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Free Fatty Acids Suppress Cellular Respiration

Also see:
PUFA Decrease Cellular Energy Production
PUFA Breakdown Products Depress Mitochondrial Respiration
The Randle Cycle
PUFA, Ketones, and Sugar Restriction Promote Tumor Growth

“Free fatty acids suppress mitochondrial respiration (Kamikawa and Yamazaki, 1981), leading to increased glycolysis (producing lactic acid) to maintain cellular energy. The suppression of mitochondrial respiration increase the production of toxic free radicals, and the decreased carbon dioxide makes the proteins more susceptible to attack by free radicals.” -Ray Peat, PhD

Jpn Heart J. 1981 Nov;22(6):939-49.
Effect of high plasma free fatty acids on the free radical formation of myocardial mitochondria isolated from ischemic dog hearts.
Kamikawa T, Yamazaki N.
Effects of high plasma free fatty acids (FFA) on the free radical formation of myocardial mitochondria, isolated from normal and ischemic dog hearts, were studied by electron spin resonance (ESR) spectrometry. Free radical concentrations in state 4 respiration were used for the evaluation of the function in the mitochondria in this study. High plasma FFA levels were induced either by intravenous injection of Intralipid and heparin, or by infusion of norepinephrine. Ischemic hearts were induced by inserting a Cournand’s 7F catheter into the left coronary artery under fluoroscopic control. Exogenous high plasma FFA induced by Intralipid and heparin caused the decrease of free radicals in state 4 respiration in the mitochondria isolated from normal and ischemic dog hearts. Endogenous high FFA induced by continuous infusion of norepinephrine also caused the decrease of free radicals. On the other hand, nicotinic acid prevented the decrease of free radicals as well as the rise of plasma FFA by the norepinephrine infusion. These results suggest that high plasma FFA itself, whether it may be exogenous or endogenous, may impair the oxidative phosphorylation of the mitochondria isolated from normal and ischemic hearts.

Suppressing fatty acid oxidation improves the contraction of the heart muscle and increases the efficiency of oxygen use (Chandler, et al., 2003). -Ray Peat, PhD

Cardiovasc Res (2003) 59 (1): 143-151.
Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia
Margaret P. Chandlera, (mpc10@po.cwru.edu), Pedro N. Chavezb, Tracy A. McElfresha, Hazel Huanga, Charles S. Harmonc and William C. Stanleya
Objective: Clinical trials in patients with stable angina show that drugs that partially inhibit myocardial fatty acid oxidation reduce the symptoms of demand-induced ischemia, presumably by reducing lactate production and improving regional systolic function. We tested the hypothesis that partial inhibition of fatty acid oxidation with oxfenicine (a carnitine palmitoyl transferase-I inhibitor) reduces lactate production and increases regional myocardial power during demand-induced ischemia. Methods: Demand-induced ischemia was produced in anesthetized open-chest swine by reducing flow by 20% in the left anterior descending coronary artery and increasing heart rate and contractility with dobutamine (15 μg kg−1 min−1 i.v.) for 20 min. Glucose and fatty acid oxidation were measured with an intracoronary infusion of [U-14C] glucose and [9,10-3H] oleate, and hearts were treated with oxfenicine (2 mmol l−1; n = 7) or vehicle (n = 7). Regional anterior wall power was assessed from the left ventricular pressure–anterior free wall segment length loops. Results: During demand-induced ischemia, the oxfenicine group had a higher rate of glucose oxidation (6.9±1.1 vs. 4. 7±0.8 μmol min−1; P<0.05), significantly lower fatty acid uptake, but no change in total or active PDH activity. The oxfenicine group had significantly lower lactate output integrals (1.11±0.23 vs. 0.60±0.11 mmol) and glycogen depletion (66±6 vs. 43±8%), and higher anterior wall power index (0.95±0.17 vs. 1.30±0.11%) and anterior wall energy efficiency index (91±17 vs. 129±10%). Conclusions: Partial inhibition of fatty acid oxidation reduced non-oxidative glycolysis and improved regional contractile power and efficiency during demand-induced ischemia.

When stress is very intense, as in trauma or sepsis, the reaction of liberating fatty acids can become dangerously counter-productive, producing the state of shock. In shock, the liberation of free fatty acids interferes with the use of glucose for energy and causes cells to take up water and calcium (depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al., 2004; van der Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often leading to death. -Ray Peat, PhD

J Physiol. 2004 Dec 1;561(Pt 2):499-513. Epub 2004 Oct 7.
Cell swelling-induced ATP release is tightly dependent on intracellular calcium elevations.
Boudreault F, Grygorczyk R.
Mechanical stresses release ATP from a variety of cells by a poorly defined mechanism(s). Using custom-designed flow-through chambers, we investigated the kinetics of cell swelling-induced ATP secretion, cell volume and intracellular calcium changes in epithelial A549 and 16HBE14o- cells, and NIH/3T3 fibroblasts. Fifty per cent hypotonic shock triggered transient ATP release from cell confluent monolayers, which consistently peaked at around 1 min 45 s for A549 and NIH/3T3, and at 3 min for 16HBE14o- cells, then declined to baseline within the next 15 min. Whereas the release time course had a similar pattern for the three cell types, the peak rates differed significantly (294 +/- 67, 70 +/- 22 and 17 +/- 2.8 pmol min(-1) (10(6) cells)(-1), for A549, 16HBE14o- and NIH/3T3, respectively). The concomitant volume changes of substrate-attached cells were analysed by a 3-dimensional cell shape reconstruction method based on images acquired from two perpendicular directions. The three cell types swelled at a similar rate, reaching maximal expansion in 1 min 45 s, but differed in the duration of the volume plateau and regulatory volume decrease (RVD). These experiments revealed that ATP release does not correlate with either cell volume expansion and the expected activation of stretch-sensitive channels, or with the activation of volume-sensitive, 5-nitro-2-(3-phenylpropylamino) benzoic acid-inhibitable anion channels during RVD. By contrast, ATP release was tightly synchronized, in all three cell types, with cytosolic calcium elevations. Furthermore, loading A549 cells with the calcium chelator BAPTA significantly diminished ATP release (71% inhibition of the peak rate), while the calcium ionophore ionomycin triggered ATP release in the absence of cell swelling. Lowering the temperature to 10 degrees C almost completely abolished A549 cell swelling-induced ATP release (95% inhibition of the peak rate). These results strongly suggest that calcium-dependent exocytosis plays a major role in mechanosensitive ATP release.

