by mechanical disturbances of vascular cells due to low oscillating sheer forces and turbulent flow creates a sensitive proinflammatory environment within the cells located at bifurcates and inside curves of arteries. The initial infiltration of inflammatory cells contributes to the hypertrophy-adaptation response to ensure adequate downstream flow, as well as to the formation of Type I and II “fatty lesions”. Poor diet, overeating, and inadequate physical activity lead to poor redox control in cells, increased formation of AGEs, increased oxidation of HDL/LDL/CHOL, increased blood pressure, and greatly enhanced PRR activation and proinflammatory signaling; greatly increasing the risk for progression to the potentially fatal Type V and VI lesions.

As mentioned in the previous slide, proinflammatory signaling is initiated as a result of mechanical stimulation of the endothelial cells of the coronary blood vessels by oscillating sheer forces and turbulent flow.

These forces are indicative of compromised flow and a normal response would be to initiate a hypertrophy/angiogenesis response in the blood vessel to increase the vessel wall thickness and enhance local pressure to increase flow.

Inflammatory signals result in the recruitment of monocytes into the blood vessel walls (between the endothelial cell layer and the smooth muscle cell layer). These monocytes mature into macrophages and they phagocytize any AGEs, oxidized lipids, and oxidized lipoproteins. These compounds bind to scavenger receptors on the macrophages cell membrane which then activate proinflammatory signaling. Another name for scavenger receptor is DAMP receptor. Thus scavenging oxidized and damaged molecules (AGEs) is a normal function of the macrophages; a function that activates the formation of phagolysosomes and ROS production. This of course, increases oxidative damage in the local area…

When these macrophages scavenge large amounts of oxidized lipids and other damaged molecules they can actually get so large that they cannot get out of the vessel wall and they eventually die. When this happens, the lipids and fragments of cellular debris are left behind. If enough macrophages accumulate in one area of the blood vessel wall, consume sufficient AGEs and lipids and then die, a variety of oxidized lipid-products and (macrophage) cellular debris will build up in the blood vessel wall; causing it to bulge into the vessel lumen. Obviously this will impede blood flow.

Unfortunately, impeded blood flow in the one spot will vastly increase both turbulence and the oscillations in sheer forces and therefor accelerate the processes of inflammation in this region and increase the infiltration and activation of macrophages. As a result of the chronic production of inflammatory signals there will be smooth muscle cell hyperplasia as well as fibrosis. Both of these processes are hallmarks of CAD and they can happen only as a result of inflammatory signals. The fatty plaque that builds up in the blood vessel wall contains both “extra” smooth muscle cells and fibrous tissue.

Monocytes adhere to the local area and bury beneath the endothelial layer where they differentiate into macrophages... and are then stimulatedto ingest foreign particles as well as any oxidized lipids; as are anyresident macrophages already in the vessel wall...

platelets start to accumulate in the injured area as well...

Macrophages engulf advanced glycation end products, oxidized lipids, any oxidized lipoproteins, and transform into foam cells; releasing even more inflammatory cytokines

Foam cells accumulate and die in the extracellular space leaving behind their necrotic components and lipids while hyperplasia of smooth muscles (caused by the various growth factors produced as a result of the inflammatory signaling process) and accumulation of connective tissue form atherosclerotic lesions

Continual expansion of lesion leads to occlusion …

With continued production of inflammatory signals there will be continual growth of the plaque and greater obstruction of the blood flow leading to greater deterioration of the endothelial cell layer. This creates an attractive rough area for platelets to adhere to in order to stimulate the local deposition of collagen and fibrin, leading to the development of a fibrous “cap”.

Continual growth of the plaque can lead to complete occlusion of blood flow. As a result of the infiltrating platelets being activated they can release a variety of factors that destabilize the plaque increasing the likelihood that a piece of the plaque can break off and become a thrombus. A thrombus is a solid particle that can lodge in a smaller blood vessel to cause an infarct in some other tissue (brain or another area of the heart, for example) and death could possibly result - not necessarily a good thing.

… while disruption can lead to thrombosis

As mentioned previously proinflammatory signaling is initiated as a result of mechanical stimulation of the endothelial cells of the coronary blood vessels by oscillating sheer forces and turbulent flow. These signaling events can be exaggerated by a variety of factors:

a)open-chain glucose / AGEs – elevated with insulin resistance/diabetes due to poor diet and inactivityb)oxidized lipoproteins – elevated with poor antioxidant control/enhanced ROS due to poor diet and inactivityc)oxidized lipids – elevated with poor antioxidant control/enhanced ROS due to poor diet and inactivity d)and the exaggerated oscillations in sheer forces due to high blood pressure – elevated with obesity due to poor diet and inactivitye)circulating proinflammatory signaling molecules that arise from other tissues – elevated with obesity due to poor diet and inactivity

Logically, the levels of any “toxic” molecules will be the same throughout the entire cardiovascular system while the blood pressure and sheer forces vary at different locations. Some of the highest blood pressures exist in the coronary vessels and the greatest oscillations in sheer forces exist at the bifurcations and inside curves of the coronary vessels – the specific locations where atherosclerosis occurs.

