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Protective Bamboo Shoots

Also see:
Ray Peat, PhD on the Benefits of the Raw Carrot
The effect of raw carrot on serum lipids and colon function
Endotoxin: Poisoning from the Inside Out
Endotoxin-lipoprotein Hypothesis
Protection from Endotoxin
Bowel Toxins Accelerate Aging

“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, which suppressing bacterial growth, seems like a convenient approach to increasing longevity.” -Ray Peat, PhD

Comprehensive Reviews in Food Science and Food Safety Volume 10, Issue 3, pages 153–168, May 2011
Nutritional Properties of Bamboo Shoots: Potential and Prospects for Utilization as a Health Food
Nirmala Chongtham, Madho Singh Bisht, Sheena Haorongbam
Bamboo is intricately associated with humans from times immemorial. Popularly known for their industrial uses, a lesser known fact of bamboos is the usage of its young shoots as a food that can be consumed fresh, fermented, or canned. The juvenile shoots are not only delicious but are rich in nutrient components, mainly proteins, carbohydrates, minerals, and fiber and are low in fat and sugars. In addition, they contain phytosterols and a high amount of fiber that can be labeled as nutraceuticals or natural medicines that are attracting the attention of health advocates and scientists alike. The shoots are free from residual toxicity and grow without the application of fertilizers. Modern research has revealed that bamboo shoots have a number of health benefits: improving appetite and digestion, weight loss, and curing cardiovascular diseases and cancer. The shoots are reported to have anticancer, antibacterial, and antiviral activity. Shoots have antioxidant capacity due to the presence of phenolic compounds. The increasing trends of health consciousness among consumers have stimulated the field of functional foods and bamboo shoots can be one of them. Bamboo fiber is now a common ingredient in breakfast cereals, fruit juices, bakery and meat products, sauces, shredded cheeses, cookies, pastas, snacks, frozen desserts, and many other food products. This review emphasizes the health benefits of bamboo shoots and their potential for utilization as a health food.

Nutrition. 2009 Jul-Aug;25(7-8):723-8. Epub 2009 Mar 13.
Effects of bamboo shoot consumption on lipid profiles and bowel function in healthy young women.
Park EJ, Jhon DY.
OBJECTIVE:
This study evaluated the short-term effect of bamboo shoot consumption as a dietary fiber source on blood glucose, lipid profiles, hepatic function, and constipation symptoms in healthy women.
METHODS:
Eight subjects, 21- to 23-y-old women, with normal health status received a dietary fiber-free diet (control), a diet containing 25 g of cellulose, and a diet containing 360 g of bamboo shoots, with each diet segment lasting 6 d. At the end of each diet, blood biochemical parameters, such as glucose, triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and atherogenic index were measured and a questionnaire test for the evaluation of fecal excretion was taken. For statistical analysis, analysis of variance was performed.
RESULTS:
Serum total cholesterol, low-density lipoprotein cholesterol, and the atherogenic index were decreased with the bamboo shoot diet feeding compared with the dietary fiber-free diet. There were no differences in serum glucose levels among the tested diets. Fecal volume and bowel movement frequency in subjects fed the bamboo shoot diet were significantly increased.
CONCLUSION:
Bamboo shoots as a dietary fiber source has beneficial effects on lipid profile and bowel function.

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By Team FPS – April 17, 2012

Calcium to Phosphorus Ratio, PTH, and Bone Health

Also see:
Calcium Paradox
Source of Dietary Calcium: Chicken Egg Shell Powder
Low CO2 in Hypothyroidism
Blood Pressure Management with Calcium & Dairy
Hypertension and Calcium Deficiency
Excess Dietary Phosphorus Lowers Vitamin D Levels
Fatty Acid Synthase (FAS), Vitamin D, and Cancer
Phosphate, activation, and aging
Parmigiano Reggiano cheese and bone health
Dairy, Calcium, and Weight Management in Adults and Children

Picture 3

Quotes by Ray Peat, PhD:
“The ratio of calcium to phosphate is very important; that’s why milk and cheese are so valuable for weight loss, or for preventing weight gain. For people who aren’t very active, low fat milk and cheese are better, because the extra fat calories aren’t needed.”

“The foods highest in phosphate, relative to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added phosphate. Foods with a higher, safe ratio of calcium to phosphate are leaves, such as kale, turnip greens, and beet greens, and many fruits, milk, and cheese.”

“Free unsaturated fatty acids turn on the stress hormones, and cortisol blocks oxidation of sugar and turns it into fatty acids and triglycerides. Keeping cortisol and stress low is the main thing. Keeping a high ratio of calcium to phosphate helps to oppose the stress metabolism.”

“Recent publication are showing that excess phosphate can increase inflammation, tissue atrophy, calcification of blood vessels, cancer, dementia, and, in general, the processes of aging.”