Prog Clin Biol Res. 1983;111:89-109.
Energy metabolism in trauma and sepsis: the role of fat.
Wolfe RR, Shaw JH, Durkot MJ.
There seems little doubt that there are signals for the increased mobilization of fat in shock, trauma, and sepsis. Whether those signals are reflected by an actual increase in mobilization is dependent on many variables including cardiovascular status. A hypothetical scheme based on our own experiments in the hyperdynamics phases of response to burn injury and to sepsis is presented in Figure 8. According to this scheme, catecholamines stimulate lipolysis in the adipose tissue, resulting in the release of glycerol and FFA into the plasma at increased rates. The glycerol is cleared by the liver and converted into glucose–a process stimulated by, among other things, glucagon. Some of the increased flux of FFA is also cleared by the liver, whereupon the fatty acids are incorporated into VLDL and released again into the plasma. The increased FFA levels also exert a dampening effect on the factors stimulating hepatic glucose production. At the periphery, plasma FFA as well as VLDL fatty acids are taken up at an increased rate. The tissues are attuned to the oxidation of fat, and as a consequence most of the energy production is derived from fat oxidation. The increased fatty acids exert an inhibitory effect on the complete oxidation of glucose, so although glucose may be taken up at an accelerated rate, the relative contribution of glucose oxidation to total energy production may fall. Rather than being completely oxidized, pyruvate is reduced to lactate and released into the plasma at an accelerated rate. The lactate then contributes to the production of glucose in the liver, completing a cyclical process called the Cori Cycle. Although all aspects of this scheme are supported by data highlighted in this paper, it certainly must be an oversimplification of the overall response of substrate metabolism to trauma and sepsis. It is presented for the purpose of highlighting the potential role of fat as a controller of the metabolic response, and to suggest that the enhanced mobilization and oxidation of fat is one of the fundamental responses to stress.

Cell Death Differ. 2004 Dec;11 Suppl 2:S172-80.
Water induces autocrine stimulation of tumor cell killing through ATP release and P2 receptor binding.
Selzner N, Selzner M, Graf R, Ungethuem U, Fitz JG, Clavien PA.
Although exposure of cells to extreme hypotonic stress appears to be a purely experimental set up, it has found an application in clinical routine. For years, surgeons have washed the abdominal cavity with distilled water to lyse isolated cancer cells left after surgery. No data are available supporting this practice or evaluating the potential mechanisms of cell injury under these circumstances. Recent evidence indicates that increases in cell volume stimulate release of adenosine triphosphate and autocrine stimulation of purinergic (P2) receptors in the plasma membrane of certain epithelial cell types. Under physiological conditions, purigenic stimulation can contribute to cell volume recovery through activation of solute efflux. In addition, adenosine triphosphate-P2 receptor binding might trigger other mechanisms affecting cell viability after profound hypotonic stress. This study demonstrates a novel pathway of cell death by apoptosis in human colon cancer cells following a short hypotonic stress. This pathway is induced by transitory cell swelling which leads to extracellular release of adenosine triphosphate (ATP) and specific binding of ATP to P2 receptors (probably P2X7). Extracellular ATP induced activation of caspases 3 and 8, annexin V, release of cytochrome c, and eventually cell death. The effect of ATP can be blocked by addition of (i) apyrase to hydrolyse extracellular ATP and (ii) suramin, a P2 receptor antagonist. Finally, (iii) gadolinium pretreatment, a blocker of ATP release, reduces sensitivity of the cells to hypotonic stress. The adenosine triphosphate-P2 receptor cell death pathway suggests that autocrine/paracrine signaling may contribute to regulation of viability in certain cancer cells disclosed with this pathway.

J Biol Chem. 2003 Oct 10;278(41):40020-5. Epub 2003 Jul 18.
Increased vesicle recycling in response to osmotic cell swelling. Cause and consequence of hypotonicity-provoked ATP release.
van der Wijk T, Tomassen SF, Houtsmuller AB, de Jonge HR, Tilly BC.
Osmotic swelling of Intestine 407 cells leads to an immediate increase in cell surface membrane area as determined using the fluorescent membrane dye FM 1-43. In addition, as measured by tetramethylrhodamine isothiocyanate (TRITC)-dextran uptake, a robust (>100-fold) increase in the rate of endocytosis was observed, starting after a discrete lag time of 2-3 min and lasting for approximately 10-15 min. The hypotonicity-induced increase in membrane surface area, like the cell swelling-induced release of ATP (Van der Wijk, T., De Jonge, H. R., and Tilly, B. C. (1999) Biochem. J. 343, 579-586), was diminished after 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid-acetoxymethyl ester loading or cytochalasin B treatment. Uptake of TRITC-dextrans, however, was not affected. Treatment of the cells with the vesicle-soluble N-ethylmaleimide-sensitive factor attachment protein receptor-specific protease Clostridium botulinum toxin F not only nearly eliminated the hypotonicity-induced increase in membrane surface area but also strongly diminished the release of ATP, indicating the involvement of regulated exocytosis. Both the ATP hydrolase apyrase and the MEK inhibitor PD098059 diminished the osmotic swelling-induced increase in membrane surface area as well as the subsequent uptake of TRITC-dextrans. Taken together, the results indicate that extracellular ATP is required for the hypotonicity-induced vesicle recycling and suggest that a positive feedback loop, involving purinergic activation of the Erk-1/2 pathway, may contribute to the release of ATP from hypo-osmotically stimulated cells.

Science 23 January 1976: Vol. 191 no. 4224 pp. 293-295
What retains water in living cells?
GN Ling, CL Walton
Three types of evidence are presented showing that the retention of cell water does not necessarily depend on the possession of an intact cell membrane. The data agree with the concept that water retention in cells is due to multilayer adsorption on proteins and that the maintenance of the normal state of water relies on the presence of adenosine triphosphate as a cardinal adsorbent, controlling the protein conformations.

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By Team FPS – April 10, 2012

Ray Peat’s Brain: Building a Foundation for Better Understanding

by Danny Roddy

Compilation of excerpts from emails from Dr. Peat on various topics. Updated regularly. Click here for Part I and here for Part II.

More emails from peatarian here.

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By Team FPS – April 10, 2012

Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)

Also see:
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Errors in Nutrition: Essential Fatty Acids
Protective “Essential Fatty Acid Deficiency”
Toxicity of Stored PUFA
PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
Protect the Mitochondria

Quotes by Ray Peat, PhD:
“Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other antiinflammatory drugs.”

“The absence of cancer on a diet lacking unsaturated fats, the increased rate of metabolism, decreased free radical production, resistance to stress and poisoning by iron, alcohol, endotoxin, alloxan and streptozotocin, etc., improvement of brain structure and function, decreased susceptibility to blood clots, and lack of obesity and age pigment on a diet using coconut oil rather than unsaturated fats, indicates that something very simple can be done to reduce the suffering from the major degenerative diseases, and that it is very likely acting by reducing the aging process itself at its physiological core.”

“Now, instead of demonstrating harm from a dietary lack of the “essential” fats, the presence of the Mead acid or omega-9 fatty acids is taken as evidence of a deficiency. Our cells (and animal cells) produce these unsaturated fats when their special desaturase enzymes are not suppressed by the presence of exogenous linoleic or linolenic acids. Normally, the inactivation of an enzyme system and the suppression of a natural biological process might be taken as evidence of toxicity of the vegetable oils, but here, the occurrence of the natural process is taken as evidence of a deficiency. To me, this seems very much like the “disease” of having tonsils, an appendix, or a foreskin–if it is there, you have a problem, according to the aggressive surgical mentality. But what is the “problem” in the case of the natural Mead or omega-9 acids? (I think the “problem” is simply that they allow us to live at a higher energy level, with greater resistance to stress, better immunity, and quicker healing.)”

“A “deficiency” of polyunsaturated fatty acids leads to altered rates of cellular regeneration and differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation, decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do, and they are the precursors for an entirely different group of prostaglandins.”

“Many types of evidence indicate that environmental PUFA and prostaglandins produced from the “essential” fatty acids are required for inflammation to progress to degeneration. The n-9 polyunsaturated fatty acids (the kind that we can make from saturated fat or sugar) seem to be positively protective against inflammation.”

