6. Causes of Chronic
Inflammation
Persistent injury or infection
Prolonged exposure to triggering
stimuli
Inappropriate inflammatory response
leading to autoimmunity
Tissue damage and loss of barrier
function
Oxidative Stress
Persistent activation of the immune
system or of inflammatory molecules
7. Fat cells are actually highly complex endocrine,
inflammatory and metabolic tissue, not just storage
depots!
Graphics from http://www.indiana.edu/~K536
11. Overview of the mechanisms by which fatty acids can influence
inflammatory cell function.
Alterations in membrane composition are likely a key mechanisms since such alterations
can influence eicosanoid profiles, membrane receptor function and cell signaling processes.
DHA and EPA oppose the pro-inflammatory actions of SFA and n-6 PUFA including ARA
through multiple interconnected mechanisms: reducing production of inflammatory
eicosanoids and cytokines and enhancing production of anti-inflammatory mediators
(Beezhold, 2013)
12. Formation
of AGEs
[Asterisks mark
the location
where flavonoids
may inhibit their
formation.]
(Beezhold, 2013)
14. Causes of Chronic
Inflammation
Persistent injury or infection
Prolonged exposure to triggering stimuli
Inappropriate inflammatory response
leading to autoimmunity
Tissue damage and loss of barrier
function
Oxidative Stress
Persistent activation of the immune
system or of inflammatory molecules
16. Endogenous Sources of Free
Radicals
Aerobic respiration
Metabolism of food
Immune activation
17.
18. Human antioxidant defense systems include
endogenous (enzymatic and non-enzymatic)
and exogenous antioxidants, with the diet
being the main exogenous source
Bouayed, 2010
19.
20.
21.
22. “The current evidence
does not support the use
of antioxidant
supplements in the
general population or in
patients with various
diseases”
Cochrane Review, 2012
23. Why?
Antioxidants:
The double-edged
swords
Antioxidants display
pro-oxidant activities
under certain conditions
such as at high doses or
in the presence of metal
ions
ROS at low doses play
a crucial role in cellular
functioning
Bouayed, 2010
26. In-Vitro ≠ In-Vivo
Free radical scavenging in vitro does not indicate
antioxidant activity in the body
Low intrinsic activity
Poorly absorbed
Highly metabolized
Rapidly eliminated
Phytochemicals may act through multiple non-antioxidant
mechanisms beyond just antioxidant
capacity.
27. USDA Withdraws ORAC
Database
“Recently the USDA’s Nutrient Data
Laboratory (NDL) removed the USDA
ORAC Database for Selected Foods
from the NDL website due to mounting
evidence that the values indicating
antioxidant capacity have no relevance
to the effects of specific bioactive
compounds, including polyphenols on
human health.”
http://www.ars.usda.gov/Services/docs.htm?docid=15866
28.
29.
30.
31. References:
Beezhold, B. NTR 625 Complementary Therapies. [PowerPoint Slides]. (2013)
Bjelakovic, Goran, Dimitrinka Nikolova, Lise Lotte Gluud, Rosa G. Simonetti, and Christian Gluud. "Antioxidant supplements for prevention of mortality in healthy participants and patients with
various diseases." Cochrane Database Syst Rev 2, no. 2 (2008).
Bouayed, Jaouad, and Torsten Bohn. "Exogenous antioxidants—double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high
doses." Oxidative Medicine and Cellular Longevity 3, no. 4 (2010): 228-237.
Buyken, Anette E., Victoria Flood, Marianne Empson, Elena Rochtchina, Alan W. Barclay, Jennie Brand-Miller, and Paul Mitchell. "Carbohydrate nutrition and inflammatory disease mortality
in older adults." The American journal of clinical nutrition 92, no. 3 (2010): 634-643.
Calder, Philip C. "Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale." Biochimie 91, no. 6 (2009): 791-795.
Chait, Alan, and Francis Kim. "Saturated fatty acids and inflammation: who pays the toll?." Arteriosclerosis, thrombosis, and vascular biology 30, no. 4 (2010): 692-693.
Dickinson, Scott, Dale P. Hancock, Peter Petocz, Antonio Ceriello, and Jennie Brand-Miller. "High–glycemic index carbohydrate increases nuclear factor-κB activation in mononuclear cells of
young, lean healthy subjects." The American journal of clinical nutrition 87, no. 5 (2008): 1188-1193.
