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RISKS OF LOW HGH FOR BOTH MEN AND WOMEN

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Risks associated with low Human Growth Hormone for Men and Women

                                          Dr. Larry Sosna N.D. PhD HHP

 

Men and women who suffer from low human growth hormone (HGH) can have extremely severe symptoms.

Please understand that the pituitary gland is called the master gland of the entire Endocrine System…that essentially means the pituitary is responsible one way or another for how all the hormones are produced and how they function.

The human body has a communication system called homeostasis which is designed to keep all structures and functions within the human body at a so called normal range. Average normal temperature is 98.6 and blood pressure is well functioning at 120/80. There is according to the laws of homeostasis a normal for virtually everything in the human body.

There is a key involved in all this homeostasis. Obviously my toe is not as important as my heart or brain so in moments of stress ones tow may forego for a few minutes some blood flow while the heart is instructed to beat somewhere between 60 and 98 beats per min.

The key most important key in homeostasis is called the Adrenal, Hypothalamic, Pituitary Axis.

Many scientists will argue this is the control panel for the entire human body just the way an advanced jet plane has a sophisticated control panel and if it does not work correctly we might not safely get back to the ground.

Think of all this as you’re potential for superb excellent health as scientists have learned much about helping out the human control panel to work and function in a greatly improved manner.

Conversely, if the anterior pituitary is not making enough (HGH) human growth hormone a massive aspect of the human control panel is malfunctioning.

We know this by a set of symptoms and by seeing a blood count of IGF-1 too low.

Sometimes, symptoms are very pronounced but IGF-1 levels seem ok….Research doctors in the field virtually always agree that vast symptoms trump a number on a test.

HGH is so important it takes up one half of the entire pituitary gland and in that half the anterior section HGH and only HGH is made. Established high level of Importance.

Functions:

Proper levels of HGH allow for all cell repair and regeneration.

It does this by activating and instructing each type of tissue like heart tissue

Or lung tissue or skin tissue to find the tissue growth factor in each type of tissue

And HGH tells all of those super important tissue growth factors to get ready and gear up to repair and regenerate.

When we get older HGH falls and once it falls too low and that can even happen to a 35 year old

If they have had way too much stress and illness in life.

So it is a great THREAT to the body not to able to complete tissue repair and regeneration.

In time scientists know that can lead to smaller organs and age related diseases of all kinds.

 

There are special symptoms and threats from Low HGH that apply to Women:

Women are very special in that they can carry on and bring forth new children. To be capable of doing such a daunting task nature gave women under her skin 2 layers of fat tissue. Fat is a living tissue. Nature gave women this extra layer that men do not have to preserve our species the human family…for in times when food is scarce and a woman is with child she may have to give up the entire second layer which surrounds the entire body just to give the baby a chance of living.

When women become low in HGH they are usually at an age when their other hormones are getting too low as well. Low HGH in women causes the second layer of fat to thicken and that is not good for the cardiovascular system, blood pressure and can even start the beginning of what is known as fatty liver disease.

Unfortunately, women lose progesterone 12 years before she starts to lose estrogen. A women losing both progesterone, and is say 40 and also losing estrogen is in all likelihood low in HGH and when proven so she is at much greater risk from cardiac issues then a man.

After menopause it has been well documented that women are at a higher rate for both heart attacks and strokes, one of the reasons why is low HGH which is highly protective of the heart and brain when HGH is optimized to more youthful levels by the addition of HGH therapy. One can avail themselves of much greater cardiovascular protection.

It may sound like a small thing but low HGH in women can be responsible for thinning hair, dry hair and dry skin. Also with low HGH women cannot grow longer nails….again to most women that is not a joke or a small matter.

Originally women in the course of life made a bit more HGH from their pituitary gland but even perimenopause will create a homeostatic signal to make less HGH and thus women start to lose collagen and elastin so needed for healthy arteries as well as joint function.

Another aspect, is when women have low HGH, there is a decline in L-Dopamine. This neurotransmitter is vital for the pleasure response, including the ability to enjoy sexual activity. Why? Because L-Dopamine levels need to be high enough to make Oxytocin, which most definitely is needed for mood elevation and sexual desire.