Br J Nutr. 2006 Sep;96(3):545-52.
High phosphorus intakes acutely and negatively affect Ca and bone metabolism in a dose-dependent manner in healthy young females.
Kemi VE, Kärkkäinen MU, Lamberg-Allardt CJ.
Ca and P are both essential nutrients for bone and are known to affect one of the most important regulators of bone metabolism, parathyroid hormone (PTH). Too ample a P intake, typical of Western diets, could be deleterious to bone through the increased PTH secretion. Few controlled dose-response studies are available on the effects of high P intake in man. We studied the short-term effects of four P doses on Ca and bone metabolism in fourteen healthy women, 20-28 years of age, who were randomized to four controlled study days; thus each study subject served as her own control. P supplement doses of 0 (placebo), 250, 750 or 1500 mg were taken, divided into three doses during the study day. The meals served were exactly the same during each study day and provided 495 mg P and 250 mg Ca. The P doses affected the serum PTH (S-PTH) in a dose-dependent manner (P=0.0005). There was a decrease in serum ionized Ca concentration only in the highest P dose (P=0.004). The marker of bone formation, bone-specific alkaline phosphatase, decreased (P=0.05) and the bone resorption marker, N-terminal telopeptide of collagen type I, increased in response to the P doses (P=0.05). This controlled dose-response study showed that P has a dose-dependent effect on S-PTH and increases PTH secretion significantly when Ca intake is low. Acutely high P intake adversely affects bone metabolism by decreasing bone formation and increasing bone resorption, as indicated by the bone metabolism markers.

Br J Nutr. 2008 Apr;99(4):832-9. Epub 2007 Oct 1.
Increased calcium intake does not completely counteract the effects of increased phosphorus intake on bone: an acute dose-response study in healthy females.
Kemi VE, Kärkkäinen MU, Karp HJ, Laitinen KA, Lamberg-Allardt CJ.
A high dietary P intake is suggested to have negative effects on bone through increased parathyroid hormone secretion, as high serum parathyroid hormone (S-PTH) concentration increases bone resorption. In many countries the P intake is 2- to 3-fold above dietary guidelines, whereas Ca intake is too low. This combination may not be optimal for bone health. In a previous controlled study, we found that dietary P dose-dependently increased S-PTH and bone resorption and decreased bone formation. The aim of the present study was to investigate the dose-response effects of Ca intake on Ca and bone metabolism with a dietary P intake higher than recommended. Each of the twelve healthy female subjects aged 21-40 years attended three 24-h study sessions, which were randomized with regard to a Ca dose of 0 (control day), 600 or 1200 mg, and each subject served as her own control. The meals on each study day provided 1850 mg P and 480 mg Ca. S-PTH concentration decreased (P < 0.001) and serum ionized Ca concentration increased (P < 0.001) with increasing Ca doses. The bone formation marker, serum bone-specific alkaline phosphatase, did not differ significantly (P = 0.4). By contrast, the bone resorption marker, urinary N-terminal telopeptide of collagen type I, decreased significantly with both Ca doses (P = 0.008). When P intake was above current recommendations, increased Ca intake was beneficial for bone, as indicated by decreased S-PTH concentration and bone resorption. However, not even a high Ca intake could affect bone formation when P intake was excessive.

Br J Nutr. 2010 Feb;103(4):561-8. Epub 2009 Sep 28.
Low calcium:phosphorus ratio in habitual diets affects serum parathyroid hormone concentration and calcium metabolism in healthy women with adequate calcium intake.
Kemi VE, Kärkkäinen MU, Rita HJ, Laaksonen MM, Outila TA, Lamberg-Allardt CJ.
Excessive dietary P intake alone can be deleterious to bone through increased parathyroid hormone (PTH) secretion, but adverse effects on bone increase when dietary Ca intake is low. In many countries, P intake is abundant, whereas Ca intake fails to meet recommendations; an optimal dietary Ca:P ratio is therefore difficult to achieve. Our objective was to investigate how habitual dietary Ca:P ratio affects serum PTH (S-PTH) concentration and other Ca metabolism markers in a population with generally adequate Ca intake. In this cross-sectional analysis of 147 healthy women aged 31-43 years, fasting blood samples and three separate 24-h urinary samples were collected. Participants kept a 4-d food record and were divided into quartiles according to their dietary Ca:P ratios. The 1st quartile with Ca:P molar ratio < or = 0.50 differed significantly from the 2nd (Ca:P molar ratio 0.51-0.57), 3rd (Ca:P molar ratio 0.58-0.64) and 4th (Ca:P molar ratio > or = 0.65) quartiles by interfering with Ca metabolism. In the 1st quartile, mean S-PTH concentration (P = 0.021) and mean urinary Ca (U-Ca) excretion were higher (P = 0.051) than in all other quartiles. These findings suggest that in habitual diets low Ca:P ratios may interfere with homoeostasis of Ca metabolism and increase bone resorption, as indicated by higher S-PTH and U-Ca levels. Because low habitual dietary Ca:P ratios are common in Western diets, more attention should be focused on decreasing excessively high dietary P intake and increasing Ca intake to the recommended level.

