Niacin Flush Protects Against Inflammatory Diseases
Part II


by Sandy Shaw

T his is the second part of my two part paper on “Why the NIACIN FLUSH May Be Surprisingly Beneficial to Your Health” based on the biochemical mechanisms showing that the niacin flush is part of a powerful protective system against inflammatory diseases that can also be activated by supplements other than niacin.

NOTE: Due to time constraints, this paper has not been reviewed by Durk Pearson. The use of “we” or “us” in this paper refers to extensive discussions Durk and I had on scientific studies reviewed in the paper. All errors are the sole responsibility of Sandy Shaw.

HYPOTHESIS: Pulsatile release of prostaglandin D2 (as occurs in the niacin flush) attenuates high chronic serum levels of prostaglandin D2, which have been associated with Alzheimer’s disease and other inflammatory diseases. Pulsatile release of prostaglandin D2 also attenuates high chronic serum levels of prostaglandin E2, as seen in some inflammatory disease models, for example, hypertension (Guan, 2007). Interestingly, the prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure.(Stock, 2001) There is a complex relationship between PGD2 and PGE2, in which PGD2 pulses (antiinflammatory) decrease PGE2 (proinflammatory) release.

  • Guan, Zhang, Wu, et al, Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. J Clin Invest. 117(9):2496-505 (2007).
  • Stock, Shinjo, Burkhardt, et al. The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure. J Clin Invest. 107(3):325-31 (2001).

NOTE FROM THE AUTHOR

As I had more literature searches done, more information kept appearing on prostaglandin D2’s pervasive effects on inflammatory diseases. What appeared at some point to be a little known or ignored piece of information would show up in a different search with a great deal more information. What you might have thought was something that you put together yourself—an original idea—from bits and pieces of data might have been put together by others at some point that you just hadn’t seen yet. The idea might, in fact, have been an original idea of yours but that doesn’t mean that nobody else had ever thought of it. The scientific literature is HUGE and at any point in time you find some scientists have ideas in advance of that of many others and being published at roughly the same time. Sorting this all out has turned out to be a job for Superman and he hasn’t shown up yet to take the job. It was a learning experience for me in attempting to review a large scientific literature.

I eventually found papers that indicated some early interest in prostaglandin D2 and its effect on the clinical efficacy of immediate release niacin. I was amazed that it appeared to have taken so long for this to get much attention. Possibly, I thought, it had to do with the complexity of prostaglandin chemistry and the difficult of designing drugs that would (say) modulate the release of prostaglandin D2 without having a lot of off-target effects. Excitingly, there is evidence that some natural products have a similar flushing effect of their own apparently also based on a pulsatile release of prostaglandin D2 that may deliver benefits similar to the niacin flush. We would certainly like to see a lot of research on that. See the last section in this paper on a list of possible candidates for the niacin flush without the niacin.

Apparently the use of niacin itself as a way to reduce high levels of prostaglandin D2 has not been considered, possibly due to the unpopularity with some patients of the niacin flush. Or, more likely, the fact that immediate release niacin is a nutrient that cannot be patented pretty well eliminates the possibility of making a large amount of money selling immediate release niacin in the face of its many competitors as a commodity item and, finally and probably of most importance, Durk points out the problem of the U.S. Food & Drug Administration’s prohibition on providing truthful nonmisleading information about a dietary supplement’s health benefits. To make a “claim” that the niacin flush may significantly reduce the risk of serious, life-threatening diseases is, to the FDA, beyond the pale, no matter how much evidence supports the idea. Your claim is flushed before it even gets printed on your product label. Earlier papers from my searches that alluded to the “niacin flush” (aka pulsatile release of prostaglandin D2) included:

  • Pike. Flushing out the role of GPR109A (HM74A) in the clinical efficacy of nicotinic acid. J Clin Invest. 115(12):3400-3 (2005).
  • Hanson, Gille, Zwykiel, et al. Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest. 129(8):2910-9 (2010).
  • Strack, Carballo-Jane, Wang, et al. Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis. J Lipid Res. 54:177-88 (2013).

