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<strong><span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: large"
><span style="font-style: normal">Phosphate, activation, and aging</span></span></span
></span></strong>
</h2>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Recent publications are showing that excess phosphate can increase inflammation, tissue atrophy,
calcification of blood vessels, cancer, dementia, and, in general, the processes of aging. This
is especially important, because of the increasing use of phosphates as food additives.</span
></span></span>
</blockquote>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Previously, the complications of chronic kidney disease, with increased serum phosphate,
were considered to be specific for that condition, but the discovery of a
phosphate-regulating gene named klotho (after one of the Fates in Greek mythology) has
caused a lot of rethinking of the biological role of phosphate. In the 19th century,
phosphorus was commonly called brain food, and since about 1970, its involvement in cell
regulation has become a focus of reductionist thinking. ATP, adenosine triphosphate, is
seen as the energy source that drives cell movement as well as the "pumps" that maintain
the living state, and as the source of the cyclic AMP that is a general activator of
cells, and as the donor of the phosphate group that activates a great number of proteins
in the "phosphorylation cascade." When tissues calcified in the process of aging,
calcium was blamed (ignoring the existence of calcium phosphate crystals in the
tissues), and low calcium diets were recommended. Recently, when calcium supplements
haven't produced the intended effects, calcium was blamed, disregarding the other
materials present in the supplements, such as citrate, phosphate, orotate, aspartate,
and lactate.</span></span></span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>I have a different perspective on the "phosphorylation cascade," and on the other functions of
phosphate in cells, based largely on my view of the role of water in cell physiology. In the
popular view, a stimulus causes a change of shape in a receptor protein, causing it to become an
active enzyme, catalyzing the transfer of a phosphate group from ATP to another protein, causing
it to change shape and become activated, and to transfer phosphate groups to other molecules, or
to remove phosphates from active enzymes, in chain reactions. This is standard biochemistry,
that can be done in a test tube.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Starting around 1970, when the involvement of phosphorylation in the activation of enzymes in
glycogen breakdown was already well known, people began noticing that the glycogen phosphorylase
enzyme became active immediately when the muscle cell contracted, and that phosphorylation
followed the activation. Phosphorylation was involved in activation of the enzyme, but if
something else first activated the enzyme (by changing its shape), the addition of the phosphate
group couldn't be considered as causal, in the usual reductionist sense. It was one participant
in a complex causal process. I saw this as a possible example of the effect of changing water
structure on protein structure and function. This view of water questions the relevance of test
tube biochemistry.</span></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Enzymes are known which suddenly become inactive when the temperature is lowered beyond a certain
point. This is because soluble proteins arrange their shape so that their hydrophobic regions,
the parts with fat-like side-chains on the amino acids, are inside, with the parts of the chain
with water-soluble amino acids arranged to be on the outside, in contact with the water. The
"wetness" of water, its activity that tends to exclude the oily parts of the protein molecule,
decreases as the temperature decreases, and some proteins are destabilized when the relatively
hydrophobic group is no longer repelled by the surrounding cooler water. </span></span
></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>In the living cell, the water is all within a very short distance of a surface of fats or
fat-like proteins. In a series of experiments, starting in the 1960s, Walter
Drost-Hansen showed that, regardless of the nature of the material, the water near a
surface is structurally modified, becoming less dense, more voluminous. This water is
more "lipophilic," adapting itself to the presence of fatty material, as if it were
colder. This change in the water's properties also affects the solubility of ions,
increasing the solubility of potassium, decreasing that of sodium, magnesium, and
calcium (Wiggins, 1973).</span></span></span></span></span>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>When a muscle contracts, its volume momentarily decreases (Abbott and Baskin, 1962). Under
extremely high pressure, muscles contract. In both situations, the work-producing
process of contraction is associated with a slight reduction in volume. During
contraction of a muscle or nerve, heat is given off, causing the temperature to rise.
