Protease Inhibitors And Cancer

Somebody should give a shout out to Dr. Troll of New York
University .. who FIRST .. discovered these as reported by .. me ..
many years .. ago ..
I believe it is .. niacin .. a natural protease inhibitor ..
Dr. Troll must be a .. scientologist ..

UCSF researchers identify new drug target for Kaposi's sarcoma
Science Centric | 30 July 2009 16:09 GMT

UCSF researchers have identified a new potential drug target for the
herpes virus that causes Kaposi's sarcoma, re-opening the possibility
of using the class of drugs called protease inhibitors against the
full herpes family of viruses, which for 20 years has been deemed too
difficult to attain.

The new drug target, which is known as a protease dimer, could serve
as a model for developing new therapeutics for diseases ranging from
cancer to Alzheimer's, the researchers say. Findings are reported in
the Advance Online Publication section of the 'Nature Chemical
Biology' web site.

Most current antiviral drugs target the active sites of viral
proteins, where enzymes and receptors work in a lock-and-key approach
to either activate or deactivate that particular protein, the
researchers explained. Traditionally, drug development has focused on
inhibiting that lock-and-key action to prevent the enzyme, or receptor
from being effective.

Some viral enzymes known as proteases, however, including those for
HIV and the herpes virus family, take the form of a dimer, or two
identical halves - much like a fully opened clamshell - in their most
stable state. Those proteases play an essential role in making the
virus infectious, but require the two clamshell halves to bind
together to be activated, according to the paper.

The HIV protease was successfully targeted for drug development in the
1980s, by blocking the active site on the surface of the dimer, but
the herpes virus protease dimer has consistently eluded efforts to
disrupt it at its active site, the researchers said.

The UCSF team set out to find ways to instead prevent the two halves
of the dimer from connecting at that clamshell joint, to prevent it
from activating. What they found was a new target on the unstable,
monomer form of the protease, which responded well to a chemical
inhibitor.

'If you disrupt the protein-protein interactions, you don't need the
key to a specific lock,' said Charles S. Craik, PhD, senior author on
the paper and a professor of pharmaceutical chemistry in the UCSF
School of Pharmacy. 'Instead, we're essentially preventing the lock
from being made in the first place.'

Craik, who also led a team that identified HIV protease inhibitors in
the late 1980s, said the 'Nature Chemical Biology' paper validates
this new site as a viable option for small-molecule drugs to treat
Kaposi's, as well as other members of this viral family.

'All known herpes virus proteases are structurally similar,' Craik
explained. 'The inhibitor we found knocks out not only KS, but also
the cytomegalovirus protease, so the site we've identified here could
be a target for a broad-acting inhibitor against the entire viral
family.'

To their knowledge, the researchers said, this is the first small-
molecule inhibitor of a herpes virus protease to not only act outside
the active site, but also to select for the partially unfolded protein
to keep it from forming the dimer interface.

Herpes viruses make up one of the most prevalent viral families,
including eight human viruses that cause a variety of devastating
illnesses, the researchers said. Those include mononucleosis (Epstein-
Barr virus), shingles (Varicella zoster virus), genital herpes (herpes
simplex), retinitis (cytomegalovirus) and cancer (Kaposi's sarcoma).
While therapies exist for these viruses, they often have negative side
effects and are facing rising viral resistance.

In addition to validating herpes virus proteases as suitable targets,
Craik said this research was also among the first to use computational
design to identify and create a potential drug to target that protease
interface.

Using high-throughput screening, the team screened a library of 182
compounds that it had specifically and rationally designed to mimic
the protease interface. The work identified six molecules that
inhibited the Kaposi's sarcoma virus protease activity by at least 50
percent, including one that was highly potent.

That discovery potentially opens myriad opportunities for drug
discovery, Craik said, by making target receptors that were
biologically validated, but then deemed undruggable, more attractive.
Protein-protein interactions have been researched as drug targets
against a range of diseases, from certain cancers to neurodegenerative
diseases. This advance could enable researchers to reconsider those
targets, he said.

Mom Accused of Beheading Baby Points to Need for Mandatory Postpartum

The savage dismembering of a Texas baby allegedly by his own mother
this past Sunday is the most recent example of why new mothers need to
be carefully monitored by their physicians during and after their
pregnancies, doctors say.

Although it only makes the news when a new mother harms her child or
children — think Andrea Yates — due to postpartum depression, the
truth is, said one doctor, there are also many cases where new mothers
harm, even kill, themselves in the months after giving birth to a
child.

“All obstetrical doctors that deliver babies need to do pre- and post-
natal assessments of new mothers,” said Dr. Manny Alvarez, managing
editor of health for FOXNews.com. “This is a real disease. It affects
15-20 percent of all pregnant women. And it’s not only dangerous for
the child, but also for the mother.”