Prostaglandin D2 In Action

Here I provide data that might support the hypothesis of antiinflammatory effects from pulsatile prostaglandin D2 in hypertension, atherosclerosis, obesity, and type 2 diabetes.

Atherosclerosis, hypertension type 2 diabetes, obesity

Prostaglandin D2 levels are predictive of coronary artery disease severity

“Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes.” (from abstract, Gleim, 2012.)

“Serum levels of Localin-type prostaglandin D synthase (L-PGDS) are strongly associated with hypertension and are predictive of coronary artery disease severity in patients undergoing diagnostic angiography. Another clinical study showed that increased serum L-PGDS correlates with increased coronary artery intima-media complex thickness and brachial-ankle pulse wave velocity. In summary, increased serum L-PGDS associates with overall risk factor profile and measures of atherosclerotic progression.” “L-PGDS knockout mice display aggravated obesity and atherosclerosis.”

  • Gleim, Stitham, Tang, et al. An eicosanoid-centric view of atherothrombotic risk factors. Cell Mol Life Sci. 69(20):3361-80 (2012 Oct).

These data strongly support the hypothesis that chronically high levels of prostaglandin D2 signaling is associated with coronary artery disease but the data here do not show (because it was not tested for) that pulsatile signals of prostaglandin D2 would alleviate these high serum levels of prostaglandin D2 or reduce the risk of disease. See more on the original paper (Inoue, 2008) below.

Atherosclerosis Retarded by Deletion of Prostaglandin E synthase-1, Which Augments Prostacyclin

Deletion of microsomal PGES-1 in mice, where PGES-1 is the synthase that makes prostaglandin E2, has been reported to result in a marked depletion of marcrophages in atherosclerotic lesions and macrophage-derived foam cells (Wang, 2006). The same paper (Wang, 2006) also reports that microsomal PGES-1 is up-regulated in the vasculature during atherogenesis in mice lacking the receptor for LDL, a common animal model for human atherosclerosis. The researchers did not test the effect of pulses of prostaglandin D2 to reduce prostaglandin E2 in this model, but our hypothesis and data supporting it suggests that it would reduce prostaglandin E2 and have the same effects as reported here, e.g., deplete macrophage in atherosclerotic lesions and reduce macrophage-derived foam cells.

The researchers (Wang, 2006) also note that selective inhibitors of COX-2 currently used for pain that have unfortunate side effects of increasing the risk of heart attacks and that the pain relief of these COX-2 inhibitors (NSAIDS) works by inhibiting mPGES-1. They suggest that drugs that specifically inhibit mPGES-1 might provide pain relief without the increased risk of heart attacks. It sounds like a fine idea to us (pulsed release of prostaglandin D2 would reduce prostaglandin E2 levels) but we would not favor actually preventing the production of prostaglandin E2, just reducing its release to alleviate pain.

  • Wang, Zukas, Hui, et al. Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Proc Nat’l Acad Sci U S A. 103(39):14507-12 (2006).

Laminar Blood Flow Shown to Induce

Prostaglandin D2 Synthase in

Endothelial Cells

A paper (Liu, 2005) cites an earlier paper (Taba, 2000) that found that laminar blood flow induced lipocalin-type prostaglandin D2 synthase in endothelial cells and that this was part of the protective (antiinflammatory) effect produced by laminar blood flow. We think that this prostaglandin D2 would be released in pulses because blood itself flows by discrete pulses as a result of heart beat contraction/relaxation. Though the pulses of PGD2 have not been shown by direct measurement, to our knowledge, this comes pretty close to proof that PGD2 pulses are importantly involved in laminar blood flow protective effects against atherosclerosis. The niacin flush strikes again!!

  • Liu, Zhang, Schmelzer, et al. The antiinflammatory effect of laminar flow; the role of PPARgamma, epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proc Nat’l Acad Sci U S A. 102(46):16747-52 (2005).
  • Taba, Sasaguri, Miyagi, et al, Fluid shear stress induces lipocalin-type prostaglandin D(2) synthase expression in vascular endothelial cells. Circ Res. 86:967-73 (2000).