During relaxation, recovering from excitation, heat is absorbed (Curtin and Woledge,
1974; Westphal, et al., 1999; Constable, et al. 1997). In the case of a nerve, following
the heating produced by excitation, the temperature of the nerve decreases below the
starting temperature (Abbot, et al., 1965). Stretching a muscle causes energy to be
absorbed (Constable, et al., 1997). Energy changes such as these, without associated
chemical changes, have led some investigators to conclude that muscle tension generation
is "entropy driven" (Davis and Rodgers, 1995). </span></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Kelvin's description (1858) of the physics of water in a soap bubble, "…if a film such as a
soap-bubble be enlarged . . . it experiences a cooling effect . . . ," describes the
behavior of nerves and muscles, absorbing energy or heat when they are relaxing (or
elongating), releasing it when they are excited/contracting. </span></span></span
></span></span>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Several groups of experimenters over the last 60 years have tried to discover what happens
to the missing heat; some have suggested electrical or osmotic storage, and some have
demonstrated that stretching generates ATP, arguing for chemical storage. Physical
storage in the form of structural changes in the water-protein-lipid system, interacting
with chemical changes such as ATP synthesis, have hardly been investigated.</span></span
></span></span></span>
</blockquote>
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<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Early studies of muscle chemistry and contraction found that adding ATP to a viscous
solution of proteins extracted from muscle reduced its viscosity, and also that the loss
of ATP from muscle caused its hardening, as in rigor mortis; if the pH wasn't too
acidic, the dead muscle would contract as the ATP content decreased. Szent-Gyorgyi found
that a muscle hardened by rigor mortis became soft again when ATP was added. </span
></span></span></span></span>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Rigor mortis is an extreme state of fatigue, or energy depletion. Early muscle studies
described the phenomenon of "fatigue contracture," in which the muscle, when it reaches
the point at which it stops responding to stimulation, is maximally contracted (this has
also been called delayed relaxation). Ischemic contracture, in the absence of blood
circulation, occurs when the muscle's glycogen is depleted, so that ATP can no longer be
produced anaerobically (Kingsley, et al., 1991). The delayed relaxation of hypothyroid
muscle is another situation in which it is clear that ATP is required for relaxation.
(In the Achilles tendon reflex test, the relaxation rate is visibly slowed in
hypothyroidism.) A delayed T wave in the electrocardiogram, and the diastolic
contracture of the failing heart show the same process of delayed relaxation.
Supplementing the active thyroid hormone, T3, can quickly restore the normal rate of
relaxation, and its beneficial effects have been demonstrated in heart failure
(Pingitore, et al., 2008; Wang, et al., 2006; Pantos, et al., 2007; Galli, et al.,
2008).</span></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>A large part of the magnesium in cells is bound to ATP, and the magnesium-ATP complex is a
factor in muscle relaxation. A deficiency of either ATP or magnesium contributes to
muscle cramping. When a cell is stimulated, causing ATP to release inorganic phosphate,
it also releases magnesium. Above the pH of 6.7, phosphate is doubly ionized, in which
state it has the same kind of structural effect on water that magnesium, calcium, and
sodium have, causing water molecules to be powerfully attracted to the concentrated
electrical charge of the ion. Increasing the free phosphate and magnesium opposes the
effect of the surfaces of fats and proteins on the water structure, and tends to
decrease the solubility of potassium in the water, and to increase the water's
"lipophobic" tendency to minimize its contacts with fats and the fat-like surface of
proteins, causing the proteins to rearrange themselves. </span></span></span></span
></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>These observations relating to the interactions of water, solutes and proteins in muscles
and nerves provide a coherent context for understanding contraction and conduction,
which is lacking in the familiar descriptions based on membranes, pumps, and
cross-bridges, but I think they also provide a uniquely useful context for understanding
the possible dangers of an excess of free phosphate in the body.</span></span></span
></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>A few people (M. Thomson, J. Gunawardena, A.K. Manrai) are showing that principles of
mass-action help to simplify understanding the networks of phosphorylation and
dephosphorylation that are involved in cell control. But independently from the
phosphorylation of proteins, the presence of phosphate ion in cell water modifies the
cell's ion selectivity, shifting the balance toward increased uptake of sodium and
calcium, decreasing potassium, tending to depolarize and "activate" the cell.</span
></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>About 99% of the publications discussing the mechanism of muscle contraction fail to
mention the presence of water, and there's a similar neglect of water in discussions of
the energy producing processes in the mitochondrion. The failure of mitochondrial energy
production leads to lipid peroxidation, activation of inflammatory processes, and can
cause disintegration of the energy producing structure. Increased phosphate decreases
mitochondrial energy production (Duan and Karmazyn, 1989), causes lipid peroxidation
(Kowaltowski, et al., 1996), and activates inflammation, increasing the processes of
tissue atrophy, fibrosis, and cancer.</span></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>For about twenty years it has been clear that the metabolic problems that cause calcium to
be lost from bones cause calcium to increase in the soft tissues, such as blood vessels.