Advanced Glycation End-products (AGEs)

Both glucose (and fructose) can exist in a closed-ring and also as an open-chain structure. In the open-chain configuration, the aldehyde of glucose and the ketone of the fructose can form a reversible Schiff base with any free amino group of any phospholipid, protein, and even on DNA; ultimately leading to the formation of Advanced Glycation End-products (AGEs). Once formed, the AGEs can activate inflammatory processes in the local tissues in which they are formed and the inflammatory process lead to additional tissue dysfunction and disease such as retinopathies, peripheral vascular disease, atherosclerosis, and stroke.

(~3-6 h to equilibrium) (> weeks to form)Glucose ↔ Schiff base → Amadori Products → various dicarbonyls → AGEs

Fructose ↔ Schiff base → Heyn’s Products → various dicarbonyls → AGEs

Removal of glucose from the blood is largely dependent on insulin while removal of fructose is not; as a result glucose levels in the blood are typically 500 times greater than those of fructose; indicating that glucose is the molecule we need to be concerned with in regard to chronic disease and that fructose is a relatively minor player.

Because the freely reversible Schiff bases need to be present for several weeks (or more) to rearrange into stable Amadori / Heyn’s products; only chronically elevated levels of glucose can lead to elevated risk for disease. With a rate of reversion that reaches equilibrium in approximately 3-6 hours, additional Schiff bases formed because of elevated glucose (or fructose) levels following a meal will essentially be back down to normal levels following a customary overnight fast. Because it takes weeks of elevated glucose to lead to additional AGE formation even a weekend of gluttony should not have a great effect as long as normal eating behaviors are followed in subsequent days. Thus, those individuals with normal insulin function shouldn’t really have to worry about carbohydrate consumption from this standpoint.

However, those with insulin resistance (pre-diabetes) or diabetes need to be aware and to try and avoid high glycemic loads throughout the day to minimize the additional risks of prolonged periods of elevated glucose.

Because the formation of AGEs is essentially dependent on glucose levels in the blood, those with insulin resistance (pre-diabetes) or diabetes would have a greater risk for CAD and other chronic diseases than those with normal insulin responses; essentially as shown below in relation to clinical “norms”…

With normal insulin responses, levels of glucose in the blood will decline to normal within 1 hour after a moderate meal or within 2 hours of a large meal. With the traditional timing of eating meals based essentially on work schedules - a timing that includes an overnight fast; normal levels of glucose will be sustained for 8 hours or more; resulting in “normal” (AGE-related) risks for chronic disease. Only with a sustained elevation in glucose levels because of insulin-resistance or diabetes will an elevated risk for CAD and other chronic diseases be produced.

Affect of Meals on Glucose Levels in the Blood

Risk for AGE formation is dependent on maintaining Schiff base levels for sustained periods of time; i.e. several weeks or more.

Schiff’s bases are freely-reversible and will equilibrate with glucose levels in approximately 3 to 6 hours. With a traditional overnight fast of 8 hours (or more) levels of glucose will have stabilized for at least 6 hours. It is this lowest level of serum-glucose that is sustained during the last 3 to 6 hours of any fasting period that defines the level of risk for Schiff base (and subsequent AGE) formation..

A slower decline in serum glucose because of insulin-resistance or diabetes will produce a greater duration of elevated glucose following a meal as well as greater fasted levels; thus producing a greater risk for AGE formation and for CAD and other chronic diseases.

Even with an “extended” eating pattern (early breakfast / late dinner / multiple snacks) the risk for A.G.E. formation will not increase in those with normal insulin responses to increase risk for chronic diseases as long as there is an ~8 hour overnight fast.

Thus, the carbohydrate content or glycemic index of foods is not an issue for chronic disease risks in those with normal insulin responses.

Only with Insulin Resistance and Diabetes, are worries about carbohydrate content and eating patterns relevant.

Another major dietary issue related to insulin resistance and increased formation of AGEs is over consumption of calories that leads to increases in the amount of adipose tissue and fat cells.

With caloric excess, endoplasmic reticulum dysfunction occurs in adipocytes. This condition reduces the ability of adipocytes to synthesize TGs so they release more FFAs into the blood. In addition, production of MCP-1, TNFα and other pro-inflammatory cytokines by adipose cells leads to the recruitment and activation of monocytes into the tissue to become new macrophages as well as the activation of resident macrophages to greatly enhance the production of proinflammatory cytokines , growth factors, and PGs, TXs, and LTs. The enhanced levels of prostaglandins activate cell division of the resident mesenchymal stem cells while the resulting daughter cells are stimulated to differentiate into new functional adipocytes through binding of the (excess) FFA to PPARα; the numerous cytokines and growth factors released by the adipocytes and inflammatory cells initiate and sustain angiogenesis to supply the expanding adipose tissue.

