Posts

No “Bones” About It…

Essential Fatty Acids and BonesEssential Fatty Acids may be a key ingredient in supporting bone health.

Essential fatty acids (EFAs) do not come to mind as the first thought in searching for nutritional answers regarding bone health.  “Recent evidence-based research, however, supports intervention with adequate amounts of specific nutrients including vitamin D, strontium, vitamin K, and essential fatty acids in the prevention and primary management of osteoporosis” (Genius, Clin Nutr. 2007).  Osteoporosis has become an epidemic in the Western World in recent years.  How do EFAs fit into this problem that plagues us especially as we get older?

When we think about osteoperosis, we think calcium.  Calcium and bone go together like salt and pepper.  Add in some vitamin D and that’s about it.  However, looking into it deeper we came up with a number of studies that say that EFAs should be right up front and strongly considered in our first line of bone defense.

Essential fatty acids are necessary to human survival, and are called essential because they must come from the diet; they cannot be made by the body.  The omega-6 and omega-3 fatty acids are the best known.  Learning that they are also important for bone health is something we need to know.

In vivo studies (that means in a living animal) have shown that supplementation with long chain n-6 poly-unsaturated fatty acids (PUFAs) in rats causes increases in intestinal Calcium absorption (Haag 2001).  Haag and his colleagues reported a higher total calcium balance and bone calcium content just by adding in either sunflower or safflower oil in their diet.

In another study pregnant female rats were made diabetic. They use a chemical called streptozotocin to duplicate the disorder in the animals.  They were then fed evening primrose oil (GLA) at 500 mg/kg/d throughout their pregnancy and found an almost complete restoration of bone ossification (process of laying down new bone) occurred just by adding in the primrose oils (Braddock, Pediatr Res. 2002).

Claassen et al, Prostaglandins 1995, found that the supplementation of essential fatty acids (EFAs) leads to increased intestinal calcium absorption and calcium balance. The main dietary EFAs they used were linoleic acid (LA) from sunflower oil and alpha-linolenic acid (ALA) from flax seed oil.  They were administered in a ratio of 3:1 which is very close to our 4:1 BodyBio Balanced oil.  The calcium balance (mg/24 h) and bone calcium (mg/g bone ash) increased significantly in the group that were on the EFAs as compared to the animals that were not given the oils.

Schlemmer et al, Prostaglandins 1999, found that if you make animal’s essential fatty acid deficient they flat out develop osteoporosis.  He then added in evening primrose oil (GLA) and completely reversed the loss of bone and reported positive effects on bone metabolism in both the growing male and female rat.

It certainly goes against what you might think.  Oils are thin, some of them even squishy, while bone is completely hard as a rock.  But leaning on our visual senses doesn’t work with body chemistry, obviously.

Bone remodeling is a life-long process where mature bone tissue is removed from the skeleton and is called resorption, while new bone tissue is formed.  It’s a process called ossification or new bone formation. These processes go on all the time and are managed by special cells that crawl along our bones and chew up excess bone growth, osteoclast.  There is another cell osteoblast, that busily does the opposite, laying down new growth where it’s needed.

In the first year of life, almost 100% of the skeleton is replaced.  In adults, remodeling proceeds at about 10% per year (Wheeless).  That means that in a span of 10 years our skeleton is brand new,  If the process is continuous those cells that do the work must be directly influenced by essential fatty acids, and if EFAs are needed to get the job done, well…

References

Genuis SJ, Schwalfenberg GK. Picking a bone with contemporary osteoporosis management: Nutrient strategies to enhance skeletal integrity. Clin Nutr. 2007 Apr;26(2):193-207

Haag M, Kearns SD, Magada ON, Mphata PR, Claassen N, Kruger MC. Effect of arachidonic acid on duodenal enterocyte ATPases. Prostaglandins Other Lipid Mediat. 2001 Aug;66(1):53-63

Braddock R, Siman CM, Hamilton K, Garland HO, Sibley CPGamma-linoleic acid and ascorbate improves skeletal ossification in offspring of diabetic rats. Pediatr Res. 2002 May;51(5):647-52.

Claassen N, Coetzer H, Steinmann CM, Kruger MC. The effect of different n-6/n-3 essential fatty acid ratios on calcium balance and bone in rats. Prostaglandins Leukot Essent Fatty Acids. 1995 Jul;53(1):13-9.

Schlemmer CK, Coetzer H, Claassen N, Kruger MC. Oestrogen and essential fatty acid supplementation corrects bone loss due to ovariectomy in the female Sprague Dawley rat. Prostaglandins Leukot Essent Fatty Acids. 1999 Dec;61(6):381-90

Wheeless Textbook of Orthopedics, Clifford R. Wheeless, III, MD.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Atopic Dermatitis / Eczema

evening-primrose-oilSome unfortunate persons are not able to convert essential fatty acids (EFA’s) from their parent forms to their more active metabolites, such as converting linoleic acid, the primary omega-6, to gamma-linolenic acid (GLA). More than twenty years of research points to the inefficiency of this active conversion pathway as causative of inflammatory skin conditions. Wherever and whenever a metabolite cannot be made by the body on its own, administration of that substance may be in order.

At the start of the twenty-first century, research scientist David Horrobin described a positive relationship between evening primrose oil as a source of pre-formed GLA and the improvement in symptoms of atopic dermatitis, namely eczema.  He relates that, “In most but not all studies, administration of GLA has been found to improve the clinically assessed skin condition, the objectively assessed skin roughness, and the elevated blood catecholamine concentrations of patients with atopic eczema.”  Understandably, the condition may be ascribed a hereditary genesis.  (Horrobin. 2000)

When one of the crowd upsets the apple cart he becomes noticed because of the chaos he spawned.  David Horrobin is such a person.  He was responsible for opening the eyes of the research community to the potential of complementary and alternative medicine in the treatment of fatty acid deficiency conditions, including inflammatory skin conditions, schizophrenia, rheumatoid arthritis, and diabetes, to name but a few.  Horrobin—and others after him— discovered that metabolic inefficiency in the conversion of linoleic acid to gamma-linolenic acid (GLA) might be responsible for inflammatory skin responses that present as eczema, despite the presence of adequate linoleic acid in blood and adipose tissue.  (Dobryniewski. 2007. p. 100)

