Iron Chelation In Ageing
ironjustice
conditions related to aging
September 23rd, 2009 Dr. Eric Blough and his colleagues at Marshall
University have shown that acetaminophen ingestion, at least in
animals, can be safely used for the treatment of age-related muscle
loss. Credit: Rick Haye, Marshall University
Recent studies conducted by Dr. Eric Blough and his colleagues at
Marshall University have shown that use of the common pain reliever
acetaminophen may help prevent age-associated muscle loss and other
conditions.
Their study examined how acetaminophen may affect the regulation of
protein kinase B (Akt), an enzyme known to play an important role in
regulation of cellular survival, proliferation and metabolism.
The researchers' data indicates that aging skeletal muscles experience
a decrease in the proper functioning of the enzyme and that
acetaminophen intervention in aged animals could be used to restore
Akt activity to a level comparable to that seen in young animals. In
turn, this improvement in Akt activity was associated with
improvements in muscle cell size and decreased muscle cell death.
"Using a model that closely mimics many of the age-associated
physiological changes observed in humans, we were able to demonstrate
that chronic acetaminophen treatment in a recommended dosage is not
only safe but might be beneficial for the treatment of the muscle
dysfunction many people experience as they get older," said Blough, an
associate professor in the university's Department of Biological
Sciences.
The lab's work, which was published in the July 29 issue of the
international research journal PLoS One, is the first study to show
that acetaminophen ingestion, at least in animals, can be safely used
for the treatment of age-related muscle loss. This finding could have
far-reaching implications, given the fact that people age 65 and older
make up the fastest-growing segment of the U.S. population.
Additional research in their laboratory, which was published in the
March issue of the journal Diabetes/Metabolism Research and Reviews,
demonstrates the medication may also be useful in diminishing the
severity of age-associated hyperglycemia, commonly referred to as high
blood sugar.
"It is thought that acetaminophen may exert its action by decreasing
the amount of reactive oxygen species," explained Dr. Miaozong Wu, the
lead author and a postdoctoral fellow in Blough's lab. "Given the
finding that increases in reactive oxygen species may play a role in
the development of several age-associated disorders, it is possible
that acetaminophen could be used to treat many different types of
conditions."
Dr. John Maher, vice president for research and executive director of
the Marshall University Research Corporation, said, "These findings
are yet another indication that Marshall's researchers are conducting
vital research in areas of great importance to human health and
safety. I could not be more pleased and wish Dr. Blough and his team
continued success."
According to Blough, scientists in his lab will now turn their
attention to examining other physiological systems, such as the heart
and blood vessels, to see if acetaminophen therapy might have similar
benefits for people with cardiovascular disease.
Source: Marshall University
----------------------
Iron Chelator Acetaminophen Normalizes Glucose
Biochem Pharmacol. 2007 Dec 15 [Epub ahead of print]
Acetaminophen normalizes glucose homeostasis in mouse models for
diabetes.
Shertzer HG, Schneider SN, Kendig EL, Clegg DJ, D'Alessio DA, Genter
MB.
Department of Environmental Health and Center for Environmental
Genetics, University of Cincinnati Medical Center, Cincinnati, OH
45267, USA.
Loss of pancreatic beta cell insulin secretion is the most important
element in the progression of type 1 and type 2 diabetes. Since
oxidative stress is involved in the progressive loss of beta cell
function, we evaluated the potential for the over-the-counter
analgesic drug and antioxidant, acetaminophen (APAP), to intervene in
the diabetogenic process. We used mouse models for type 1 diabetes
(streptozotocin) and type 2 diabetes (high-fat diet) to examine the
ability of APAP to intervene in the progression of diabetes. In
C57BL/
6J mice, streptozotocin caused a dosage dependent increase in fasting
blood glucose (FBG), from 100 to >600mg/dl. Daily APAP (20mg/kg BW,
gastric gavage), significantly prevented and partially reversed the
increase in FBG levels produced by streptozotocin. After 10 weeks on
a
high-fat diet, mice developed fasting hyperinsulemia and impaired
glucose tolerance compared to animals fed a control diet. APAP
largely
prevented these changes in insulin and glucose tolerance.
Furthermore,
APAP prevented most of the increase in body fat in mice fed the high-
fat diet. One protective mechanism for APAP is suggested by studies
using isolated liver mitochondria, where low micromolar
concentrations
abolished the production of reactive oxygen that might otherwise
contribute to the destruction of pancreatic beta-cells. These
findings
suggest that administration of APAP to mice, in a dosage used safely
by humans, reduces the production of mitochondrial reactive oxygen
and
concomitantly prevents the development of type 1 and type 2 diabetes
in established animal models.