Lipocalin-type Prostaglandin D2 Synthase

Is a Powerful Biomarker for Severity of Coronary

Artery Disease

Another paper (Inoue, 2008) reports a large multicenter study involving 1013 consecutive patients thought to have stable coronary artery disease who had undergone coronary angiography. Their multiple regression analysis indicated that the most powerful independent indicator of the coronary severity score was the serum L-PGDS (lipocalin-type prostaglandin D2 synthase) level. There was no way to determine from the paper’s data whether this level represented a chronically high level of L-PGDS or a pulsatile level, but it appears to us most unlikely to be a pulsatile measurement as it would be much more difficult to confine a measurement to L-PGDS in a pulse than at a chronic level.

The serum level of L-PGDS was the most powerful independent predictor of coronary disease in both males and females. It was also mentioned in the paper (Inoue, 2008) that a study had recently (recent as of 2008) demonstrated that “L-PGDS strongly accumulated within the fibrous plaque in the atherosclerotic stenotic lesion of human coronary arteries...” We would expect that the pulsatile release of PGD2 would attenuate this PGD2 accumulation by decreasing its chronically high level.

  • Inoue, Eguchi, Matsumoto, et al. Lipocalin-type prostaglandin D synthase is a powerful biomarker for severity of stable coronary artery disease. Atherosclerosis. 201:385-91 (2008).

EXERCISE

One particular paper (Nikolaidis, 2011) provided a considerable amount of information on prostaglandin chemistry in relation to different types of exercise. Interestingly, the paper begins by noting that, “the level of one abundant IsoP stereoisomer, 15-F2t-Isoprostane [of the 15 series of F2-isoprostanes, chemically related to the 8 series of F2-isoprostanes that includes PGF2alpha] in blood or urine is widely regarded as the ‘gold standard’ marker for the assessment of oxidative stress. As a result, the number of studies measuring IsoP levels in the biomedicine field has been increasing exponentially every year since the 1990, when the IsoP were discovered.” The authors note that IsoP has been assessed (as of 2011, when this paper was published) in more than 60 exercise studies.

The authors go on to explain why the 15 series IsoP has been specifically studied: “These intermediates [of arachidonic acid] are then reduced to F2-IsoP or rearranged to form prostaglandin E2- and D2-regioisomers. Four different F2-IsoP regioisomers (5-, 8-, 12- and 15-series regioisomers—depending on the carbon atom to which the allylic hydroxyl is attached) can be generated ... The most studied of the IsoP is a 15 series IsoP called ‘15-F2t-IsoP’ (due essentially to its widespread commercial availability...” The authors note that there is some disagreement over the nomenclature of these many forms of IsoP (whether that is still the case now, as it was in 2011, we do not know).

After this highly technical explanation of the different forms of IsoP, the authors go on to describe details of the methods they used to measure the IsoPs and then their experiments with exercise and the isoprostanes they found in plasma and urine.

EXERCISE AND F2-ISOPROSTANES:

ARE WE GETTING TO THE BOTTOM LINE?

Pretty close.

The purpose of this exercise (the explanation itself plus the actual exercise that was performed to determine how exercise affects prostaglandin chemistry) was reported in the paper after all the preliminary information that provided necessary background for it was explained.

The authors (Nikolaidis, 2011) sum up the conclusions on acute exercise from their review paper as follows:

1. Acute exercise clearly increases F2-isoprostane levels in plasma and this effect is generally short lived.

2. Acute exercise and increased contractile activity markedly increases F2-isoprostane levels in skeletal muscle.

3. Chronic exercise exhibits trend for decreased F2 isoprostane levels in urine but further research is needed.

The interpretation is complex. However, the increased F2 isoprostane levels in plasma that have a short-lived effect MAY suggest a pulsatile release of certain F2 isoprostanes (prostaglandin D2?) A pulsatile release of PGD2, if it occurs, would be antiinflammatory.

