Iron Chelator Suppresses Replication of HIV-1

ironjustice · Guest

"Deferiprone suppressed replication of HIV-1"

Journal Metadata Search: Elsevier - Biochemical Pharmacology
Antiretroviral Effects of Deoxyhypusyl Hydroxylase Inhibitors - A
review
Andrus, L., Szabo, P., Grady, R.W., Hanauske, A.-R., Huima-Byron, T.,
Slowinska, B., Zagulska, S., Hanauske-Abel, H.M.,
Biochemical Pharmacology
Vol. 55, No. 11, pages 1807-1818 (1998)
ISSN 0006-2952
Publisher Elsevier
Abstract

The HIV-1 protein Rev, critical for translation of incompletely
spliced retroviral mRNAs encoding capsid elements, requires a host
cell protein termed **eukaryotic initiation factor 5A** (eIF-5A). This
is the only protein containing hypusine, a lysine-derived hydroxylated
residue that determines its proposed bioactivity, the translation of a
subset of cellular mRNAs controlling G"1-to-S transit of the cell
cycle.
We postulated that inhibiting the hypusine-forming deoxyhypusyl
hydroxylase (DOHH) should, by depleting eukaryotic initiation factor
5A, compromise Rev function and thus reduce HIV-1 multiplication.
We now report that the @a-hydroxypyridones, specifically mimosine, a
natural product, and deferiprone, an experimental drug, inhibited
deoxyhypusyl hydroxylase in T-lymphocytic and promonocytic cell lines
and, in a concentration-dependent manner, suppressed replication of
HIV-1. However, the @a-hydroxypyridones did not affect the formation
of unspliced or multiply spliced HIV-1 transcripts.
Rather, these agents caused Rev-dependent incompletely spliced HIV-1
mRNA such as gag, but not cellular **housekeeping** mRNAs, to
disappear from polysomes.
Consequently, @a-hydroxypyridone-mediated depletion of eIF-5A
decreased biosynthesis of structural HIV-1 protein encoded by gag,
measured as p24, whereas the induced formation of cellular protein
like tumor necrosis factor alpha remained unaffected.
By interfering with the translation of incompletely spliced retroviral
mRNAs, these compounds restrict HIV-1 to the early, nongenerative
phase of its reproductive cycle.
In the inducibly HIV-1 expressing T-cell line ACH-2, the deoxyhypusyl
hydroxylase inhibitors triggered extensive apoptosis, particularly of
cells that actively produce HIV-1.
Selective suppression of retroviral protein biosynthesis and
preferential apoptosis of retrovirally infected cells by @a-
hydroxypyridones point to a novel mode of antiretroviral action.

American Association of Pharmaceutical Scientists
----------------------------------------------------------

NEJM -- Iron-Chelation Therapy with Oral Deferiprone in
Patients ...Background To determine whether the orally active iron
chelator deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) is
efficacious in the treatment of iron ...
https://content.nejm.org/cgi/content/abstract/332/14/918 - Similar
pages - Note this
Biochem Pharmacol 1995 Jun 16;49(12):1821-6 Related Articles, Books,
LinkOut

----------------------------------------------------------

Brain iron in the ferrocene-loaded rat: its chelation and influence on
dopamine
metabolism.

Ward RJ, Dexter D, Florence A, Aouad F, Hider R, Jenner P, Crichton
RR.

Department of Clinical Biochemistry, Kings College, London, U.K.

After administration of the ferrocene derivative 3,5,5-trimethyl
hexanoyl
ferrocene to rats for 4 weeks various brain regions including
substantia nigra,
cerebellum and cerebral cortex showed up to 50% increase in iron
content.
Subsequent administration of one of the hydroxypyridones CP20, CP24
and CP94,
or the siderophore desferrioxamine caused a significant decrease in
the iron
content of these various brain regions. Each of the hydroxypyridones
and the
siderophore influenced dopamine metabolism by causing significant
variations in
both homovanillic acid and dopamine turnover.