PMID: 18237716 [PubMed - as supplied by publisher]
---------------------------------
Annals of Clinical & Laboratory Science 37:22-33 (2007)
(c) 2007 Association of Clinical Scientists
Acetaminophen Protects Against Iron-Induced Cardiac Damage in Gerbils
Ernest M. Walker, Jr.1,2, Christopher P. Epling2, Cordel Parris2,
Silvestre Cansino2, Protip Ghosh3, Devashish H. Desai4, Ryan G.
Morrison4, Gary L. Wright4, Paulette Wehner2, Elsa I. Mangiarua4,
Sandra M. Walker5 and Eric R. Blough6
1 Pathology, 2 Cardiovascular Services, 3 Geology, 4 Physiology,,and
6
Biology Departments, Marshall University; 5 Marshall Community &
Technical College and St Mary's Medical Center, Huntington,
WestVirginia
Address correspondence to Ernest M. Walker, Jr., M.D., Ph.D.,
Pathology Department, Marshall University Medical School, 1542 Spring
Valley Drive, Huntington, WV 25704, USA; tel 304 696 72766; fax 304
696 6777; e-mail wal...@marshall.ucla.edu.
There are few effective agents that safely remove excess iron from
iron-overloaded individuals. Our goal was to evaluate the iron-
removing effectiveness of acetaminophen given ip or orally in the
gerbil iron-overload model. Male gerbils were divided into 5 groups:
saline controls, iron-overloaded controls, iron-overloaded treated
with ip acetaminophen, iron-overloaded treated with oral
acetaminophen, and iron-overloaded treated with ipdeferoxamine. Iron
dextran was injected iptwice/wk for 8 wk. Acetaminophen and
deferoxamine treatments were given on Mondays, Wednesdays, and
Fridays
during the same 8 wk and continued for 4 wk after completion of iron-
overloading. Echocardiograms were performed after completion of the
iron-overloading and drug treatments. Liver and cardiac iron contents
were determined by inductively coupled plasma atomic emission
spectrometry (ICP-AES). Iron-overloaded controls had 232-fold and 16-
fold increases in liver and cardiac iron content, respectively,
compared to saline controls. In iron-overloaded controls,
echocardiography showed cardiac hypertrophy, right and left
ventricular distension, significant reduction in left ventricular
ejection fraction (-22%), and fractional shortening (-31%) during
systole. Treatments with acetaminophen (ip or oral) or deferoxamine
(ip) were equally effective in reducing cardiac iron content and in
preventing cardiac structural and functional changes. Both agents
also
significantly reduced excess hepatic iron content, although
acetaminophen was less effective than deferoxamine. The results
suggest that acetaminophen may be useful for treatment of iron-
induced
pathology.
Keywords: acetaminophen, deferoxamine, echocardiogram, iron-overload,
gerbils, hemochromatosis
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ironjustice
wrote:decreasing
the amount of reactive oxygen species <<
Superoxides Harm Muscle Tissue And May Lead To Age-related Muscle
Decline
ScienceDaily (Sep. 23, 2009) — If you think the air outside is
polluted, a new research report in the September 2009 issue of the
journal Genetics might make you to think twice about the air inside
our bodies too. That's because researchers show how about 3 percent of
the air we breathe gets converted into harmful superoxides, which
ultimately harm our muscles.
Specifically, these superoxides lead to the creation of a toxic
molecule called "reactive oxygen species" or ROS, which is shown to be
particularly harmful to muscle tissue, and may lead to problems
ranging from aging and frailty to Parkinson's disease and cancer.
"At a minimum, we hope this research leads to new ways of addressing
inevitable declining physical performance and other age-dependent
infirmities among the elderly," said Atanu Duttaroy, associate
professor of biology at Howard University in Washington, D.C. and one
of the researchers involved in the work.
To make their discovery, Duttaroy and colleagues built on their
previous research showing that ROS-induced cellular damage happens in
the same way in fruit flies and in mice. They started with fruit flies
that lack mitochondrial superoxide dismutase enzyme (SOD), which
provides the primary line of defense against ROS by capturing the
superoxides and converting them to water. This lack of SOD caused the
fruit flies to die within a day after hatching. Then, through genetic
manipulation, the researchers "turned on" the production of SOD
separately in nerves and muscles. SOD in nerves did not appear to make
a significant difference in prolonging the fruit flies' lives, but it
did make a difference when it was activated in their muscles. The
survival of fruit flies with SOD "turned on" in their muscles
increased, and for several days, they remained as active as their
normal counterparts. Measurement of their muscle activity also showed
that SOD helped the muscle work normally, helping survival.