Estela Guardado Yordi, Enrique Molina Pérez, Maria João Matos and Eugenio Uriarte Villares (2012). Antioxidant and Pro-Oxidant Effects of Polyphenolic Compounds and Structure-Activity
Relationship Evidence, Nutrition, Well-Being and Health, Dr. Jaouad Bouayed (Ed.), ISBN: 978-953-51-0125-3, InTech, DOI: 10.5772/29471. Available from:
http://www.intechopen.com/books/nutrition-well-being-and-health/antioxidant-and-prooxidant-effect-of-polyphenol-compounds-and-structure-activity-relationship-eviden
http://www.hsph.harvard.edu/nutritionsource/antioxidants/
Franz M. Nutrition, Inflammation, and Disease. Today’s Dietitian. 2014; 16(2):44
Gans K. How much do you really know about antioxidants? http://www.huffingtonpost.com/2013/08/12/what-are-antioxidants_n_3732238.html Published August 12, 2013.
Ilkay J. Debate on Antioxidants — Some Studies Suggest Efficacy While Others Question Safety. Today’s Dietitian. 2010; 12(4):14.
National Center for Complementary and Alternative Medicine (NCCAM). Antioxidants and Health: An Introduction. http://nccam.nih.gov/health/antioxidants/introduction.htm#safety Published
May 2010. Updated November 2013.
Ritchie, SA1, and J. M. C. Connell. "The link between abdominal obesity, metabolic syndrome and cardiovascular disease." Nutrition, Metabolism and Cardiovascular Diseases 17, no. 4
(2007): 319-326.
Siri-Tarino, Patty W., Qi Sun, Frank B. Hu, and Ronald M. Krauss. "Saturated fat, carbohydrate, and cardiovascular disease." The American journal of clinical nutrition 91, no. 3 (2010): 502-
509.
Wallace JP. K536 Physiology of Adipose. Indiana University.
http://www.indiana.edu/~k536/adipo.html#endo Updated September 9, 2010.
Notas do Editor
Who knows the golden rule of real estate? Location, Location, Location! In medicine, science and nutrition- I think the buzzword is inflammation, inflammation, inflammation.
Of course, inflammation isn’t entirely evil. Acute inflammation- the kind that protects and heals the body after injury or infection is in fact normal and also essential. Acute inflammation is the initial response of the body to harmful stimuli and involves the increased movement of plasma and leukocytes (mostly granulocytes) from the body into the injured tissue. It produces a cascade of biochemical events involving the local vascular system and the immune system and is evident by the 5 cardinal signs of Heat, Redness, Swelling, Pain and Loss of Function.
The goals of acute inflammation are to: eliminate initial cause of injury or insult, remove damaged cells/tissues & begin the healing process. This process is normally well controlled and self-limited and therefore, the purpose of the inflammatory response is obvious and the response is beneficial- as long as it does not become unnecessarily destructive or long lasting.
Shift in the type of cells present at the site of inflammation
Net result: Simultaneous destruction of tissue from the healing process
So there is the good, the bad and then there is of course the deadly side of inflammation. Not a new discovery or concept, but inflammation has been linked to several chronic diseases and leading causes of death including but not limited to cancer, cardiovascular disease, hypertension, Alzheimer’s, obesity and diabetes. And there are also immediate consequences of systemic inflammation that I am sure many of you may see in your practice everyday such as delayed healing, delayed progress and or delayed performance.
So what causes that normally beneficial, well-controlled, self-limited system to go awry? The why remains largely unknown, although several mechanisms have been proposed and supported. First, persistent insult (chronic infection, continued exposure to the triggering stimuli) may provide a continued proinflammatory stimulus. The components of inflammation that are capable of destroying microbes or injured tissue can also injury bystander normal tissue or cause a loss of barrier function and the subsequent release of pro-inflammatory messengers or cytokines. Thirdly, inappropriate inflammatory responses associated with autoimmunity cause excess inflammatory reactions. And there is a strong interaction between oxidative stress and inflammation. And last but certainly not least, chronic inflammation can result from the persistent activation of the immune system or of inflammatory molecules from sources such as stress, poor nutrition, insufficient sleep and obesity.
Fat cells are actually highly complex endocrine, inflammatory and metabolic tissue, not just storage depots. In fact adipose tissue is now hypothesized to be the largest endocrine organ in the body. Adipose tissue is able to express many pro-inflammatory molecules, with macrophage infiltration which then propagates the inflammatory cascade. Additionally, visceral adiposity is associated with elevated FFA. The processing of excess FFA causes mitochondrial uncoupling and the release of the most detrimental free radical, Reactive Oxygen Species.