Low HGH in women means they are subject to early bone loss as it is HGH that creates new bone cells, osteoporosis is a terrible burden, it is very painful and once it starts the only thing that can change it course fully is to restore HGH levels, back to a more youthful level. When it is has gone too far and HGH has been too low for too long that is when women get that hump curved shape to the upper spine. Women this is 100% avoidable with restored youthful levels of HGH but one must start at the correct time.

Women, who start just before perimenopause say at age 36, are so different looking than their counterparts who have not done this. They have wonderful muscle tonality, their skin looks youthful, and there is an undefinable ineffable golden glow that shows in their face…after all these years I can almost always spot women who took action and availed herself of HGH before premature aging.

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Are we on the Verge of Curing Cancer?

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                         Are We on the Verge of Curing Cancer?

I have always viewed cancer as a radical illness that needs a wide range of different kinds of treatments. This excellent article featured on CNN is just what I have been talking about using Immune-Therapy from your own body to kill off cancer tumors before they overwhelm the body.       Larry Sosna N.D. PhD HHP

 

Source: CNN

Fighting cancer by targeting its ‘Achilles’ heel’ 01:51

Story highlights

  • Scientists have discovered possible new ways to attack core mutations in a patient’s cancer cells
  • There are several limitations, including cost and the speed at which treatments could be developed

(CNN)A new breakthrough in cancer research could lead to a novel form of cancer treatment — one that is highly specialized for each patient.

Researchers discovered that even though cancer cells mutate wildly within a person’s body, the cancer cells within each patient also have common mutations — ones that could be isolated and fought off by certain immune cells.

Think of it this way: A patient’s cancer cells all start off with the same tree trunk, but then grow different kinds of branches. The new research shows certain immune cells can “chop the tree at the trunk rather than just pruning the branches,” Dr. Sergio Quezada told CNN.

WHO urges cancer prevention 02:42

Quezada, from the University College London’s Cancer Institute, co-authored the study, which was published Thursday by Science magazine.

For years, one of the biggest obstacles in fighting cancer has been the fact that a tumor’s cancer cells are not all the same.

“The tumor is an evolving mass. Mutations change here and there. Mutations in one area of the tumor are usually different from mutations in other parts of the tumors,” Quezada said.

Read: These dogs can sniff out cancer better than some tests

In a statement to Cancer Research UK, he likened the fight against cancer to police chasing a wide array of criminals.

“The body’s immune system acts as the police trying to tackle cancer, the criminals. Genetically diverse tumours are like a gang of hoodlums involved in different crimes — from robbery to smuggling. And the immune system struggles to keep on top of the cancer — just as it’s difficult for police when there’s so much going on,” he said.

“Our research shows that instead of aimlessly chasing crimes in different neighborhoods, we can give the police the information they need to get to the kingpin at the root of all organized crime — or the weak spot in a patient’s tumor — to wipe out the problem for good.”

What this means for treatment

Quezada told CNN this discovery could lead to two kinds of treatment:

1) Making customized vaccines to target the core mutations in each patient.

2) Identifying which immune cells, or T-cells, can fight off those core mutations, then multiplying those T-cells in a lab.

Quezada said the customized vaccines would be “the ultimate personalized form of therapy.”

Billionaire behind Cancer Moonshot 2020 02:49

“This would mean basically taking a cancer tumor, finding the trunk, and then designing a vaccine (to) inject in the patent,” he said.

“The second approach is to ‘fish’ these cells — T-cells — that recognize the trunk, expand them outside the patient” and inject them in the body.

Quezada said no human trials have started using either approach in light of the study, but said he hopes trials will begin within five years.

Read: Blindsided by cancer? 5 things to do

The limitations

But the discovery doesn’t mean all cancer patients will be cured soon. The potential for new treatment also has several limitations.

First is “the speed at which you can generate personalized therapy,” Quezada said. “Some cancers go really fast.”

Pharmaceutical CEO speaks about $1 cancer drug 03:32

Developing a customized vaccine, for example, could take more time than a cancer patient has.