Authorities say Otty Sanchez, of San Antonio, Texas, dismembered her
newborn son and ate some of his body parts before stabbing herself
during a grisly rampage.

Police say Sanchez told them she "didn't mean to kill her child" and
that the devil made her do it.

Scott W. Buchholz, the infant's father, said Sanchez suffered from
postpartum depression and that she told him she was schizophrenic a
week before the slaying. Buchholz, who said he is also schizophrenic,
said he wants her to receive the death penalty.

A family member has said Sanchez had been undergoing psychiatric
treatment and that a hospital called looking for her several months
ago. Gloria Sanchez, the mother's aunt, said her niece had been "in
and out of a psychiatric ward."

Sanchez has been charged with capital murder and is being held on $1
million bond. Bucholz wants Sanchez to get the death penalty.

Having a history of mental illness puts women at an increased risk for
postpartum depression. The reported events surrounding the Sanchez
case, if proven true, could point to an even more severe form of
postpartum depression called postpartum psychosis in which women
hallucinate, hearing voices that aren't there.

“Postpartum depression is common enough that any obstetrician or
pediatrician should be alert to the signs of that condition developing
in new mothers, particularly in any new mother with a history of
affective illness including major depression or bipolar disorder, said
Dr. Keith Ablow, a psychiatrist and FOX News Channel contributor. “One
of the reasons is that people with depression or bipolar disorder
become delusional and come to have fixed beliefs about the world
around them, which can include bizarre thoughts about their babies.”

Currently, a number of states require doctors to screen mothers for
postpartum depression, including the state of New Jersey, where
Alvarez is chairman of the Department of Obstetrics & Gynecology at
Hackensack University Medical Center.

“In New Jersey, if you’re not assessing mothers both during and after
pregnancy for postpartum depression, then you’re breaking the law,” he
said. “And there’s a group, Postpartum Support International, that’s
working to get Congress to pass legislation to make it a national
law.”

Ablow said it wouldn’t be a bad idea for maternity wards to give new
mothers a diagnostic test before they are discharged to assess whether
they are starting to feel the effects of postpartum depression.
However, the condition can set in at any point after giving birth,
said Ablow, adding that some women don’t feel depressed until several
months after their baby is born.

Ablow said it is important for women who have a history of depression
– or women experiencing it for the first time – not to dismiss
medication just because they are pregnant or breast-feeding.

“There are several helpful medicines you can take while you are
pregnant and breast-feeding for depression, including some of the
antidepressants,” Ablow said. “Not every woman needs to be taken off
medication if she is depressed and pregnant.”

Alvarez, who recorded a government public service announcement in
Spanish on the dangers of postpartum depression, said the signs of
this disease can be subtle, which is why doctors should be aware of
patients’ risk factors for the disease including previous mental
health problems.

Other risk factors include having previously suffered postpartum
depression, being pregnant with multiples, having medical problems
such as hypertension and diabetes, and having suffered the previous
loss of a child including miscarriages.”

Ablow said the following questions should be asked:

— Have you experienced a change in mood?

— Has your sleep or appetite changed?

— Do you have suicidal thoughts?

— Do you have peculiar thoughts about the baby?

— Have you become hopeless or lost interest in your daily activities?

Alvarez added, “You need to ask questions like ‘Do you feel sad?’ ‘Are
you having difficulties?’ And if you’re patient says, ‘Yes I’m having
a terrible time,’ you need to intervene.”

Alvarez said intervention can include putting moms in touch with
psychologists and psychiatrists that specialize in postpartum
depression, giving them information on support groups and emergency
call centers and using medication to control symptoms when necessary.
Who loves ya.
Tom

Oxidative Stress In HIV

Total antioxidant capacity – a novel early bio-chemical marker of
oxidative stress in HIV infected individuals
Journal of Biomedical Science 2009, 16:61doi:10.1186/1423-0127-16-

61
DR Suresh1 , Vamseedhar Annam2 , K Pratibha1 and BV Maruti Prasad3
1Department of Biochemistry, Sri Siddhartha Medical College, Tumkur,
India
2Department of Pathology, Sri Siddhartha Medical College, Tumkur,
India
3Department of Biochemistry, Bangalore Medical College, Bangalore,
India


Abstract
Background
Oxidative stress induced by the production of reactive oxygen species
may play a critical role in the stimulation of HIV replication and
the
development of immunodeficiency. This study was conducted as there
are
limited and inconclusive studies on the significance of a novel early
marker of oxidative stress which can reflect the total antioxidant
capacity in HIV patients,


Methods
Total antioxidant capacity (TAC) and lipid peroxidation were
evaluated
in 50 HIV-1 seropositive patients (including HIV-1 symptomatics and
asymptomatics). Controls included 50 age and sex matched and
apparently healthy HIV-1 seronegative subjects. Serum malondialdehyde
(MDA), Total antioxidant capacity [TAC] (by ferric reducing
antioxidant power assay), vitamin E, vitamin C and superoxide
dismutase (SOD) enzyme activity were estimated among controls and
cases. Statistical comparisons and correlations at 5% level of
significance were determined.