These proinflammatory molecules also enter the circulation to enhance inflammatory functions throughout the entire body. In addition, the enhanced levels of TNFα and FFA leads to both mitochondrial dysfunction and insulin resistance (IR) in both adipocytes and skeletal muscle. Thus: Systemic Proinflammatory Signaling + Systemic IR → high risk for all chronic diseases

Abdominal fat is more “pro-inflammatory” than subcutaneous fat with a preferential infiltration by macrophages and it is known that adipogenesis in abdominal fat pads is a more substantial risk associated with CHD, cancer, and other chronic diseases than subcutaneous fat.

Calorie overload → TG synthesis → Adipocyte Hypertrophy → ER Dysfunction → Inflammatory Signaling → Adipocyte Hyperplasia → Adipose Angiogenesis & ↑TNFα and FFA → IR

With continuing caloric overload the expanding size of the adipose tissue accumulates much greater numbers of inflammatory cells, producing a tissue that is even more sensitive to proinflammatory stresses of caloric overload: a vicious cycle of accelerating risk with constant gains in adiposity.

In addition to the dietary factors that contribute to increased TNFα production that causes systemic insulin resistance, an increase in local production of ROS in skeletal muscles due to inactivity mediates a stress-mediated induction of TNF-α synthesis that in turn enhances phosphorylation of IRS-1 on lysine to enhance its degradation as well as impair its ability to complex with p85; thus further reducing insulin signaling in muscle resulting in increased glucose levels in the blood and therefor increased AGEs.

Signal Transduction Issues in CAD

The proximate cause of CAD is oscillating sheer forces and turbulent flow and the normal proinflammatory/hypertrophy signaling responses to these. Anything that can enhance activity of the signal transduction pathways (STPs) that lead to synthesis of proinflammatory signaling molecules will therefor increase the production of proinflammatory signaling molecules at any degree of “normal activation and enhance risk for CAD.

ERK-MAPK - p38 MAPK - JNK-MAPK - PI3K/Akt

The major STPs that regulate transcription and translation of many different proteins are the ERK-MAPK, p38-MAPK, JNK-MAPK, PI3K/Akt, and the “Nfκβ” pathways.

These STPs regulate synthesis of the many proteins that are necessary for maintaining cell function and for producing proinflammatory molecules following various stresses.

They also regulate synthesis of proteins in our stem cells and progenitor cells that are necessary for the different functions of cell division.

Regulation of Signal Transduction Pathways (STPs)

Activities of STPs are regulated by a variety of growth factors, hormones, calcium, and ROS. Note that both Calcium and ROS affect enzymes that activate S-T pathways.

Thus control of Calcium and of ROS are very important for

controlling S-T.

If excessive STP activity happens for an extended period of time (many hours to many days; or all the time…) then they will produce a variety of inflammatory signaling molecules that produces an inflammatory response…

Leading to even more deregulated STP activity and more ROS…

DAMAGE

A variety of molecules that are produced through normal biological functions can lead to damage…

Reactive oxygen species (ROS) from inflammatory cells, from normal metabolic reactions, and even from sources outside the body can cause damage.

Some of the ROS and Calcium can disrupt the signal transduction pathways by interfering with their normal regulation

©C. Murray Ardies, 2014

The major antioxidant nutrients that help to reduce damage from ROS are Vitamin E & Vitamin C.

These compounds help to maintain the cellular redox state within “normal;” limits… and because normal metabolic reactions of cells constantly produce a variety of Reactive Oxidant Species (ROS) these vitamins are essential for normal cellular function.

They also help to get rid of ROS that enter the cell from other sources such as inflammatory cells.©C. Murray Ardies, 2014

Two other major antioxidant compounds that help to reduce the damage are β-Carotene and Glutathione


Antioxidant / Redox Control Enzymes

A variety of antioxidant & redox control enzymes are synthesized in cells in order to help maintain the cellular redox state within “normal” limits…

Thioredoxin (Trx), Peroxyredoxin (Prx), Glutathione Peroxidase (GPX), Superoxide Dismutase (SOD), and Catalase (CAT)

are essential enzymes that control the redox state of a cell.

They also help to get rid of ROS that enter the cell from other sources such as inflammatory cells.


Thioredoxin and Peroxyredoxin are very important regulators of the p38 and JNK S-T pathways in addition to being important antioxidant proteins…

In a sense, they are cellular redox sensors that help to quench ROS when there are elevated levels of them and they also enhance the p38 and ERK S-T pathways when there are elevated levels of ROS to help produce the proper response…


STPs and Inflammatory Signaling

Recall that entry of calcium into the cytosol and ROS-mediated events can lead to PLA-2 as well as p38-MAPK and JNK-MAPK via Trx-Ask1. ROS-caused single and double-strand breaks in DNA activates repair by ATM which also activates NFκβ and ROS-mediated PI3K activity also enhances mTORC1 via Akt to enhance overall rates of protein synthesis. The result of all these effects is the synthesis of a variety of proinflammatory molecules in response to cellular stress.