"It's long been known that the oxygen we breath can be toxic, and this
work provides a concrete example of that with real consequences." said
Mark Johnston, Editor-in-Chief of the journal Genetics. "As baby
boomers get older, the need to help older people stay mobile and fit
has never been greater in our lifetimes. This study helps address this
need by providing insight into what causes physical decline, and in
turn, bringing us a step closer toward finding ways to stop or reverse
it."
--------------------------------------------------------------------------------
1.Godenschwege et al. Mitochondrial Superoxide Radicals Differentially
Affect Muscle Activity and Neural Function. Genetics, 2009; 183 (1):
175 DOI: 10.1534/genetics.109.103515
Adapted from materials provided by Genetics Society of America, via
EurekAlert!, a service of AAAS.
Who loves ya.
Tom
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Man Is A Herbivore!
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DEAD PEOPLE WALKING
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> Research shows safe dosages of common pain reliever may help prevent
> 696 6777; e-mail walk...@marshall.ucla.edu.
ironjustice
loss. <<
Iron accumulation with age, oxidative stress and functional decline.
Xu J, Knutson MD, Carter CS, Leeuwenburgh C
Research Support, N.I.H., Extramural, Research Support, Non-U.S.
Gov't]
PLoS ONE 2008; 3(8):e2865.
Identification of biological mediators in sarcopenia is pertinent to
the development of targeted interventions to alleviate this
condition.
Iron is recognized as a potent pro-oxidant and a catalyst for the
formation of reactive oxygen species in biological systems.
It is well accepted that iron accumulates with senescence in several
organs, but little is known about iron accumulation in muscle and how
it may affect muscle function.
In addition, it is unclear if interventions which reduced age-related
loss of muscle quality, such as calorie restriction, impact iron
accumulation.
We investigated non-heme iron concentration, oxidative stress to
nucleic acids in gastrocnemius muscle and key indices of sarcopenia
(muscle mass and grip strength) in male Fischer 344 X Brown Norway
rats fed ad libitum (AL) or a calorie restricted diet (60% of ad
libitum food intake starting at 4 months of age) at 8, 18, 29 and 37
months of age.
Total non-heme iron levels in the gastrocnemius muscle of AL rats
increased progressively with age.
Between 29 and 37 months of age, the non-heme iron concentration
increased by approximately 200% in AL-fed rats.
Most importantly, the levels of oxidized RNA in gastrocnemius muscle
of AL rats were significantly increased as well.
The striking age-associated increase in non-heme iron and oxidized RNA
levels and decrease in sarcopenia indices were all attenuated in the
calorie restriction (CR) rats.
These findings strongly suggest that the age-related iron accumulation
in muscle contributes to increased oxidative damage and sarcopenia,
and that CR effectively attenuates these negative effects.
PLoS ONE [PLoS ONE]
--------------------------------------------------------------------------------
----------
"Iron might contribute to muscle atrophy"
Increased iron content and RNA oxidative damage in skeletal muscle
with aging and disuse atrophy.
Hofer T, Marzetti E, Xu J, Seo AY, Gulec S, Knutson MD, Leeuwenburgh
C, Dupont-Versteegden EE
Exp Gerontol 2008 Feb 29.
Muscle atrophy with aging or disuse is associated with deregulated
iron homeostasis and increased oxidative stress likely inflicting
damage to nucleic acids.
Therefore, we investigated RNA and DNA oxidation, and iron homeostasis
in gastrocnemius muscles.
Disuse atrophy was induced in 6- and 32-month old male Fischer 344/
Brown Norway rats by 14 days of hind limb suspension (HS).
We show that RNA, but not DNA, oxidative damage increased 85% with age
and 36% with HS in aged muscle.
Additionally, non-heme iron levels increased 233% with aging and 83%
with HS at old age, while staining for free iron was strongest in the
smallest fibers. Simultaneously, the mRNA abundance of transferrin
receptor-1 decreased by 80% with age and 48% with HS for young
animals, while that of the hepcidin regulator hemojuvelin decreased
37% with age, but increased about 44% with disuse, indicating a
dysregulation of iron homeostasis favoring increased intracellular
free iron in atrophied muscles.
RNA and DNA concentrations increased with age and were negatively
correlated with muscle mass, whereas protein concentrations decreased
with aging, indicating a preferential loss of protein compared to
nucleic acids.
Furthermore, xanthine oxidase activity increased with age, but not
with HS, while mRNA abundance of the Y box-binding protein-1, which
has been suggested to bind oxidized RNA, did not change with age or
HS.
These results suggest that RNA oxidation, possibly mediated by
increased non-heme iron, might contribute to muscle atrophy due to
disuse particularly in aged muscle.