“The enzyme that produces the Mead fatty acid is strongly inhibited by PUFA seed oils (less strongly by fish oils), and so the presence of the Mead acid in the tissues is taken as evidence that the animal is suffering damage resulting from the absence of PUFA. The Mead acid happens to have some valuable anti-inflammatory effects, and is associated with many biological advantages, but research in that direction is prevented by the lack of funding.”

“When mitochondria are functioning fully, either glucose or saturated fats can safely
provide energy. Some glucose or saturated fat can be converted to polyunsaturated fats, that can be used as regulators or signals, for example to activate the formation of stem cells. But those PUFA don’t create disruptive cascades of increasing excitation or inflammation or excessive growth, and, from the evidence of animals that are fed fat free diets, or diets lacking omega -3 and omega -6 fatty acids, they aren’t toxic to mitochondria.”

J Immunol. 1990 Sep 1;145(5):1523-9.
Manipulation of the acute inflammatory response by dietary polyunsaturated fatty acid modulation.
Lefkowith JB, Morrison A, Lee V, Rogers M.
Dietary polyunsaturated fatty acid modulation has been used as an anti-inflammatory strategy in experimental models of disease as well as in clinical trials. To elucidate the mechanisms underlying the anti-inflammatory effects of manipulating dietary polyunsaturated fatty acids, the in vivo effects of essential fatty acid (EFA) deficiency and (n-3) fatty acid supplementation were contrasted using a model of acute inflammation induced by the i.p. injection of zymosan into mice. Both diets led to a substantial decrease in tissue (n-6) fatty acid content. EFA deficiency was also characterized by the accumulation of (n-9) fatty acids, particularly 20:3 (n-9), the fatty acid that uniquely characterizes the deficiency state. Dietary (n-3) fatty acid supplementation led instead to marked increases in (n-3) fatty acids, especially 20:5 (n-3). With respect to the antiinflammatory effects of the two diets, EFA deficiency, but not (n-3) fatty acid supplementation, depleted levels of resident peritoneal macrophages. EFA deficiency was also more effective than (n-3) fatty acid supplementation in inhibiting the influx of polymorphonuclear neutrophils in response to zymosan. The effect of the two diets on the in vivo generation of leukotriene(LT)B also differed markedly. EFA deficiency completely inhibited the synthesis of LTB. Dietary (n-3) fatty acid supplementation, in contrast, reduced the production of LTB4 by only 50%. With (n-3) fatty acid supplementation LTB5 was produced. The more modest effect of (n-3) fatty acid supplementation in decreasing LTB4 generation was not due to blockade of the cyclooxygenase pathway. EFA deficiency, but not (n-3) fatty acid supplementation, was associated with the decreased synthesis of thromboxane. Although dietary fatty acid modulation has been shown to diminish platelet activating factor (PAF) synthesis, studies using the PAF receptor blocker, L659989, established that PAF was not a significant factor in the elicitation of leukocytes in this model of inflammation. In summary, the anti-inflammatory effect of EFA deficiency was more marked that that of dietary (n-3) fatty acid supplementation in acute inflammation. This difference in anti-inflammatory potential appeared to be due to either the greater effect of EFA deficiency in decreasing levels of resident peritoneal macrophages or in suppressing the in vivo generation of LTB4.

LIPIDS Volume 31, Number 8, 829-837, DOI: 10.1007/BF02522978
Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue phospholipids
L. G. Cleland, M. A. Neumann, R. A. Gibson, T. Hamazaki, K. Akimoto and M. J. James
n-9 Eicosatrienoic acid (ETrA), also known as Mead acid, is a minor fatty acid in essential fatty acid (EFA)-sufficient healthy subjects but is found at increased levels in EFA deficiency. This study examined the influence of dietary ETrA from a biological source on plasma and tissue ETrA. A synthetic fat-free diet was prepared to which was added Mut 48 oil which contains 19% ETrA (wt%) as well as other n-9 fatty acids. Blends of vegetable oils were used to achieve overall diets with 5% fat (wt%) and varying amounts of ETrA at two different dietary levels of linoleic acid (LA), approximately 4.4 and 19% of total fatty acids. These diets were fed to 5-week-old Dark Agouti rats for four weeks. Plasma lipid fractions and liver, spleen, and peritoneal exudate (PE) cells were analyzed for fatty acid composition. ETrA was present at up to 20% total fatty acids in plasma triglyceride, cholesterol ester, and phospholipid fractions. ETrA also accumulated to substantial levels in phospholipids of liver and spleen (up to 15% of total fatty acids) and PE cells (up to 11%). ETrA was found in plasma and tissue phospholipids in proportion to the amount of ETrA present in the diet. The incorporation was reduced in diets with higher LA content compared to diets containing similar amounts of ETrA but lower LA. All rats remained apparently healthy, and histological survey of major organs revealed no abnormality. While the long-term implications for health of ingestion of diets rich in ETrA remain to be established, rats appear to tolerate high levels of dietary ETrA without adverse effects. Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis adversely.

J Nutr. 1996 Jun;126(6):1534-40.
Dietary (n-9) eicosatrienoic acid from a cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic acid.
Cleland LG, Gibson RA, Neumann MA, Hamazaki T, Akimoto K, James MJ.
Eicosatrienoic acid (ETrA) is the (n-9) homologue of (n-6) arachidonic acid (AA) and (n-3) eicosapentaenoic acid (EPA). ETrA can be synthesized endogeneously, but tissue levels are normally undetectable except in essential fatty acid (EFA) deficiency. An ETrA-rich oil extracted from a cultured fungus was used to prepare diets which had varying levels of ETrA (0-8 g/kg diet) in combination with one of two levels of linoleic acid (LA, 2.2 or 9.5 g/kg diet). All diets were sufficient in essential fatty acids. Groups of rats were fed these diets for 4 wk after which leucocyte fatty acid content and leukotriene B4 (LTB4) synthesis were measured. The influence of dietary LA on ETrA accumulation in cells was studied and correlations with LTB4 synthesis determined. ETrA was efficiently incorporated into peritoneal exudate cell (PEC) phospholipids with no evident saturation being observed with levels up to 10 mol/100 mol total fatty acids in peritoneal exudate cells. Cellular ETrA levels were lower (P < 0.001) in rats fed the higher level of LA. ETrA accumulation in peritoneal exudate cells correlated (r(2) = 0.63, P < 0.05) with reduced LTB4 synthesis which was attributable to LTA hydrolase inhibition. Thus, dietary ETrA from a biological source can accumulate in leucocytes and suppress inflammatory eicosanoid synthesis. The findings justify further studies into the biochemical and anti-inflammatory effects of dietary ETrA, which could be incorporated into palatable food additives.