Academic Dissertation by Virpi Kemi
Effects of dietary phosphorus and calcium-to phosphorus ratio on calcium and bone metabolism in healthy 20- to 43-year-old Finnish women
“This thesis contributes novel information related to the effects of dietary phosphorus (P) and the combined effects of P and calcium (Ca) on Ca and bone metabolism in healthy individuals. It is already well established that high P intake is detrimental for patients with impaired renal functioning, but the effects of high P intake in healthy humans have been investigated seldom. In this thesis, an excessively high P intake, which is common in Western countries, was observed to negatively affect Ca and bone metabolism. Moreover, P doses affected Ca and bone metabolism in a dose-dependent manner, and P sources also differed in their effects on the essential regulator of Ca and bone metabolism. Finally, we demonstrated that by increasing dietary Ca intake the negative effects of a high P intake could be reduced. However, based on the findings of the controlled study, even a high dietary Ca intake could not completely overcome all of the negative effects caused by a high dietary P intake.

Specific findings of each study were as follows:

Study I
In a controlled study with healthy young women, the oral intake of P in doses
comparable with normal dietary intakes (495, 745, 1245 and 1995 mg/d) with a low
Ca intake (250 mg/d) increased serum parathyroid hormone (S-PTH) concentration in
a dose-dependent manner. The highest P dose had the most negative effects, as with
the highest dose there was also a decrease in serum ionized Ca (S-iCa) concentration
and bone formation and an increase in bone resorption. Furthermore, a high P intake
(1995 mg/d) inhibited the increase in serum 1,25(OH)2D in response to a low dietary
Ca intake, implying that the normal relationship between Ca intake and Ca absorption
is disturbed in diets high in P and low in Ca. This study showed that P has a dose dependent effect on S-PTH and increases PTH secretion significantly when Ca intake
is low. An acutely high P intake adversely affects bone metabolism by decreasing bone
formation and increasing bone resorption.

Study II
In a controlled study of healthy 20-to 40-year-old women with a dietary P intake that was 3-fold above the dietary guidelines (1850 mg/d), by increasing the Ca intake from 480 mg/d to 1080 mg/d and then to 1680 mg/d, the S-PTH concentration decreased,
the S-iCa concentration increased and bone resorption decreased dose-dependently.
This study showed that a dietary Ca intake above the recommended level offers
several advantages in preventing the negative effects of a high P intake. However, not
even the highest Ca intake (1680 mg/d) could counteract the effect of high dietary P on
bone formation, as indicated by unchanged bone formation activity.

Study III
In a cross-sectional study with healthy 31- to 43-year-old women, a high habitual
dietary P intake was associated with increased S-PTH and decreased S-iCa concentrations. These results are in line with observations in our controlled short-term
study. Furthermore, in the habitual diets, phosphate additives, unlike other P sources,
were associated with higher mean S-PTH concentrations. The association of S-PTH
with natural P was the opposite of that with foods containing phosphate additives.
Thus, these results suggest that P sources might differ in their effects on the central
regulator of Ca and bone metabolism, parathyroid hormone.

Study IV
In a cross-sectional study of healthy 31- to 43-year-old women with an adequate Ca
intake, low habitual dietary Ca:P ratios (Ca:P molar ratio 0.50) were associated with
both higher S-PTH and U-Ca levels. Interestingly, the lowest Ca:P quartile with a Ca:P
molar ratio 0.50 differed from all other quartiles by having the most deleterious
associations with Ca metabolism. These results imply that a cut-off Ca:P ratio may
exist that is lower than the suggested Ca:P molar ratio of 1, below which the effects on
mineral metabolism and bone health are more severe. None of the study subjects
achieved the suggested dietary Ca:P molar ratio of 1.

A question arising from the findings of this thesis is how to reduce the current excessively high dietary P intake. The answer to this is not straightforward, as the current P intakes are not well known since the use of phosphate additives has not been taken into consideration when establishing food composition databases. In the future, food composition databases should be updated and the actual P contents of foodstuffs determined by laboratory analyses. In addition, it is impossible for an individual to know how much P foods contain because P is not included in the compulsory food ingredient list. While waiting for these issues to be addressed, one can reduce dietary P intake by restricting the consumption of highly processed foods and increasing the consumption of raw or unprocessed foods.