In order to ensure that we can maintain appropriate levels of our antioxidant compounds, antioxidant enzymes, and redox-sensor proteins we need to have the proper nutrients.


Dietary Notes On Some Antioxidant Vitamins

RDA Food Sources

Ascorbic Acid 75 & 90 mg/day ♀ & ♂ Citrus fruits and strawberries, tomatoes, potatoes, broccoli, cauliflower, spinach,cabbage, and Brussels sprouts

α-tocopherol 15 mg/day ♀ & ♂ Vegetable oils and wheat germ

Carotenoids N/A Tomatoes, green & yellow vegetables(ß-carotene, lutein,lycopene . . .)


Food Group Sources of Antioxidant Compounds

Dairy Fruits Veggies Meats & Beans & Nuts & Breads & Oils Eggs Legumes Seeds Cereals

Ascorbic Acid X Green

α-tocopherol X X (vegetable)

Selenium X X

Carotenoids greenyellow


Dietary Notes On Requirements for Some Antioxidant Enzymes

RDA Food Sources

Iron 18 & 8 mg/day ♀ & ♂ Dried fruits, nuts, cereal products, - component of catalase organ & other meats, seeds, green

leafy vegetables

Zinc 11 & 8 mg/day ♀ & ♂ Wheat germ, whole grains, beef,- component of cytosolic & poultry, oystersextracellular superoxide dismutase Copper 900 ug ♀ & ♂ Whole grains, liver, legumes, eggs, - component of cytosolic & meats, shellfishextracellular superoxide dismutase

Manganese 1.8 & 2.3 mg/day ♀ & ♂ Wheat bran, nuts, poultry, legumes,- component of mitochondrial meat superoxide dismutase

Selenium 35 µg/day ♀ & ♂ Seafood, organ and red-meats, whole - component of glutathione peroxidase grains, dairy


Food Group Sources of Minerals for Antioxidant Enzymes

Dairy Fruits Veggies Meats & Beans & Nuts & Breads & Oils Eggs Legumes Seeds Cereals

Iron X X X X XGreenleafy

Zinc X Xbeef/poultryoysters

Copper X X Xeggs/meatsshellfish

Manganese X X Xbeef/poultry

Selenium X X Xorgan/red meatsfish


Unfortunately, the average

American dietReally Sucks . . .


With obvious results,,,

AntioxidantVitamins

Minerals for Antioxidant & Redox ControlEnzymes


Insufficiencies in antioxidant and redox control-related nutrients lead to exaggerated ST responses as well as enhanced damage due to lack of protection from excessive oxidizing agents.

Only through optimal nutrient intake can appropriate regulation of STP-activities will occur along with both enhanced redox control and enhanced protection from various oxidants will result.

SUMMARY CONCEPT OF THE CAUSE OF CAD

CAD is caused by oscillating sheer forces and turbulent flow and the normal proinflammatory/hypertrophy signaling responses to these.

These processes are exaggerated by poor antioxidant and redox control that leads to enhanced ROS damage and to exaggerated signal transduction activities that leads to additional proinflammatory signaling arising from resident macrophages that are further activated via their normal scavenging functions.

Poor antioxidant control and excess proinflammatory signaling are due primarily to poor diet and inactivity that results in insulin resistance, adipose tissue-gain, and hypertension; each of which adds to risks for CAD through enhancing proinflammatory signaling.

SUMMARY CONCEPT FOR PREVENTION

By targeting the actual “causal” mechanisms of the disease, it is possible to attenuate the disease process and thereby greatly reduce risk for the disease.

A variety of phytochemicals are known to interfere with different components of the signaling pathways that lead to synthesis of the proinflammatory cytokines and eicosanoids.

By inhibiting production of both proinflammatory cytokines and eicosanoids, inflammatory signaling will be attenuated which will reduce the activation of monocytes and macrophages as well as reduce the recruitment of monocytes into the vessel wall.

Synthesis of the various antioxidant and redox control enzymes and compounds can be enhanced to optimize antioxidant and redox control.

These enhanced protective effects are mediated by binding of the Nrf2 transcription factor to the antioxidant (electrophile) response element along with the small nuclear Maf proteins.

Exercise stimulates the release of IGF-1 from muscle and activates various mechanoreceptors leading to the transient activation of PI3K, PLC, AMP-PK, and the MAPKs as well as transient increases in cellular hydrogen peroxide. Subsequent activation of Nrf2, p50/p65, PGC-1α, ER, and many other transcription factors enhances expression of SOD, CAT, Prx, Trx, GPX, GSR, GLUT4, and IRS1. Longer-term exercise increases release of IL-6 from muscle, activating expression of sTNFr, sIL-1r, sIL-1ra and of SOCS via IL 10/STAT3.