J Exp Med. 1993 Dec 1;178(6):2261-5.
Effect of dietary supplementation with n-9 eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid synthesis.
James MJ, Gibson RA, Neumann MA, Cleland LG.
Studies were undertaken to assess the biochemical effects of dietary supplementation with n-9 eicosatrienoic acid (ETrA), an arachidonic acid analogue that is normally present in cell membranes at very low levels but is raised in the presence of essential fatty acid deficiency (EFAD). The incorporation of dietary ETrA into rat neutrophils and its effect on A23187-stimulated 5-lipoxygenase metabolism in these cells was examined; in addition, the effect of ETrA was compared with that of another arachidonic acid analogue, eicosapentaenoic acid (EPA), which is known to accumulate in cell membranes and inhibit synthesis of leukotriene B4 (LTB4) a product of the 5-lipoxygenase metabolic pathway. Rats were fed a defined diet that was sufficient in essential fatty acids and that contained EPA or ETrA (0.014% of energy) or no added fatty acid, for 3 wk. In the cells from ETrA-fed rats, LTB4 synthesis was inhibited relative to control values, but synthesis of the other products of 5-lipoxygenase metabolism, 5-hydroxyeicosatetraenoic acid (5-HETE) and the all-trans isomers of LTB4, were not inhibited. This pattern indicates inhibition of LTA hydrolase in ETrA-fed rats. In EPA-fed rats, there was inhibition of LTB4 and the all-trans isomers of LTB4, but there was no inhibition of 5-HETE. This pattern indicates inhibition of LTA synthase in EPA-fed rats. The results establish that dietary ETrA effectively inhibits synthesis of the inflammatory mediator, LTB4, and suggest that ETrA may confer antiinflammatory benefits similar to those observed with EFAD or dietary fish oil (which contains EPA). Because ETrA is substantially less unsaturated than EPA, it can be expected to have greater chemical stability, which could be an important practical advantage when used as a dietary constituent or supplement.

“Many types of evidence indicate that environmental PUFA and prostaglandins produced from the “essential” fatty acids are required for inflammation to progress to degeneration. The n-9 polyunsaturated tatty acids (the kind we can make make from saturated fat or sugar) seems to be positively protective against inflammation. For example, rats fed a diet with 2% hydrogenated coconut oil for two weeks had lower levels of IL-6 and C-reactive protein than when a small amount of arachidonic acid and docosahexaenoic acid (DHA) were added. Mead acid (20:3n9) was lower in the group with the PUFA supplement, and the inflammatory reaction to endotoxin was greater in the supplemented group (Ling, et aI., 2012).” -Ray Peat, PhD

Metabolism. 2012 Mar;61(3):395-406. Epub 2011 Sep 23.
Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid-deficient diet alters the response to endotoxin in rats.
Ling PR, Malkan A, Le HD, Puder M, Bistrian BR.
This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid-deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase-1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Surg Today. 2003;33(8):600-5.
Beneficial effects of n-9 eicosatrienoic acid on experimental bowel lesions.
Yoshida H, Soh H, Sando K, Wasa M, Takagi Y, Okada A.
PURPOSE:
Dietary fortification of n-9 polyunsaturated fatty acids (PUFA) or 5,8,11-eicosatrienoic acid (ETrA) as well as n-3 PUFA might contribute to the suppression of leukotriene B4 (LTB4) synthesis and thereby reduce inflammatory bowel lesions. As a result, the effect of an ETrA-enriched diet on experimental bowel lesions was examined in this study.
METHODS:
In Expt. 1, rats were freely fed either an ETrA-enriched or a standard diet. After 7 days of feeding, acute bowel lesions were induced by the subcutaneous injection of 10 mg/kg indomethacin. In Expt. 2, chronic bowel lesions were made by performing subcutaneous injections of 7.5 mg/kg indomethacin twice. After the first injection, the rats were freely fed either an ETrA-enriched or a standard diet for 7 days.
RESULTS:
In both experiments, the rats fed an ETrA-enriched diet showed increased levels of ETrA in the plasma and intestinal mucosa, and a decreased inflammation score. However, there was no significant decrease in plasma and intestinal mucosal LTB4 in the ETrA-enriched diet-fed rats.
CONCLUSION:
These results suggest that the dietary supplementation of ETrA may have both prophylactic and therapeutic effects on experimentally produced bowel lesions. Further investigations are necessary to clarify the effects of ETrA on bowel lesions and its mechanisms.

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By Team FPS – April 10, 2012

Glucocorticoids, Cytochrome Oxidase, and Metabolism

Also see:
Fat Deficient Animals – Activity of Cytochrome Oxidase
Blue Light, Cytochrome Oxidase, and Eye Injury

Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by red light, thyroid, and progesterone. -Ray Peat, PhD

A crucial enzyme in the mitochondrion is cytochrome oxidase, which reacts directly with oxygen, completing (or beginning) the process of chemical respiration. It is this enzyme (which is most sensitive to cyanide) which appears to be a “choke point” for energy production in various situations. Learning how to preserve and promote the activity of this enzyme is an important issue for everything having to do with biological energy. -Ray Peat, PhD

FEBS Lett. 1998 Sep 11;435(1):25-8.
Glucocorticoids decrease cytochrome c oxidase activity of isolated rat kidney mitochondria.
Simon N, Jolliet P, Morin C, Zini R, Urien S, Tillement JP.
The importance of mitochondria is rising as a target in pathologic processes such as ischemia. We have investigated the effects of hydrocortisone, prednisolone, dexamethasone and triamcinolone on oxidative phosphorylation, Ca2+ fluxes, swelling and membrane potentials in isolated kidney mitochondria. The measurement of respiration state 3 showed a significant decrease in presence of glucocorticoids whereas the other respiration states were not modified. When mitochondria were uncoupled and either the complexes III and IV or the complex IV were stimulated, the O2 consumption was decreased by glucocorticoids. These results suggest the cytochrome c oxidase is a target of the glucocorticoid effect on the respiratory chain. Indeed, the other mitochondrial functions investigated were unchanged, ruling out a direct effect on Ca2+ fluxes or swelling. A regulation of cytochrome c oxidase activity by glucocorticoids will be of particular interest in pathology involving metabolic insult.

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By Team FPS – April 7, 2012

Caffeine and Skin Protection

Also see:
Sunburn, PUFA, Prostaglandins, and Aspirin
Unsaturated Fats and Age Pigment
PUFA Accumulation & Aging
Topical Vitamin E and ultraviolet radiation on human skin
Niacinamide and the Skin

Topically applied caffeine, even after sun exposure, can reduce local tissue damage (Koo, et all, 2007). -Ray Peat, PhD

Br J Dermatol. 2007 May;156(5):957-64. Epub 2007 Mar 28.
Protection from photodamage by topical application of caffeine after ultraviolet irradiation.
Koo SW, Hirakawa S, Fujii S, Kawasumi M, Nghiem P.
BACKGROUND:
Characterization of mechanisms that can reverse residual damage from prior skin exposure to ultraviolet (UV) would be of considerable biological and therapeutic interest. Topical caffeine application to mouse skin that had previously been treated with UV has been shown to inhibit the subsequent development of squamous cell carcinomas.
OBJECTIVES:
We used an established mouse photodamage model to investigate other possible effects of topical caffeine application after UV.
METHODS:
SKH-1 hairless mice were treated with ultraviolet B (UVB) followed immediately by topical application of caffeine or vehicle three times weekly for 11 weeks.
RESULTS:
Caffeine applied topically after UV treatment resulted in a significant decrease in UV-induced skin roughness/transverse rhytides as assessed by treatment-blinded examiners. Histologically, topical caffeine application after a single dose of UVB more than doubled the number of apoptotic keratinocytes as evaluated by sunburn cell formation, caspase 3 cleavage and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) staining. A trend towards decreased solar elastosis was noted in the caffeine-treated group although this was not statistically significant. Other histological parameters including epidermal hyperplasia, solar elastosis and angiogenesis were increased in mice treated with UV but topical application of caffeine did not alter these particular UV effects.
CONCLUSIONS:
These findings support the concept that topical application of caffeine to mouse skin after UV irradiation promotes the deletion of DNA-damaged keratinocytes and may partially diminish photodamage as well as photocarcinogenesis.