  • Nikolaidis, Kyparos, Vrabas. F₂-isoprostane formation, measurement and interpretation: the role of exercise. Prog Lipid Res. 50(1):89-103 (2011 Jan).

Additional clues on the effect of acute exercise are to be found in another paper (Schenk and Horowitz, 2007), in which the effects of acute exercise in sedentary humans were studied. As the authors point out, insulin resistance is associated with excessive fatty acid mobilization (lipolysis). Abdominal obesity increases fatty acid mobilization and insulin resistance. Interestingly, immediate release niacin is a powerful anti-lipolytic agent and improves insulin resistance. When you consider the findings of Schenk and Horowitz, 2007, IT IS TEMPTING TO SPECULATE THAT THE NIACIN FLUSH MAY ACT AS A MIMIC FOR ACUTE EXERCISE. They found that one session of acute exercise resulted in a complete “[r]eversal of insulin resistance accompanied [by] enhanced lipogenic capacity within skeletal muscle, reducing accumulation of highly bioactive fatty acid metabolites [proinflammatory F2 isoprostanes] and suppressed activation of proinflammatory pathways known to impair insulin action,”

  • Schenk, Horowitz. Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest. 117(6):1690-8 (2007 Jun).

HYPERLIPIDEMIA

A recent paper (Hellmann, 2013) reports that saturated free fatty acids are elevated in obesity after the resolution of an acute sterile (no infection by microorganisms) inflammation. They identified the mechanism as the survival of neutrophils (which are normally supposed to die after the resolution of inflammation) and the decrease below normal levels of macrophage phagocytosis, resulting from stimulation by the saturated fatty acid palmitic acid. Using a sophisticated detection system (targeted mass spectrometry-based lipidomics), they found that in db/db mice a model of obesity, Prostaglandin E2 and prostaglandin D2 levels were elevated in inflammatory exudates during the development of acute peritonitis and this resulted in defective resolution of the inflammation, with the survival of neutrophils and the defective macrophage phagocytosis mentioned above. They found that these defects in the resolution of inflammation were mimicked by elevated levels of PGE2 and PGD2 and were reversed in their experiments with cyclooxygenase inhibition (to decrease the production of the PGE2 and PGD2) or prostanoid receptor antagonism (to prevent the PGE2 and PGD2 receptors from carrying the signal from the elevated levels of PGE2 and PGD2.

The authors say, “[t]ogether, these studies provide new insights into the mechanisms underlying altered innate immune responses in obesity and suggest that targeting specific prostanoid receptors may represent a novel strategy for resolving inflammation and restoring phagocyte defects in obese and diabetic individuals.”

The niacin flush, resulting from the release of a PULSE of PGD2 is effective in reducing elevated blood levels of PGD2 and of PGE2, as we have described in other model systems in this paper. Hence, the niacin flush could be beneficial in reducing serious defects in the resolution of inflammation seen in the immune responses in obesity and diabetes.

  • Hellmann, Zhang, Tang, et al. Increased saturated fatty acids in obesity alter resolution of inflammation in part by stimulating prostaglandin production. J Immunol. 191(3):1383-92 (2013).

DIABETES AND OBESITY

Lipocalin Prostaglandin D Synthase Regulates the Activity of Brown Fat

Controls the Switch from Carbohydrates to Lipids

A recent paper (Virtue, 2012) reports that lipocalin-type prostaglandin D synthase (which induces the synthesis of the D type prostaglandins that includes prostaglandin D2, the releaser of the niacin flush) signals the switch from the use of carbohydrate fuel in the postprandial state to lipid fuels during the fasted state as is supposed to occur in normal metabolism. In diabetes and obesity, the switch is blunted. Our hypothesis (and no doubt that of some others) is that under conditions of diabetes and obesity, the lipocalin-type Prostaglandin D synthase is releasing prostaglandin D at a chronically high level, thus blunting the signal that is supposed to take place to switch from one fuel to another.