The role of phosphate in forming calcium phosphate crystals had until recently been
assumed to be passive, but some specific "mechanistic" effects have been identified. For
example, increased phosphate increases the inflammatory cytokine, osteopontin
(Fatherazi, et al., 2009), which in bone is known to activate the process of
decalcification, and in arteries is involved in calcification processes (Tousoulis, et
al., 2012). In the kidneys, phosphate promotes calcification (Bois and Selye, 1956), and
osteopontin, by its activation of inflammatory T-cells, is involved in the development
of glomerulonephritis, as well as in inflammatory skin reactions (Yu, et al., 1998).
High dietary phosphate increases serum osteopontin, as well as serum phosphate and
parathyroid hormone, and increases the formation of tumors in skin (Camalier, et al.,
2010). Besides the activation of cells and cell systems, phosphate (like other
ions with a high ratio of charge to size, including citrate) can activate viruses
(Yamanaka, et al., 1995; Gouvea, et al., 2006). Aromatase, the enzyme that synthesizes
estrogen, is an enzyme that's sensitive to the concentration of phosphate (Bellino and
Holben, 1989).</span></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>More generally, increased dietary phosphate increases the activity of an important
regulatory enzyme, protein kinase B, which promotes organ growth. A high phosphate diet
increases the growth of liver (Xu, et al., 2008) and lung (Jin, et al., 2007), and
promotes the growth of lung cancer (Jin, et al., 2009). An extreme reduction of
phosphate in the diet wouldn't be appropriate, however, because a phosphate deficiency
stimulates cells to increase the phosphate transporter, increasing the cellular uptake
of phosphate, with an effect similar to the dietary excess of phosphate, i.e., promotion
of lung cancer (Xu, et al., 2010). The optimum dietary amount of phosphate, and its
balance with other minerals, hasn't been determined.</span></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>While increased phosphate slows mitochondrial energy production, decreasing its
intracellular concentration increases the respiratory rate and the efficiency of ATP
formation. A "deficiency" of polyunsaturated fatty acids has this effect (Nogueira, et
al., 2001), but so does the consumption of fructose (Green, et al., 1993; Lu, et al.,
1994).</span></span></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>In a 1938 experiment (Brown, et al.) that intended to show the essentiality of unsaturated fats, a
man, William Brown, lived for six months on a 2500 calorie diet consisting of sucrose syrup, a
gallon of milk (some of it in the form of cottage cheese), and the juice of half an orange,
besides some vitamins and minerals. The experimenters remarked about the surprising
disappearance of the normal fatigue after a day's work, as well as the normalization of his high
blood pressure and high cholesterol, and the permanent disappearance of his frequent life-long
migraine headaches. His respiratory quotient increased (producing more carbon dioxide), as well
as his rate of resting metabolism. I think the most interesting part of the experiment was that
his blood phosphate decreased. In two measurements during the experimental diet, his fasting
plasma inorganic phosphorus was 3.43 and 2.64 mg. per 100 ml. of plasma, and six month after he
had returned to a normal diet the number was 4.2 mg/100 ml. Both the deficiency of the
"essential" unsaturated fatty acids, and the high sucrose intake probably contributed to
lowering the phosphate.</span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>In 2000, researchers who were convinced that fructose is harmful to the health, reasoned
that its harmful effects would be exacerbated by consuming it in combination with a diet
deficient in magnesium. Eleven men consumed, for six months, test diets with high
fructose corn syrup or starch, along with some fairly normal U.S. foods, and with either
extremely low magnesium content, or with slightly deficient magnesium content. The
authors' conclusion was clearly stated in the title of their article, that the
combination adversely affects the mineral balance of the body. </span></span></span
></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>However, looking at their results in the context of these other studies of the effects of
fructose on phosphate, I don't think their conclusion is correct. Even on the extremely
low magnesium intake, both their magnesium and calcium balances were positive, meaning
that on average their bodies accumulated a little magnesium and calcium, even though men