It is such that omega-6 and omega-3 fatty acids compete for the enzymes that transform them into super hero molecules known to control the inflammation activities that promote health. The omega-3 fatty acids prevail at the expense of the omega-6s, leading to a deficit of omega-6 metabolites and their benefits.  Therefore, it makes sense to overcome deficiencies by administering these metabolites directly, as in the oral and/or topical use of evening primrose oil (EPO), an omega-6 fatty acid accepted for its GLA content.  Horrobin’s desire to herald the attributes of GLA spread to the European continent, where scientists from Poland agreed that GLA is one of the most frequently deficient fatty acids, and that supplementation brings hopeful effects in the treatment of eczema and other conditions.  (Horrobin. 1993)  (Dobryniewski. 2007. p. 91)

There are predisposing factors in acute or chronic skin disease, including family history of allergic disorders and sensitivity to contact allergens or to certain foods.  Chronic disease is difficult to treat.  Itching causes scratching, which increases inflammation, which causes itching … The cycle is hard to break.  But evening primrose oil (EPO), with a history of efficacy that predates Dr. Horribin’s interest, has produced “…significant clinical improvement on atopic eczema.” (Ebden. 1989)  In meta analyses conducted in the late 1980’s, the British Journal of Dermatology recounted significant improvement in eczema symptoms using a commercial EPO product called Epogam (the name seemingly gleaned from EPO and GLA), after which use, “ The effects on itch were particularly striking.” (Morse.1989).

BodyBio evening Primrose Oil contains ten percent GLA and a sufficient amount of its precursor, linoleic acid, to help the body make the molecules that inhibit the pro-inflammatory series 2 prostaglandins and series 4 leukotrienes.  There is a distinct correlation between improvements in clinical scoring devices and an elevation of fatty acid levels.  Compared to placebo, children treated with EPO significantly improved the symptoms of atopic eczema.  (Bordoni. 1988)

References

Horrobin DF.
Essential fatty acid metabolism and its modification in atopic eczema.
Am J Clin Nutr. 2000 Jan;71(1 Suppl):367S-72S.

Dobryniewski J, Szajda SD, Waszkiewicz N, Zwierz K.
The gamma-linolenic acid (GLA)–the therapeutic value.  [Article in Polish]
Przegl Lek. 2007;64(2):100-2.

Horrobin DF.
Fatty acid metabolism in health and disease: the role of delta-6-desaturase.
Am J Clin Nutr. 1993 May;57(5 Suppl):732S-736S; discussion 736S-737S.

Dobryniewski J, Szajda SD, Waszkiewicz N, Zwierz K.
Biology of essential fatty acids (EFA). [Article in Polish]
Przegl Lek. 2007;64(2):91-9.

Ebden P, Bevan C, Banks J, Fennerty A, Walters EH.
A study of evening primrose seed oil in atopic asthma.
Prostaglandins Leukot Essent Fatty Acids. 1989 Feb;35(2):69-72.

P.F. MORSE, D.F. HORROBIN,, M.S. MANKU, J.C.M. STEWART, R. ALLEN, et al
Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and clinical response
British Journal of Dermatology. Volume 121, Issue 1, pages 75–90, July 1989

Bordoni A, Biagi PL, Masi M, Ricci G, Fanelli C, Patrizi A, Ceccolini E.
Evening primrose oil (Efamol) in the treatment of children with atopic eczema.
Drugs Exp Clin Res. 1988;14(4):291-7.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Essential Fats Explained

fattyacid-sourceThe essential fatty acids (EFA’s) are just that—essential, meaning they have to come from the diet because the body can’t manufacture them. They might be used as fuel, but they are absolute components of the biological processes that make us work. Only two fatty acid families are vital to humans, omega-6’s and omega-3’s. It’s been shown that their ratio is more important than their volume. The parent fatty acid (FA) in the omega-6 (n-6) line is linoleic acid, abundant in many vegetable oils and ultimately responsible for the biosynthesis of arachidonic acid and related prostaglandins, which are compounds that regulate physiological activities. Alpha-linolenic acid (ALA) is the mother omega-3 (n-3) fatty acid, commonly extracted from seed oils such as flaxseed and hemp, but also found in walnuts. Nearly every aspect of human physiology is affected by essential fats, receptors for which are located in practically every cell.

The n-6 fatty acids have been denigrated in recent years because their excess has been linked to several metabolic upsets. Unbalanced diets are harmful to health, and the n-6’s that overpopulate processed foods and rancid supermarket oils have contributed to myriad health woes. What possibly started out as a 1 to 1 or 2 to 1 ratio of n-6 fatty acids to n-3 fatty acids in the human diet eons ago has become a physiological disaster of imbalance, where the ratio exceeds 10 to 1 in the typical Western diet, and may even approach 20 to 1, or worse, in personal food intake. All fatty acids go through a process of desaturation and elongation to become eminently bioactive compounds. The ultimate products of the process are beneficial to human health, especially if they are made step-by-step by the body and not forced upon it through manufactured meals, unnaturally finished meat products, stale/oxidized vegetable oils, and fossilized eggs, not to mention horrific snack foods. In a healthy body, linoleic acid is converted to gamma-linolenic acid (GLA), which becomes arachidonic acid, from which come the chemicals that control inflammation. After adulthood, the body’s ability to make those conversions is uncertain, so starting with GLA gives us a head start. However, mother linoleic acid is anti-inflammatory in its own right and even a marginal conversion to GLA has been held effective in the management of conditions as diverse as rheumatoid arthritis, eczema and ADD/ADHD.

The n-3 parent, ALA, also must come from diet because humans lack the enzymes necessary to convert it from other fats. But it’s the downstream omega-3’s that get the publicity:  EPA and DHA. Like the n-6’s, the conversion of ALA to EPA and later to DHA is an uncertain proposition in adulthood, which is why most adults use fish oil, a source of pre-made fatty acids. Even in the absence of the requisite conversion co-factors (vitamin B6, Mg, biotin, vitamin B3, vitamin C and Zn), ALA is anti-inflammatory and cardiac friendly (Pan, 2012) (Vedtofte, 2012), with recent scrutiny heralding its potential to inhibit progression of atherosclerosis (Bassett, 2011). The most readily available source of ALA is flaxseed, although chia, the newest kid on the block, is entering the marketplace.