PMID: 7598744 [PubMed - indexed for MEDLINE]

----------------------------------------------------------
http://tinyurl.com/2yeldk

Although hydroxypyridones have been used in clinical practice for the
last 30 years, their mode of action is still poorly understood.
Nonetheless, it is well established that, in contrast to other
antifungal agents such asazoles or polyenes, hydroxypyridones do not
produce anti-fungal activity by inhibition of ergosterol synthesis
(Gupta,2001).
CPO is well known as a chelating agent that forms complexes with iron
cations such as Fe31, inhibiting the iron-containing enzymes, such as
catalase and peroxidase, that play a part in the intracellular
degradation of toxic peroxides (Niewerth et al., 2003).
----------------------------------------------------------

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Carole · Guest

"ironjustice" <ironjustice@cashette.com> wrote in message
news:1cf4b120-9995-4974-a71c-32590f638720@o10g2000hsf.googlegroups.com...

ironjustice@aol.com · Guest

On Mar 1, 4:57 pm, "Carole" <hub...@iimetro.com.au> wrote:There is a
group of people in the community who build up too much iron but they
are a minority, and it is a disease. <<

Wrong .. everyone who eats meat is in a state of abnormal iron stores.

On Mar 1, 4:57 pm, "Carole" <hub...@iimetro.com.au> wrote: Most people
need iron and especially <<

Wrong .. you are BORN with sufficient iron STORES .. seven months
worth of iron stores .. you RECYCLE this same iron all of your life ..
you never delete these seven months worth of iron stores.

On Mar 1, 4:57 pm, "Carole" <hub...@iimetro.com.au> wrote: and
especially pregnant women. <<

Wrong.
Iron supplementation in women has been shown to be .. detrimental ..
during pregnancy.
Encephalitis .. premature .. low birth weight .. miscarriage .. etc.
How have women survived for sooooo .. long .. without iron filings in
their food during pregnancy.. ?
How come the 'problem' with 'control' of burgeoning population in
underdeveloped countries is the HIGH RATE of healthy births .. in
supposed anemic people .. ?

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Guest

There is a daily intake of iron to replace the small amounts lost. 2/3
of the iron in our bodies is in the form of heme iron. The body
controls levels at the cell and system levels and intake by control in
the gut of dietary iron.

The iron notion is a dud, dead as a dodo.

Jesus ate a mediterranean diet.

ironjustice@aol.com · Guest

On Mar 3, 7:58 am, ferr...@paris.com wrote:The body
controls levels at the cell and system levels and intake by control in
the gut of dietary iron. <<

You are wrong.
This recent article shows heme iron is "not substantially reduced' ..
that would be .. heme iron absorption is NOT controlled ..
significantly.

"Heme iron absorption is not substantially reduced"

Research Project: Mineral Utilization and Bioavailability in the 21st
Century, with Changing Diets and Agricultural Practices
Location: Grand Forks Human Nutrition Research Center

Title: ABSORPTION OF NONHEME, BUT NOT HEME IRON, IS SUBSTANTIALLY
REDUCED WITH HIGH IRON STORES
Author Hunt, Janet

Submitted to: American Dietetic Association Annual Meeting
Publication Type: Abstract
Publication Acceptance Date: April 1, 2006
Publication Date: August 1, 2006
Citation: Hunt, J.R. 2006. Absorption of nonheme, but not heme iron,
is substantially reduced with high iron stores [abstract]. Journal of
the American Dietetic Association. 106(8)S2:A-42.