aged 22 to 40 presumably weren't growing very much. To steadily accumulate both calcium
and magnesium, with the calcium retention much larger than the magnesium, the minerals
were probably mostly being incorporated into their bones. Their phosphate balance,
however, was slightly negative on the "high fructose" diet. If the sugar was having the
same effect that it had on William Brown in 1938 (and in animal experiments), some of
the phosphate loss was accounted for by the reduced amount in blood and other body
fluids, but to continue through the months of the experiment, some of it must have
represented a change in the composition of the bones. When there is more carbon dioxide
in the body fluids, calcium carbonate can be deposited in the bones (Messier, et al.,
1979). Increased carbon dioxide could account for a prolonged negative phosphate
balance, by taking its place in the bones in combination with calcium and
magnesium. </span></span></span></span></span>
</blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Another important effect of carbon dioxide is in the regulation of both calcium and
phosphate, by increasing the absorption and retention of calcium (Canzanello, et al.,
1995), and by increasing the excretion of phosphate. Increased carbon dioxide (as
dissolved gas) and bicarbonate (as sodium bicarbonate) both increase the excretion of
phosphate in the urine, even in the absence of the parathyroid hormone. Below the normal
level of serum bicarbonate, reabsorption of phosphate by the kidneys is greatly
increased (Jehle, et al., 1999). Acetazolamide increases the body's retention of carbon
dioxide, and increases the amount of phosphate excreted in the urine. </span></span
></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Much of the calcium dissolved in the blood is in the form of a complex of calcium and bicarbonate,
with a single positive charge (Hughes, et al., 1984). Failure to consider this complexed form of
calcium leads to errors in measuring the amount of calcium in the blood, and in interpreting its
physiological effects, including its intracellular behavior. Hyperventilation can cause cramping
of skeletal muscles, constriction of blood vessels, and excitation of platelets and other cells;
the removal of carbon dioxide from the blood lowers the carbonic acid, changing the state and
function of calcium. Hyperventilation increases phosphate and parathyroid hormone, and decreases
calcium (Krapf, et al., 1992).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Since estrogen tends to cause hyperventilation, lowering carbon dioxide, its role in phosphate
metabolism should be investigated more thoroughly. Work by Han, et al. (2002) and Xu, et al.
(2003) showed that estrogen increases phosphate reabsorption by the kidney, but estrogen also
increases cortisol, which decreases reabsorption, so the role of estrogen in the whole system
has to be be considered. </span></span></span>
</blockquote>
<blockquote></blockquote>
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<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>This calcium solubilizing effect of bicarbonate, combined with its phosphaturic effect,
probably accounts for the relaxing effect of carbon dioxide on the blood vessels and
bronchial smooth muscles, and for the prevention of vascular calcification by the
thyroid hormones (Sato, et al., 2005, Tatar, 2009, Kim, et al., 2012). Distensibility of
the blood vessels and heart, increased by carbon dioxide, is decreased in
hypothyroidism, heart failure, and by phosphate. </span></span></span></span></span
>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>While fructose lowers intracellular phosphate, it also lowers the amount that the intestine
absorbs from food (Kirchner, et al.,2008), and the Milne-Nielsen study suggests that it
increases phosphate loss through the kidneys. The "anti-aging" protein, klotho,
increases the ability of the kidneys to excrete phosphate (Dërmaku-Sopjani, et al.,
2011), and like fructose, it supports energy production and maintains thermogenesis
(Mori, et al., 2000). </span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Lowering the amount of phosphate in the blood allows the parathyroid hormone to decrease.
While the parathyroid hormone also prevents phosphate reabsorption by the kidneys, it
causes mast cells to release serotonin (and serotonin increases the kidneys'
reabsorption of phosphate), and possibly has other pro-inflammatory effects. For
example, deleting the PTH gene compensates for the harmful (accelerated calcification
and osteoporosis) effects of deleting the klotho gene, apparently by preventing the