As there are still many open questions concerning the effects of high P intake on bone health, we will continue to investigate whether dietary P intakes and different P sources affect bone mass and structure in adult Finns. However, nowadays, when considering public health, it is not only osteoporosis but also other public health diseases in which a high P intake may play an important role in a negative sense. An alarming rise has been seen among Western populations in the incidence of type 2 diabetes, a major cause of end stage renal disease, in which dietary P restriction is a part of the treatment. Among patients with end-stage renal disease and diabetes, vascular calcification correlates highly with cardiovascular disease mortality. Recent results suggest that an excessive P intake may be involved in this vascular calcification process, even in healthy humans. Therefore, in the near future, our studies will expand to investigate the relationship between dietary P and vascular calcification in Finnish adults.” (pp. 85, 86)

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By Team FPS – April 17, 2012

Source of Dietary Calcium: Chicken Egg Shell Powder

Also see:
Calcium Paradox
Hypertension and Calcium Deficiency
Blood Pressure Management with Calcium & Dairy
Calcium to Phosphorus Ratio, PTH, and Bone Health
Low CO2 in Hypothyroidism
Fatty Acid Synthase (FAS), Vitamin D, and Cancer
Parmigiano Reggiano cheese and bone health
Phosphate, activation, and aging

Poult Sci. 2000 Dec;79(12):1833-8.
Mineral, amino acid, and hormonal composition of chicken eggshell powder and the evaluation of its use in human nutrition.
Schaafsma A, Pakan I, Hofstede GJ, Muskiet FA, Van Der Veer E, De Vries PJ.
Chicken eggshell powder (ESP) might be an attractive source of Ca for human nutrition. To study its nutritional value, we analyzed minerals, amino acids, and hormones in commercially available Slovakian ESP. The mineral composition was compared with three Dutch ESP samples that differed in feed and housing, a Japanese ESP, refined CaCO3, and an oyster shell supplement. Chicken eggshell powder contains high levels of Ca (mean +/- SD/g EPS: 401+/-7.2 mg) and Sr (372+/-161 microg) when compared with recommended or estimated daily intakes for humans 51 to 70 yr of age. Levels of potentially toxic Pb, Al, Cd, and Hg were very low as were levels of V, B, Fe, Zn, P, Mg, N, F, Se, Cu, and Cr. Large differences in the levels of F, Se, Cu, Cr, and Sr in the Dutch and Slovakian ESP indicated a strong influence of feed and environment. The small protein fraction of ESP contains high levels of Gly and Arg. Furthermore, small amounts of transforming growth factor-beta1 (0.75 to 7.28 ng/g ESP), calcitonin (10 to 25 ng/g ESP), and progesterone (0.30 to 0.33 ng/g ESP) were detected. Estradiol-17beta and calcitriol were below the detection limit of the methods used. Compared with ESP, refined CaCO3 was found to contain increased levels of Cd, and the oyster shell supplement showed increased levels of Al and Cd. Therefore, ESP seems to have a beneficial composition with about 39% of elemental Ca, relevant amounts of Sr, and low levels of Al, Pb, Cd and Hg. It may be used as a Ca source in human nutrition.

Br J Nutr. 2002 Mar;87(3):267-75.
Positive effects of a chicken eggshell powder-enriched vitamin-mineral supplement on femoral neck bone mineral density in healthy late post-menopausal Dutch women.
Schaafsma A, van Doormaal JJ, Muskiet FA, Hofstede GJ, Pakan I, van der Veer E.
Although bone metabolism is largely under genetic control, the role of nutrition is considerable. The present study evaluates the effects of chicken eggshell powder, a new source of dietary Ca, and purified CaCO3 on bone mineral density (BMD) of the lumbar spine and hip. Besides BMD we also looked at biochemical markers of bone and Ca metabolism. Both Ca sources were provided in combination with minerals and vitamins including Mg, cholecalciferol and phylloquinone. We designed a randomised, double-blind, placebo-controlled study to take place over 12 months. Healthy Caucasian women (n 85), selected by age (> or =50 and <70 years), from the databases of general practitioners were recruited by telephone calls. They had to be at least 5 years post-menopausal, with lumbar spine T-score being > – 2.5. At baseline, their mean habitual daily Ca intake was adequate. The women were randomly allocated to: eggshell powder-enriched (group A; n 24), purified CaCO3-enriched (group B; n 22), or a placebo product (group C; n 27). BMD was measured at baseline and then after 6 and 12 months of supplementation as were the biochemical markers bone-specific alkaline phosphatase, amino-terminal propeptide extension of type I collagen, deoxypyridinoline, calcitonin, intact parathyroid hormone, calcidiol, and urinary Ca. After 12 months of supplementation, only mean BMD of the femoral neck in group A was significantly increased (P=0.014) by 1.75% (95% CI 0.18, 3.32) compared with a decrease of -0.60% (95% CI -1.92, 0.72) in group C. This increase coincided with significant decreases in markers of bone resorption and formation. No significant changes were seen in BMD at other sites, including lumbar spine, nor in groups B and C. No differences were found between groups A and B, or B and C. The present study indicates that healthy late post-menopausal women with an adequate Ca intake at baseline may increase BMD of the hip within 12 months following supplementation with the chicken eggshell powder-enriched supplement.