From all of this dietary and mechanistic information one can conclude that:

consumption of a large variety of fresh fruits and vegetables,

omega-3 fatty acids from cold water fish,

alcohol, esp. red wine (in moderation)

combined with regular stressful physical activity

greatly reduces risk for heart disease

such that “high risk” behaviors such as smokingmay pose little or no risk.

Based on the mechanistic evidenceatherosclerosis is

NOT a disease of “abnormal” serum lipids,

it is an

INFLAMMATORY DISEASE(initiated by normal cellular responses to blood flow characteristics that imply inadequate blood

flow)

&

greatly exacerbated by

DIETARY & EXERCISE INADEQUACIES

Based on the epidemiological evidence, cancer also has a very important dietary source of risk and (kinda like with CAD) only by understanding the mechanisms of cancer can we understand the complex relationship between diet and cancer

So, what exactly is cancer?

In essence, cancer is simply uncontrolled cell division.

The terms neoplasm and tumor are often used to indicate a cancerous growth;

ie: neoplasm ~ tumor ~ cancer.

Cancer comes in two types: Benign and Malignant.

The process of developing cancer is generally called Carcinogenesis while the overall process is divided into three phases:

Initiation: Oxygen radicals or chemical radicals form adducts with DNA bases of Stem Cells... unrepaired DNA damage leads to mutations in daughter cells following mitosis (well, there are other sources of

mutations but these will suffice to start).

Promotion: Accelerated cell division leads to the accumulation of more mutations (less time to repair DNA) and clonal expansion of the mutated cells.

Progression: Accumulation of “appropriate” mutations leads to unrestrained cell division... acquisition of additional “appropriate mutations” leads to malignancy.

Thus, there appear to be two basic processes responsible for the carcinogenesis process:

ROS- or Chemical radical-mediated DNA Damage (caused by mutagens: anything which causes DNA damage which results in mutations; of course repair infidelity or duplication errors also can do this ie. cause mutations) or,

Enhanced rates of Cell Division to fix and accumulate DNA mutations; eventually leading to tumorigenesis (caused by mitogens; anything which results in abnormally high rates of cell division resulting in enhanced risk for cancer)

Normal, controlled cell division is thus turned into mutated, uncontrolled cell division.

Normal cells enter the cell cycle only when stimulated by “well-controlled” growth signals.

Cancer cells continuously divide in an uncontrolled fashion“Initiation”

“Promotion”

“Progression”

Obviously DNA damage is really important for causing mutations and cancer.

So, the big question is:

How is DNA damage caused?

OXYGEN RADICALS CHEMICAL RADICALS (ROS) (carcinogens)

Errors inherent in the process of Repair & DNA replication are also very important in

producing mutations

Some Endogenous Sources of Reactive Oxygen Species

- Cytochrome P450 (CYP) autooxidation - Xanthine oxidase - Ubiquinone and NADH oxidase in mitochondria - NADPH oxidase of phagocytic cells

Some Sources of Chemical Radicals (aka carcinogens)

- Cytochrome P450 (CYP) activation of xenobiotics

We’ll deal with chemical carcinogens first

For the purposes of this discussion, xenobiotics refers to any compound not made by our tissues. Those which are not useful must be excreted. Fat soluble xenobiotics are usually metabolized to water-soluble products for excretion and it is this process which results in the formation of both ROS and carcinogens.

Different types of enzymes perform the chemical reactions necessary for these processes with CYP enzymes predominating in the activation of xenobiotics to carcinogens

Essentially, CYP enzymes take oxygen, reduce it, and the oxygen radical reacts with the xenobiotic to hydroxylate it concomitant with the release of water.

If CYP enzymes do not work properly (uncoupled) they release ROS

Benzo(a)pyrene is a common xenobiotic found in smoke from burning plants & is a major carcinogen in tobacco smoke.

NNK is a major carcinogen found predominantly in tobacco smoke.

ROS also are responsible for producing DNA damage

If all the adducts are added up one finds some interesting results:The majority of DNA damage and mutations in P53 – even in smokers – comes from ROS-mediated processes.

Events which alter the cell division cycle also are very important in carcinogenesis

Stem cells are the predominant source of tumor cells.

Under normal conditions Stem cells (SC) divide slowly to replenish the population of faster-dividing, short-term progenitor cells (PC). When progenitor cells divide, the displacement of their daughter cells toward the tissue environment forces cell:cell contact which, in concert with TGF and other factors, induces differentiation into mature tissue cells. These processes are under tight control by a variety of cell-signaling factors that modify activity of the various signal-transduction pathways

Tissue RegenerationThe Predominant

Site of Tumorigenesis

Elevated PGE2 and other growth factors activate various MAPK signal-transduction pathways in Stem Cells to initiate the activation and synthesis of a variety of proteins that are necessary for activating growth of the stem cell and the synthesis of DNA to duplicate the chromosomes in order to proceed to the mitosis phase.