Second, it would be expensive. Quezada said he doesn’t have an estimate on how much either type of treatment would cost, but given the highly customized nature of each, it could be extremely expensive.

“That’s going to be an important point of this discussion,” he said.

Finally, such treatments would likely work better for some types of cancer than others. Quezada said he believes lung cancer and melanoma would be the most likely to respond well to such treatment.

Read: Why cancer drugs worth $3B are wasted

A massive collaboration

A team of 36 international researchers worked on the study, which included scientists from the London, the United States, Denmark and Germany. The study was funded by Cancer Research UK and the Rosetrees Trust.

“It’s the most amazing collaboration I’ve ever worked on, Quezada said. “It’s been an amazing roller coaster.”

The next roller coaster will be determining when patients could receive the treatments — and learning how well they might work.

CNN’s Dominique Heckels contributed to this report.

 

 

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Healing Injured Spinal Discs

Healing Injured Spinal Discs even ones which have Herniated

Larry Sosna N.D. PhD HHP

There have literally been several hundred peer reviewed research articles on how Human Growth Hormone works to regenerate all cells, tissues and organs, in the human body. The process is a very elegant one which gives rise to a much greater understanding of how the human body heals itself after injuries. In general this is how the HGH system of bodily healing and repair works.

If a person has youthful blood levels of HGH any injury anywhere sends out signals through the biofeedback communication loops to send HGH to the liver were IGF-1 is made. IGF-1 signals all the cells, tissues and organs of the body to release its specific Embryonic Tissue Growth Factors (ETGF.) The ETGF mobilize to do protein synthesis to the point where the tissues build up until repair is complete. Let’s look at a small example and then we can look at something which almost everyone needs repair and healing of…that being the discs of the spine… as many millions of people have hurt their backs…I have heard estimates can go as high as 3 out of 4 people in their life time have had painful back problems. First, allow me to get back to the small example of HGH in the healing process.

 

You are cooking and using a sharp knife to cut vegetables, time is of the essence and you cut faster then suddenly you go ouch! I cut my finger. You quickly clean the wound and then you notice it is a real cut but not down to the bone. In this case, it is called healing by first Intension, which means you will not need stitches and there will be a very little scar that with enough time will fade away completely. In this and all other cases what proceeds is exactly what I described above… Please notice how the very youthful heal from a cut finger much faster than a person 50 or 60 this is because at age 50 most folks are making roughly 70% less HGH than a person 18 years old. BUT, and I have experienced this for myself many times as have many other folks 40 and up who take shots of HGH to get  back to youthful blood levels of HGH… my finger cut will heal very quickly. I, and many of my clients on HGH report the very same thing…cuts heal about twice as fast as a person age 40 and up who does not take injections of HGH. The reason for this small example is I cut my finger with a very sharp knife I was making dinner about 4 days ago… when a friend called out to me  I turned my head to look at her and the next thing I knew blood was all over my kitchen floor. I have personally been on supplemental injections of HGH for 23 years and in just 4 days a fairly deep cut is almost completely gone.

 

Let’s look at the HGH healing formulation again. Youthful blood levels of HGH = a speedy regeneration of all types of wounds including rebuilding new discs which have been wounded through herniation of the disc. Once again, please allow me to illustrate how to regenerate a new healed disc from an old injured one.

What are the discs subcomponents? In other words what is the disc made of? Problematically, it is made of Fibrocartilage. Why do I say it is problematic? Because, Cartilage has no vascularity and thus no blood supply to quickly bring in the embryonic Mesenchyme Tissue Growth Factor and HGH which does regenerate Cartilage, BUT very slowly. Why? Because without a blood supply, Cartilage must get all nutrients and healing Growth Factors plus IGF-1 through the very slow process of osmosis. How did I learn to make the process go faster? First, by heating the affected disc with hot packs for 25 min each day, This gets more blood into the affected area .Next I showed folks how repeated soft movement 5 to 6 times a day makes the process of osmosis go much faster. Why? Because correct movement is like a pump…pumping all the healing agents mentioned above through the disc. Thus if you are one of the many millions who have injured discs and you want to regenerate them as I have for myself one will need to avail themselves of both HGH and Embryonic Mesenchyme Growth Factor which you can obtain right here at the SOSNA ANTI-AGING Rejuvenation Center…where we not only deeply care for all of our family of clients…BUT we also engage in the most cutting edge regenerative protocols… which is why we justly say about competition…They may be catching on but they are NOT catching up. It is our unyielding commitment to ourselves and to you are family of clients we care for.