Technical Abstract:
Humans absorb heme iron from meat, poultry and fish more efficiently
than nonheme iron, and high consumption may increase body iron stores,
and possibly oxidative stress.
Results from previous studies of heme and nonheme iron
bioavailability, measured separately for men and for women, were
combined to model the relative absorption of each form of iron in
relation to body iron stores.
Iron absorption was measured in healthy men (n=14) and premenopausal
women (n=1 Cool

consuming controlled, high bioavailability diets.
Adjusted for individual energy intake, the diets provided 10-14 oz/d
of meat or poultry, refined grains and cereal products, no coffee or
tea, and greater than or equal to 75 mg ascorbic acid with each meal.
By analysis, the diet contained 12.9 mg iron/2500 kcal, with 1.4 mg or
11% as heme iron.
Iron absorption was measured by radiolabeling the 2-d menu with
59FeCl3 and 55Fe hemoglobin, and measuring whole body and erythrocyte
retention after 2 wk.
With all variables logarithmically transformed, total iron absorption
(0.4 to 4.5 mg/d) and nonheme iron absorption, but not heme iron
absorption, were inversely related to serum ferritin (4 to 308 micro g/
L) (R2 = 0.66, p<0.01).
Subjects with the lowest iron stores absorbed iron mostly in the
nonheme form, and heme iron accounted for 15-20% of the iron
absorbed.
With higher iron stores, nonheme iron absorption decreased, with the
result that heme iron accounted for half of the iron absorbed by
subjects with serum ferritin greater than or equal to 150 micro g/L.
Unlike nonheme iron, heme iron absorption is not substantially reduced
as iron stores increase.

Project Team

Hunt, Janet
Yan, Lin
Combs, Gerald - Jerry
Canfield, Wesley

Who loves ya.
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Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Guest

Subjects with the lowest iron stores absorbed iron mostly in the nonheme
form, and heme iron accounted for 15-20% of the iron absorbed. With
higher
iron stores, nonheme iron absorption decreased, with the result that
heme
iron accounted for half of the iron absorbed by subjects with serum
ferritin greater than or equal to 150 micro g/L. Unlike nonheme iron,
heme
iron absorption is not substantially reduced as iron stores increase.

So in higher iron half is of both types. If one wanted to press the
case, evolution makes sure we get heme iron for some reason. Here is
the skinny on absorption:

Intestinal epithelial cells or enterocytes take up the predominating
ferric iron from the diet through the combined action of an iron
reductase (duodenal cytochrome B or DcytB is a strong candidate) and
a
ferrous iron transporter known as divalent metal-ion transporter
(DMT1) on the brush border membrane^[1,2]. Heme iron, on the other
hand, appears to be absorbed through a separate system, and a
recently
identified apical membrane protein, HCP1, has emerged as a candidate
heme transporter[3]. Irrespective of the form in which iron crosses
the brush border, enterocytes export iron into the circulation by the
combined action of an iron reductase, hephaestin, and a basolateral
membrane iron transporter, ferroportin (FPN). The newly absorbed iron
is then bound to circulating transferrin which distributes it around
the body to sites of utilization and storage.

The amount of iron transported across the enterocytes is ultimately
influenced by body iron requirements. Thus, for example, when body
iron levels are low or when erythropoietic demand is increased, iron
absorption is elevated. The factors that alter iron absorption exert
their effects by influencing the duodenal expression of the major
iron
transport molecules, particularly DMT1, Dcytb1 and
ferroportin[1,2,4].

And how much iron do we need and why:

On a daily basis, adult humans
absorb 1-2 mg of iron from the diet to compensate for non-specific
iron losses, for example, due to desquamation or blood loss. The
higher iron assimilation in children results in accumulation of an
iron pool of 3-5 g in the adult state. Under normal conditions, more
than 70% of this amount is utilized for heme synthesis in
erythropoietic cells. The rest is primarily distributed in the liver
and the muscles, and to a lesser extent, in all other tissues

ironjustice@aol.com · Guest

On Mar 3, 12:36 pm, ferr...@paris.com wrote: Here is the skinny on
absorption: <<

Wrong .. everyone who eats meat is in a state of abnormal iron
stores.

"Iron accumulates as a function of age."