Photochem Photobiol. 2008 Mar-Apr;84(2):330-8. Epub 2008 Jan 7.
Effect of caffeine on UVB-induced carcinogenesis, apoptosis, and the elimination of UVB-induced patches of p53 mutant epidermal cells in SKH-1 mice.
Conney AH, Kramata P, Lou YR, Lu YP.
Oral administration of green tea or caffeine to SKH-1 mice during UVB irradiation for several months inhibited the formation of skin cancer. Similar effects were observed when green tea or caffeine was given to tumor-free UVB-initiated mice with a high risk of developing skin tumors in the absence of further UVB irradiation (high risk mice). Mechanistic studies indicated that topical application of caffeine stimulated UVB-induced apoptosis as well as apoptosis in UVB-induced focal hyperplasia and tumors in tumor-bearing mice. Oral or topical administration of caffeine enhanced the removal of patches of epidermal cells with a mutant form of p53 protein that appeared early during the course of UVB-induced carcinogenesis, and oral administration of caffeine altered the profile of p53 mutations in the patches. In additional studies, topical application of caffeine was shown to have a sunscreen effect, and topical application of caffeine sodium benzoate was more active than caffeine as a sunscreen and for stimulating UVB-induced apoptosis. Caffeine sodium benzoate was also highly active in inhibiting carcinogenesis in UVB-pretreated high risk mice. Our studies indicate that caffeine and caffeine sodium benzoate may be useful as novel inhibitors of sunlight-induced skin cancer.

Carcinogenesis. 2005 Aug;26(8):1465-72. Epub 2005 Apr 7.
Administration of green tea or caffeine enhances the disappearance of UVB-induced patches of mutant p53 positive epidermal cells in SKH-1 mice.
Lu YP, Lou YR, Liao J, Xie JG, Peng QY, Yang CS, Conney AH.
Irradiation of female SKH-1 hairless mice with UVB (30 mJ/cm2) twice a week for 10-20 weeks resulted in the formation of a large number of cellular patches (>8 adjacent cells/patch) that are recognized with an antibody (Pab240) which recognizes mutated but not wild-type p53 protein. These patches are not recognized by an antibody (Pab1620) to wild-type p53 protein. The patches, which are considered putative early cellular markers of the beginning of tumor formation, started appearing after 4-6 weeks of UVB treatment, and multiple patches were observed after treatment for 10 weeks. The number and size of the patches increased progressively with continued UVB treatment. Discontinuation of UVB for 4 weeks resulted in an 80-90% decrease in the number of these patches. The number of the remaining patches did not decrease any further but remained relatively constant for at least 4-9 weeks. Oral administration of green tea (6 mg tea solids/ml) or caffeine (0.4 mg/ml) as the sole source of drinking fluid during irradiation with UVB, twice a week for 20 weeks, inhibited UVB-induced formation of mutant p53 positive patches by approximately 40%. Oral administration of green tea (6 mg tea solids/ml) as the sole source of drinking fluid or topical applications of caffeine (6.2 micromol) once a day 5 days a week starting immediately after discontinuation of UVB treatment enhanced the rate and extent of disappearance of the mutant p53-positive patches. Topical applications of caffeine to the dorsal skin of mice pretreated with UVB for 20 weeks resulted in enhanced apoptosis selectively in focal basal cell hyperplastic areas of the epidermis (putative precancerous lesions), but not in areas of the epidermis that only had diffuse hyperplasia. Our studies indicate that the chemopreventive effect of caffeine or green tea may occur by a proapoptotic effect preferentially in early precancerous lesions.

Carcinogenesis. 2005 Nov;26(11):1965-74. Epub 2005 Jun 23.
Effect of administration of caffeine or green tea on the mutation profile in the p53 gene in early mutant p53-positive patches of epidermal cells induced by chronic UVB-irradiation of hairless SKH-1 mice.
Kramata P, Lu YP, Lou YR, Cohen JL, Olcha M, Liu S, Conney AH.
Irradiation of SKH-1 mice with UVB light for 20 weeks resulted in a large number of patches of epidermal cells, which was visualized with an antibody that recognizes mutated p53 protein. Oral treatment of mice with caffeine (0.4 mg/ml) or green tea (6 mg tea solids/ml) as the drinking fluid during UVB irradiation decreased the number of patches by approximately 40%. Sequencing analysis of the p53 gene (exons 3 to 9) detected 88, 82 or 39 point mutations in 67, 70 or 29 patches from water, caffeine or tea treated mice, respectively. A major hotspot at codon 270 (Arg–>Cys) accounted for 47.7% (water), 70.7% (caffeine) or 46.2% (tea) of all mutations. Patches from caffeine treated mice had fewer types of mutations than patches from mice treated with water or tea. Administration of caffeine or tea during 20 weeks of UVB irradiation eliminated mutations at codons 149 (Pro–>Ser) and 210 (Arg–>Cys) but increased the frequency of mutations at codon 238 (Ser–>Phe). Topical applications of caffeine (1.2 mg in 100 microl acetone) once a day, five times a week for 6 weeks after stopping UVB decreased the number of patches by 63% when compared with mice treated with acetone. DNA sequencing analysis detected 63 and 68 mutations in 48 and 57 patches from acetone or caffeine treated mice, respectively. Although no differences in the frequency, position or types of mutations were observed, the caffeine group harbored less homozygous mutations (12.3% of the total) than the acetone group (31.3% of the total, P = 0.029). In summary, oral treatment of mice with caffeine or green tea during chronic UVB irradiation changed the mutation profile of the p53 gene in early mutant p53 positive epidermal patches, and topical applications of caffeine after discontinuation of chronic UVB irradiation specifically eliminated patches harboring homozygous p53 mutations.

Carcinogenesis. 2007 Jan;28(1):199-206. Epub 2006 Jul 24.
Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice.
Lu YP, Lou YR, Xie JG, Peng QY, Zhou S, Lin Y, Shih WJ, Conney AH.
Topical application of caffeine sodium benzoate (caffeine-SB) immediately after UVB irradiation of SKH-1 mice enhanced UVB-induced apoptosis by a 2- to 3-fold greater extent than occurred after the topical application of an equimolar amount of caffeine. Although topical application of caffeine-SB or caffeine enhanced UVB-induced apoptosis, both substances were inactive on non-UVB-treated normal skin. Topical application of caffeine-SB or caffeine (each has UVB absorption properties) 0.5 h before irradiation with a high dose of UVB decreased UVB-induced thymine dimer formation and sunburn lesions (sunscreen effect). Caffeine-SB was more active than an equimolar amount of caffeine in exerting a sunscreen effect. In additional studies, caffeine-SB strongly inhibited the formation of tumors in UVB-pretreated ‘high-risk mice’ and in tumor-bearing mice, and the growth of UVB-induced tumors was also inhibited. Caffeine-SB and caffeine are the first examples of compounds that have both a sunscreen effect and enhance UVB-induced apoptosis. Our studies suggest that caffeine-SB and caffeine may be good agents for inhibiting the formation of sunlight-induced skin cancer.