 

Peer Reviewed References

·         Evaluation of patient satisfaction with second intention healing versus primary surgical closure

  • Journal of the American Academy of Dermatology,Volume 73, Issue 5, November 2015, Pages 865-867.e1
  • William G. Stebbins, Julia Gusev, H. William Higgins II, Andrew Nelson, Usha Govindarajulu, Victor Neel

 

 

Zone-specific integrated cartilage repair using a scaffold-free tissue engineered construct derived from allogenic synovial mesenchymal stem cells: Biomechanical and histological assessments.

Fujie H, Nansai R, Ando W, Shimomura K, Moriguchi Y, Hart DA, Nakamura N.

J Biomech. 2015 Oct 19. pii: S0021-9290(15)00563-1. doi: 10.1016/j.jbiomech.2015.10.015. [Epub ahead of print]

 

Journal of Biological Chemistry 2003, Oct,24 Shi-Wen X, Abraham D.J. Denton C, Black, CM.

 

Effect of Human Adipose Tissue Mesenchymal Stem Cells on the Regeneration of Ovine ArticularCartilage.

Zorzi AR, Amstalden EM, Plepis AM, Martins VC, Ferretti M, Antonioli E, Duarte AS, Luzo AC, Miranda JB.

Int J Mol Sci. 2015 Nov 9;16(11):26813-26831.

 

Synergistic effect of ascorbic acid and collagen addition on the increase in type 2 collagen accumulation incartilage-like MSC sheet.

Sato Y1Mera H2,3Takahashi D4Majima T5Iwasaki N4Wakitani S6Takagi M7.

Author information

  • 1Division of Biotechnology and Macromolecular Chemistry, Graduate School of Engineering, Hokkaido University, Kita-ku, N13W8, Sapporo, 060-8628, Japan.
  • 2School of Health and Sports Sciences, Mukogawa Women’s University, 6-46 Ikebiraki, Nishinomiya, Hyogo, 663-8558, Japan.
  • 3Foundation for Biomedical Research and Innovation, International Medical Device Alliance, 1-6-5, Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
  • 4Department of Orthopaedic Surgery, Graduate School of Medicine, Hokkaido University, Kita-ku, N15W7, Sapporo, 060-8638, Japan.
  • 5Department of Joint Replacement and Tissue Engineering, Graduate School of Medicine, Hokkaido University, Kita-ku, N15W7, Sapporo, 060-8638, Japan.
  • 6Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 739-8553, Japan.
  • 7Division of Biotechnology and Macromolecular Chemistry, Graduate School of Engineering, Hokkaido University, Kita-ku, N13W8, Sapporo, 060-8628, Japan.

Mesenchymal stem cells: clinical applications and biological characterization

Received 22 September 2003, Revised 30 October 2003, Accepted 3 November 2003, Available online 24 January 2004

 

Volume 28, Issue 8, August 2000, Pages 875–884

Review

Mesenchymal stem cells: Biology and potential clinical uses

Annemarie B. Moseley

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The Power of D-Ribose How to make Pure Energy in every Human Cell

 