increase of osteopontin (Yuan, et al., 2012).</span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Niacinamide is another nutrient that lowers serum phosphate (Cheng, et al., 2008), by
inhibiting intestinal absorption (Katai, et al., 1989), and also by reducing its
reabsorption by the kidneys (Campbell, et al., 1989). Niacinamide's reduction of free
fatty acids by inhibiting lipolysis, protecting the use of glucose for energy, might be
involved in its effect on phosphate (by analogy with the phosphate lowering action of a
deficiency of polyunsaturated fatty acids). Aspirin is another antilipolytic substance
(de Zentella, et al., 2002) which stimulates energy production from sugar and lowers
phosphate, possibly combined with improved magnesium retention (Yamada and Morohashi,
1986).</span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>A diet that provides enough calcium to limit activity of the parathyroid glands, and that
is low in phosphate and polyunsaturated fats, with sugar rather than starch as the main
carbohydrate, possibly supplemented by niacinamide and aspirin, should help to avoid
some of the degenerative processes associated with high phosphate: fatigue, heart
failure, movement discoordination, hypogonadism, infertility, vascular calcification,
emphysema, cancer, osteoporosis, and atrophy of skin, skeletal muscle, intestine,
thymus, and spleen (Ohnishi and Razzaque, 2010; Shiraki-Iida, et al., 2000; Kuro-o, et
al., 1997; Osuka and Razzaque, 2012). The foods naturally highest in phosphate, relative
to calcium, are cereals, legumes, meats, and fish. Many prepared foods contain added
phosphate. Foods with a higher, safer ratio of calcium to phosphate are leaves, such as
kale, turnip greens, and beet greens, and many fruits, milk, and cheese. Coffee, besides
being a good source of magnesium, is probably helpful for lowering phosphate, by its
antagonism to adenosine (Coulson, et al., 1991).</span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Although increased phosphate generally causes vascular calcification (increasing rigidity, with
increased systolic blood pressure), when a high level of dietary phosphate comes from milk and
cheese, it is epidemiologically associated with reduced blood pressure (Takeda, et al.,
2012).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Phosphate toxicity offers some interesting insights into stress and aging, helping to
explain the protective effects of carbon dioxide, thyroid hormone, sugar, niacinamide,
and calcium. It also suggests that other natural substances used as food additives
should be investigated more thoroughly. Excessive citric acid, for example, might
activate dormant cancer cells (Havard, et al., 2011), and has been associated with
malignancy (Blüml, et al., 2011). Nutritional research has hardly begun to investigate
the optimal ratios of minerals, fats, amino acids, and other things in foods, and how
they interact with the natural toxicants, antinutrients, and hormone disrupters in many
organisms used for food.</span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"><h3>REFERENCES</h3></span></span
></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Physiology 1962; 161, 379-391. Volume changes in frog muscle during contraction. Abbott C &
Baskin RJ.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Physiol. 1965 May; 178(2): 368–383. The initial heat production associated with the nerve impulse
in crustacean and mammalian non-myelinated nerve fibbers. Abbott BC, Howarth JV, and Ritchie
JM.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Fiziol Zh SSSR Im I M Sechenova. 1982 Jan;68(1):59-63. [Oxygen, carbon dioxide and calcium control
of the mechanisms of relaxation in the cerebral artery smooth musculature]. [Article in Russian]
Azin AL.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biochem Biophys Res Commun. 1989 Jul 14;162(1):498-504. Placental estrogen synthetase (aromatase):
evidence for phosphatase-dependent inactivation. Bellino FL, Holben L.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Neuro Oncol. 2011 Oct;13(10):1107-17. Elevated citrate in pediatric astrocytomas with malignant
progression. Blüml S, Panigrahy A, Laskov M, Dhall G, Krieger MD, Nelson MD, Finlay JL,
Gilles</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>FH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1956 Sep;187(1):41-4. Effect of corticoids on the resistance of the kidney to an
excess of phosphates. Bois P, Selye H.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J. Nutrition 1938;16(6), Effects of prolonged use of extremely low-fat diet on an adult human
