09.09.08
Nutrition has seen many changes since early man, especially in the last 150 years. The dietary intake of modern society is lacking in several essential vitamins and nutrients, especially essential fatty acids (EFA). There are two types of EFAs required through dietary intake since your body cannot produce them; the omega-3 type, including alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the omega-6s, including linoleic acid (LA), Dihomo-gamma linolenic acid (DGLA) and arachidonic acid (AA). Throughout the course of history, both types of EFAs (omega-3 and omega-6) were consumed in relatively similar quantities (UN Das 2006). Hunter-gatherers obtained omega-3s from foods such as fish, meat, wild plants, nuts and eggs. These foods provided plentiful amounts of EPA and DHA which are largely missing from today’s diet. Unfortunately, due to technological advances, the dietary needs of today’s society are met with cereal type grains, such as wheat and rice, which make up a whopping 75% of the worlds grain production (Cordain, 1999). Defectively, cereal grains are extremely high in carbohydrates and omega-6 fatty acids, and severely low in omega-3s. This has led to a tremendous deficiency in omega-3 fatty acids, whereby the ratio of omega-3 to omega-6 is a shocking 1:15 instead of an optimal ratio of 1:1 (Eaton, Konner, 1985).
Medical research has clearly demonstrated that a decreased amount of omega-3 relative to omega-6 in the diet results in a shift of biochemical homeostasis and an increased risk of degenerative disease. One of the most damaging effects of EFA unbalance is the development of chronic inflammation. Advances is EFA science and extensive clinical research has established a link between chronic inflammation and a broad range of degenerative conditions such as heart disease, cancer, immune dysfunction, arthritis and psychiatric disorders (Simopoulos, 1991).
EFA’s and Chronic Inflammation
Inflammation is a crucial aspect of the human body’s defense against injury and infection, and is necessary for survival. However, inflammation can become dangerous and can worsen the symptomology of chronic diseases such as cancer, rheumatic conditions, and sepsis. Therefore, inflammation has a diametrical effect - both beneficial and harmful. Inflammation can be classified as either acute or chronic. Acute inflammation is a short-lived process, demonstrating redness, swelling, heat, pain, and loss of function. It lasts until the exogenous stimuli has been broken down, removed, or walled via the process of scarring, and is typically seen after an injury, surgery, or infection (Baniyash, 2006). If the inflammation persists and becomes pathological, it is then classified as chronic. Chronic inflammation is characterized by synchronal tissue destruction, active inflammation, and attempts at repair. The removal and attack of a harmful stimulus or infection requires the production of compounds which can be toxic not only to the exterior stimulus, but to the human body as well (Simopoulos, 2001). Chronic inflammation can lead to several dangerous side effects, and as mentioned can result in diseased states such as cancer, vascular disease, fungal infections, inflammatory bowel diseases, and psoriasis.(Artemis & Simopoulos, 2002).
How the Inflammatory Pathway is modulated by AA, DGLA, EPA and DHA
The body’s inflammatory response is modulated by the action of essential fatty acids from both the omega-3 family (EPA/DHA) and omega-6 family (AA/DGLA). The fatty acids AA, EPA, and DGLA (but not DHA) are metabolized via specific enzymes to produce a series of hormone-like molecules called eicosanoids which includes a large variety of different compounds consisting of prostaglandins (PG), thromboxanes (TX), leukotrienes (LTs) and lipoxins (LXs). The pathways for eicosanoid synthesis are catalyzed by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX). These enzymatic pathways are upregulated due to inflammatory stimuli including various cytokines (e.g. interleukin (IL)-1) and phospholipase proteins. When the COX and LOX enzymes act on the omega-6 fatty acid AA they produce primarily inflammatory eicosanoids. EPA and DGLA on the other hand produce eicosanoids that are far less inflammatory than those derived from AA. Due to the similar molecular structure of AA and EPA, these two fatty acids directly complete for incorporation into cellular membranes. By displacing AA at the cellular level increased intake of EPA leads to a marked reduction of the potent pro-inflammatory AA derived eicosanoids. This is the primary action by which EPA is considered as anti-inflammatory. In addition to this displacement, EPA, and to lesser degree DGLA compete with AA for access to the lipoxygenase and cyclooxygenase enzymes, thus lowering the output of AA type eicosanoids (Guivernau, Meza, Barja & Roman, 1994). Finally, omega-3 compounds are able to reduce AA by counteraction. The enzymatic oxidation of EPA yields prostacyclin PGI3 and LTB5 which together act to impede the production of the inflammatory leukotriene LTB4 (Prescott, 1984).
Although DHA does not play a direct role in the balance of eicosanoid synthesis it does however have an effect on the inflammatory response by affecting cellular transcription factors. It is hypothesized that DHA influences how cells respond to inflammatory cytokines buy acting on the expression of specific genes (De Caterina, Cybulsky, Clinton, et al. 1994). Essentially a lack of cellular DHA may cause the cell to over-react in the presence of inflammatory stimuli thus upregulating the inflammatory pathways.
The degree of inflammation experienced by the body is thereby influenced by dietary intake of omega-3 and omega-6 fatty acids. A dietary increase of the omega-3 fatty acids EPA and DHA results in a more favorable inflammatory response and reduced risk of chronic inflammation and associated pathologies.