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By Team FPS – April 7, 2012

Niacinamide and the Skin

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A year of treatment with nicotinamide, a form of vitamin B3, significantly lowered the risk of common, non-melanoma skin cancer in high-risk patients, according to University of Sydney research published in the New England Journal of Medicine.

J Cosmet Dermatol. 2004 Apr;3(2):88-93.
Nicotinic acid/niacinamide and the skin.
Gehring W.
Nicotinic acid (also generally known as niacin) and niacinamide (also known as nicotinamide) are similarly effective as a vitamin because they can be converted into each other within the organism. The blanket term vitamin B(3) is used for both. Niacinamide is a component of important coenzymes involved in hydrogen transfer. Here, the two codehydrogenases, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are of central importance. Topical application of niacinamide has a stabilizing effect on epidermal barrier function, seen as a reduction in transepidermal water loss and an improvement in the moisture content of the horny layer. Niacinamide leads to an increase in protein synthesis (e.g. keratin), has a stimulating effect on ceramide synthesis, speeds up the differentiation of keratinocytes, and raises intracellular NADP levels. In ageing skin, topical application of niacinamide improves the surface structure, smoothes out wrinkles and inhibits photocarcinogenesis. It is possible to demonstrate anti-inflammatory effects in acne, rosacea and nitrogen mustard-induced irritation. Because of its verifiable beneficial effects, niacinamide would be a suitable component in cosmetic products for use in disorders of epidermal barrier function, for ageing skin, for improving pigmentary disorders and for use on skin prone to acne.

N Engl J Med 2015; 373:1618-1626October 22, 2015DOI: 10.1056/NEJMoa1506197
A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention
Andrew C. Chen, M.B., B.S., Andrew J. Martin, Ph.D., Bonita Choy, M.Med., Pablo Fernández-Peñas, Ph.D., Robyn A. Dalziell, Ph.D., Catriona A. McKenzie, M.B., B.S., Richard A. Scolyer, M.D., Haryana M. Dhillon, Ph.D., Janette L. Vardy, M.D., Anne Kricker, Ph.D., Gayathri St. George, M.Sc.Med., Niranthari Chinniah, M.B., B.S., Gary M. Halliday, D.Sc., and Diona L. Damian, Ph.D.
BACKGROUND
Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses.
METHODS
In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide.
RESULTS
At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, −6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued. CONCLUSIONS Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.)

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By Team FPS – April 7, 2012

The AIDS Debate That Isn’t

WALL STREET JOURNAL, 2/26/88
Copyright Dow Jones & Co. Inc.
By Katie Leishman
SOURCE

Last week the Presidential Commission on the Human Immunodeficiency Virus Epidemic held hearings in New York.

Among the witnesses was Peter Duesberg, a professor of virology at the University of California at Berkeley, who is one of the world s foremost retrovirologists and a member of the National Academy of Sciences. Mr. Duesberg explained why he does not believe, with the majority of AIDS researchers, that the disease is caused by HIV, a retrovirus discovered in 1983.

According to Mr. Duesberg the viral model for AIDS contradicts too many principles of virology. HIV is said to destroy T4 cells, which are footsoldiers in the body’s immune system. But retroviruses, Mr. Duesberg counters, do not destroy cells. Moreover, he argues, HIV infects fewer than one in 10,000 to 100,000 cells, a number easily replaced by the body in a day. When the virus is most active it triggers no AIDS symptoms, whereas when AIDS symptoms arise, the virus is, paradoxically, inactive. Mr. Duesberg observes that no other virus, indeed no other infectious agent, is known to cause disease in this way.

In the year since Mr. Duesberg first advanced his theories in a paper in Cancer Research, leading AIDS investigators have been unanimous in their refusal to rebut him, despite requests from universities and press forums like the “MacNeil/Lehrer NewsHour.” They have been willing, however, to justify their silence at length. Anthony Fauci, coordinator of AIDS research at the National Institutes of Health, recently explained on National Public Radio, “Critiquing a dubious theory would take time away from more productive efforts.” A proposed White House seminar (“How Does HIV Cause AIDS? “) in which Mr. Duesberg was to participate was abruptly canceled when no AIDS researcher from the National Institutes would agree to attend. Mr. Duesberg has kept his views alive through occasional radio interviews, university addresses and a brief appearance on CNN. Mr. Duesberg was asked to speak by the Presidential Commission, although a member of one commissioner s staff readily acknowledged that Mr. Duesberg “was invited to discredit him.” Nowhere was this clearer than in his treatment by Commissioner Frank Lilly, chairman of the department of genetics at the Albert Einstein College of Medicine. At the conclusion of Mr. Duesberg s testimony, Mr. Lilly remarked: “You ve made your usual very charming presentation…I would like to recommend that perhaps you could sit through our graduate course on animal virology.”

That opening shot raised expectations that Mr. Lilly was about to put Mr. Duesberg away. Yet Mr. Lilly s reply to Mr. Duesberg s arguments contained several strange assertions. (His claim that the causative role of the polio virus was only proved by the discovery of its vaccine drew stares from the audience, which included physicians and research scientists as well as gay activists. An animal model of infection existed long before the vaccine.) Mr. Lilly noted that hepatitis virus, although inactive following that disease’s course, could cause liver cancer up to 20 years later. Mr. Duesberg asked if he might reply to that point and was told that he could not. In fact, the relationship between the virus and cancer remains entirely speculative.

Mr. Lilly conceded that scientists have offered no definitive mechanism by which HIV destroys the immune system and that retroviruses classically do not kill cells. In the middle of his summation he said: “You may be right. There is a slight possibility that HIV does not cause AIDS. The evidence to date is in fact circumstantial.”

This striking admission did not prevent another commission member, William Walsh, president of Project Hope, from joining in the scolding. He admonished Mr. Duesberg to confine his opinions to professional circles and to have “the scientific integrity” to resist appearing on television programs “until you have something more substantial to say.”

Dr. Walsh added: “Don’t confuse the public. Don’t confuse the poor people suffering from this disease.” Whether Mr. Duesberg is right or wrong, there is nothing confusing about his contentions. Moreover, the suggestion that the public and patients must be protected from confusion is not merely condescending but faintly sinister. America is spending a billion dollars in research on the assumption that HIV causes AIDS, and treating patients with AZT — one of the most toxic yet hastily approved drugs ever released. The commission heard testimony concerning AZT’s use as a prophylactic measure in HIV-infected but still healthy individuals, a practice that Mr. Duesberg believes verges on the irresponsible.

AZT works by blocking production of DNA in the cell, both viral DNA and cellular DNA. Yet, as Mr. Duesberg told the commission, no one has been able to detect viral DNA production in any AIDS patient. All that is known for certain about the drug’s activity is that it is killing healthy cells.

The only subject about which the public needs to be spared confusion is behavioral risk factors for AIDS, which Mr. Duesberg s questions do not concern. As for confusing the patients, clearly their medical “right to know” should include the right to any information that might affect their choice of treatment.

Mr. Duesberg is frequently challenged, “If HIV isn’t the cause, what is? ” He responds that his expertise permits him to suggest only what AIDS is not. He is often asked about the growing epidemiological evidence linking syphilis and AIDS.