By Dr. Larry Sosna N.D. PhD HHP

SOSNA LABORATORIES® 02/2015  Corvalen® Chews are an all natural D-ribose supplement clinically proven to help restore and replenish core energy. D-ribose is a natural pentose sugar that is designed for the support of cardiovascular health, fatigue, energy production, and mitochondrial function†. Corvalen® chewable tablets are great tasting with natural orange/vanilla flavoring sweetened with xylitol, and readily absorbed into the body. FUNCTIONS Corvalen® contains pure D-ribose, a safe and clinically researched ingredient that supports the natural way our bodies produce adenosine triphosphate (ATP), the energy currency of the cell. †Ribose is the vital structural backbone of critical cellular compounds called purines and pyrimidines. Our bodies must have an adequate supply of purines and pyrimidines to form major cellular constituents such as our genetic material (DNA and RNA), numerous cofactors, certain vitamins, and, importantly, adenosine triphosphate (ATP). Ribose is the starting point for the synthesis of these fundamental cellular compounds, and the availability of ribose determines the rate at which they can be made by our cells and tissues. D-ribose is a structural component of DNA, RNA, ATP, GTP, flavins (FAD, riboflavin) and other important nucleotides found in all living cells. Ribose is formed naturally via the pentose phosphate pathway. This pathway is slow and rate-limited in cardiac and skeletal muscle due to an inherently low concentration (lack of expression) of the enzymes, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. The product of this pathway is ribose-5-phosphate, which in turn is converted to 5-phosphoribosyl-1- pyrophosphate (PRPP), the primary driver in the synthesis and salvage of purine nucleotides. No other compound can be used by the body for this metabolic purpose. Purine nucleotides (ATP and its precursors) lost due to ischemia, hypoxia, or genetic predisposition are replaced via the purine nucleotide pathway. This pathway is rate limited by the availability of ribose in tissue. Administration of exogenous ribose bypasses the rate-limiting steps in the pentose phosphate pathway, resulting in a significant acceleration of PRPP. Renewed concentration of ATP is accompanied by an increased energy potential in the cell, also known as the “energy charge.” Cardiac and skeletal muscle functions (i.e. contraction, cell wall maintenance, relaxation, polarization of the cell membrane) each require a different, quantifiable energy charge to drive or provide allosteric regulation for each function. Restoration of cellular energy charge restores function consistent with the degree of energy charge restored. D-ribose is indicated for sports and fitness activities because it helps to reduce the loss of energy during stress and accelerate energy and tissue/muscle recovery†. Endurance athletes and strength training athletes may both benefit from the effects of supplemental D-ribose. Unless our hearts have an adequate supply of ribose, they simply cannot satisfy their astonishing energy demand. Our bodies make ribose naturally, but in times of stress the need is greater than our supply to satisfy the loss of energy from our cells. That is why supplementing with d-ribose can support proper heart function and helps maintain healthy stroke volume during and after high intensity exercise†. A study by Olman et al. in 2003 showed beneficial effects on diastolic function and quality of life in compromised patients after only 3 weeks of supplemental D-ribose. Although D-ribose is a five-carbon monosaccharide, it does not raise blood sugar. Corvalen® D-ribose is non-GMO. D-ribose is rapidly and readily (~95%) absorbed with peak blood levels found within 30 – 45 minutes. Ribose not taken up by the cell is excreted unchanged in the urine. Corvalen® D-ribose is GRAS (generally recognized as safe), a determination that results only after considerable toxicology studies are performed and an expensive and time consuming FDA process is completed.

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Risks Associated with Low HGH in Men

Men are extremely different than woman when it comes to the risks which arise from low

(HGH) Human Growth Hormone. Men with risky low levels of HGH will suffer from

extraordinary lack of energy and motivation.

HGH in men is exceptionally crucial as the man’s two most significant hormones which build

them up physically and even emotionally are HGH and Testosterone. Women are much more

complicated hormonally speaking.

Please let us make this very clear Protein has been scientifically proven to build human beings

up. Therefore we call the building up process Anabolic…which has NOTHING to do with

steroids…HGH is NOT a steroid but it is the single most important hormone in a man’s body.

Conversely, there are substances that tear the body down and that is called the Catabolic

process and this is highly dangerous for men to be in a catabolic state, ever.

Simply put, if a man is low in HGH he is automatically catabolic.

What exactly does that mean and just how dangerous a risk is this?

It means that when a man is in a catabolic state from low HGH he is not able to replace cells

and tissues faster than his body is breaking them down. What exactly does that mean?

According to Dr. Sam Baxus, one of the world’s foremost authorities for over 40 years on low

HGH…it means that you as a man are needlessly slowly dying faster than their male friends who

do not yet have low human growth hormone blood levels.