Signs of fatty acid deficiency include a dry scaly rash, impoverished growth in youngsters, increased susceptibility to infections and poor wound healing, but are uncommon. The enzymes that convert the parent fatty acids act preferentially toward the n-3’s. By the time these enzymes deal with the omega-3 fats, some of the omega-6’s have been used for energy, hence the need to get more 6’s than 3’s, in a ratio of about 4 to 1, as evidenced by intensive research done in the 1990’s and early-mid 2000’s (Yahuda, 1993, 1996) (Simopoulos, 2002, 2008). But this ratio is based on the body’s own manufacture of the downstream fatty acids, GLA and arachidonic acid (ARA) along the n-6 line (the latter now included in products designed for infants to insure proper brain development) and EPA/DHA down the n-3 line. Deficiency of essential fatty acids sometimes strikes those suffering from cystic fibrosis or fat malabsorption issues. If patients receive total parenteral nutrition without the inclusion of EFA’s, deficit will appear in about a week or two.

The dry weight of the brain is about 80% lipids, the highest of any organ. The long-chain polyunsaturated fats, especially the n-6 and n-3, are crucial in modulating neural function. They occupy as much as 30% of the brain’s dry weight, making their influence on neural membrane dynamics profound. The shift away from EFA’s in the Western—typically American—diet parallels a rise in mental disorders. The need to address EFA supplementation is real and current, with the inclusion of omega-6 fats a necessity, since GLA, the downstream scion of linoleic acid, has held its own in mental health studies (Vaddadi, 2006). Together, the n-6’s and n-3’s cooperate in a number of cellular functions that affect membrane fluidity, allowing the passage of food and energy into the cell and wastes out. Arachidonic acid is a precursor to signaling molecules in the brain and is a key inflammatory intermediate, while EPA and DHA work to support the cardiovascular system, and the brain and retina.

It is arachidonic acid that supports membrane fluidity in the hippocampus, the part of the brain that directs memory, spatial relations and inhibition (Fukaya, 2007). It is arachidonic acid that protects the brain against oxidative stress and activates proteins in charge of the growth and repair of neurons (Darios, 2006). There is conjecture that ARA supplementation during the early stages of Alzheimer’s disease may slow its progress and stave off symptoms (Schaeffer, 2009). That’s a pretty good promise for something that’s been spurned…for lack of knowledge. Of the n-3’s, EPA may be effective in addressing depressive conditions and behavioral anomalies, besides being able to reduce inflammation (Brind, 2001) (Song, 2007). There had been some concern that EPA adversely affects clotting factors and fibrinogen concentrations, increasing the likelihood of bleeding. That is not so (Finnegan, 2003). It does, however, improve blood viscosity and red blood cell deformity, which allows red cells to adjust their shape to squeeze through narrow blood vessels, like capillaries. Downstream from EPA is DHA, a major fatty acid in sperm, brain phospholipids and the retina of the eye, and found to lower triglycerides. But its claim to fame is its rapid accrual in the developing brain during the third trimester of pregnancy and early postnatal period (Auestad, 2003) (Wainwright, 2000).

You can safely bet the farm that endogenous (made by the body itself) substances are more tightly regulated than exogenous. For example, the arachidonic acid your body makes from linoleic acid is more respectable than that from a haphazardly slaughtered steer, which may or may not be completely lifeless before the abattoir starts to dress it. In fear and pain, the animal releases a torrent of adrenal hormones throughout its flesh, confounding the integrity of its innate fatty acids. Endogenous fatty acids are, therefore, more wholesome.

How do we acquire the parent fatty acids?  You could buy oils that boast omega-6 and omega-3 fatty acid content from the supermarket, but it’s almost guaranteed that the balance will be too far out of whack to deliver a benefit, and the purity of the oils is possibly iffy. In fact, they might upset the apple cart. An overabundance of n-3’s can shut the immune system down for lack of guidance by the n-6 inflammation directors. On the other hand, BodyBio Balance Oil is a blend of organic, cold-pressed sunflower and flaxseed oils that are purposely geared to supply a 4 to 1 ratio of fatty acids that the body needs to initiate the cascade to longer chain fats that present vibrant physiological activity. Just the anti-inflammatory properties of the mother fatty acids, linoleic from sunflower and alpha-linolenic from flax, are enough to warrant using the oils to bolster the body’s well-being and to work out some metabolic kinks. Used to make salad dressings or to dress vegetables in place of butter, Balance Oil has the potential to set straight that which is awry, and the essential fatty acid metabolites can help to clear the brain fog on a hazy day. Cerebral lipids, especially the long-chain fatty acids, have significant direct and indirect activity on cerebral function. Not only do they affect the membranes, but also many are converted to neurally active substances. There is good evidence that mental challenges are related to EFA depletion, the supplementation of which can ameliorate the most defiant state of affairs.

References

Auestad N, Scott DT, Janowsky JS, Jacobsen C, Carroll RE, Montalto MB, Halter R, Qiu W, et al
Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age.
Pediatrics. 2003 Sep;112(3 Pt 1):e177-83.

Bassett CM, McCullough RS, Edel AL, Patenaude A, LaVallee RK, Pierce GN.
The α-linolenic acid content of flaxseed can prevent the atherogenic effects of dietary trans fat.
Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2220-6. doi: 10.1152/ajpheart.00958.2010. Epub 2011 Sep 30.

Caramia G.
The essential fatty acids omega-6 and omega-3: from their discovery to their use in therapy.
Minerva Pediatr. 2008 Apr;60(2):219-33.

Chang CS, Sun HL, Lii CK, Chen HW, Chen PY, Liu KL.
Gamma-Linolenic Acid Inhibits Inflammatory Responses by Regulating NF-kappaB and AP-1 Activation in Lipopolysaccharide-Induced RAW 264.7 Macrophages.
Inflammation. 2009 Oct 20.

Darios F, Davletov B.
Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3.
Nature. 2006 Apr 6;440(7085):813-7.

da Rocha CM, Kac G.
High dietary ratio of omega-6 to omega-3 polyunsaturated acids during pregnancy and prevalence of post-partum depression.
Matern Child Nutr. 2012 Jan;8(1):36-48. doi: 10.1111/j.1740-8709.2010.00256.x. Epub 2010 Jun 21.