The Link between abdominal obesity, metabolic syndrome and cardiovascular disease. Ritchie
Many dietary components have been found to influence various elements of inflammation. Therefore, nutrition can play a role in predisposing one to inflammatory conditions, and on the positive side nutrition can be useful in the prevention or therapy of such conditions. In fact there are dietary factors that act as direct causal factors for inflammation and dietary factors that are modifiers or regulators of the inflammatory response.
Hi GI carbohydrates, trans fatty acids and saturated fatty acids have all been consistently shown to be direct triggers for inflammation due to an increase in free radical production, an increase in pro-inflammatory cytokines and or in the stimulation of macrophages and the innate immune system.
High-GI diets rich in refined carbohydrates has been linked to low-grade chronic inflammation due to recurrent postprandial hyperglycemic peak resulting in the overproduction of reactive free radicals and a greater release of pro-inflammatory cytokines.
SFA have been shown to stimulate macrophage production as well as adipose tissue inflammation.
A lot of research has been done identifying the family of Omega-6 Polyunsaturated Fatty Acids as a pro-inflammatory nutrient and more specifically the ratio of Omega-6 to Omega-3 intake. Omega-6 FAs (soybean, corn, safflower, sunflower) are precursors to proinflammatory eicosanoids, or signaling molecules that help regulate immune function and are active in the inflammatory process. In contrast, those from the Omega-3 family produce eicosanoids that are anti-inflammatory or less pro-inflammatory than those from Omega-6 and the Omega-3s block the effects produced from Arachidonic Acid. As mentioned it is more about the ratio of Omega-6:Omga-3 which is linked to inflammation. Ideally the ratio should be about 1-4:1 but American diet is upwards of 10-20:1
And the last pro-inflammatory nutrient to highlight is AGE’s or Advanced Glycation Endproducts.
AGE’s form when proteins or fats chemically react or combine with sugar. This can occur during food processing and high heat cooking as well as naturally in the body. AGEs are particularly high in animal-derived foods that are high in fat and protein (like red meat and full fat dairy products), which are prone to AGE formation through cooking. And sugary foods and highly processed and packaged products are also high in AGEs. The body naturally rids itself of harmful AGE compounds, but is ineffective at eliminating all of them when too many are eaten through food. Inflammatory cells express receptors for AGEs (RAGEs) and RAGE induces inflammatory signaling.
So then looking at the Pro-inflammatory nutrients which have been identified, High GI carbs, trans and saturated fats, Omega-6 Fatty Acids, and AGE’s the anti-inflammatory nutrients include the opposing nutrients to some of those including low Gi carbs and Omega-3 Fatty Acids, as well as Probiotics and Antioxidants.
Breakdown of barrier function as mentioned can be a cause of chronic inflammation. The gastrointestinal barrier directly blocks pathogens from entering into circulation. And prebiotics and probiotics positively interact directly with the gut epithelium cells.
So going back to this slide listing some of the major causes for low grade systemic inflammation, there is a strong interaction between oxidative stress and inflammation. Many of the biological processes that occur within the body are redox reactions or the coupling of oxidation and reduction with the gain and loss of electrons. The loss of electrons from oxidation produces free radicals which are unstable molecules that can attack cell membranes, DNA and protein through a cascading effect which ultimately leads to cell damage. The most potent of free radicals is Reactive Oxygen Species or ROS.
Cells and extracellular spaces are exposed to a large variety of reactive species from our environments. Yet as bad as pollutants and radiation sound…
exposure to endogenous sources is much more extensive
An increase in ROS production or diminished antioxidants can lead to progressive cell damage and a decline in physiological function. When oxidant capacity exceeds the antioxidant capacity, the imbalance is oxidative stress.
Considering that all cells in the body are capable of producing free radicals and ROS. 95-98% of 02 that enters mitochondria is converted into water in order to produce energy for the body. 2-5% oxygen is used to generate free radicals. Thankfully the human body has an internal antioxidant defense system including superoxide dismutase, catalase, glutathione, and glutathione peroxidase. The system is however incomplete without exogenous antioxidants. The antioxidants found in our diet include vitamin C, vitamin E, carotenoids such as beta-carotene and lutein, and all of the phytochemicals, including flavonoids and other polyphenols. All fruits and vegetables contain some vitamin C with the highest sources being citrus fruits and their juices, strawberries, broccoli, peppers, and tomatoes. Nuts, seeds, and vegetable oils, including sunflower, canola, olive, and soybean oils, are among the highest sources of vitamin E in the American diet. Beta-carotene and other carotenoids are found in most yellow and orange fruits and vegetables like cantaloupe, carrots, and winter squash, as well as in leafy greens like spinach and kale. Because there are thousands of different phytochemicals, they are present in a broad array of plant- based foods and beverages including all fruits, vegetables, whole grains, beans and legumes, nuts and seeds, green, black, and herbal teas, coffee, dark beer, red wine, cocoa, herbs and spices.