There also exits a direct relationship between HGH and testosterone in men such that if a man

is low in HGH it is very likely to have a negative impact Testosterone production. Thus more

muscle weakness, fatigue, more fat lower lean muscle mass, and depression in men.

It means, that every aspect, every part of your body is being torn down piece by piece.

And the leading first symptom for men is lack of energy and low motivation.

Then men notice an increase in fat around the belly area and a loss of tone to their muscles.

This alone is a risk which is certainly not acceptable once a man understands that inner fat

increased around the waistline has clearly been established by cardiologists as an INCREASED

risk of having a sudden and severe Heart Attack.

Demographic studies at the University of North Carolina (chapel Hill) often referred to as the

little Harvard of the South… is known to produce the best studies of risk for illnesses of every

type according to age and the numbers of folks in each age group.

Regarding their study on HGH by age groups something enormously profound was gleaned.

Age 18, is the best age group nationwide according to HGH levels and the almost complete lack

of illness in that age group. We noticed that every 8 years after age 18 there was and is a

dramatic rise in age related disease so if one takes age 18 as nearly perfect for HGH purposes

and we times 18 by 3 we get age 54 the highest group of men by age for heart attacks each

year. Between age 45 and 55 men are at severe risk for heart attacks

Thus if we look at all age related disease due to lack of HGH by this best demographic study

ever done so far, we find an enormous mistake. Generally it has been said we lose 50% of our

HGH output every 30 years past age 20. So it has been said for years that age 50 you make only

half the HGH as you did at 20

BUT if one delves deeply into the University of North Carolina’s massive demographic research

study on age related illness and relationship to HGH levels we easily see that after age 18 we

lose 50% of our HGH output every 8 years after the age 18.

So for men the risks come on generally around age 35 to 40 with belly fat and lack of energy

and motivation.

Next there are changes in the make-up of cholesterol with an increase in the bad LDL and also

an increase in the dangerous Triglyceride levels going up for men.

A man’s stamina decreases when HGH levels are low.

Men experience less lean muscle with low HGH

Men also complain about being more sensitive to heat and cold with low HGH. Men are more

sensitive to light. Especially bright light, which is an indication of breakdown of eye tissue.

Men experience as an early warning sign of low HGH a lack of sexual desire and function.

Eventually, bones density becomes more porous and fractures from a simple trip fall can occur

The immune system starts to breakdown for men if they do not take action and get themselves

on more optimal youthful blood levels of HGH.

Men, you can forgo all these dangerous risks. AAI provides true expert advice and expert HGH

treatment protocols. Women live 10 years longer than men. Come on guys 10 years is a mini

lifetime.

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Is it time for a new paradigm in mental health?

Are non-drugs, like virgin coconut oil, a safer and more effective alternative to stress and depression?

A new study conducted in Malaysia looked at the effects of consuming high-antioxidant

virgin coconut oil on mental health.

Published in the journal Experimental and Therapeutic Medicine and believed to be the

first study of its kind, researchers evaluated the anti-stress and antioxidant effects of

virgin coconut oil in mice with stress-induced injuries. The title of the study is “Anti-

stress and antioxidant effects of virgin coconut oil in vivo.”

The researchers performed several stress tests on groups of mice. Control groups

included untreated mice and mice not subjected to stress and virgin coconut oil was

compared to a commonly prescribed psychiatric drug, Diazepam.

Their results were quite impressive, and suggest that using a high quality virgin coconut

oil can rival antidepressant drugs without the dangerous side effects. The researchers

attributed the success in treatment to the unique mixture of medium chain fatty acids

found in coconut oil rich in saturated fats, and to the antioxidants present in higher

grade, less processed virgin coconut oils.

While we do not endorse the supposed “science” behind psychiatric drugs, which

attempts to measure such things as “neurotransmitters” and “biochemical profiles” as

true indicators of mental health that can be altered by chemical drugs, it is encouraging

to see researchers consider natural foods as alternatives, given the fact that they do

not have all the serious side effects that psychiatric drugs do.