Dupasquier CM, Dibrov E, Kneesh AL, Cheung PK, Lee KG, Alexander HK, Yeganeh BK, Moghadasian MH, Pierce GN.
Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2394-402. Epub 2007 Jul 6.

Fernandes FS, de Souza AS, do Carmo Md, Boaventura GT.
Maternal intake of flaxseed-based diet (Linum usitatissimum) on hippocampus fatty acid profile: implications for growth, locomotor activity and spatial memory.
Nutrition. 2011 Oct;27(10):1040-7.

Finnegan YE, Howarth D, Minihane AM, Kew S, Miller GJ, Calder PC, Williams CM.
Plant and marine derived (n-3) polyunsaturated fatty acids do not affect blood coagulation and fibrinolytic factors in moderately hyperlipidemic humans.
J Nutr. 2003 Jul;133(7):2210-3.

Fukaya T, Gondaira T, Kashiyae Y, Kotani S, Ishikura Y, Fujikawa S, Kiso Y, Sakakibara M.
Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats.
Neurobiol Aging. 2007 Aug;28(8):1179-86. Epub 2006 Jun 21.

C. Gómez Candela, L. M.ª Bermejo López and V. Loria Kohen
Importance of a balanced omega 6/omega 3 ratio for the maintenance of health.Nutritional recommendations
Nutr Hosp. 2011;26(2):323-329.

Ángeles Guinda, M. Carmen Dobarganes, M. Victoria Ruiz-Mendez, Manuel Mancha
Chemical and physical properties of a sunflower oil with high levels of oleic and palmitic acids
European Journal of Lipid Science and Technology. 105(3-4); Apr 2003: 130-137

BRIAN HALLAHAN, MRCPsych and MALCOLM R. GARLAND, MRCPsych
Essential fatty acids and mental health
The British Journal of Psychiatry (2005); 186: 275-277

William S. Harris, PhD, FAHA, Chair;  Dariush Mozaffarian, MD, DrPH, FAHA;  et al
Omega-6 Fatty Acids and Risk for Cardiovascular Disease
A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention
Circulation. 2009; 119: 902-907

Kakutani S, Ishikura Y, Tateishi N, Horikawa C, Tokuda H, Kontani M, Kawashima H, Sakakibara Y, Kiso Y, Shibata H, Morita I.
Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids, but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: a randomized controlled study.
Lipids Health Dis. 2011 Dec 22;10:241.

Lands B.
Consequences of essential Fatty acids.
Nutrients. 2012 Sep;4(9):1338-57.

Eric L. LIEN, Kurt STEINER and John C. WALLINGFORD
The Proper Balance of Essential Fatty Acids for Life
Journal of Oleo Science. Vol. 50 (2001) , No. 5 399-405

Maekawa M, Takashima N, Matsumata M, Ikegami S, Kontani M, Hara Y, Kawashima H, Owada Y, Kiso Y, Yoshikawa T, Inokuchi K, Osumi N.
Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses.
PLoS One. 2009;4(4):e5085. doi: 10.1371/journal.pone.0005085. Epub 2009 Apr 8.

Osumi N.
Fatty acid signal, neurogenesis, and psychiatric disorders
Nihon Shinkei Seishin Yakurigaku Zasshi. 2010 Jun;30(3):141-8.

Pan A, Chen M, Chowdhury R, Wu JH, Sun Q, Campos H, Mozaffarian D, Hu FB.
α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis.
Am J Clin Nutr. 2012 Dec;96(6):1262-73. doi: 10.3945/ajcn.112.044040. Epub 2012 Oct 17.

Pawels EK, Volterrani D.
Fatty acid facts, Part I. Essential fatty acids as treatment for depression, or food for mood?
Drug News Perspect. 2008 Oct;21(8):446-51. doi: 10.1358/dnp.2008.21.8.1272136.

Peet M, Brind J, Ramchand CN, Shah S, Vankar GK.
Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia.
Schizophr Res. 2001 Apr 30;49(3):243-51.

Sakayori N, Maekawa M, Numayama-Tsuruta K, Katura T, Moriya T, Osumi N.
Distinctive effects of arachidonic acid and docosahexaenoic acid on neural stem /progenitor cells.
Genes Cells. 2011 Jul;16(7):778-90. doi: 10.1111/j.1365-2443.2011.01527.x. Epub 2011 Jun 13.

Sanders TA, Rana SK.
Comparison of the metabolism of linoleic and linolenic acids in the fetal rat.
Ann Nutr Metab. 1987;31(6):349-53.

Schaeffer EL, Forlenza OV, Gattaz WF.
Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease.
Psychopharmacology (Berl). 2009 Jan;202(1-3):37-51.

Simopoulos AP.
The importance of the ratio of omega-6/omega-3 essential fatty acids.
Biomed Pharmacother. 2002 Oct;56(8):365-79.

Artemis P. Simopoulos
The Importance of the Omega-6/Omega-3 Fatty Acid Ratio in Cardiovascular Disease and Other Chronic Diseases
Experimental Biology and Medicine  233:674-688 (2008)

Meharban Singh
Essential fatty acids, DHA and human brain
Indian Journal of Pediatrics. Volume 72, Number 3 / March, 2005: 239-242

Song C, Zhao S.
Omega-3 fatty acid eicosapentaenoic acid. A new treatment for psychiatric and neurodegenerative diseases: a review of clinical investigations.
Expert Opin Investig Drugs. 2007 Oct;16(10):1627-38.

Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE.
Essential fatty acids in visual and brain development.
Lipids. 2001 Sep;36(9):885-95.

Vaddadi K.
Essential fatty acids and mental illness.
Int Rev Psychiatry. 2006 Apr;18(2):81-4.

Vedtofte MS, Jakobsen MU, Lauritzen L, Heitmann BL
The role of essential fatty acids in the control of coronary heart disease.
Curr Opin Clin Nutr Metab Care. 2012 Nov;15(6):592-6.

Wainwright P.
Nutrition and behaviour: the role of n-3 fatty acids in cognitive function.
Br J Nutr. 2000 Apr;83(4):337-9.

Yehuda S, Carasso RL.
Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio.
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10345-9.