subject. Brown WR, Hansen AE, Burr GO, & McQuarrie I. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Pharmacol Exp Ther. 1989 Oct;251(1):188-92. Specific inhibition of rat renal Na+/phosphate
cotransport by picolinamide. Campbell PI, al-Mahrouq HA, Abraham MI, Kempson SA.</span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Lab Clin Med. 1995 Jul;126(1):81-7. Effect of chronic respiratory acidosis on calcium metabolism
in the rat. Canzanello VJ, Kraut JA, Holick MF, Johns C, Liu CC, Madias NE.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Clin J Am Soc Nephrol. 2008 Jul;3(4):1131-8. A randomized, double-blind, placebo-controlled trial
of niacinamide for reduction of phosphorus in hemodialysis patients. Cheng SC, Young DO, Huang
Y, Delmez JA, Coyne DW.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Physiol. 1997 Nov 15;505 ( Pt 1):205-15. Energetics of lengthening in mouse and toad skeletal
muscles. Constable JK, Barclay CJ, Gibbs CL.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1991 Jun;260(6 Pt 2):F921-8. Adenosine stimulates phosphate and glucose transport in
opossum kidney epithelial cells. Coulson R, Johnson RA, Olsson RA, Cooper DR, Scheinman
SJ.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Physiol. 1974 Apr;238(2):437–446. Energetics of relaxation in frog muscle. Curtin NA, Woledge
RC. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10482-6. Indirect coupling of phosphate release to de
novo tension generation during muscle contraction. Davis JS, Rodgers ME.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Cell Physiol Biochem. 2011;28(2):251-8. Downregulation of NaPi-IIa and NaPi-IIb Na-coupled
phosphate transporters by coexpression of Klotho. Dërmaku-Sopjani M, Sopjani M, Saxena A,
Shojaiefard M, Bogatikov E, Alesutan I, Eichenmüller M, Lang F.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Res Commun Chem Pathol Pharmacol. 1989 Mar;63(3):361-72. A rapid phosphate-induced depression of
heart subsarcolemmal mitochondrial oxidative phosphorylation. Duan J, Karmazyn M.</span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Med Princ Pract. 2011 Dec 16. Inflammatory Biomarkers in Patients with Asymptomatic Primary
Hyperparathyroidism. Emam AA, Mousa SG, Ahmed KY, Al-Azab AA.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J of Dental Res. JDR January 2009 vol. 88 no. 1 39-44. Phosphate Regulates Osteopontin Gene
Transcription. Fatherazi S, Matsa-Dunn D, Foster BL, Rutherford RB, Somerman MJ, Presland
RB. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>J Clin Invest. 1968 May;47(5):983-91. The phosphaturic effect of sodium bicarbonate and
acetazolamide in dogs. Fulop M, Brazeau P.</span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biochemistry. 2006 Oct 3;45(39):12083-9. Kosmotropic salt activation and substrate specificity of
poliovirus protease 3C. Gouvea IE, Judice WA, Cezari MH, Juliano MA, Juhász T, Szeltner Z,
Polgár L, Juliano L.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1993 Sep;265(3 Pt 2):F440-8. Acute phosphate depletion inhibits the Na+/H+ antiporter
in a cultured renal cell line. Green J, Foellmer O, Kleeman CR, Basic MM.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1987 Jul;253(1 Pt 2):F34-40. Effect of acute hypercapnia on PTH-stimulated
phosphaturia in dietary Pi-deprived rat. Guntupalli J, Matthews B, Carlin B, Bourke E.</span
></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Exp Nephrol. 2002;10(5-6):355-64. Estradiol-17beta stimulates phosphate uptake and is mitogenic for
primary rabbit renal proximal tubule cells. Han HJ, Lee YH, Park KM, Taub M.</span></span></span
>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Biol Chem. 2011 Dec 23;286(51):44177-86. A dormant state modulated by osmotic pressure controls
clonogenicity of prostate cancer cells. Havard M, Dautry F, Tchénio T.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Lab Clin Med. 1984 Jan;103(1):93-103. The effect of the bicarbonate anion on serum ionized
calcium concentration in vitro. Hughes WS, Aurbach GD, Sharp ME, Marx SJ.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1999 Jan;276(1 Pt 2):F46-53. Type II Na-Pi cotransport is regulated transcriptionally
by ambient bicarbonate/carbon dioxide tension in OK cells. Jehle AW, Hilfiker H, Pfister MF,
Biber J, Lederer E, Krapf R, Murer H.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Toxicol Sci. 2007 Nov;100(1):215-23. High dietary inorganic phosphate affects lung through altering
protein translation, cell cycle, and angiogenesis in developing mice. Jin H, Chang SH, Xu CX,
Shin JY, Chung YS, Park SJ, Lee YS, An GH, Lee KH, Cho MH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Respir Crit Care Med. 2009 Jan 1;179(1):59-68. High dietary inorganic phosphate increases lung