Venereal-disease clinics in several major cities are reporting increases in the incidence of syphilis in heterosexuals of nearly 100% in a one-year period — after a 20-year decline. The syphilis being seen is distinctively aggressive, and many public-health officials are speculating about the new outbreak and its relationship to the emergence of AIDS in the syphilis-ridden gay community of nearly a decade ago.

Mr. Duesberg allows that syphilis may play a key role in many cases of AIDS. But, as he testified, he doubts that any single pathogen could explain all the conditions embraced in the Centers for Disease Control’s definition of AIDS.

It is unsettling to be offered Mr. Duesberg’s hypothesis seven years into the epidemic, but that seems no excuse for the disdainful treatment it has received. AIDS research is based on the assumption that all that remains to be found is a cure. But this urgency to put all resources behind what appear to be promising solutions has created an instant orthodoxy, which resists review.

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By Team FPS – April 7, 2012

Soy and Behavior

Br Poult Sci. 2001 Mar;42(1):33-42.
Development of pecking damage in layer pullets in relation to dietary protein source.
McKeegan DE, Savory CJ, MacLeod MG, Mitchell MA.
1. In recent years, the UK egg industry has become increasingly dependent on plant protein sources, in particular soyabean meal, and it has been suggested that this trend (and/or the concomitant absence of animal protein in layer diets) might be causally related to increased feather pecking and cannibalism. 2. This study examined the development of pecking damage in relation to dietary protein source, by rearing 12 groups of 12 layer pullets to 24 weeks of age on diets based on ‘animal’ (fishmeal) or ‘plant’ (soyabean meal) protein. 3. Damaging pecking began at 6 weeks of age, in three groups (one plant and two animal). Injurious pecking began at 18 weeks of age, and affected four groups (two plant and two animal). 4. Greater numbers of vigorous pecks/pulls were observed in plant protein groups throughout the experiment, although they were significantly higher only between 13 to 16 weeks of age. Pecking damage scores did not differ between treatments. 5. Dietary protein source did not affect plasma oestradiol, progesterone or egg production. 6. These results do not support the notion that inclusion of fishmeal in laying hen diets prevents or alleviates feather pecking and cannibalism.

Horm Behav. 2004 Apr;45(4):278-84.
Increased aggressive behavior and decreased affiliative behavior in adult male monkeys after long-term consumption of diets rich in soy protein and isoflavones.
Simon NG, Kaplan JR, Hu S, Register TC, Adams MR.
Estrogen produced by aromatization of gonadal androgen has an important facilitative role in male-typical aggressive behavior that is mediated through its interaction with estrogen receptors (ER) in the brain. Isoflavones found in soybeans and soy-based dietary supplements bind ER and have dose- and tissue-dependent effects on estrogen-mediated responses. Yet, effects of isoflavone-rich diets on social and aggressive behavior have not been studied. We studied the effects of long-term (15 months) consumption of diets rich in soy isoflavones on spontaneous social behavior among adult male cynomolgus macaques (Macaca fascicularis) (n = 44) living in nine stable social groups. There were three experimental conditions which differed only by the source of dietary protein: casein and lactalbumin (no isoflavones), soy protein isolate containing 0.94 mg isoflavones/g protein, and soy protein isolate containing 1.88 mg isoflavones/g protein. In the monkeys fed the higher amount of isoflavones, frequencies of intense aggressive (67% higher) and submissive (203% higher) behavior were elevated relative to monkeys fed the control diet (P’s < 0.05). In addition, the proportion of time spent by these monkeys in physical contact with other monkeys was reduced by 68%, time spent in proximity to other monkeys was reduced 50%, and time spent alone was increased 30% (P's < 0.02). There were no effects of treatment on serum testosterone or estradiol concentrations or the response of plasma testosterone to exogenous gonadotropin-releasing hormone (GnRH). The results indicate that long-term consumption of a diet rich in soy isoflavones can have marked influences on patterns of aggressive and social behavior.

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By Team FPS – April 6, 2012

Check Your Labels – Guar Gum

Also see:
Fermentable Carbohydrates, Anxiety, Aggression
Carrageenan, Inflammation, Cancer, ImmunityRay Peat, PhD on the Benefits of the Raw Carrot
Estrogen, Serotonin, and Aggression
Endotoxin: Poisoning from the Inside Out
Scanning Electron Microscope (SEM) images of plant cell microparticles in urine sediment
THE PHENOMENON OF PERSORPTION: PERSORPTION, DISSEMINATION, AND ELIMINATION OF MICROPARTICLES

“The food industry is promoting the use of various gums and starches, which are convenient thickeners and stabilizers for increasing self-life, with the argument that the butyric acid produced when they are fermented by intestinal bacteria is protective. However, intestinal fermentation increases systemic and brain serotonin, and the short-chain fatty acids can produce a variety of inflammatory and cytotoxic effect. Considering the longevity and stress-resistance of germ-free animals, choosing foods (such as raw carrots or cooked bamboo shoots or cooked mushrooms) which accelerate peristalsis and speed transit through the bowel, while suppressing bacterial growth, seems like a convenient approach to increasing longevity. -Ray Peat, PhD

Proc Soc Exp Biol Med. 1986 Dec;183(3):299-310.
Relationship between dietary fiber and cancer: metabolic, physiologic, and cellular mechanisms.
Jacobs LR.
The relationships between fiber consumption and human cancer rates have been examined, together with an analysis of the effects of individual dietary fibers on the experimental induction of large bowel cancer. The human epidemiology indicates an inverse correlation between high fiber consumption and lower colon cancer rates. Cereal fiber sources show the most consistent negative correlation. However, human case-control studies in general fail to confirm any protective effect due to dietary fiber. Case-control studies indicate that if any source of dietary fiber is possibly antineoplastic then it is probably vegetables. These results may mean that purified fibers alone do not inhibit tumor development, whereas it is likely that some other factors present in vegetables are antineoplastic. Experiments in laboratory animals, using chemical induction of large bowel cancer, have in general shown a protective effect with supplements of poorly fermentable fibers such as wheat bran or cellulose. In contrast, a number of fermentable fiber supplements including pectin, corn bran, oat bran, undegraded carageenan, agar, psyllium, guar gum, and alfalfa have been shown to enhance tumor development. Possible mechanisms by which fibers may inhibit colon tumorigenesis include dilution and adsorption of any carcinogens and/or promoters contained within the intestinal lumen, the modulation of colonic microbial metabolic activity, and biological modification of intestinal epithelial cells. Dietary fibers not only bind carcinogens, bile acids, and other potential toxins but also essential nutrients, such as minerals, which can inhibit the carcinogenic process. Fermentation of fibers within the large bowel results in the production of short chain fatty acids, which in vivo stimulate cell proliferation, while butyrate appears to be antineoplastic in vitro. Evidence suggests that if dietary fibers stimulate cell proliferation during the stage of initiation, then this may lead to tumor enhancement. Fermentation also lowers luminal pH, which in turn modifies colonic microbial metabolic acidity, and is associated with increased epithelial cell proliferation and colon carcinogenesis. Because dietary fibers differ in their physiochemical properties it has been difficult to identify a single mechanism by which fibers modify colon carcinogenesis. Clearly, more metabolic and physiological studies are needed to fully define the mechanisms by which certain fibers inhibit while others enhance experimental colon carcinogenesis.

