Friday, May 14, 2010

Fruits and Vegetables Reduce Inflammation - Relevance to Cancer Prevention and Healthy Aging

Fruits and Vegetables

We all know we are supposed to eat our fruits and vegetables (FV), that they are good for us and all that. Hell, some people even claim that doing so might prevent cancers from growing in our bodies. The direct evidence for that claim is lacking, but a new study suggests we are getting closer.

A new article just released online connects the intake of more FV in healthy young adults with lower levels or pro-inflammatory chemical markers in the body. While this does not directly demonstrate a cancer prevention activity, nearly all of the pro-inflammatory markers that are reduced with higher FV intake are associated with cancer progression (and reduced risk of coronary artery disease and heart disease).

Not only that, but we also know that obesity increases ALL of these pro-inflammation markers, that these markers are associated with metabolic syndrome (leading to type-II diabetes), and that inflammation is thought to be the cause of many diseases (including cardio vascular disease, Alzheimer's Disease, several forms of cancer, insulin resistance, inflammatory-bowel diseases (IBDs), inflammatory arthritis, sepsis, and even the aging process itself).

After looking at the research, I will offer dietary suggestions. Now on to the study.

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Helen Hermana M Hermsdorff, Maria Angeles Zulet, Blanca Puchau, and Jose Alfredo Martinez. (2010). Fruit and vegetable consumption and proinflammatory gene expression from peripheral blood mononuclear cells in young adults: a translational study. Nutrition & Metabolism 2010, 7:42doi:10.1186/1743-7075-7-42. Published online 13 May, 2010.

Abstract (provisional)

Background

Fruits and vegetables are important sources of fiber and nutrients with a recognized antioxidant capacity, which could have beneficial effects on the proinflammatory status as well as some metabolic syndrome and cardiovascular disease features. The current study assessed the potential relationships of fruit and vegetable consumption with the plasma concentrations and mRNA expression values of some proinflammatory markers in young adults.

Methods

One-hundred and twenty healthy subjects (50 men/70 women; 20.8+/-2.6 y; 22.3+/-2.8 kg/m2) were enrolled. Experimental determinations included anthropometry, blood pressure and lifestyle features as well as blood biochemical and inflammatory measurements. The mRNA was isolated from peripheral blood mononuclear cells (PBMC) and the gene expression concerning selected inflammatory markers was assessed by quantitative real-time PCR. Nutritional intakes were estimated by a validated semi-quantitative food-frequency questionnaire.

Results

The highest tertile of energy-adjusted fruit and vegetable consumption (>660 g/d) was associated with lower plasma concentrations of C-reactive protein (CRP) and homocysteine and with lower ICAM1, IL1R1, IL6, TNF-alpha and NF-kappa-B1 gene expression in PBMC (P for trend <0.05),>19.5g/d) from fruits and vegetables (P for trend <0.05).>11.8 mmol/d) of dietary total antioxidant capacity showed lower plasma CRP and mRNA values of ICAM1, IL1R1, IL6, TNF-alpha and NF-kappa-B1 genes (P for trend <0.05).>

Conclusion

A higher fruit and vegetable consumption was independently associated not only with reduced CRP and homocysteine concentrations, but also with a lower mRNA expression in PBMC of some relevant proinflammatory markers in healthy young adults.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

The following text from the full paper offers some background on the study:

Background
A low-chronic inflammatory status is a recognized link between excessive adiposity and metabolic syndrome features, diabetes, and atherosclerosis [1, 2]. In fact, a number of studies has demonstrated an increased expression of transcription nuclear factors such as nuclearfactor-kappa-B (NFκB) as well as of interleukins (IL) and tumor necrosis factor-alpha (TNFα) in obese subjects [1, 3]. These changes appear to involve a higher production of proinflammatory and pro-atherogenic molecules such as C-reactive protein (CRP), homocysteine, selectins and adhesion molecules as well as some cytokines [1, 3]. Furthermore, circulating peripheral blood mononuclear cells (PBMC) may have an important role in all these complex inflammatory processes, which are mediated by transcriptional nuclear-factors, cytokines and other pro-atherogenic molecules [4].

In turn, fruits and vegetables contain components such as plant proteins, potassium, magnesium, fiber, and others compounds with antioxidant capacity, whose consumption may reduce the risk of suffering metabolic syndrome manifestations [5-8]. Thus, the intake of fruits and vegetables has been related to marked reductions in proinflammatory and oxidative stress markers [9-12]. These previous findings indicate that a targeted emphasis on fruit and vegetable consumption could potentially help individuals in preventing and/or reducing the onset of cardiovascular diseases and metabolic syndrome complications by means of a beneficial modulation of low-grade inflammation and oxidative stress mediated processes. In this context, nutrigenomic studies have demonstrated the healthy effect of specific nutrients and calorie-restriction on PBMC proinflammatory gene expression [13, 14]. However, the effect of fruit and vegetable consumption on the expression of proinflammatory-related molecules in PBMC has not yet been apparently investigated.