Do you .. understand .. ?

http://www.annalsnyas.org/cgi/content/abstract/1019/1/365

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Guest

"Iron accumulates as a function of age and is associated with^ the
pathology
of numerous age-related diseases. These changes^ may be caused by
altered
iron homeostasis at the cellular level,^ yet this is poorly understood.
Therefore, changes in iron content^ in primary human fibroblasts were
studied in culture models^ of cellular senescence."

snip

"Thus, iron accumulation^ is not a cause, but a consequence of normal
cellular senescence^ in vitro."

In other words, in normal old age the processes which control iron
levels become weakened. As it says, iron levels are a result not a
cause.

Not to mention that this is cells in a glass dish not the body. Iron
levels are controlled at the gut level.

Thus there we have it, the body controls iron levels, the iron notion is
a dud, dead as a dodo.

Jesus ate a mediterranean diet.

ironjustice@aol.com · Guest

On Mar 3, 4:23 pm, ferr...@paris.com wrote: this is cells in a glass
dish not the body. <<

The Eskimos in Greenland were .. not .. in a petri .. dish .. and
their iron stores ROSE as per the **amount** of **meat** .. eaten.
"The differences in body iron stores can be explained by differences
in the dietary intake of haem iron."
IE: "Iron accumulates"

Heme iron is "not substantially reduced" .. that would be .. heme iron
absorption is NOT controlled ..
significantly.

"Heme iron absorption is not substantially reduced"

Research Project: Mineral Utilization and Bioavailability in the 21st
Century, with Changing Diets and Agricultural Practices
Location: Grand Forks Human Nutrition Research Center

Title: ABSORPTION OF NONHEME, BUT NOT HEME IRON, IS SUBSTANTIALLY
REDUCED WITH HIGH IRON STORES
Author Hunt, Janet

Submitted to: American Dietetic Association Annual Meeting
Publication Type: Abstract
Publication Acceptance Date: April 1, 2006
Publication Date: August 1, 2006
Citation: Hunt, J.R. 2006. Absorption of nonheme, but not heme iron,
is substantially reduced with high iron stores [abstract]. Journal of
the American Dietetic Association. 106(8)S2:A-42.

Technical Abstract:
Humans absorb heme iron from meat, poultry and fish more efficiently
than nonheme iron, and high consumption may increase body iron
stores,
and possibly oxidative stress.
Results from previous studies of heme and nonheme iron
bioavailability, measured separately for men and for women, were
combined to model the relative absorption of each form of iron in
relation to body iron stores.
Iron absorption was measured in healthy men (n=14) and premenopausal
women (n=1 Cool

consuming controlled, high bioavailability diets.
Adjusted for individual energy intake, the diets provided 10-14 oz/d
of meat or poultry, refined grains and cereal products, no coffee or
tea, and greater than or equal to 75 mg ascorbic acid with each meal.
By analysis, the diet contained 12.9 mg iron/2500 kcal, with 1.4 mg
or
11% as heme iron.
Iron absorption was measured by radiolabeling the 2-d menu with
59FeCl3 and 55Fe hemoglobin, and measuring whole body and erythrocyte
retention after 2 wk.
With all variables logarithmically transformed, total iron absorption
(0.4 to 4.5 mg/d) and nonheme iron absorption, but not heme iron
absorption, were inversely related to serum ferritin (4 to 308 micro
g/
L) (R2 = 0.66, p<0.01).
Subjects with the lowest iron stores absorbed iron mostly in the
nonheme form, and heme iron accounted for 15-20% of the iron
absorbed.
With higher iron stores, nonheme iron absorption decreased, with the
result that heme iron accounted for half of the iron absorbed by
subjects with serum ferritin greater than or equal to 150 micro g/L.
Unlike nonheme iron, heme iron absorption is not substantially
reduced
as iron stores increase.