Results and Discussion
The mean MDA concentrations were significantly elevated in both HIV-1
asymptomatic (CD4+ count > 500 cells/microliter) and HIV-1
symptomatic
(CD4+ count <500> asymptomatic >
symptomatic) compared to controls (p <> asymptomatics > controls. TAC can be used as a novel early bio-


chemical marker of oxidative stress in HIV-1 infected patients which
may result in reduced tissue damage by free radicals and help to
monitor and optimize antioxidant therapy in such patients.

This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/
licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly
cited.
The electronic version of this article is the complete one and can be
found online at: http://www.jbiomedsci.com/content/16/1/61

Search Engine Submission - AddMe

Iron In Diabetic Wounds

"Heal small cuts 10 days faster"

Deferoxamine could help diabetics heal wounds
28. July 2009 02:08

A drug used to remove iron from the body could help
doctors fight one of diabetes' cruelest complications:
poor wound healing, which can lead to amputation of
patients' toes, feet and even legs.
The drug, deferoxamine, helped diabetic mice heal small
cuts 10 days faster than those who did not receive treatment,
according to researchers from Stanford University School
of Medicine and the Albert Einstein College of Medicine.
The team is now working to arrange human trials for deferoxamine.
If the results translate, it could help doctors combat such
diabetic complications as foot ulcers, an "unmet medical need
of gigantic proportions," said Geoffrey Gurtner, MD, professor
of surgery and senior author on the paper to be published
Monday, July 27, in the Proceedings of the National Academy
of Science.

"As soon as some more studies are done on its efficacy,
it's not going to be difficult to get clinicians to pick
[deferoxamine] up," said Richard Clark, MD, a biomedical
engineer at Stony Brook University of New York who
researches treatments for wound healing and was not
involved in the study. "It's quite a significant work."

Blisters, cuts or pressure sores on diabetic patients'
lower limbs often heal slowly or not at all, putting
patients at risk for infection and amputation.
Internal injuries are an issue, as well: More than 40 percent
of patients hospitalized for heart attacks have clinical
diabetes, and they are less likely to recover fully than
their non-diabetic counterparts.
The reason, say researchers, is that diabetic tissue fails
to reconnect oxygen-deprived areas to the bloodstream with
new vessels.
What they didn't know was why the vessels don't form.

Now, Gurtner and colleagues say the culprit is a transcription
factor that can't thrive in the high-sugar environment of
diabetic tissue.
Their potential treatment, deferoxamine, is already Food and
Drug Administration-approved for the management of chronic
iron-overload disorders.

To tease out a treatment, the researchers first focused on
the mechanisms of healing.
They isolated fibroblasts, the cells that secrete fibers to
heal wounds and bind cells together in an extracellular
matrix.
Normally, such fibroblasts ramp up production of a protein
called vascular endothelial growth factor in response to
low oxygen.
This factor prompts the formation of new blood vessels.
In diabetic cells, however, growth factor production
remained flat.

Previous studies suggested that high glucose-a symptom
of diabetes-might be to blame.
To investigate, the researchers grew healthy fibroblasts
in low or high glucose environments for four weeks,
mimicking healthy and diabetic tissue.
They then exposed the cells to low oxygen.

In response, cells grown in high-glucose ramped up production
of growth factor by only 20 percent, compared with 200 percent
in cells grown in low glucose.
Similar experiments with diabetic and non-diabetic mice
confirmed the findings: High glucose was consistently associated
with minimal growth factor production in low-oxygen environments.

But what was the glucose doing to hobble growth factor production?
The team next looked at hypoxia-inducible factor-1a (HIF-1a), a
protein that acts, Gurtner said, as a "second-to-second oxygen
sensor" in the cell.
When oxygen gets low, HIF-1a binds to DNA to trigger a cellular
response, including production of vascular endothelial growth
factor.

To work efficiently, HIF-1a must bind with a molecule called p300.
That's where the system broke down, the researchers found.
When cells were grown in high-sugar environments, the two molecules
decreased their binding by half.

The problem, said Michael Brownlee, MD, a molecular cell biologist
at the Einstein College of Medicine in New York and co-author on
the paper, is that high glucose inside cells results in the creation
of free radicals, which oxidize iron.
The iron then interacts with other cellular molecules to form
DNA-damaging hydroxyl radicals.
That damage causes a cascade of problems, including malformation
of the p300 protein.
Once damaged, p300 can't effectively bond with HIF-1a.

"What you need to do is interrupt this cascade," Brownlee said.