A decline in the levels of PGE2 and of growth factors induces G0 arrest via reducing MAPK activities.

Progenitor cells divide more-or-less continually in response to normal levels of the same stress-response signaling with the displaced daughter cells differentiating into tissue cells.

Regulation of Tissue Regeneration

ERK-MAPK - p38 MAPK - JNK-MAPK - PI3K/Akt

The major signal transduction pathways (STPs) involved in regulating the growth and development of stem cells and progenitor cells are the ERK-MAPK, p38-MAPK, JNK-Mapk, PI3K/Akt, and the “Nfκβ” pathways.

These STPs regulate synthesis of many different proteins; including those that are necessary for the different phases of cell division.

If any of the genes that code for the various proteins of the STPs acquire an enabling mutation that renders them constitutively active then the constant activity of the associated STP might enhance risk for increasing rates of cell division and subsequently: tumorigenesis.

Such a mutation would be called a DRIVER MUTATION.

Mutations in any of the genes that code for the various proteins that are involved in regulating cell division are called driver mutations: i.e. mutations that affect one or another function of dividing cells that increases the likelihood of them becoming tumor cells.

Enabling mutations in any of the genes that code for proteins that stimulate different aspects of the cell division cycle and disabling mutations in any of the genes that code for proteins that block entry into cell division will enhance proliferative activity.

Disabling mutations in the genes of any of the proteins involved in activating cell-cycle arrest, DNA repair, and apoptosis will not only enhance proliferative activity but greatly enhance the likelihood of mutations due to DNA damage.

DNA damage is central to theprocess of tumorigenesis. Thereis no shortage of oxidizing andalkylating species that arecapable of reacting with DNAmolecules t alter theirstructure and render themunrecognizable to the DNApolymerases; resulting in a variety of mutationsproduced during the S-phase.

In addition to the types ofmutations caused by oxidationevents and alkylation events:predominantly transitions(A↔G, C↔T) andtransversions (A↔C, T↔G);a variety of other consequences

of DNA damage can occur: ∙OH can abstract ahydrogen from C5 of deoxyribose to leave a carbon-centeredallyl radical which reacts with O2 to produce anoxyl-radical; leading to single strand breaks. Whensingle-strand breaks are not repaired, they often lead to double-strand breaks during the S-phase; resulting in a variety of chromosomal mutations formed during mitosis. DNA:DNA and DNA:protein crosslinks also occur and these lead to chromosomal mutations as well.

As driver mutations accumulate in SCs they start to acquire self-stimulating properties and not only do they divide inappropriately, the PCs they produce also can acquire these properties to produce an array of mutated SCs and PCs that also produce abnormal tissue cells. As the cells continue to divide they expand within the tissue spaces to displace the

blood vessels and create a relatively hypoxic environment within the tissue. The resulting activation ofHIF-1 synthesis leads to profound changes in thecomposition if the tissue.

HIF-1 induces expression ofglycolytic enzymes, PDH kinase,growth factors (including IGF,TGFα, and VEGF), and MCP-1.The increase in PDK inhibitsglycolysis to enhance thepentose phosphate pathway toHelp increase synthesis of DNA/RNA and the enhanced glycolyticenzymes enhances survivability in the face of inhibited glycolysis under hypoxic conditions.In addition to the growth advantages incurred through HIF-1, MCP-1 synthesis is intimately involved in the development of tumors through stimulating infiltration with inflammatory stromal cells.

Infiltration of the tissue with inflammatory cells provides a steady supply of growth factors and proliferative signaling to enhance the growth of the developing tumor. As the cancer cells continue to divide they acquire additional mutations that reduce

their ability toarrest the division cycleand to repair DNA damage; greatly

enhancing the accumulation of additional mutations.The inflammatory cells also contribute to angiogenesis, a hallmark function of

tumors. The other hallmark functions include the ability to activate their own cell division, an

inability to differentiate, loss of check-point controls, processes of cell-cycle arrest and apoptosis are disabled, indefinite cell division, and the ability to invade other tissues and metastasize. This last is due to the continued proinflammatory signaling that stimulates the production of CD40 from platelets that leads to the release of a variety of proteinases from the inflammatory cells that then degrade collagen, fibronectin, and other connective tissue proteins.

Because inflammatory signaling is so important to the tumorigenesis process a diet not only needs to include all of the appropriate nutrients but it also should contain a sufficient intake of non-nutritive compounds that can attenuate inflammatory signaling…

…and it is the phytochemical components of fruits, vegetables, oils, and whole-grains that provide the antiinflammatory effects.

It is highly instructive that a traditional “Mediterranean diet” with which incidence of many chronic diseases is much lower than with a “US diet” has a phytochemical content that averages 1.5 g/day for men and 1.3 g/day for women while the average intake of phytochemicals in the US diet is ~ 0.4 g/day.