Yehuda S, Brandys Y, Blumenfeld A, Mostofsky DI.
Essential fatty acid preparation reduces cholesterol and fatty acids in rat cortex.
Int J Neurosci. 1996 Sep;86(3-4):249-56.

Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI.
Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life.
Int J Neurosci. 1996 Nov;87(3-4):141-9.

Yehuda S, Rabinovitz S, Mostofsky DI.
Essential fatty acids are mediators of brain biochemistry and cognitive functions
J Neurosci Res. 1999 Jun 15;56(6):565-70.

Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI.
The role of polyunsaturated fatty acids in restoring the aging neuronal membrane.
Neurobiol Aging. 2002 Sep-Oct;23(5):843-53.

Young G, Conquer J.
Omega-3 fatty acids and neuropsychiatric disorders.
Reprod Nutr Dev. 2005 Jan-Feb;45(1):1-28.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

You Expect Me To Believe That?

fishoil-hookSome things just belong together. Not too many of us eat only the meringue from the lemon pie. Sauerkraut on a bun without the sausage isn’t quite the same gustatory delight. And sometimes the aunt is more fun when in the company of the uncle. Such is the case with essential fatty acids. The omega-3’s can do their job without the omega-6’s, but the outcome will eventually be out of whack. It’s this imbalance that wrought the nefarious genius of a twisted, fear-huckstering fish oil report, so carefully crafted that the typical reader comes to believe that black is white.

The study reported in the Journal of the National Cancer Institute determined a positive relationship of non-vegetable sourced omega-3 fatty acids to prostate cancer. If non-vegetable, that leaves fish oil, known better for its downstream n-3 fats, EPA and DHA, than for the mother n-3, alpha-linolenic acid. The concern with this proposition is that the authors seem to have gone from home plate to home plate, in a 360-foot path without ever touching any of the bases. Healthy incredulity befits the reading of a ‘scientific’ paper. That leaves questions that most of us don’t ponder, including these:  Why would anyone take n-3 fats without also taking n-6 complements? Did any of the subjects bear a pre-existing pathology? Were the supplements, if used, of sufficiently high quality, as you would expect from a cGMP-obligated company? (The term “pharmaceutical grade” means only that toxins have been removed, and is otherwise unregulated, since many products that call themselves fish oil are not oils but ethyl esters instead of triglycerides.) Is it possible that individuals were removed from the study because they got healthy all of a sudden? Not to be too picky, but what were the capsules themselves made from, if supplements are to blame? Could the supplements have been combined with active pharmaceuticals or with contraindicated other supplements? Not finally, but at least additionally, why is it so that countries whose cuisine is dominated by fish—Scandinavia or Japan—do not also present a high level of prostate cancer? Funny thing:  this study failed to tell us where the men in this investigation got their omega-3 fats. The dollar store? Canned tuna? Maybe from the fish they ate an hour prior to the blood draw?

The Public Library of Science has a journal called PLoS One. It covers primary research in science and medicine, submissions of which are subjected to intense scrutiny and peer review. However, the Journal does invite post-publication discussion and critique. In its April, 2013 issue, it printed an Icelandic study on consumption of fish products and the risk of prostate cancer. There were almost 2300 men, aged 67 and up, in this four-year project. Except for processed fish that was salted or smoked, fish oil or very high fish consumption was determined not to be associated with early or midlife prostate cancer risk (Torfadottir, 2013). Hmm. Go figure. Earlier Canadian meta-analysis discovered a 63% reduction in prostate-cancer-specific mortality among fish eaters, but no incipient protective effect by fish ingestion (Szymanski, 2010). That means eating fish did not prevent disease. There are other causes, such as too much conventionally raised red meat.

There is a strong suggestion in a Harvard study that total fat and certain saturated fatty acids may be implicated in prostate disease incidence, but that, “Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer,” adding that “…high marine omega-3 fatty acid intake may improve disease-specific survival for all men” (Epstein, 2012). Although the source of DHA is not identified in the study in question, an Italian work cited the 22:6 n-3 as protective against physiological activities involved in the progression of prostate cancer cells (Bianchini, 2012).  Marshall University mice that were fed a high n-3 diet containing fish oil concentrate presented with a decreased expression of genes expected to increase proliferation of prostate cancer cells by virtue of lowering estradiol values (Akinsete, 2012).

What about the n-6 to n-3 ratio we mentioned earlier?  Glad you asked. In no particular order, try reading these authors  to get the picture that n-3 fats need the accompaniment of the n-6 fats: (vanJaarsveld, 1997) (Ramirez0Silve, 2011) (Caramia, 2008) (Wijendran, 2004) (Simopoulos, 2002, 2008) (Gomez, 2011) (Yehuda, 1993, 1996). The additional info you need to find these is at the end of this piece. The ideal omega-6 to omega-3 ratio is generally agreed to be 4 to 1. That’s four times the omega-6 as omega-3. How come?  The enzymes that desaturate and elongate fatty acids prefer to work along the n-3 pathway, and by the time they get to the n-6 fats, part of the n-6’s have been burned for energy. Also, the enzyme pathway could be interrupted by age, booze, trans-fats, disease and overdose of dietary cholesterol (which is a good thing that can be overdone).

If fish oil is held culpable, which form?  The ethyl ester form (EE) is made when the glycerol backbone of fish body oil is removed during molecular distillation and replaced by an ethanol, allowing the process to be completed at a lower temperature. It isn’t a fat any more, and really shouldn’t be allowed to be called an oil. This is now an ester that is not digested and absorbed by the body in the same manner as the original triglyceride. Once distilled, true fish oil has its triglyceride put back in a process called re-esterification, or re-concentration, a procedure that adds about 40% to the cost of the finished product. But this replacement of the glycerol—fish oil is a triglyceride—returns the substance to its natural state. Fish oil that has an alcohol head is metabolized just like an alcohol from liquor, and that’s not what we expect from a supplement that’s supposed to be a boon to health. Bioavailability of re-esterified triglycerides is superior to all other forms of fish oil (Dyerberg, 2010).