Project Team

Hunt, Janet
Yan, Lin
Combs, Gerald - Jerry
Canfield, Wesley

Eur J Haematol 2001 Feb;66(2):115-25

Iron status markers in 224 indigenous Greenlanders: influence of age,
residence
and traditional foods.

Milman N, Byg KE, Mulvad G, Pedersen HS, Bjerregaard P

Department of Medicine, Naestved Hospital, Naestved, Denmark.
m...@cn.stam.dk

OBJECTIVE: To evaluate iron status in indigenous Greenlanders and
its
relationship to gender, age and intake of traditional Greenlandic
foods. Methods: Serum ferritin, serum transferrin saturation and
haemoglobin were evaluated in a population survey in 1993-1994
comprising 224 Greenlandic individuals (109 men) aged 19-82 yr.
The
participants were residents in the capital Nuuk (n=73) with a
predominantly Western style of living, the town Ilulissat (n=60)
with
a mixture of Western and Greenlandic style of living, and the
small
town Uummannaq (n=91) with a predominantly Greenlandic style of
living. Consumption of traditional foods was assessed by
questionnaire. RESULTS: Intake of traditional foods was more
prevalent
among elderly than among young individuals and more frequent in
Uummannaq than in Ilulissat and Nuuk. Ferritin levels were higher
in
men than in women (p<0.0001). Median ferritin levels were lowest
in
Nuuk (men, 92 microg/L; women, 40 microg/L), higher in Ilulissat
(men,
104 microg/L; women, 69 microg/L) and in Uummannaq (men, 118 microg/
L;
women, 46 microg/L) (p<0.001). The prevalence of iron load
(ferritin

Guest

Subjects with the lowest iron stores absorbed iron mostly in the nonheme
form, and heme iron accounted for 15-20% of the iron absorbed. With
higher
iron stores, nonheme iron absorption decreased, with the result that
heme
iron accounted for half of the iron absorbed by subjects with serum
ferritin greater than or equal to 150 micro g/L. Unlike nonheme iron,
heme
iron absorption is not substantially reduced as iron stores increase.

So in higher iron half is of both types. If one wanted to press the
case, evolution makes sure we get heme iron for some reason. Here is
the skinny on absorption:

Intestinal epithelial cells or enterocytes take up the predominating
ferric iron from the diet through the combined action of an iron
reductase (duodenal cytochrome B or DcytB is a strong candidate) and
a
ferrous iron transporter known as divalent metal-ion transporter
(DMT1) on the brush border membrane^[1,2]. Heme iron, on the other
hand, appears to be absorbed through a separate system, and a
recently
identified apical membrane protein, HCP1, has emerged as a candidate
heme transporter[3]. Irrespective of the form in which iron crosses
the brush border, enterocytes export iron into the circulation by the
combined action of an iron reductase, hephaestin, and a basolateral
membrane iron transporter, ferroportin (FPN). The newly absorbed iron
is then bound to circulating transferrin which distributes it around
the body to sites of utilization and storage.

The amount of iron transported across the enterocytes is ultimately
influenced by body iron requirements. Thus, for example, when body
iron levels are low or when erythropoietic demand is increased, iron
absorption is elevated. The factors that alter iron absorption exert
their effects by influencing the duodenal expression of the major
iron
transport molecules, particularly DMT1, Dcytb1 and
ferroportin[1,2,4].

And how much iron do we need and why:

On a daily basis, adult humans
absorb 1-2 mg of iron from the diet to compensate for non-specific
iron losses, for example, due to desquamation or blood loss. The
higher iron assimilation in children results in accumulation of an
iron pool of 3-5 g in the adult state. Under normal conditions, more
than 70% of this amount is utilized for heme synthesis in
erythropoietic cells. The rest is primarily distributed in the liver
and the muscles, and to a lesser extent, in all other tissues

"Iron accumulates as a function of age and is associated with^ the
pathology
of numerous age-related diseases. These changes^ may be caused by
altered
iron homeostasis at the cellular level,^ yet this is poorly understood.
Therefore, changes in iron content^ in primary human fibroblasts were
studied in culture models^ of cellular senescence."

snip

"Thus, iron accumulation^ is not a cause, but a consequence of normal
cellular senescence^ in vitro."