J Nutr. 1996 Aug;126(8):1979-91.
Dietary guar gum alters colonic microbial fermentation in azoxymethane-treated rats.
Weaver GA, Tangel C, Krause JA, Alpern HD, Jenkins PL, Parfitt MM, Stragand JJ.
To assess the effects of guar gum on colonic microbial fermentation and cancer development, azoxymethane-treated rats were fed a partially hydrolyzed guar or control diet. Anaerobic fecal incubations were conducted at 8-wk intervals, either without added substrate or with cornstarch or hydrolyzed guar as substrates. Short-chain fatty acids in colonic contents and colonic carcinoma areas were measured at 27 wk. Fecal in vitro fermentation rates were higher for guar-fed rats than for control rats [three-way ANOVA (diet, time, in vitro substrates), P = 0.002]. Fecal in vitro butyrate production was greater for guar-fed rats than for control rats after 3-11 weeks of diet treatment (three-way ANOVA, P = 0.027). Butyrate concentrations of colonic contents at 27 wk were higher in guar-fed than in control rats and higher in the cecum than in the post-cecal colon (two-way ANOVA, P = 0.0001). A regression equation predicting colonic carcinoma area (r2 = 0.279) using propionate and butyrate concentrations of the contents of the post-cecal colon showed propionate as a positive predictor (P < 0.001) and butyrate as a negative predictor (P = 0.033). Our results show that patterns of short-chain fatty acid production may affect the results of fiber-carcinogenesis experiments. Dietary addition of hydrolyzed guar is associated with fecal fermentation low in propionate and high in butyrate; short-chain fatty acid concentrations are greater proximally than distally. These results suggest that butyrate protects against colonic neoplasia, whereas propionate enhances it, and demonstrate that colonic microbiota adapt to produce more butyrate if given time and the proper substrate.

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By Team FPS – April 6, 2012

Carbohydrates and Bone Health

Also see:
Sugar (Sucrose) Restrains the Stress Response
Calcium Paradox
Thumbs Up: Fructose
Intestinal Serotonin and Bone Loss
Bone Health and Vitamin K
Parmigiano Reggiano cheese and bone health
Calcium Paradox
Estrogen Dominance and Magnesium Deficiency
Benefits of Aspirin

Picture 5

Ann Nutr Aliment. 1975;29(4):305-12.
[Effects of administering diets with starch or sucrose basis on certain parameters of calcium metabolism in the young, growing rat].
[Article in French]
Artus M.
The important role of many carbohydrates on calcium metabolism has been demonstrated by FOURNIER and DUPUIS. Starch, however, neither influences the absorption nor the retention of calcium. Less is known about the effects of sucrose. In this study the influence of starch on calcium metabolsim has been compared with that of sucrose. Male weanling Wistar rats were divided into three groups according to their diets. The first group received a refined and well-balanced diet (except for the absence of vitamin D), containing 68 p. 100 of starch. The second group received the same diet except sucrose was substituted for the starch. The third group received the same diet as Group 1, with the addition of vitamin D. Plasma calcium citrate and urinary citrate and calcium were determined. At the age of 2 months after one night of fasting, each group of rats was injected intraperitoneally with a 1 ml, aqueous solution containing 1 mg calcium and 0, 6 mu Ci45Ca. Twenty-four hours later the animals were sacrificed and the calcium femur percentage, radioactivity p. 1,000 of the injected dose of 45Ca, and specific radioactivity were determined. When performance data from Group 3 were compared to Group 1 and Group 2, the following results were obtained: —Group 1 (starch diet without vitamin D) had very low plasma calcium levels; urinary calcium, plasma citrate and urinary citrate levels were lowered, and the calcium femur percentage was smaller. Bone avidity for calcium was found. –Group 2 (sucrose diet without vitamin D) had normal plasma calcium levels. Urinary calcium and citrate and plasma citrate did not show significant differences from those of animals receiving vitamin D. No significant differences were found in the specific radioactivity and radioactivity p. 1,000 of the administered dose. Contrary to starch, sucrose maintained calcium homeostasis, and apparently, normal ossification, although the femur was lighter than those of animals receiving vitamin D. Further work is necessary to determine whether the fructose component of the sucrose molecule is responsible for the increased calcium utilization and, if so, what levels of ingestion are necessary for this activity.

Bone. 2008 May;42(5):960-8. Epub 2008 Feb 15.
The effect of feeding different sugar-sweetened beverages to growing female Sprague-Dawley rats on bone mass and strength.
Tsanzi E, Light HR, Tou JC.
Consumption of sugar beverages has increased among adolescents. Additionally, the replacement of sucrose with high fructose corn syrup (HFCS) as the predominant sweetener has resulted in higher fructose intake. Few studies have investigated the effect of drinking different sugar-sweetened beverages on bone, despite suggestions that sugar consumption negatively impacts mineral balance. The objective of this study was to determine the effect of drinking different sugar-sweetened beverages on bone mass and strength. Adolescent (age 35d) female Sprague-Dawley rats were randomly assigned (n=8-9/group) to consume deionized distilled water (ddH2O, control) or ddH2O containing 13% w/v glucose, sucrose, fructose or high fructose corn syrup (HFCS-55) for 8weeks. Tibia and femur measurements included bone morphometry, bone turnover markers, determination of bone mineral density (BMD) and bone mineral content (BMC) by dual energy X-ray absorptiometry (DXA) and bone strength by three-point bending test. The effect of sugar-sweetened beverage consumption on mineral balance, urinary and fecal calcium (Ca) and phosphorus (P) was measured by inductively coupled plasma optical emission spectrometry. The results showed no difference in the bone mass or strength of rats drinking the glucose-sweetened beverage despite their having the lowest food intake, but the highest beverage and caloric consumption. Only in comparisons among the rats provided sugar-sweetened beverage were femur and tibia BMD lower in rats drinking the glucose-sweetened beverage. Differences in bone and mineral measurements appeared most pronounced between rats drinking glucose versus fructose-sweetened beverages. Rats provided the glucose-sweetened beverage had reduced femur and tibia total P, reduced P and Ca intake and increased urinary Ca excretion compared to the rats provided the fructose-sweetened beverage. The results suggested that glucose rather than fructose exerted more deleterious effects on mineral balance and bone.

Am J Clin Nutr. 1989 Jun;49(6):1290-4.
Dietary fructose or starch: effects on copper, zinc, iron, manganese, calcium, and magnesium balances in humans.
Holbrook JT, Smith JC Jr, Reiser S.
A balance study was conducted to assess the effects of consuming low-copper diets, high in fructose or cornstarch. The study involved 19 apparently healthy males, aged 21-57 y. The two experimental diets averaged 0.35 mg Cu/1000 kcal and provided 20% of the calories from fructose or cornstarch. Cu, zinc, calcium, magnesium, and iron balances were determined 1 wk before the study (pretest) when the subjects consumed self-selected diets and after consuming the experimental diets for 6 wk. No major differences in mineral balances were evident between the two groups during the pretest study when the subjects ate self-selected diets. In contrast, when fed the test diets, the group consuming the low-Cu fructose diet had significantly more positive balances for all minerals studied than the group fed the low-Cu cornstarch diet. The results indicate that dietary fructose enhances mineral balance.

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By Team FPS – April 6, 2012