The study in question (Brasky, 2013) is of an observational nature, not experimental, such as a randomized, controlled, double-blinded trial would be.  Observational studies are not used as reliable sources, though they can help to formulate hypotheses to be used in subsequent experiments (Nahin, 2012). Additionally, cause-effect has not been established. The paper was quick to point the finger at a dietary supplement. True, many supplements are misused for lack of direction by a qualified health care practitioner, such as a dietitian or clinical nutritionist. But that can be resolved with a phone call and an appointment. Mega-doses of fish oil do not mix well with drugs or supplements that thin the blood. If a person doesn’t know that, he needs to. Though there is no established upper limit for fish oil, six grams might be too much, while two or three grams might just be on the mark for most adults. Actual dosage depends on the fish species and the levels of EPA and DHA in the product.

To balance the omega-3 fatty acids, evening primrose oil (EPO) is a good source of omega-6 fats, particularly of gamma-linolenic acid (GLA), which is the preferred launching point for conversion to the longer derivatives. Yes, borage oil has more GLA than EPO, but also contains alkaloids that can tax the liver.

An interesting comment from the University of Guelph in Ontario, Canada is, “I have no idea how this paper got accepted for publication.”  (Professor Gopinadhan Paliyath)

Refere

References

Akinsete JA, Ion G, Witte TR, Hardman WE.
Consumption of high ω-3 fatty acid diet suppressed prostate tumorigenesis in C3(1) Tag mice.
Carcinogenesis. 2012 Jan;33(1):140-8.

Astorg P.
Dietary N-6 and N-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence.
Cancer Causes Control. 2004 May;15(4):367-86.

Beckermann B, Beneke M, Seitz I.
Comparative bioavailability of eicosapentaenoic acid and docasahexaenoic acid from triglycerides, free fatty acids and ethyl esters in volunteers.
Arzneimittelforschung. 1990 Jun;40(6):700-4.

Bianchini F, Giannoni E, Serni S, Chiarugi P, Calorini L.
22 : 6n-3 DHA inhibits differentiation of prostate fibroblasts into myofibroblasts and tumorigenesis.
Br J Nutr. 2012 Dec 28;108(12):2129-37

Brasky TM, Crowe FL, Kristal AR.
n-3 Fatty acids and prostate cancer risk.
Br J Nutr. 2012 Nov 14;108(9):1721.

Theodore M. Brasky, Amy K. Darke, Xiaoling Song, Catherine M. Tangen, Phyllis J. Goodman, et al
Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial
JNCI J Natl Cancer Inst (2013) doi: 10.1093/jnci/djt174 First published online: July 10, 2013

Caramia G.
The essential fatty acids omega-6 and omega-3: from their discovery to their use in therapy
Minerva Pediatr. 2008 Apr;60(2):219-33.

Chua ME, Sio MC, Sorongon MC, Morales ML Jr.
The relevance of serum levels of long chain omega-3 polyunsaturated fatty acids and prostate cancer risk: A meta-analysis.
Can Urol Assoc J. 2013 May;7(5-6):E333-43.

Dyerberg J, Madsen P, Møller JM, Aardestrup I, Schmidt EB.
Bioavailability of marine n-3 fatty acid formulations.
Prostaglandins Leukot Essent Fatty Acids. 2010 Sep;83(3):137-41.

Epstein MM, Kasperzyk JL, Mucci LA, Giovannucci E, Price A, Wolk A, Håkansson N, Fall K, Andersson SO, Andrén O
Dietary fatty acid intake and prostate cancer survival in Örebro County, Sweden.
Am J Epidemiol. 2012 Aug 1;176(3):240-52.

Fradet V, Cheng I, Casey G, Witte JS.
Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk.
Clin Cancer Res. 2009 Apr 1;15(7):2559-66.

Edward Giovannucci, Eric B. Rimm, Graham A. Colditz, Meir J. Stampfer, Alberto Ascherio,
Chris C. Chute and Walter C. Willett
A Prospective Study of Dietary Fat and Risk of Prostate Cancer
JNCI J Natl Cancer Inst. Volume 85, Issue 19; Pp. 1571-1579.

C. Gómez Candela, L. M.ª Bermejo López and V. Loria Kohen
Importance of a balanced omega 6/omega 3 ratio for the maintenance
of health. Nutritional recommendations

Nutr Hosp. 2011;26(2):323-329.

Richard Nahin, PhD, MPH
Observational Studies and Secondary Data Analyses to Assess Outcomes in Complementary and Integrative Health Care
NCCAM Research Blog. 25 June, 2012

Neubronner J, Schuchardt JP, Kressel G, Merkel M, von Schacky C, Hahn A.
Enhanced increase of omega-3 index in response to long-term n-3 fatty acid supplementation from triacylglycerides versus ethyl esters.
Eur J Clin Nutr. 2011 Feb;65(2):247-54.

Pettersson A, Kasperzyk JL, Kenfield SA, Richman EL, Chan JM, Willett WC, Stampfer MJ, Mucci LA, Giovannucci EL.
Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death.
Cancer Epidemiol Biomarkers Prev. 2012 Mar;21(3):428-36.

Ivonne Ramírez-Silva, Salvador Villalpando, Jessica E Moreno-Saracho and Daniel Bernal-Medina
Fatty acids intake in the Mexican population. Results of the National Nutrition Survey 2006
Nutrition & Metabolism 2011, 8:33

Reese AC, Fradet V, Witte JS.
Omega-3 fatty acids, genetic variants in COX-2 and prostate cancer.
J Nutrigenet Nutrigenomics. 2009;2(3):149-58.

Schuchardt JP, Neubronner J, Kressel G, Merkel M, von Schacky C, Hahn A.
Moderate doses of EPA and DHA from re-esterified triacylglycerols but not from ethyl-esters lower fasting serum triacylglycerols in statin-treated dyslipidemic subjects: Results from a six month randomized controlled trial.
Prostaglandins Leukot Essent Fatty Acids. 2011 Dec;85(6):381-6.

Simopoulos AP.
The importance of the ratio of omega-6/omega-3 essential fatty acids.
Biomed Pharmacother. 2002 Oct;56(8):365-79.

Artemis P. Simopoulos
The Importance of the Omega-6/Omega-3 Fatty Acid Ratio in Cardiovascular Disease and Other Chronic Diseases
Experimental Biology and Medicine  233:674-688 (2008)

Sorongon-Legaspi MK, Chua M, Sio MC, Morales M Jr.
Blood level omega-3 Fatty acids as risk determinant molecular biomarker for prostate cancer.
Prostate Cancer. 2013;2013:875615.