Antioxidants are divided into two groups: scavengers- help slow or stop the damaging chain reaction by removing free radical intermidiates; or preventative antioxidants- stabilize free radicals by donating electrons and become oxidized themselves, forming less active radicals.
Antioxidants- 92% of Americans cannot give an accurate description of an “anotioxidant” In addition, 91% cannot recognize one or more sources of foods rich in antioxidants, even though 75% of Americans say they try to eat foods full of this nutrient and upwards of 20% of Americans regularly take specifically antioxidant supplements.
Since dietary antioxidants represent a crucial line of defense against oxidative and inflammatory insult and because the potentially protective role of dietary antioxidants is supported by extensive basic scientific evidence and an abundance of epidemigical data- it is not surprising to say that antioxidant supplements represent a $500 million dollar industry that continues to grow- antioxidants being added to breakfast cereals, sports bars, energy drinks and sold in single antioxidant capsules. But, the question Beneficial when bottled should be asked.
The answer is controversial and the available research is contradictory. Much like the start of this talk about inflammation there are investigative research studies that show antioxidant supplementation is good, that it is bad and that it may even be deadly.
So, then why? If extensive epidemiological studies reveal that high consumption of fruits and veggies is associated with decreased inflammation and inflammatory diseases and in-vitro studies prove that antioxidants can break or stop the chain reaction of free radicals, why does the current evidence not support the use of antioxidant supplementation? First: antioxidants have been recently referred to as the double-edged swords. In certain situations such as at high doses or in the presence of metal ions antioxidants may display pro-oxidant activities. Additionally, ROS has a received a very bad rap, but at low doses actually plays a crucial role in cellular functioning in cell signaling, gene expression, the regulation of the immune system and believe it or not, fostering antioxidant defense mechanisms. At low doses ROS is essential for cell signaling and therefore cell functioning and free radicals stimulate endogenous antioxidant defense systems. Remembering that oxidative stress occurs when there is a disequilibrium between oxidant production and antioxidant protection…high doses of antioxidants may cause disequilibrium or flip the balance scale in the other direction.
Many antioxidant supplements can contain upwards of 100 times the amount naturally occurring in food. You would need to eat 8 cantaloupe ( a good source of vitamin C) to get just under 1000mg of Vitamin C . One tablet can contain as much as those 8 cantaloupes or twice or three times as much, completely by passing the potentially protective effect of satiety. And this supplement is on top of other natural sources of antioxidants found in someone’s diet or other antioxidant fortified products out there.
Secondly, evidence of antioxidant activity based on capabilities to scavenge free radicals in a laboratory setting is not proof of biologic physiological effects. Factors such as low intrinsic activity, metabolism and elimination of the antioxidant have an impact. And the absorption of antioxidants is dependent on the microflora of the intestines which is highly variable from person to person.
And lastly, the most recent research within the past few years is beginning to show that polyphenol compounds are most likely protective or beneficial for several mechanisms beyond just antioxidant capacity. Research is so compelling that the USDA has recently withdrawn the ORAC Database, or scale commonly used to rank the antioxidant capacity of selected foods from their website.
Because biochemical and molecular studies in the area of nutrition have primarily focused on discovering mechanisms of dietary effects in biologic systems, a reductionist approach using single nutrients or dietary constituents has dominated the research. Following linear cause-effect constructs, meaning that the whole can be explained by the sum of its parts. However, increasing evidence is pointing to the fact that health advantageous effects of fruits and vegetables may not be attributed to a specific compound, but rather to the whole plant food and the synergistic relationship of all of its parts. The research surrounding antioxidants today is where vitamins were about 60 years ago. We are still trying to characterize what these compounds are, their bioavaliblity and active principles. So stay tuned. Evidence supporting the diet’s role both in promoting and hindering the inflammatory process is mounting. Additional research is needed to identify the independent and interactive effects of nutrients and food. You can help your clients by emphasizing dietary changes that will help reduce inflammation levels in the body and begin to restore normal immune function. Encourage an increased consumption of fruits, veggies, whole grains, nuts, olive oil, fatty fish and cultured dairy products and advise clients to reduce their consumption of refined carbohydrates, sweets, processed foods and those loaded with trans and saturated fat.