Overall, the present study assessed the potential association of fruit and vegetable consumption with plasma concentrations of CRP, homocysteine, IL6, and TNFα as well as gene expression profiles, which were assessed through messenger RNA (mRNA) levels of genes encoding intercellular adhesion molecule-1 (ICAM1), interleukin-1 receptor-type 1 (IL1R1), interleukin-6 (IL6), tumor necrosis factor-alpha (TNFα), subunit-1 or p50 (NFκB1) and subunit-3 or p65 (RELA) of NFκB in PBMC, from young adults.

It's worth noting that many of the pro-inflammatory markers here are also associated with obesity, which suggests that obesity itself may be connected to higher low-grade inflammation, and in turn leading to higher rates of CVD and heart disease, as well as cancer.

This comes from the discussion section:

An altered expression of ILs, TNFα, ICAM1 genes and of their respective receptors in adipose tissue as well as in PBMC has been implicated in the higher risk of suffering metabolic syndrome and cardiovascular disease [3, 4, 35]. In addition, NFκB is a redox-sensitive transcription factor implicated in the transmission of different signals from the cytoplasm to the nucleus, which are involved in the regulation of inflammatory and immune genes, apoptosis, and cell proliferation [36]. In this regard, the activation of this transcription factor has been involved in atherosclerosis [37]. Therefore, the reported inverse association between fruits and vegetable consumption and the selected proinflammatory gene expression measurements suggest a new clinically relevant mechanism concerning the prevention of subclinical inflammation status in healthy adults by a high intake of fruits and vegetables.

In this study, we also found a statistically significant inverse association of fruit and vegetable consumption with CRP and homocysteine concentrations. These results are consistent with some earlier cross-sectional studies carried out on children and adolescents [38, 39] as well as middle-age adults [7, 40]. Moreover, in a randomized crossover study, the addition of vegetables to the diet has been able to reverse the increase in circulating vascular adhesion molecule-1 (VCAM1), ICAM1, IL6, and TNFα levels, as induced by a single high-fat (saturated) meal consumption [11]. Furthermore, in a randomized controlled 4-week trial, a high consumption (eight vs. two servings/day) of fruits and vegetables also significantly reduced CRP levels [12].

In a 2004 study by Scott M. Grundy, et al, (Definition of Metabolic Syndrome) published in Arteriosclerosis, Thrombosis, and Vascular Biology (2004;24:e13), it was suggested that based on current evidence, people who exhibit metabolic syndrome have higher levels of all of the pro-inflammatory markers discussed in the study above. The term metabolic syndrome describes a variety of factors originally termed syndrome X and then insulin resistance syndrome.

In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X, and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors.

More to the point, metabolic syndrome is associated with a variety of conditions, including polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some forms of cancer - and type II diabetes.

Grundy outlines the components of metabolic syndrome as follows:
ATP III1 identified 6 components of the metabolic syndrome that relate to CVD:

  • Abdominal obesity
  • Atherogenic dyslipidemia
  • Raised blood pressure
  • Insulin resistance ± glucose intolerance
  • Proinflammatory state
  • Prothrombotic state
These components of the metabolic syndrome constitute a particular combination of what ATP III terms underlying,major, and emerging risk factors. According to ATP III, underlying risk factors for CVD are obesity (especially abdominal obesity), physical inactivity, and atherogenic diet; the major risk factors are cigarette smoking, hypertension, elevated LDL cholesterol, low HDL cholesterol, family history of premature coronary heart disease (CHD), and aging; and the emerging risk factors include elevated triglycerides, small LDL particles, insulin resistance, glucose intolerance, proinflammatory state, and prothrombotic state. For present purposes, the latter 5 components are designated metabolic risk factors.
I bring this up only to demonstrate that the findings from the new article above have implications beyond the reduced risk of CVD. One of the primary proinflammatory markers is Il-6. In a 2008 paper, Naugler & Karin, in "The wolf in sheep’s clothing: the role of
interleukin-6 in immunity, inflammation and cancer
" (Trends in Molecular Medicine:474; 11 Pages), the authors look at IL-6 and its relationship to cancer.
For years, IL-6 has been known to have a key role in the maturation of B cells, as well being as a member of the trio of cytokines [tumor necrosis factor (TNF)-a and IL-1 complete the triumvirate] that drives the acute inflammatory response. More recent reports have shown how dysregulation of IL-6 signaling contributes to inflammation-associated disease conditions, including obesity and insulin resistance, inflammatory-bowel diseases (IBDs), inflammatory arthritis, sepsis and even the aging process itself.