Szymanski KM, Wheeler DC, Mucci LA.
Fish consumption and prostate cancer risk: a review and meta-analysis.
Am J Clin Nutr. 2010 Nov;92(5):1223-33.

Torfadottir JE, Steingrimsdottir L, Mucci L, Aspelund T, Kasperzyk JL, Olafsson O, Fall K, et al
Milk intake in early life and risk of advanced prostate cancer.
Am J Epidemiol. 2012 Jan 15;175(2):144-53. .

Torfadottir JE, Valdimarsdottir UA, Mucci L, Stampfer M, Kasperzyk JL, Fall K, Tryggvadottir L et al
Rye bread consumption in early life and reduced risk of advanced prostate cancer.
Cancer Causes Control. 2012 Jun;23(6):941-50.

Torfadottir JE, Valdimarsdottir UA, Mucci LA, Kasperzyk JL, Fall K, Tryggvadottir L, et al
Consumption of fish products across the lifespan and prostate cancer risk.
PLoS One. 2013 Apr 17;8(4):e59799.

P.J. van Jaarsveld, C.M. Smuts, H.Y. Tichelaar, M. Kruger, C.J. Lombard, A.J.S. Benadé
The influence of different ratios and dosages of an ω6:ω3 fatty acid supplement on the lipoprotein cholesterol and fatty acid profile in nonhuman primates on a western atherogenic diet
Nutrition Research. 17(11-12); Nov-Dec 1997: 1733-1747

Vasuki Wijendran and K.C. Hayes
DIETARY n-6 AND n-3 FATTY ACID BALANCE AND CARDIOVASCULAR HEALTH
Annual Review of Nutrition. July 2004; 24: 597-615

Yehuda S, Carasso RL.
Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio.
Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10345-9.

Yehuda S, Brandys Y, Blumenfeld A, Mostofsky DI.
Essential fatty acid preparation reduces cholesterol and fatty acids in rat cortex.
Int J Neurosci. 1996 Sep;86(3-4):249-56.

Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI.
Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life.
Int J Neurosci. 1996 Nov;87(3-4):141-9.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

The Rumors on Rheumatoid Arthritis

hands-jarAunt Martha’s mother was the kindest, gentlest soul you’d ever meet. She went out of her way to make you feel at home. Food and drink were hallmarks of her cordial greeting. But she couldn’t open a package, twist open a jar or cut a cake. Her fingers were so badly gnarled that no two pointed in the same direction. Some of the joints formed the letter “Z.” Yet, despite the pain she must have borne, her loving smile prevailed. She was victimized by rheumatoid arthritis (RA) in an era when research was in its infancy, barely crawling.

This nefarious disease causes pain, swelling, stiffness and loss of function in joints— mostly hands and fingers, though it can strike any. It hits women more often than men, starting between ages twenty-five and fifty-five, though some statisticians start at forty. Unlike osteoarthritis, RA is an autoimmune condition that can affect body parts besides joints, such as the eyes, mouth and lungs. Nobody knows the cause. It could be genes, maybe the environment, or maybe hormones that direct the immune system to attack the body’s own tissues. Whatever it is, RA afflicts more than a million Americans, a sizeable fraction being kids.

The inflammation of RA can reach to the tendons, ligaments and muscles in some patients. Its chronic nature causes degradation of cartilage, bone and the ligaments that bind bones, causing deformity. Active disease presents with fatigue, appetite loss, low-grade fever, muscle and joint aches, and stiffness, the last being most notable in the morning or following periods of inactivity. Because RA is a systemic ordeal, its malevolence can inflame the glands around the eyes and mouth, causing Sjögren’s syndrome. RA-induced pleuritis is the inflammation of lung lining that causes pain with a deep breath. Because the number of red blood cells is reduced, anemia occurs, while a drop in white cells can be associated with an enlarged spleen and increased risk of infection.

Following examination of inflammatory blood markers and other criteria, the doctor can make a proper diagnosis, at which time medications probably will be prescribed. Cortisone and aspirin have been first-line drugs for decades because they act quickly. The slower ones are called disease-modifying anti-rheumatic drugs—DMARD’s—and include some heavy duty chemistry, not all of which is anti-inflammatory, but most of which has truly nasty side effects, many you have learned from television ads. What may not be realized is that some drugs destroy the substances your body needs to work the right way. The package insert that comes with the drug doesn’t tell you this, so you’ll think the absence of pain has all the bases covered. This is sufficient reason to visit an integrative dietitian or holistic-minded physician, the rare one who knows about nutrition.

Keeping your physician in the loop, you may opt to explore integrative measures to deal with RA. The good news is that there are recognized mediators of inflammation-induced bone damage (Nanjundaiah, 2013). Because of space constraints, we’ll address those with a pretty reliable track record, starting with gamma linolenic acid (GLA), an omega-6 fatty acid found in borage and evening primrose oils. While it is true that borage contains almost twice the levels of GLA as evening primrose, it is also true that borage contains pyrrolizidine alkaloids that can tax the liver. Though possibly in non-toxic amounts, these alkaloids are nonetheless there.  For that reason, EPO is often a preferred source of GLA. On the other hand, borage oil is used in clinical and observational studies because of its higher GLA values, thus requiring a smaller dosage (that may influence subject participation) and reducing cost. A University of PA study done in the early 90’s found that patients who took borage oil capsules for three months experienced reductions in pro-inflammatory prostaglandins and leukotrienes, leading to noticeable clinical improvement in RA symptoms (Pullman-Mooar, 1990).

Supplementing GLA at 3.0 and 6.0 grams a day enhances its conversion to the anti-inflammatory dihommo-gamma-linolenic-acid (DGLA), causing neutrophils to synthesize less pro-inflammatory leukotriene and platelet-activating factor (PAF—a major trigger of thrombosis), thereby attenuating discomfort (Johnson, 1997).  Compared to placebo in a six-month trial in Philadelphia, GLA was found to reduce the number of tender joints by more than a third and swollen joint count by more than a fourth, in a study from which no one withdrew (Leventhal, 1993).