Clin Calcium. 2005 Jan;15(1):95-100.
[Hen’s eggshell calcium].
[Article in Japanese]
Masuda Y.
In Japan, insufficient calcium (Ca) intake is serious problem for health which may be associated with the high prevalence of osteoporosis among the aged. The intake of most nutrients has been sufficient, however, the Ca intake has never been sufficient. Eggshell Ca has as much as 38% of Ca and low phosphorus content. Eggshell Ca was more soluble than Ca carbonate and was as much as milk products. Eggshell Ca has been shown to exhibit higher absorptivity and availability than Ca carbonate. Furthermore, it has been reported that eggshell Ca is more effective in increasing bone mineral density in ovariectomized osteoporotic rats. These results suggest that eggshell Ca could be beneficial for bone and we propose Ca fortified foods which contain eggshell Ca as a nutraceutical.

Int J Clin Pharmacol Res. 2003;23(2-3):83-92.
Eggshell calcium in the prevention and treatment of osteoporosis.
Rovenský J, Stancíková M, Masaryk P, Svík K, Istok R.
In this paper the most significant biological and clinical aspects of a biopreparation made of chicken eggshells are reviewed. Eggshell powder is a natural source of calcium and other elements (e.g. strontium and fluorine) which may have a positive effect on bone metabolism. Experimental and clinical studies performed to date have shown a number of positive properties of eggshell powder, such as antirachitic effects in rats and humans. A positive effect was observed on bone density in animal models of postmenopausal osteoporosis in ovariectomized female rats. In vitro eggshell powder stimulates chondrocyte differentiation and cartilage growth. Clinical studies in postmenopausal women and women with senile osteoporosis showed that eggshell powder reduces pain and osteoresorption and increases mobility and bone density or arrests its loss. The bioavailability of calcium from this source, as tested in piglets, was similar or better than that of food grade purified calcium carbonate. Clinical and experimental studies showed that eggshell powder has positive effects on bone and cartilage and that it is suitable in the prevention and treatment of osteoporosis.

Bratisl Lek Listy. 1999 Dec;100(12):651-6.
Short-term effects of a chicken egg shell powder enriched dairy-based products on bone mineral density in persons with osteoporosis or osteopenia.
Schaafsma A, Pakan I.
Based on the high calcium content, chicken egg shells are an interesting source of calcium. We studied the short-term effects on bone mineral density (BMD) of the lumbar spine and hip in 9 women and one man (mean age +/- SD, 63.9 +/- 8.1 years) with osteoporosis or osteopenia. Also the effects on pain and general well-being were monitored. Ten women (62.5 +/- 5.0 years) from a population study on BMD served as a control group. During a study period of 4-8 months, the intervention group consumed twice daily a dairy-based supplement which resulted in a daily intake of, among others, 3.0 g of egg shell powder, 400 IU of vitamin D3 and 400 mg of magnesium. BMD of the lumbar spine (anteroposterior (AP) and lateral (LA) position) and hip were measured by dual-energy X-ray absorptiometry. After the intervention period, BMDs of the lumbar spine, total proximal femur and trochanter were significantly (p < 0.05) increased with (median) 4.4%: (range) 1.7 to 10.4% (lumbar spine AP), 5.7%: -1.3 to 15.9% (lumbar spine LA), 2.2%: -1.9 to 9.4% (total proximal femur), 1.8%: -1.8 to 9.0% (trochanter). Within a period of 4 months, an important reduction in pain was reported and as a consequence an improvement in general well-being. In the control group, BMDs of the lumbar spine AP and of the femoral neck significantly decreased over a period of 8 months with -0.7% (-1.3 to 0.2%) and -0.9% (-2.4 to -0.1%) respectively. Six women of the intervention group continued to use the supplement on their own free will and without any check on compliance, up to 24 months. They consumed the supplement only once daily except for the last three months when they were asked to take the double dosage again. After 24 months BMDs did not differ from baseline. This study shows that egg shell powder is a source of bioavailable calcium. Furthermore, this pilot study indicates that the chicken egg shell powder enriched dairy-based supplement increases BMD of subjects with a low bone mass in the short term and as a consequence delays bone demineralisation for a longer period.