Studying mice that had the lipocalin-type prostaglandin D synthase gene knocked out, the authors found that these mice had improved glucose tolerance when fed a high fat diet whereas when fed a high glucose diet, the animals consumed more glucose and, hence, had impaired glucose tolerance. What this shows is that without the prostaglandin D2 signal, the animals continue to use glucose for fuel, even when there is plentiful fat available in the diet.

The authors describe the metabolic fuel switch in diabetics or those at risk of diabetes because of familial factors: “When fed a high fat diet for 3 days, subjects with a family history or type 2 diabetes showed a lower change in respiratory quotient between fasted and fed states that did subjects without a family history of type 2 diabetes.” The purpose of their study in mice was to try to determine the mechanism for this.

We think that immediate release niacin, resulting in a pulsed release of prostaglandin D2 (the flush) ought to improve the choice of fuels used in the postprandial and fasted states. Indeed, immediate release niacin does improve the use of metabolic fuels in mechanistic and animal studies. In human studies, the results can be inconsistent for a reason that is explained in the next paragraph. In the study being discussed here (Virtue, 2012), they found that mice that had no L-PGDS (it was knocked out) had increased carbohydrate and decreased lipid utilization. Of course, the inability to metabolize lipids following a meal resulted in increased circulating levels of fats in the knockout mice (Virtue, 2012), which is as undesirable as not utilizing enough carbohydrate. Hence, diabetes could not be “cured” by knocking out L-PGDS.

As I explain in the last section of this paper, there are more ways to get a niacin flush than niacin! So the antiinflammatory effects of the pulsatile release of prostaglandin D2 can be obtained through the use of a variety of supplements.

In principle, the release of a pulse of PGD2 to signal the switch from glucose in the postprandial state to (largely) lipid fuels in the fasted stated could explain why niacin can cause a small decrease in glucose tolerance in some people who take it. It would depend on the timing, e.g., when the niacin was taken in relation to a meal. If the PGD2 pulse released by immediate release niacin occurs at a time when there is considerable glucose in the system (before the signal should induce the switch from glucose to lipids), it might cause a switch to lipid fuels while leaving excess glucose circulating in the bloodstream. The excess glucose would look like glucose intolerance. What this might suggest is that a good time to take immediate release niacin, mimicking the timing of the physiological release of postprandial PGD2, is a couple of hours after a meal when in the fasted state. (That assumes you are in the fasted state. Some people eat chronically and are never really in the fasted state.)

  • Virtue, Feldmann, Christian, et al. A new role for l ipocalin prostaglandin D synthase in the regulation of brown adipose tissue substrate utilization. Diabetes. 61:3139-47 (2012).

8-ISOPROSTANE AS A BIOMARKER OF YOUR COMMUNITY’S HEALTH AS SUGGESTED BY ITS LEVEL IN YOUR LOCAL SEWAGE

As I discuss in the section on EXERCISE above, 8-isoprostane is a metabolite of arachidonic acid, in the 8-series of F2 isoprostanes that includes PGF2alpha, a prostaglandin notably called the “gold standard” for measuring oxidative stress in blood or urine. It is particularly stable in urine, making it an excellent way of detecting the community level of oxidative stress by its level in sewage. (Santos, 2015) In fact, this is a widely used test that can be done with a commercial test kit. (8-isoprostane ELISA kit, available from Detroit R&D, Inc. (info@detroitrandd.com or phone 313-961-1606

As the company notes. stress-related health factors found to correlate with 8-isoprostane levels can include obesity, cardiovascular disease, diabetes, smoking, cancer, and alcohol consumption.” Thus, it is indeed a useful test for evaluating community health. The company also offers the 8-isoprostane oxidative stress ELISA kit for determining 8-isoprostane levels in blood, urine, and tissues as a biomarker of oxidative stress in vivo.

The company wants you to know:
BUY IN QUANTITY AND SAVE!

References:

  • Santos, Jurban, Kim. Could sewage epidemiology be a strategy to assess lifestyle and wellness of a large scale population? Med Hypotheses. pii: S0306-9877(15)00239-X. doi: 10.1016/j.mehy.2015.06.020. [Epub ahead of print] (June 26 2015).
  • Daughton. Using biomarkers in sewage to monitor community-wide human health: isoprostanes as conceptual prototypes. Sci Total Environ. 424:16-38 (2012).
  • Montuschi, Barnes, Roberts. Isoprostanes: markers and mediators of oxidative stress. FASEB J. 18(15):1791-800 (2004).