In other words, in normal old age the processes which control iron
levels become weakened. As it says, iron levels are a result not a
cause.

Not to mention that this is cells in a glass dish not the body. Iron
levels are controlled at the gut level.

Thus there we have it, the body controls iron levels, the iron notion is
a dud, dead as a dodo.

Jesus ate a mediterranean diet.

ironjustice@aol.com · Guest

On Mar 4, 8:00 am, ferr...@paris.com wrote: Unlike nonheme iron, heme
iron absorption is not substantially reduced as iron stores increase.
<<

http://groups.google.ca/group/sci.med.nutrition/msg/2af638f4de80b528

Just can't let go of it?

"In healthy individuals there is little if any unbound iron
circulating in the blood. In all disease states, however, unbound
iron
(also called free iron) is released at sites of inflammation and can
spark uncontrolled oxidation."

Griffiths, E. Iron and Infection: Molecular, Physiological and
Clinical Aspects, Second Edition. New York: John Wiley & Sons.

http://www.wiley.com/WileyCDA/WileyTitle/productCd-0471939404.html

Guest

"Just can't let go of it?"

It appears you are having trouble doing so, there is a term for it in
the dsm. " "In healthy individuals there is little if any unbound iron
circulating in the blood. In all disease states, however, unbound iron
(also called free iron) is released at sites of inflammation and can
spark uncontrolled oxidation.""

Correct, in states of disease inflammation causes damage to cells which
releases its bound iron, the iron is an effect not the cause of the
disease. This is confirmed by the post you use recently which showed
that in the test of aging cells iron was an effect not a cause.

The iron notion is a dud, dead as a dodo.

Jesus ate a mediterranean diet.

ironjustice · Guest

On Mar 4, 12:06 pm, ferr...@paris.com wrote:This is confirmed by the
post you use recently which showed
that in the test of aging cells iron was an effect not a cause. <<

Actually that post was included ONLY because of the .. **phrase** ..
the **accepted** .. it seems by everyone .. but .. YOU .. that iron
accumulates as you age.

This .. phrase .. "Iron accumulates as a function of age." .. is
called .. age-related iron .. **accumulation** ..

That post simply explains the aging of cells ..

I'm surprised you understood .. that ..

Now do you think the iron from a diseased / destroyed / senescent ..
red blood cell is .. recycled .. ? .. crapped out .. ? .. urinated
out .. ? .. or does it .. accumulate .. ?

Everyone seems to think iron accumulates / "Iron accumulates as a
function of age." ..

How come you don't .. believe .. everyone .. ?
_________________________________________________________________

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Guest

"Now do you think the iron from a diseased / destroyed / senescent ..
red blood cell is .. recycled .. ? .. crapped out .. ? .. urinated
out .. ? .. or does it .. accumulate .. ?"

I'm shocked, you an iron expert and you don't know what happens to the
iron of a normal red blood cell after its useful life span. Any
physiology 101 student can answer that, oh, excuse me , I forgot.

The iron notion is a dud, quite senescent, dead as a dodo.

Jesus ate a mediterranean diet.

ironjustice · Guest

On Mar 4, 1:53 pm, ferr...@paris.com wrote:
I'm shocked, you an iron expert and you don't know what happens to
the
iron of a normal red blood cell after its useful life span. <<

I noticed .. you .. didn't .. answer the question ..

I'll ask it again ..

Now do you think the iron from a diseased / destroyed / senescent ..
red blood cell is .. recycled .. ? .. crapped out .. ? .. urinated
out .. ? .. or does it .. accumulate .. ?

I'll even give you a hint ..

"Iron accumulates as a function of age."

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://jesuswasavegetarian.7h.com

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

I've t