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By Team FPS – April 15, 2012

Bone Health and Vitamin K

Also see:
Intestinal Serotonin and Bone Loss
Carbohydrates and Bone Health
Parmigiano Reggiano cheese and bone health
Calcium Paradox

J Med Assoc Thai. 2009 Sep;92 Suppl5:S1-3.
The role of vitamin K2 on osteoblastic functions by using stem cell model.
Bunyaratavej N, Sila-Asna M, Bunyaratavej A.
Vitamin K2 (MK4) functions were investigated by using the induced skin cell into osteoblast compared with the control media.The real time PCR measured gene expression in both cultures at the fourth, seventh, fourteenth, twenty first, twenty eighth, thirty fifth and forty second days of culture. The gene expressions of osteocalcin, osteonectin, osteopontin, bone sialoprotein, CBFA1, Interleukin-6, Estrogen receptors and collagen type) were monitored by real time PCR. MK4 had strong power to stimulate gene expression of osteocalcin and osteonectin after one week of culture but MK4 showed weak action on gene of osteopontin, bone sialoprotein and interleukin-6. The gene of estrogens showed the marked expression of estrogen receptor beta at the fourteenth day of culture while estrogen receptor alpha did not respond. MK4 could stimulate genes of RANKL and collagen type 1. This study supported the action of vitamin K2 for enhancing the bone matrix.

Nutrition. 2001 Oct;17(10):880-7.
Vitamin K and bone health.
Weber P.
In the past decade it has become evident that vitamin K has a significant role to play in human health that is beyond its well-established function in blood clotting. There is a consistent line of evidence in human epidemiologic and intervention studies that clearly demonstrates that vitamin K can improve bone health. The human intervention studies have demonstrated that vitamin K can not only increase bone mineral density in osteoporotic people but also actually reduce fracture rates. Further, there is evidence in human intervention studies that vitamins K and D, a classic in bone metabolism, works synergistically on bone density. Most of these studies employed vitamin K(2) at rather high doses, a fact that has been criticized as a shortcoming of these studies. However, there is emerging evidence in human intervention studies that vitamin K(1) at a much lower dose may also benefit bone health, in particular when coadministered with vitamin D. Several mechanisms are suggested by which vitamin K can modulate bone metabolism. Besides the gamma-carboxylation of osteocalcin, a protein believed to be involved in bone mineralization, there is increasing evidence that vitamin K also positively affects calcium balance, a key mineral in bone metabolism. The Institute of Medicine recently has increased the dietary reference intakes of vitamin K to 90 microg/d for females and 120 microg/d for males, which is an increase of approximately 50% from previous recommendations.

Clin Calcium. 2007 Nov;17(11):1752-60.
[Experience of vitamin K2 in Thailand].
[Article in Japanese]
Bunyaratavej N.
Vitamin K(2) has dual actions, stimulates osteoblastic functions, for synthesis of osteocalcin, osteonectin and other matrix bone proteins, in addition, new finding, in stem cell culture found osteoblast producing gene expression of collagen type 1, the other action, vitamin K(2) contains mild antiresorpion by inducing the osteoclastic apoptosis. Our study found that postmenopausal and elderly women have high risk of vitamin K(2) deficiency, comparing to the normal value of young, reproductive females. The efficacy of vitamin K(2) will be fulfill benefit after 6 months of administration, prolong use will enhance of bone quality that prevent fracture.

Clin Calcium. 2008 Oct;18(10):1476-82.
[Vitamin K2].
[Article in Japanese]
Ishida Y.
Vitamin K2 has been approved for the treatment of osteoporosis in Japan since 1995. Vitamin K2 treatment in osteoporosis has been shown to inhibit the occurrence of new bone fractures and to maintain BMD. The uniqueness of the prevention of bone fractures by vitamin K2 is that there has been no direct evidence of the relationship between increase of BMD and a decrease in the occurrence of bone fractures. A recent systematic review of seven Japanese randomized controlled trials by Cockayne has also shown that supplementation with phytonadione (Vitamin K1) and menaquinone (Vitamin K2) , particularly menaquinone-4, is associated with increased BMD and reduced fracture incidence. To confirm these results, a larger well design RCT using fractures as the primary endpoint is clearly needed.

Am J Clin Nutr January 1999 vol. 69 no. 1 74-79
Vitamin K intake and hip fractures in women: a prospective study
Diane Feskanich, Peter Weber, Walter C Willett, Helaine Rockett, Sarah L Booth and Graham A Colditz
Background: Vitamin K mediates the γ-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. However, data are limited on the effects of dietary vitamin K.
Objective: We investigated the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women.
Design: We conducted a prospective analysis within the Nurses’ Health Study cohort. Diet was assessed in 72327 women aged 38–63 y with a food-frequency questionnaire in 1984 (baseline). During the subsequent 10 y of follow-up, 270 hip fractures resulting from low or moderate trauma were reported.
Results: Women in quintiles 2–5 of vitamin K intake had a significantly lower age-adjusted relative risk (RR: 0.70; 95% CI: 0.53, 0.93) of hip fracture than women in the lowest quintile (<109 µg/d). Risk did not decrease between quintiles 2 and 5 and risk estimates were not altered when other risk factors for osteoporosis, including calcium and vitamin D intakes, were added to the models. Risk of hip fracture was also inversely associated with lettuce consumption (RR: 0.55; 95% CI: 0.40, 0.78) for one or more servings per day compared with one or fewer servings per week), the food that contributed the most to dietary vitamin K intakes.
Conclusions: Low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a reassessment of the vitamin K requirements that are based on bone health and blood coagulation.