MORE ON DIABETES

The regulation of the use of metabolic fuels is a key factor in normal metabolism. The ability to make the switch from glucose to lipids is called metabolic flexibility and can be measured by determining the change in respiratory quotient between fed and fasted states (Virtue, 2012). “A reduction in metabolic flexibility has been suggested to be a primary defect leading to insulin resistance.”

Because brown fat (BAT) can utilize both glucose and fat as fuels, scientists studied the effect of lipocalin prostaglandin D synthase (L-PGDS) in the use of these fuels in BAT, finding improved metabolic efficiency as a result of the action of the L-PGDS.

  • Virtue et al. A new role for lipocalin prostaglandin D synthase in the regulation of brown adipose tissu s ubstrate utilization. Diabetes. 61:3139-47 (2012).

DIABETES MELLITUS

I note this finding in a 1999 paper (Davi, 1999): “We conclude that DM is associated with increased formation of F2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation.” See the next section on DIABETES AND OBESITY for more on this.

As I discussed in an earlier part of this paper, the upregulation of prostaglandin D2 as a pro-resolution mediator is reported in individuals in long-term remission from ulcerative colitis. In that paper (Vong, 2010), the authors noted that patients with active ulcerative colitis have been shown to have elevated levels of PGE2, PGI2, and PGF2alpha. PGF2alpha is the prostaglandin found in the 1999 paper we mentioned just above to be produced at elevated levels in diabetes mellitus. The authors of that paper considered the elevation of 8-iso-prostaglandin F2alpha (PGF2alpha) to be a biochemical link between impaired glycemic control and persistent platelet activation in DM.

  • Davi, Ciabattoni, Consoli, et al. In vivo formation of 8-iso-prostaglandin F2alpha and platelet activation in diabetes mellitus. Circulation. 99:224-9 (1999).
  • Vong, Ferraz, Panaccione. A pro-resolution mediator, Prostaglandin D2, is specifically up-regulated in individuals in long-term remission from ulcerative colitis. Proc Natl Acad Sci U S A. 107(26):12023-7 (2010).

Eicosanoids in Metabolic Syndrome

DIABETES, A DISEASE OF CHRONIC PERSISTENT INFLAMMATION

A very recent paper (Hardwick, 2013) brings us up to date (as of 2013) to reveal the developing evidence implicating inflammatory prostaglandins in diabetes and related conditions collectively called the metabolic syndrome (which includes, in addition to diabetes, obesity, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia). This is an excellent review paper.

As the authors explain, “ ... the role of eicosanoids in the regulation of metabolic pathways of lipid and carbohydrate metabolism in obesity, hyperlipidemia, hypertriglyceridemia, hypertension, and insulin resistance has only recently been studied with the use of eicosanoid metabolic enzyme transgenic and global knockout mouse models. These studies in PLA2, 5-lipoxygenase, and 12/15-LOX pathwys and knockout mice of fatty acid desaturase (FADS) and elongase (Elov1) in the formation of AA [arachidonic acid] from alpha linoleic acid (ALA) have strongly supported eicosanoids as key regulatory molecules in MetS [metabolic syndrome] and the progression of hepatic steatosis [fatty liver] to steatohepatitis in nonalcoholic fatty liver disease (NAFLD).”

The review paper continues with an analysis of the myriad biochemical pathways that are involved in this regulatory system, but the continuation of my report to these details is beyond the scope of this paper. Hence, this is it, folks. I am glad I did this study of the niacin flush, feel it was of considerable value to my understanding of inflammatory diseases, and recognize that at a certain point one has to call it ...