The GLA Paradox
Gamma-linolenic acid, an omega-6 fatty acid, is found in several types of foods, including human milk, organ meats, and certain plant seed oils such as evening primrose and borage. There exists however, a paradox in the nutritional benefits of GLA. Dietary intake of GLA leads to an increase of DGLA which can then be oxidized via the COX and LOX pathways. The result of this action is the production of anti-inflammatory eicosanoids. However, DGLA can also be efficiently converted into AA leading to the production of pro-inflammatory eicosanoids. The question is, which factors influence whether DGLA is converted to the pro-inflammatory AA? Although the process is likely multifactorial it has been demonstrated that an increased intake of the omega-3 EPA can directly inhibit the conversion of DGLA to AA (Barham, Edens, Fonteh et al 2000). This demonstrates yet another mechanism by which EPA modulates the inflammatory pathways.
Chronic Inflammation and the Diseases Prevalent in Today’s Society.
Recent research has begun to suggest that dietary intake of essential fatty acids could provide relief for chronic inflammation. Evidence first began to emerge from population studies, demonstrating that cultures consuming a significant amount of polyunsaturated fatty acids depict a lower incidence of inflammatory disorders and autoimmune deficiencies (Kromann & Green, 1980).
A strong relationship has been ascertained between vascular inflammation and coronary artery disease. This relationship is thought to be causal, whereby inflammation acts to increase the risk of heart disease (Ross, 1993). Consistent with this, inflammatory markers such as C-Reactive Protein are significantly higher in patients with coronary diseases and vascular disease, and the degree of inflammation corresponds to the severity of the disease (Artemis & Simopoulos 2003).
Studies have also demonstrated positive outcomes with the supplementation of omega-3 fatty acids in cases of rheumatoid arthritis. Consumption of EPA and DHA reduced morning stiffness, decreased the amount of LTB4, and reduced the tenderness of joints (Kramar & Jubitz et al, 1985).
The therapeutic use of omega-3s in persons with inflammatory bowel disease has also been suggested. Belluzzi et al (1996) showed a reduced rate of relapse in patients with Crohn’s disease who were given an oral dose of omega-3 fish oil, whereas other studies have found significant improvements in steroid-sparing (Endres et al, 1999).
EFA’s, Cancer, and Chronic Inflammation
Several studies have found that omega-3 type EFAs, especially eicosapentaenoic acid (EPA) have a positive effect on carcinogenesis, whereas the omega-6 type EFAs, such as arachidonic acid exacerbate cancer and tumor production (Maillard & Bougnoux, et al. 2002). One of the proposed mechanisms for omega-3 induced anticarcinogenic effects is the modulation of prostanoid biosynthesis. Prostanoids derived from omega-6 EFAs, such as prostaglandin E2 have been shown to increase the risk of breast cancer (Roland & Martin, et al, 1980). Consistent with this, cyclooxygenase-2 (COX-2), the enzyme that catalyzes the production of prostaglandins is frequently used as a biomarker for cancer (Parret & Harris etal, 1997). Rose and Conneley, et al. (1997) affirmed that EPA and DHA are able to suppress the growth of tumor cells by reducing the concentration of AA and PGE2 production.
Research has also confirmed that there exists a strong relationship between cancer and chronic inflammation. Inflammation can both predispose an individual to cancer, and can perturbate the prognosis of cancer development. On the other hand, cancer development and tumor synthesis induces a state of chronic inflammation, exasperating and enhancing the development of tumors (Clevers, 2004).
Chronic inflammation and free radical generation
Chronic inflammation has been shown to induce an over-expression of several free radicals and reactive oxygen species. Agents such as nitric oxygen synthase, lipoxygenase, and COX-2 are present in much higher amounts than normal. An accumulation of such agents, is highly un-adaptive, and can help to escalate malignant growth, and can contribute to the progression of several types of cancer. Chronic inflammation also results in increased concentrations of self-destructive compounds such as DNA-damaging reactive oxygen species (Bartsch and Nair, 2006). When production of such by-products overtakes the body’s antioxidant range of effectiveness, oxidation and damage to proteins, nucleic acids, and lipids ensues, resulting in an increased drive to carcinogenesis. Inflammation of tissues results in an increase in concentration of inducible nitric oxide synthase, which contributes to an increase in nitric oxide. This increase in nitric oxide subsequently increases reactive nitrogen synthase which contributes to tumoresis and carcinogenic cells. Nitric Oxide (NO) is one of the most dangerous of the free radicals. It is highly diffusible, making it a key molecule in inflammation type driven diseases. Other types of superoxides can react with NO to create intermediates such as peroxynitrite and nitrogen dioxide, which can cause severe DNA and lipid peroxidation leading to cytotoxic effects (Li, & Wogan, 2005). Increased lipid peroxidation has a direct effect on carcinogenesis and inflammation via modulation of several signaling molecules and enzymes, such as cyclooxygenase-2, nitric oxide synthase, and nuclear transcription factor (Sawa, Tatamichi & Ohshima 2006). Mitochondrial DNA is an extremely sensitive target for nitrogen oxide, resulting in the propagation of DNA mutations and modifications, further driving malignant cellular growth (Nair , Gal, & Tamir, 1999).
Twenty percent of new cancer patients with an infection based type of cancer are attributable to hepatitis B, bacteria, and human papolomavirus among others types of infections (Parkin, 2006). These biological agents, in addition to several chemical type agents induce chronic inflammation which contributes to, and adds to the risk of developing several types of cancer (Balkwill, Mantovani, 2001). Through conditions such as pancreatitis and hepatitis; pro-inflammatory molecules and cytokines become activated.
The relationship between chronic inflammation and several diseased states has been both described and confirmed. The therapeutic use of essential fatty acids has been extensively examined. In part by exerting anti-inflammatory effects, omega-3 fatty acids have proven to be effective in both the prevention and improvement of inflammatory related illnesses. It is clear that omega-3 fatty acids are extremely beneficial to the human organism, and will remain at the frontier of health research for some time to come.
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