Clin Calcium. 2005 Apr;15(4):605-10.
[Vitamin K2 as a protector of bone health and beyond].
[Article in Japanese]
Kaneki M.
Several lives of evidence indicate a protective effect of vitamin K against osteoporosis. Epidemiological studies showed that low vitamin K intake is associated with the increased risk of osteoporosis. Vitamin K2 (menatetrenone, MK-4) has been clinically used in the treatment of patients with osteoporosis in Japan, Korea and Thailand. Previous studies demonstrated the efficacy of vitamin K2 (45 mg/day) to prevent bone loss and reduce the rate of vertebral fractures, although a large, randomized intervention study is anticipated to provide more detailed evidence. Recently, vitamin K2 has been shown to reduce the progression of hepatocarcinoma. Moreover, it has been proposed that vitamin K may also have beneficial effects to prevent atherogenesis. The clarification of molecular mechanisms by which vitamin K2 exerts these salutary effects deserve further investigations.

Int J Gynaecol Obstet. 1997 Jan;56(1):25-30.
Serum vitamin K level and bone mineral density in post-menopausal women.
Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F.
OBJECTIVE:
Vitamin K is known to influence bone metabolism by facilitating the synthesis of osteocalcin (BGP). The bone mineral density decreases drastically after menopause. We investigated the relationship of bone mineral density, vitamin K levels and other biological parameters of bone metabolism in post-menopausal women.
METHODS:
Serum levels of vitamin K, BGP and other markers of bone metabolism were measured in 71 post-menopausal women (19 with reduced bone mineral density and 52 with normal bone density), and 24 women with climacteric symptoms receiving hormone replacement therapy (HRT), (6 with reduced bone mineral density and 18 with normal density).
RESULTS:
In the first group, women with reduced bone mineral density showed lower levels of vitamin K1 and K2 than those with normal bone mineral density. In the other group, the level of BGP decreased but levels of vitamin K showed no increase during HRT.
CONCLUSION:
The present findings suggested that vitamin K was related to post-menopausal bone mineral loss.

Annu Rev Nutr. 1995;15:1-22.
Role of vitamin K in bone metabolism.
Vermeer C, Jie KS, Knapen MH.
Vitamin K is a cofactor required for the formation of gamma-carboxyglutamate (Gla) residues in proteins. Osteoblasts produce at least three different Gla-containing proteins: osteocalcin, matrix Gla-protein, and protein S. After cellular secretion of these proteins, the main part of each remains bound to the hydroxyapatite matrix in bone, but their function remains unclear. Part of the newly synthesized osteocalcin is also set free into the bloodstream, where it may be used as a diagnostic marker for bone formation. Several studies have demonstrated that a poor vitamin K status is associated with an increased risk of osteoporotic bone fractures. Whether vitamin K supplementation will reduce the rate of bone loss in postmenopausal women remains a matter of debate.

J Gravit Physiol. 1998 Oct;5(2):65-9.
Bone markers during a 6-month space flight: effects of vitamin K supplementation.
Vermeer C, Wolf J, Craciun AM, Knapen MH.
Rapid bone loss is a serious health problem for astronauts during long lasting missions in space. We have recorded the changes of biochemical markers for bone metabolism in one of the astronauts during the 6-month space flight of the EUROMIR-95 mission. Immediately after launch both bone resorption markers and urinary calcium excretion increased about two fold, whereas bone formation markers remained unchanged. After 12 1/2 weeks the astronaut received vitamin K1 (10 mg/day for 6 weeks). Vitamin K is known to be involved in the formation of gamma-carboxyglutamate (Gla) in proteins, such as the calcium-binding bone Gla-proteins osteocalcin and matrix Gla-protein. Concomitant with the start of vitamin K treatment, the calcium-binding capacity of osteocalcin increased, and so did the urinary excretion of free Gla. This is suggestive for a subclinical vitamin K-deficiency in the astronaut before vitamin K-supplementation. During periods of high vitamin K status markers for bone formation (osteocalcin and bone alkaline phosphatase) had increased as compared to the first part of the flight. The mean increases were 14 and 23%, respectively. Our data suggest that increased intake of vitamin K may contribute to counteracting microgravity-induced loss of bone mass during long lasting space missions, but need confirmation in more astronauts.