A Table of the Phenolic Content of Common Foods follows:

Herbs - Spices>5,000 mg/100g: cloves, Ceylon cinnamon, dried pot marjoram, dried spearmint, dried wild-marjoram oregano>3000 mg/100g: dried summer-savory, dried sweet-basil, dried sweet bay, dried marjoram, capers> 1000mg/100g: dried common sage, caraway, dried rosemary, dried coriander, dried turmeric, dried cumin, nutmeg, dried winter

savory, dried common thyme, star anise, dried parsley, dried dill, curry, black pepper Dried Fruits ~1,000 mg/100g: prunes, raisins, figs Fruits> 500mg/100g: black elderberry, black chokeberry, skunk current, black raspberry, blackcurrant, Canada blueberry, gooseberry>200 mg/100g: plum, lowbush blueberry, orange, American cranberry, sour cherry, strawberry, peach>50 mg/100g: grapes, apple, kiwi, banana, pineapple, mango, pear, star fruit, guava Nuts>1000 mg/100g: chestnut, pecan, walnut, pistachio>200 mg/100g: hazelnut, almond, Brazil nut, cashew>50 mg/100g: Macadamia nut, dehulled almond, dehulled peanut

Beans >500 mg/100g: raw whole Adzuki bean, raw whole lentils, raw dehulled black bean, raw whole bean, raw whole broad bean10 - 150 mg/100g: raw whole white bean, raw whole dried pea, raw whole climbing bean, raw whole lima bean; Vegetables >500 mg/100g: Swiss chard>200 mg/100g: raw dandelion, red cabbage, raw green bean, chili pepper, spinach, sweet pepper, raw Brussels sprouts; broccoli,

cauliflower< 100 mg/100g: raw green cabbage, sauerkraut, tomato, squash, zucchini, lettuce, onion, carrot, asparagus, sweet potato, potato,

celery; Oils~500 mg/100g: peanut oil~20 mg/100g: virgin/refined olive oil~20 mg/100g: Canola/rape~2 mg/100g: sesame oil Grains 700+ mg/100g: whole wheat buckwheat flour, wheat germ~180 mg/100g: whole grain hard wheat, corn flour~70-100mg/100g: whole-grain common flour, oat flour, corn flour, rice flour

A variety of phytochemicals are known to interfere with different components of the signaling pathways that lead to synthesis of the proinflammatory cytokines and eicosanoids.

By inhibiting production of both proinflammatory cytokines and eicosanoids, progression of tumors will be significantly inhibited

Synthesis of the various antioxidant and redox control enzymes and compounds can be enhanced to optimize antioxidant and redox control.

These enhanced protective effects are mediated by binding of the Nrf2 transcription factor to the antioxidant (electrophile) response element along with the small nuclear Maf proteins.

In addition to these, NADPH:quinone oxidoductase, UDP-glucuronosyl transferase, and glutathione-S-transferase (along with other phase II enzymes) are induced. These enzymes eliminate activated carcinogens by adding a water-soluble group to the reactive component of the carcinogen and contribute to the reduction in risk for tumorigenesis through a phytochemical-rich diet.

Some Common Phenolics(food sources listed from high to low):

Flavonoids: quercetin (black elderberry, dark chocolate, oregano, capers, and some in vinegar, tomatoes, shallots, and red onions); apigenin (extra virgin olive oil, Welsh onion, Italian oregano, and pistachios); epigallocatechin-3-gallate/EGCG (green tea, Oolong tea, black tea, pecan, hazelnut, pistachio, banana); theaflavin (black tea); genestein (soy products); anthocyanins (blueberries, strawberries, cherries, common black beans); kaempferol (capers, cloves, black tea, broccoli, apples, cherry tomatoes, onions);

phenolic acids: ellagic acid (chestnut, Japanese walnut, walnut, blackberry, black raspberry, pomegranate juice); capsaicin (hot peppers, Hungarian peppers, sweet peppers), curcumin (turmeric, curry powder), caffeic acids (coffee)

stilbenoids: resveratrol (red wine, red/black grapes, lingonberry, European cranberry, vinegar, roasted peanuts)

In putting the information together from the phenolic data and the nutrient composition of foods data (that is already incorporated into the dietary recommendations); a list of recommendations can be made:

Number of Food Servings for Daily Caloric Intakes:

Food Group Standard Approximate ~ 2000 ~ 2200 ~ 2500 ~ 2800 Serving Size Calories / kcal kcal kcal kcal

Serving

Fruits 0.5 cup 71 5 5 5 5

Vegetables 0.5 cup 38 6 6 6 6

Cold-Water Fish 4 ounces 120 2/wk 2/wk 2/wk 2/wk

(Lean Meats on 3 ounces 120 - - - -remaining days are optional)