To do so, the team chose deferoxamine, an off-patent drug that
binds to and removes iron from the environment.
Experiments in cell cultures suggested that deferoxamine brought
hypoxia-inducible factor-1a and p300 back together, but would
that translate to better wound healing?

To find out, the researchers gave diabetic mice small cuts.
Rodents, unlike people, have a thin muscle layer under their
skin that allows them to pull the edges of wounds together.
That makes it difficult to compare a mouse's healing process
to a human's.
To solve this problem, the researchers glued a tiny,
washer-shaped stent around the wounds, preventing muscle
contraction.
They then treated some of the mice with deferoxamine cream.

The results were promising: Mice treated with the drug healed
in 13 days, compared with 23 days in untreated mice.
Treated mice also produced almost threefold more vascular
endothelial growth factor.

"By understanding the science of why is it that diabetics
generate wounds more readily and don't heal wounds, we're
able to start to target those mechanisms," Gurtner said.

The next step, said Gurtner and Brownlee, is to test the
drug on human wounds.
Deferoxamine is currently given in the form of an injection
and can have side effects ranging from mild stomach upset to,
in rare cases, susceptibility to serious bacterial infection.
However, in collaboration with Stanford chemical engineer
Jayakumar Rajadas, PhD, the team is now developing a
dissolvable sheet, similar in consistency to a Listerine
breath strip, which could be placed on the wound to deliver
the medication.
This dressing would keep the dose and side effects low,
Gurtner said, as well as making application of the drug
less painful for patients.

The first author on the paper is Hariharan Thangarajah, MD,
of the Department of Surgery at Stanford.
Other researchers at Stanford and Einstein participated in
the study.
The research was funded by the National Institute of Diabetes
and Digestive and Kidney Diseases.

http://stanfordmedicine.org

How to Cure Hemroids

In some cases, natural therapy is actually better than modern
medicine.
Hemorrhoids are ugly expressions of an ailment.
I learned how to cure hemroids.
Here 5 of the most recommended simple home remedies can help
hemorroids cure
1. Get more fiber in your diet.
2. Get regular.
3. Lose weight.
4. Drink plenty of plain water.
5. Go for regular walks.
But I found another No 5, The Magical No. 5. Has worked wonders for
me.
Are you hemorrhoids suffer? Go and take it!
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Virgin Coconut Oil

What is extra virgin coconut oil?

It is oil extracted from the meat of fresh coconuts using natural processes such as cold pressing, fermentation or centrifuging. Extra virgin coconut oil has a coconut aroma and is a clear liquid at temperatures above 22 degrees Celsius and a solid, white mass at temperatures below 22 degrees Celsius. In the warm tropics, coconut oil kept at room temperature will almost always remain in a liquid form and can be poured from a bottle. In temperate climates, for part or all of the year coconut oil will be a solid and may need to be kept in a wide-mouthed jar to facilitate scooping out with a spoon.

Extra virgin coconut oil should not be confused with industrial coconut oil which is made from aged copra. This oil has been refined, bleached and deodorized and subjected to high temperature, high pressure and chemical solvents in the process. Industrial coconut oil is yellowish, has no aroma and is always a liquid at room temperature

Paradise Extra Virgin Coconut Oil (coconut oil ful of saturated fat)

Yes, coconut oil is about 90% saturated fat. However, the saturated fats in coconut oil are natural, medium-chain fatty acids which are stable, easily digested, easily metabolized, and are not stored as fat in the body. The fatty acids in extra virgin coconut oil are in the cis form which is the form in which most fats are found in nature.

Extra virgin coconut oil does not contain harmful trans-fatty acids which have been linked to heart disease and banned in some parts of the world such as New York City because of their detrimental effects on health. In fact, coconut oil is arguably the best oil to use for cooking because its fats are naturally saturated and highly resistant to being converted into trans-fatty acids during the cooking process. In contrast, vegetable oils promoted for their high mono-unsaturated and poly-unsaturated fatty acid contents are actually highly susceptible to becoming trans-fatty acids during cooking.

The other problem with vegetable oils, such as canola oil, soybean oil, sunflower oil and even olive oil, is that they are composed of a high percentage of long-chained fatty acids which are not readily metabolized by the body and are consequently stored as fat. Extra virgin olive oil is great if you consume it raw, however, for cooking you cannot beat the stability of extra virgin coconut oil.

Beauty Tip:
Many women deal with dry skin at some time during the year (usually
winter). There are simple beauty tips you can follow to reduce the
affects dry skin such as drinking plenty of water, avoid over-washing
and taking vitamin E.

Water for Crispness:

Our bodies consist of at least two-thirds water; young people have even more, older ones a little less. Water dissolves and transports hte water soluble nutrients in our body. It balances temperature and removes hazardous materials. Water makes the skin firm and smooth.