Am J Clin Nutr. 2000 May;71(5):1201-8.
Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women.
Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW, Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP.
BACKGROUND:
Vitamin K has been associated with bone mineral density (BMD) and risk of hip fracture. The apolipoprotein (apo) E4 allele (APOE*E4) has been associated with bone fracture through a putative effect on vitamin K transport in blood.
OBJECTIVE:
The objective was to determine the associations between vitamin K intake, apo E genotype, BMD, and hip fracture in a population-based cohort of elderly men and women.
DESIGN:
Dietary vitamin K intake was assessed with a food-frequency questionnaire in 335 men and 553 women (average age: 75.2 y) participating in the Framingham Heart Study in 1988-1989. Incidence of hip fractures was recorded from 1988 to 1995. BMD at the hip, spine, and arm was assessed on 2 separate occasions (1988-1989 and 1992-1993). Comparisons between apo E genotype and BMD were made relative to E4 allele status (at least 1 epsilon4 allele compared with no epsilon4 allele).
RESULTS:
Individuals in the highest quartile of vitamin K intake (median: 254 microg/d) had a significantly lower fully adjusted relative risk (0.35; 95% CI: 0. 13, 0.94) of hip fracture than did those in the lowest quartile of intake (median: 56 microg/d). There were no associations between vitamin K intake and BMD in either men or women. No association was found between the E4 allele and BMD, and there were no significant interactions between the E4 allele and phylloquinone intake and BMD or hip fracture.
CONCLUSIONS:
Low vitamin K intakes were associated with an increased incidence of hip fractures in this cohort of elderly men and women. Neither low vitamin K intake nor E4 allele status was associated with low BMD.

Am J Clin Nutr. 2003 Feb;77(2):512-6.
Vitamin K intake and bone mineral density in women and men.
Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, Dawson-Hughes B, Wilson PW, Cupples LA, Kiel DP.
BACKGROUND:
Low dietary vitamin K intake has been associated with an increased risk of hip fracture in men and women. Few data exist on the association between dietary vitamin K intake and bone mineral density (BMD).
OBJECTIVE:
We studied cross-sectional associations between self-reported dietary vitamin K intake and BMD of the hip and spine in men and women aged 29-86 y.
DESIGN:
BMD was measured at the hip and spine in 1112 men and 1479 women (macro x +/- SD age: 59 +/- 9 y) who participated in the Framingham Heart Study (1996-2000). Dietary and supplemental intakes of vitamin K were assessed with the use of a food-frequency questionnaire. Additional covariates included age, body mass index, smoking status, alcohol use, physical activity score, and menopause status and current estrogen use among the women.
RESULTS:
Women in the lowest quartile of vitamin K intake (macro x: 70.2 microg/d) had significantly (P < or = 0.005) lower mean (+/- SEM) BMD at the femoral neck (0.854 +/- 0.006 g/cm(2)) and spine (1.140 +/- 0.010 g/cm(2)) than did those in the highest quartile of vitamin K intake (macro x: 309 microg/d): 0.888 +/- 0.006 and 1.190 +/- 0.010 g/cm(2), respectively. These associations remained after potential confounders were controlled for and after stratification by age or supplement use. No significant association was found between dietary vitamin K intake and BMD in men.
CONCLUSIONS:
Low dietary vitamin K intake was associated with low BMD in women, consistent with previous reports that low dietary vitamin K intake is associated with an increased risk of hip fracture. In contrast, there was no association between dietary vitamin K intake and BMD in men.

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By Team FPS – April 15, 2012

Parmigiano Reggiano cheese and bone health

Also see:
Intestinal Serotonin and Bone Loss
Carbohydrates and Bone Health
Bone Health and Vitamin K
Calcium Paradox
Nutritional Values – Parmigiano Reggiano

Clin Cases Miner Bone Metab. 2011 Sep;8(3):33-6.
Parmigiano Reggiano cheese and bone health.
Pampaloni B, Bartolini E, Brandi ML.
Osteoporosis is a multifactorial disease characterized by loss of bone mass and microarchitectural deterioration of bone tissue, which leads to a consequent increase in the risk of skeletal fractures. Diet awakes a critical interest in osteoporosis, because it is one of the few determinants that can be safely modified. A healthy well balanced nutrition can play an important role in prevention and pathogenesis of osteoporosis, but also in support of a pharmacological therapy. Numerous evidences have already established that dietary calcium, proteins and vitamin D are essential nutrients for achieved peak bone mass and maintaining skeletal health. Dairy products, by providing both calcium and proteins, represent the optimal source of highly bioavailable nutrients for bone health. Among dairy foods in particular cheese results one of the major source of calcium in the adults western diet and also in the Italian adults diet. Parmigiano Reggiano cheese is an homemade Italian food whose denomination “Protected Designation of Origin” is linked to an artisanal manufacturing process in limited geographic area of Northern Italy and is an optimal source of essential nutrients for acquisition and maintenance of bone health. Parmigiano Reggiano is a cheese easy digested, for the presence of ready to use proteins and lipids, lactose free, rich in calcium, with possible prebiotic and probiotic effect. On the basis of its nutritional characteristics and of its easy digestibility Parmigiano Reggiano cheese is recommended in all feeding age groups.

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By Team FPS – April 12, 2012

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