Two of the most exciting recent advances involve inflammation-associated carcinogenesis and the innate–adaptive immunity interface, in both of which IL-6 has an important role. The inflammatory process is increasingly linked to carcinogenesis, most notably to the promotion and progression of cancers. Several new reports of different experimental models of cancer show a requirement for IL-6 signaling and several epidemiological reports linking IL-6 signaling to human cancers have appeared.
I want to offer one more passage from this article because I think it is related to the main article above, and because I think it offers a pathway for understanding the re-emergence of some forms of cancer years after the original tumor was removed.
Chronic inflammation describes a state in which inflammatory cells are recruited to a site, undergo expansion and differentiation and are prevented from undergoing apoptosis. Apoptosis normally limits inflammation but becomes dysregulated in states of chronic inflammation. A key regulator of these effects is NF-kB [75], which integrates stress stimuli and, depending on the cell-type studied, prevents apoptosis or initiates signals that enhance or perpetuate the inflammatory process.

The emergence of neoplasia requires several elements, including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, tissue invasion and metastasis and sustained angiogenesis [76]. Most of these functions occur through the activation of NF-kB [77]. IL-6 is a growth signal and blocks apoptosis and, as such, is one of the effector signals of activated NF-kB in the promotion of neoplasia. IL-6 signals through STAT3, which is in turn activated in diverse cancers [78].

The obvious cancer in which to find IL-6 involvement is multiple myeloma (MM), a neoplasm of terminally differentiated B-cells (plasma cells), which is dependent on IL-6. Although it was thought initially that MM cells produced their own IL-6, which perpetuated the malignancy through autocrine action, it was later discovered that bone marrow stroma was the main source of IL-6 in this tumor [79].
One of the known ways in which prostate cancer kills men is that the cancer cells (generally stem cells) migrate to an area in the body where there is active bone marrow and take up residence, essentially escaping detection and any impact of chemo or radiation therapies.

The fact that IL-6 is also associated with bone marrow suggests a mechanism for understanding why the cancer cells seek out active marrow - the feed off of the inflammatory response. So, and I am speculating here, if we can control the production and expression of IL-6 through diet (and exercise, among other ways, including meditation), we might be able to delay or suppress the re-emergence of these cancer stem cells. Doing so effectively saves the lives of those who die from prostate cancer since few men actually die from the original tumor but, rather, from the metastatic spread of the cancer stem cells into the lower back (the only site of active bone marrow in middle aged men) and then into the rest of the body.

So What Do We Do?

Based on the feature article and other research I have done, I can make the following suggestions. Do as many of these as you can and your health will improve, your weight will go down, and you'll feel better, not to mention reducing all inflammation related illnesses, including cancer.

We'll start with foods we need LESS OF in our diets:

Avoid ALL sugar, especially high fructose corn syrup.

Avoid ALL trans-fats (deep-fried foods, margarine, processed foods).

Avoid pro-inflammatory fats (saturated fats contain arachidonic acid, which we need, but too much causes inflammation responses in the body). Also limit or or avoid butter, cream, cheese and other full-fat dairy products; unskinned chicken and fatty meats; and products made with coconut and palm kernel oils.

Avoid most vegetable oils: regular safflower and sunflower oils, corn oil, cottonseed oil, and mixed vegetable oils.

Limit all refined grains and non-fruit/vegetable carbohydrates in general. Carbohydrates are basically sugars, and sugars increase insulin levels, and higher insulin levels increase inflammation.

Now some foods we need MORE OF in our diets:

We need to eat more fruits and vegetables. Among the most studied for their anti-inflammatory benefits:
  • all dark berries
  • tart cherries
  • cruciferous vegetables (horseradish, kale, collard greens, cabbage, brussels sprouts, broccoli, cauliflower, bok choy, and others)
  • higher fiber vegetables (pumpkin, yams)
Use extra-virgin olive oil as a main cooking oil. If you want a neutral tasting oil, use expeller-pressed, organic canola oil. High-oleic versions of sunflower and safflower oil are acceptable also, preferably non-GMO (genetically modified).

Include avocados and nuts, especially walnuts, cashews, almonds, and nut butters made from these nuts. (Peanuts are less healthy.)

Try to eat 40 grams of fiber a day. This is easy to do by increasing your consumption of fruit (especially berries and apples), vegetables (especially pumpkin, cruciferous veggies, and to a lesser extent, beans), and unrefined whole grains (whole grain rice, quinoa, and steel cut oats).

Consume more omega-3 fatty acids: eat salmon (preferably fresh or frozen wild or canned sockeye), sardines packed in water or olive oil, herring, and black cod (sablefish, butterfish); omega-3 fortified eggs; hemp seeds and flaxseeds (preferably freshly ground); or take a fish oil supplement (see below), pumpkin seeds, and walnuts.

Eat plain dark chocolate in moderation (minimum cocoa content of 70 percent), and moderation means an ounce or two a day.

Eat organic as much as possible.

For more info on the anti-inflammation diet, see Dr. Andrew Weil - and ignore his high carbohydrate recommendations. Protein intake (lean meats, fish, chicken, turkey, low-fat dairy, and eggs) should be 40% of calories, healthy fats should be 30%, carbohydrates (mostly from fruits and vegetable) should be 30%.


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