Not to be outdone by its omega-6 counterpart, omega-3 fish oil flexed its anti-inflammatory muscle in trials that included non-steroidal anti-inflammatory drugs (NSAIDS) as part of the treatment. Swelling index and duration of early morning stiffness were used as markers for RA severity, and were found to have improved in subjective assessment by virtue of a decrease in pro-inflammatory leukotrienes (van der Tempel, 1990). Patients who received fish oil in combination with naproxen fared better in similar assessments than those without the fish oil or with placebo oil in studies carried out in Norway (Kjeldsen-Kragh, 1992) and New York (Kremer, 2000). A Canadian meta-analysis of seventeen n-3 studies concluded that morning stiffness and number of tender joints were reduced in those who used n-3 PUFA’s (Goldberg, 2007). Those who supplemented their OTC medications with omega-3’s from cod liver oil were able to reduce their dependence on NSAIDS (Galarraga, 2008).

In early reports, Danish scientists found that RA patients were deficient in the only mineral with anti-oxidant properties—selenium. They noted that those with the most active disease had the lowest values, and that there is significant correlation of selenium status with the number of affected joints (Tarp, 1985). Almost a decade later, the same researchers confirmed their initial findings, but also found that some subjects lack the physiological wherewithal to convert selenium to functional anti-oxidant enzymes, a state that can be overcome by supplemental mineral (Tarp, 1994).

From frankincense through ginger, to the resveratrol of grapes, science is takinga deliberate look at additions to the arsenal of RA treatments.

References

Astorga G, Cubillos A, Masson L, Silva JJ.
Active rheumatoid arthritis: effect of dietary supplementation with omega-3 oils. A controlled double-blind trial.
Rev Med Chil. 1991 Mar;119(3):267-72.

Galarraga B, Ho M, Youssef HM, Hill A, McMahon H, Hall C, Ogston S, Nuki G, Belch JJ.
Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis.
Rheumatology (Oxford). 2008 May;47(5):665-9.

Goel, F. J. Ahmad, R. M. Singh, and G. N. Singh
3-Acetyl-11-keto-β-boswellic acid loaded-polymeric nanomicelles for topical anti-inflammatory and anti-arthritic activity
Journal of Pharmacy and Pharmacology, vol. 62, no. 2, pp. 273–278, 2010.

Goldberg RJ, Katz J.
A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain.
Pain. 2007 May;129(1-2):210-23.

Johnson MM, Swan DD, Surette ME, Stegner J, Chilton T, Fonteh AN, Chilton FH.
Dietary supplementation with gamma-linolenic acid alters fatty acid content and eicosanoid production in healthy humans.
J Nutr. 1997 Aug;127(8):1435-44.

Kjeldsen-Kragh J, Lund JA, Riise T, Finnanger B, Haaland K, Finstad R, Mikkelsen K, Førre O.
Dietary omega-3 fatty acid supplementation and naproxen treatment in patients with rheumatoid arthritis.
J Rheumatol. 1992 Oct;19(10):1531-6.

Knekt P, Heliövaara M, Aho K, Alfthan G, Marniemi J, Aromaa A.
Serum selenium, serum alpha-tocopherol, and the risk of rheumatoid arthritis.
Epidemiology. 2000 Jul;11(4):402-5.

Kremer JM.
n-3 fatty acid supplements in rheumatoid arthritis.
Am J Clin Nutr. 2000 Jan;71(1 Suppl):349S-51S.

Lau CS, Morley KD, Belch JJ.
Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis–a double-blind placebo controlled study.
Br J Rheumatol. 1993 Nov;32(11):982-9.

J. H. Lee, H. Jin, H. E. Shim, H. N. Kim, H. Ha, and Z. H. Lee
Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-κB signal
Molecular Pharmacology, vol. 77, no. 1, pp. 17–25, 2010.

M. Lei, S. Q. Liu, and Y. L. Liu
Resveratrol protects bone marrow mesenchymal stem cell derived chondrocytes cultured on chitosan-gelatin scaffolds from the inhibitory effect of interleukin-1β
Acta Pharmacologica Sinica, vol. 29, no. 11, pp. 1350–1356, 2008.

Leventhal LJ, Boyce EG, Zurier RB.
Treatment of rheumatoid arthritis with gammalinolenic acid.
Ann Intern Med. 1993 Nov 1;119(9):867-73.

S. A. Levy, O. Simon, J. Shelly, and M. Gardener
6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund’s adjuvant
BMC Pharmacology, vol. 6, article 12, 2006.

D. O. Moon, M. O. Kim, Y. H. Choi, Y. M. Park, and G. Y. Kim
Curcumin attenuates inflammatory response in IL-1β-induced human synovial fibroblasts and collagen-induced arthritis in mouse model
International Immunopharmacology, vol. 10, no. 5, pp. 605–610, 2010.

Morinobu, W. Biao, S. Tanaka et al.,
 (-)-Epigallocatechin-3-gallate suppresses osteoclast differentiation and ameliorates experimental arthritis in mice
Arthritis and Rheumatism, vol. 58, no. 7, pp. 2012–2018, 2008.

Nanjundaiah SM, Astry B, Moudgil KD.
Mediators of inflammation-induced bone damage in arthritis and their control by herbal products.
Evid Based Complement Alternat Med. 2013;2013:518094.

Pullman-Mooar S, Laposata M, Lem D, Holman RT, Leventhal LJ, DeMarco D, Zurier RB.
Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma-linolenic acid.
Arthritis Rheum. 1990 Oct;33(10):1526-33.

M. L. Sharma, S. Bani, and G. B. Singh
Anti-arthritic activity of boswellic acids in bovine serum albumin (BSA)-induced arthritis
International Journal of Immunopharmacology, vol. 11, no. 6, pp. 647–652, 1989.

Tarp U, Overvad K, Hansen JC, Thorling EB.
Low selenium level in severe rheumatoid arthritis.
Scand J Rheumatol. 1985;14(2):97-101.
Tarp U.
Selenium and the selenium-dependent glutathione peroxidase in rheumatoid arthritis.
Dan Med Bull. 1994 Jun;41(3):264-74.

van der Tempel H, Tulleken JE, Limburg PC, Muskiet FA, van Rijswijk MH.
Effects of fish oil supplementation in rheumatoid arthritis.
Ann Rheum Dis. 1990 Feb;49(2):76-80.

G. Xuzhu, M. Komai-Koma, B. P. Leung, et al.
Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function
Annals of the Rheumatic Diseases, vol. 71, no. 1, pp. 129–135, 2012.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.