Nuts & Seeds 0.25 cup 240 1 1 1 1

Beans & Legumes 0.5 cup 110 2 3 3 3

Dairy 1.0 cup/2 oz. 86 3 3 3 3

Breads & Cereals 1 slice/1 oz 78 5 6 7 7

Red Wine 4 oz 85 1 1 1 1

Added Fats 1 Tbsp (EVOO) 110 2 2 3 3

Discretionary Calories - - 200 400

Fruits - Minimum of 3 cups each day with at least one ½-cup selection from each category each day:A elderberries, blueberries, pomegranate, blackberries, raspberries, Saskatoon

berries, blackcurrant, raisons, figs or prunes.B plums, oranges, grapefruit, lemons, cantaloupe, cherries, cranberries, strawberries, peaches, red/black grapes, or apples.C kiwi, bananas, pineapples, mangoes, pears, star fruit, guava or any other fruit. Vegetables - Minimum of 4 one-cup servings each day with at least one different 1/2-cup selection from each category each day:A chili peppers, broccoli, water cress, garden cress, spinach, arugula, Brussels

sproutsB cauliflower, tomato, lettuce, green beans, sweet peppers, red cabbageC onion, garlic, celery, green cabbageD squash, zucchini, pumpkin, sweet potatoes, carrots Nuts and Seeds - Minimum of 1 one-quarter cup serving each day with a minimum of 2 different selections from each category each week:A chestnuts, pecans, walnuts, pistachiosB hazelnut, almonds, Brazil nuts, cashews, Macadamia nuts, or peanuts. Beans and Peas - Minimum of 1 one-cup servings each day with a minimum of 2 different 1-cup selections from each category each week:A black beans, Adzuki beans, kidney beans, peas/pea pods, lima beanB lentils, pinto beans, chili beans, chick peas, navy beans

Beans and Peas - Minimum of 1 one-cup servings each day with a minimum of 2 different 1-cup selections from each category each week:A black beans, Adzuki beans, kidney beans, peas/pea pods, lima beanB lentils, pinto beans, chili beans, chick peas, navy beans Whole Grains and Cereals - Minimum 5 one-ounce servings of whole grains each day with a minimum of 1 selection from each category each week:A buckwheat, wheat, bulgurB oats, corn, barleyC wild rice, rice Oils - used for cooking, salads, and dipping - Approximately 2 Tbsp/dayA Extra virgin olive oil Meats - Minimum of 2 servings of high EPA/DHA fish each week

Brief Summary of Sources of Risk (Cause)

Reactive oxygen species -based carcinogens are a majority cause of DNA mutations that are causal in most human cancers

Reactive Chemical Species-based carcinogens are a minority cause of DNA mutations that are causal in most human cancers

Errors that occur during repair of DNA damage contribute to formation of mutations and are a significant contributor to some human cancers

Errors that occur during the DNA replication phase of cell division contribute to the formation of mutations and are a significant contributor to some human cancers

ROS are formed through a variety of normal metabolic reactions, normal function of inflammatory phagocytes, as well as (inappropriate) autoxidation of various enzymes and co-factors

ROS also are present in smoke (cigarette, vehicle exhaust, grass, leaves, BBQ, etc.)

A large majority of reactive chemical species are formed by the process of converting lipid-soluble compounds into water soluble compounds by Phase I enzyme reactions: CYP -mediated and similar reactions

Hormonal and inflammatory-associated Growth Factors promote cellular growth and, in susceptible cells: cell-division .

Mutations in genes associated with regulating cell-division & apoptosis and in DNA repair & replication are apparently the vast majority of mutations responsible for the cause of cancer…

Nutrient insufficiencies, calorie overload, and inactivity lead to compromised antioxidant and redox status, enhanced proinflammatory signaling, and elevated ROS/oxidant-mediated damage. These lead to increased cell proliferation and the ultimate production of a variety of enabling and disabling mutations that drive the cancer processes and may account for as much as 80% or more of the total risk. These effects are enhanced through voluntary and involuntary exposures to a variety of procarcinogenic compounds from the environment.

Consumption of a calorie-balanced, phytochemical-rich diet along with 60 continuous minutes daily exercise will optimize redox and antioxidant control, DNA repair, Phase II activities, and attenuate proinflammatory signaling to minimize both cell proliferation and mutagenesis. Altering behavior to reduce the voluntary use of higher-risk products such as tobacco, BBQ meats, pesticides, and plastic products also will reduce risk for a large minority of the risks.

Add in the benefits of exercise and a substantial reduction in risk for these chronic diseases, beyond diet alone, can be realized!

Remember this from earlier…

Exercise stimulates the release of IGF-1 from muscle and activates various mechanoreceptors leading to the transient activation of PI3K, PLC, AMP-PK, and the MAPKs as well as transient increases in cellular hydrogen peroxide. Subsequent activation of Nrf2, p50/p65, PGC-1α, ER, and many other transcription factors enhances expression of SOD, CAT, Prx, Trx, GPX, GSR, GLUT4, and IRS1. Longer-term exercise increases release of IL-6 from muscle, activating expression of sTNFr, sIL-1r, sIL-1ra and of SOCS via IL 10/STAT3.

heart disease & cancer

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