tumorigenesis and alters Akt signaling. Jin H, Xu CX, Lim HT, Park SJ, Shin JY, Chung YS, Park
SC, Chang SH, Youn HJ, Lee KH, Lee YS, Ha YC, Chae CH, Beck GR Jr, Cho MH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nephrol Dial Transplant. 1999 May;14(5):1195-201. Nicotinamide inhibits sodium-dependent phosphate
cotransport activity in rat small intestine. Katai K, Tanaka H, Tatsumi S, Fukunaga Y, Genjida
K, Morita K, Kuboyama N, Suzuki T, Akiba T, Miyamoto K, Takeda E.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Thyroid. 2012 May 24. Association between low serum free thyroxine concentrations and coronary
artery calcification in healthy euthyroid subjects. Kim ES, Shin JA, Moon S, Shin JY, Han JH,
Son HY.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Thyroid. 2012 Sep;22(9):870-6. Association between low serum free thyroxine concentrations and
coronary artery calcification in healthy euthyroid subjects. Kim ES, Shin JA, Shin JY, Lim DJ,
Moon SD, Son HY, Han JH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol. 1991 Aug;261(2 Pt 2):H469-78. Ischemic contracture begins when anaerobic glycolysis
stops: a 31P-NMR study of isolated rat hearts. Kingsley PB, Sako EY, Yang MQ, Zimmer SD, Ugurbil
K, Foker JE, From AH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Clin Nutr. 2008 Apr;87(4):1028-38. Luminal fructose inhibits rat intestinal sodium-phosphate
cotransporter gene expression and phosphate uptake. Kirchner S, Muduli A, Casirola D, Prum K,
Douard V, Ferraris RP.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Biol Chem. 1996 Feb 9;271(6):2929-34.Effect of inorganic phosphate concentration on the nature of
inner mitochondrial membrane alterations mediated by Ca2+ ions. A proposed model for
phosphate-stimulated lipid peroxidation. Kowaltowski AJ, Castilho RF, Grijalba MT, Bechara EJ,
Vercesi AE.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Kidney Int. 1992 Sep;42(3):727-34. Chronic respiratory alkalosis induces renal PTH-resistance,
hyperphosphatemia and hypocalcemia in humans. Krapf R, Jaeger P, Hulter HN.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nature. 1997 Nov 6;390(6655):45-51. Mutation of the mouse klotho gene leads to a syndrome
resembling ageing. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y,
Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R,
Nabeshima YI.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Magn Reson Med. 1994 May;31(5):469-81. In vivo and in vitro 31P magnetic resonance spectroscopic
studies of the hepatic response of healthy rats and rats with acute hepatic damage to fructose
loading. Lu W, Locke SJ, Brauer M.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Undersea Biomed Res. 1979;6 Suppl:S57-70. Calcium, magnesium, and phosphorus metabolism, and
parathyroid-calcitonin function during prolonged exposure to elevated CO2 concentrations on
submarines. Messier AA, Heyder E, Braithwaite WR, McCluggage C, Peck A, Schaefer KE. "It is
suggested that during prolonged exposure to low levels of CO2 (up to 1% CO2), calcium metabolism
is controlled by the uptake and release of CO2 in the bones."</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biochem Biophys Res Commun. 2000 Nov 30;278(3):665-70. Disruption of klotho gene causes an abnormal
energy homeostasis in mice. Mori K, Yahata K, Mukoyama M, Suganami T, Makino H, Nagae T,
Masuzaki H, Ogawa Y, Sugawara A, Nabeshima Y, Nakao K. "Uncoupling protein-1 gene expression of
BAT and body temperature in klotho mice are lower than those in wild-type mice, suggesting that
klotho mice have less energy expenditure than wild-type mice." "All these changes of parameters
for energy homeostasis in klotho mice are very similar to those reported under food-restricted
conditions.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Bioenerg Biomembr. 2001 Feb;33(1):53-61. Mitochondrial adaptation to in vivo polyunsaturated
fatty acid deficiency: increase in phosphorylation efficiency. Nogueira V, Piquet MA, Devin A,
Fiore C, Fontaine E, Brandolin G, Rigoulet M, Leverve XM.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>FASEB J. 2010 Sep;24(9):3562-71. Dietary and genetic evidence for phosphate toxicity accelerating
mammalian aging. Ohnishi M, Razzaque MS.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Bone Miner Metab. 2012 Jan;30(1):10-8. Can features of phosphate toxicity appear in
normophosphatemia? Osuka S, Razzaque MS.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Clin Sci (Lond). 2011 Feb;120(3):91-7. Phosphate toxicity: new insights into an old problem.