THE END

NOT QUITE THE END

Natural Substances Other Than Niacin That May
Provide Antiinflammatory Effects by Decreasing

Signaling by Inflammatory Prostaglandins

The niacin flush is a mechanism for (among other things) modulating signaling by inflammatory prostaglandins (such as chronically high levels of PGD2), but it is by no means the only natural substance able to do this and there are a number of different mechanisms for achieving this result. Here we give a few examples.

CLA (CONJUGATED LINOLEIC ACID)

This nutrient has been shown to decrease the activity of delta6-desaturase, an enzyme that controls the conversion of linoleic acid to arachidonic acid. (Stawarska, 2015) Arachidonic acid is the starting material for the body’s manufacture of a large number of inflammatory prostaglandins (under some circumstances, these can be antiinflammatory).

Other inhibitors of delta6-desaturase include zinc, calcium, vitamin B12, folic acid, and others. (Stawarska, 2015).

  • Stawarska, Bialek, Stanimirova, et al. The effect of conjugated linoleic acids (CLA) supplementation on the activity of enzymes participating in the formation of arachidonic acid in liver microsomes of rats—probable mechanism of CLA anticancer activity. Nutr Cancer. 67(1):145-55 (2015).

SELENIUM

A recent paper (Gandhi, 2011) reports that, using mouse macrophages, they show that selenium shunts arachidonic acid metabolism toward the production of antiinflammatory prostaglandin D2 metabolites, which, they suggest, “might have clinical implications.” In a previous paper published by this group, they demonstrated that selenium increased the production of arachidonic acid derived anti-inflammatory 15-deoxy-delta12,14 prostaglandin J2 (a metabolite of prostaglandin D2) and decreased the proinflammatory PGE2. In this latest paper (Gandhi, 2011), they found that selenium dose-dependently increased the expression of hematopoietic PGD2 synthase with a corresponding increase in delta12-PGJ2 and 15-PGJ2 in RAW 264.7 macrophages and primary hone marrow derived macrophages.

The authors suggest that these effects may contribute to the anti-cancer effect of selenium and to the improvement in the condition of patients with inflammatory diseases such as septic shock, autoimmune thyroiditis, pancreatitis, allergic asthma, and rheumatoid arthritis (Gandhi, 2011).

  • Gandhi, Kaushal, Ravindra, et al. Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D2 synthase in macrophages is mediated through the activation of peroxisome proliferator-activated receptor (PPAR) gamma. J BIOL CHEM 286(31):27471-27482 (2011).

RESVERATROL

This molecule reduces the production of inflammatory prostaglandins by inhibiting COX-2. (Han, 2007)

HYDROXYTYROSOL

A constituent of extra virgin olive oil, this molecule prevents inflammatory eicosanoid production. (Han, 2007)

EGCG, ECG, MYRICETIN

These molecules are reported to inhibit PGE2 production. (Han, 2007)

APIGENIN

Inhibits inflammatory prostaglandin synthesis. (Han, 2007)

CURCUMIN

Downregulates COX-2, thus reducing the synthesis of inflammatory prostaglandins. (Han, 2007)

  • Han, Shen, Lou. Dietary polyphenols and their biological significance. Int J Mol Sci. 8:950-88 (2007).

A different paper reports that curcumin’s antiinflammatory activity is “mainly due to inhibition of arachidonic acid metabolism, cyclooxygenase (COX), lipoxygenase (LOX), cytokines interleukin (IL) and tumor necrosis factor (TNF), and nuclear factor kappa B (NFkappaB)” (Yuan, 2006).

  • Yuan, Wahlqvist, He, et al. Natural products and antiinflammatory activity. Asia Pac J Clin Nutr. 15(2):143-52 (2006).

GINGER

Antiinflammatory activity includes Inhibition of prostaglandin E2 and thromboxane B2. (Shen, 2003)

  • Shen, Hong, Kim. Effects of ginger (Zingiber officinale Rosc.) on decreasing the production of inflammatory mediators in sow osteoarthritic cartilage explants. J Med Food. 6(4):323-8 (2003).

There is a LOT more in the literature, but this sample will have to do, as this paper is a WRAP!


© 2015 by Sandy Shaw

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