Experimental gerontology [Exp Gerontol]
--------------------------------------------------------------------------------
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> Research shows safe dosages of common pain reliever may help prevent
> 696 6777; e-mail walk...@marshall.ucla.edu.
ironjustice
Iron accumulation with age, oxidative stress and functional decline.
<<
I nominate the common sugar maltol.
Research to develop small-molecule drug that blocks excess iron
absorption
25. September 2009 06:53
While most people are familiar with anemia - or lack of iron in the
blood - they are less familiar with diseases of too much iron.
Excess iron in the body, if left unchecked, can form toxic deposits
in
major organs leading to serious conditions including heart failure,
diabetes, liver cirrhosis, arthritis, and even infertility. Iron
overload can be a consequence of a genetically mutated gene known as
hereditary hemochromatosis, or a consequence of red blood cell
transfusions, required as life saving treatments, for patients with
diseases such as thalassemia.
Patients with hemochromatosis and thalassemia both absorb too much
iron from their diet which either causes or exacerbates their iron
overloading to levels that are toxic.
The mutated gene for hemochromatosis is carried by 1 in 9 Canadians.
Currently over 100,000 Canadians and several million people in the US
have hemochromatosis, with many of these patients still undiagnosed.
"Part of the problem is that this condition of hemochromatosis will
present itself in disguised ways and is often unrecognized by
physicians. A patient may have arthritis, or extreme fatigue or even
diabetes, but often it's not linked to the real genetic cause, which
is iron overload," says Dr. Paul Goldberg of Xenon Pharmaceuticals.
Goldberg is the lead investigator on the $7.5 million project
entitled
Enabling Studies for a DMT1 inhibitor - A Novel Therapeutic Approach
for Treatment of Iron Overload Disorders.
The research, funded by Xenon Pharmaceuticals and Genome BC will
tackle the disease, by creating a small-molecule drug to block excess
iron absorption at its source: directly in the gut.
Currently, hemochromatosis patients are treated with lifelong
phlebotomies - invasive and sometimes painful treatments that require
regular trips to the hospital or clinic to remove about half a litre
of blood, allowing the patient to produce new blood with less iron.
While phlebotomies work well in many of the patients, they can be
problematic, causing recipients to feel unwell for a while following
the procedure. "Patients are rendered anemic temporarily so the
procedure is not suitable for people with heart conditions or needle
intolerance," says Goldberg. He also points out that patient
compliance can be a problem with this form of treatment.
As such, Goldberg's research is focused on creating a safe and
effective oral therapy as an alternative or adjunctive treatment for
those affected by iron overload.
"Patients with hemochromatosis are hyper-absorbing iron he says. The
drug that we are developing would block the key transporter for this
excess iron uptake, known as DMT1."
Thalassemia patients may also directly benefit from the DMT1
blockers.
These patients become severely iron overloaded at a young age due to
the requirement for regular life saving blood transfusions and the
additive complication of excessive iron absorption from their diet.
Patients who chronically receive blood transfusions are currently
treated with iron chelators to control their iron levels. However
chelators have severe dose limiting side effects and it remains
challenging for clinicians to maintain normal iron balance in these
patients. In addition, chelation therapy is extremely expensive,
sometimes costing up to $50,000 per patient and may require for some
patients frequent and prolonged intravenous administration.
"The Xenon drug provides an oral alternative and is being optimized
for patient safety," says Dr. Simon Pimstone, President and CEO of
Xenon Pharmaceuticals. "Our DMT1 blockers could lower the dosage of
iron chelator drugs making them safer or could make them more
effective, either way, improving patient outcomes. Our goal is to
test
this drug in iron overload patients within two to three years."
"Genome BC is pleased to co-support this innovative research, which
may develop an innovative, safe and valuable treatment alternative to
patients suffering from iron overload disorders," says Dr. Alan
Winter, President and CEO of Genome BC.
Tags: Adjuvant Therapy, Anemia, Arthritis, Cell, Cirrhosis, Diabetes,
Diet, Genetics, Genomics, Heart Failure, Hemochromatosis, Hospital,
Infertility, Metabolism, Thalassemia, Xenon
--------------------------
You take a can of cream of mushroom soup.
You add half a quarter can of milk.
You heat the soup .. up ..
You smear it on a piece of quality bread and you broil it for five
minutes.
Mmmm ..
You may add more mushrooms if you like ..
The sugar you taste is maltol ..
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> On Sep 24, 9:51 am, ironjustice <ironjust...@gawab.com> wrote:
> --------------------------------------------------------------------------------
> --------------------------------------------------------------------------------
>
> Who loves ya.
> Tom
>
> Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh
>
> Man Is A Herbivore!http://tinyurl.com/4rq595
>
> DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk
> ...
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