Razzaque MS.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Circ Res. 1960 Jul;8:788-93. Distensibility and water content of heart muscle before and after
injury. Salisbury PF, Cross CE, Rieben PA.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Circ Res. 2005 Sep 16;97(6):550-7. Thyroid hormone targets matrix Gla protein gene associated with
vascular smooth muscle calcification. Sato Y, Nakamura R, Satoh M, Fujishita K, Mori S, Ishida
S, Yamaguchi T, Inoue K, Nagao T, Ohno Y.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Gene Med. 2000 Jul-Aug;2(4):233-42. Improvement of multiple pathophysiological phenotypes of
klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene. Shiraki-Iida T, Iida
A, Nabeshima Y, Anazawa H, Nishikawa S, Noda M, Kuro-o M, Nabeshima Y.J </span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nutr Rev. 2012 Jun;70(6):311-21. Dietary phosphorus in bone health and quality of life. Takeda E,
Yamamoto H, Yamanaka-Okumura H, Taketani Y.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: georgia, times, serif"><span
style="font-size: medium"
><span style="font-style: normal"><span style="font-weight: normal"
>Clin J Am Soc Nephrol. 2011 Sep;6(9):2240-6. Associations of triiodothyronine levels with
carotid atherosclerosis and arterial stiffness in hemodialysis patients. Tatar E,
Kircelli F, Asci G, Carrero JJ, Gungor O, Demirci MS, Ozbek SS, Ceylan N, Ozkahya M, Toz
H, Ok E.</span></span></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Int J Cardiol. 2012 May 26. Serum osteoprotegerin and osteopontin levels are associated with
arterial stiffness and the presence and severity of coronary artery disease. Tousoulis D, Siasos
G, Maniatis K, Oikonomou E, Kioufis S, Zaromitidou M, Paraskevopoulos T, Michalea S, Kollia C,
Miliou A, Kokkou E, Papavassiliou AG, Stefanadis C. "Osteopontin (OPN) and osteoprotegerin (OPG)
have recently emerged as </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>key factors in both vascular remodeling and development of atherosclerosis." "These preliminary
results suggest that OPG and OPN levels are significantly correlated with vascular function
contributing to the pathogenesis of atherosclerosis in CAD." </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Science 2 July 1999: Vol. 285 no. 5424 pp. 93-96. Regulation of NMDA Receptors by an Associated
Phosphatase-Kinase Signaling Complex. Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser
IDC, Langeberg LK, Sheng M, Scott JD.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Biophys J. 1973 Apr;13(4):385-98. Ionic partition between surface and bulk water in a silica gel. A
biological model. Wiggins PM.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G654-63. High dietary inorganic phosphate
enhances cap-dependent protein translation, cell-cycle progression, and angiogenesis in the
livers of young mice. Xu CX, Jin H, Lim HT, Kim JE, Shin JY, Lee ES, Chung YS, Lee YS, Beck G
Jr, Lee KH, Cho MH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nutr Cancer. 2010;62(4):525-32. Low dietary inorganic phosphate stimulates lung tumorigenesis
through altering protein translation and cell cycle in K-ras(LA1) mice. Xu CX, Jin H, Lim HT, Ha
YC, Chae CH, An GH, Lee KH, Cho MH.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Am J Physiol Gastrointest Liver Physiol. 2003 Dec;285(6):G1317-24. Regulation of intestinal
NaPi-IIb cotransporter gene expression by estrogen. Xu H, Uno JK, Inouye M, Xu L, Drees JB,
Collins JF, Ghishan FK.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>"These studies demonstrate for the first time that estrogen stimulates intestinal sodium-dependent
phosphate absorption in female rats. This stimulation is associated with increased NaPi-IIb mRNA
and protein expression."</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Nihon Yakurigaku Zasshi. 1986 Nov;88(5):395-401. [Effect of sodium salicylate on renal handling of
calcium, phosphate and magnesium]. [Article in Japanese] Yamada S, Morohashi T. "On the
other hand, we observed increased urinary excretion of Pi and decreased Mg excretion, which
resulted from the changes in tubular</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>reabsorption of Pi and Mg, respectively."</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Biol Chem. 1995 Dec 15;270(50):30168-72. Stimulation of the herpes simplex virus type I protease
by antichaeotrophic salts. Yamanaka G, DiIanni CL, O'Boyle DR 2nd, Stevens J, Weinheimer SP,
Deckman IC, Matusick-Kumar L, Colonno RJ.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>Proc Assoc Am Physicians. 1998 Jan-Feb;110(1):50-64. A functional role for osteopontin in
experimental crescentic glomerulonephritis in the rat. Yu XQ, Nikolic-Paterson DJ, Mu W,
Giachelli CM, Atkins RC, Johnson RJ, Lan HY.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>PLoS Genet. 2012;8(5):e1002726. Deletion of PTH rescues skeletal abnormalities and high osteopontin
levels in Klotho-/- mice. Yuan Q, Sato T, Densmore M, Saito H, Schüler C, Erben RG, Lanske
B.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: georgia, times, serif"><span
style="font-size: medium"
>J Pharm Pharmacol. 2002 Apr;54(4):577-82. Non-steroidal anti-inflammatory drugs inhibit
epinephrine- and cAMP-mediated lipolysis in isolated rat adipocytes. de Zentella PM,
Vázquez-Meza H, Piña-Zentella G, Pimentel L, Piña E.</span></span></span>
</blockquote>
<p></p>
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