One of the more interesting tests conducted in this study was a measurement of

“immobility time” after a forced swim test. The researchers found that the untreated

mice had a longer immobility time than mice treated with virgin coconut oil. They

attributed this to the high medium-chain fatty acid content of coconut oil, which is

known to produce thermogenesis and increased energy.

One area where virgin coconut oil (VCO) really outperformed the drug Diazepam was in

the area of oxidation and elimination of free radicals. This is something that can be

measured with lipid peroxidation (MDA) and antioxidant enzyme SOD levels. Stress is

known to increase oxidation and the creation of free radicals, leading to neuronal cell

damage and death. Antioxidants, on the other hand, reverse this trend and help

prevent further neuronal damage.

The researchers found:

VCO was able to reduce lipid peroxidation and increase the activity of SOD in the serum

of mice undergoing the forced swim test and the brains of mice subjected to chronic

cold restraint. It was previously reported that VCO is rich in polyphenols and these

antioxidants may contribute to the increased levels of antioxidant enzymes, which

subsequently reduce lipid peroxidation and inflammation in VCO-treated mice.

Restoration of antioxidant levels in the brain may help prevent further neuronal damage

and avoid subsequent depletion of monoamines, including DA. In conclusion, the

present study demonstrated the potential of VCO in preventing exercise- and chronic

cold restraint stress-induced damage and restoring the antioxidant balance. This

promising anti-stress activity may be attributed to the polyphenols and medium-chain

fatty acids present in VCO.

It is high time for a new paradigm in mental health. Drugs are not the solution to stress

and depression. Non-drug alternatives are not only safer, but can be more effective

than pharmaceutical drugs as well.

Reference

Anti-stress and antioxidant effects of virgin coconut oil in vivo.  Experimental and

Therapeutic Medicine – Jan 2015; 9(1): 39–42

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Reversing Atherosclerosis and Cardiovascular Disease

Healthy senior couple over fresh fruits and vegetables background.

Healthy senior couple over fresh fruits and vegetables background.

by: Larry Sosna N.D. PhD HHP

The Medical establishment would have all of us believe that coronary heart disease is irreversible and must lead to

either the eventual so called heart attack due to clogged arteries; or to by-pass operations, stents, followed by

balloon angioplasty. They tell us with Statin drugs the patient will then be ok. The statistics paint a very different

picture. Two out of every three people who have had cardiac by-pass surgery will need it again within 10 years.

Ten out of ten cardiovascular patients who have had stent procedures will need them again within 6.4 years.

Clearly, even with massive doses of statin drugs the treatment protocol for cardiovascular patients in use today by

the medical establishment is a failure in the sense that it’s not a cure and the above protocol is an ongoing radical

process for the body to endure.

One need  look no further than the case of former President Bill Clinton who had Quadruple by-pass heart surgery,

stent after stent, balloon angioplasty again and again, massive statins and still he had advanced coronary artery

disease(CAD) until he finally discovered a natural, yet very scientific integrative treatment protocol which has

reversed his CAD.

In the 1960’s and 1970’s Nathan Pritikin M.D. developed a unique diet rich in massive amounts of fruits and

vegetables and very low in total calories and fats. Dr. Pritikin developed this protocol after he was diagnosed with

severe atherosclerosis of the coronary arteries. He was so convinced his protocol reversed CAD he left instructions

in his will that when he died he was to have a cardiologist examine the condition of his arteries. Meanwhile

thousands of his patients went off all medications and never had any more coronary artery problems. After Dr.

Pritikin died in 1987, his heart was dissected; the arteries were determined by cardiologists to be clean and in the

condition of a 25 year old.

In 1987, two years after Dr. Pritikin’s death, the Journal of the American Medical Association announced a study

that showed the reversal of atherosclerosis in the coronary arteries of humans who were on the Pritikin protocol as

administered at the Pritikin Longevity centers had been a success.1 Numerous subsequent studies confirmed Dr.

Pritikin was scientifically correct and the medical establishment’s position fatally flawed.2,3

Tens of millions of Americans needlessly perished because the medical establishment refuses to understand the

true causes of Coronary Artery Disease.

The over-promotion of “Statin” drugs has resulted in today’s cardiologists focusing on getting their patients’ total

cholesterol and LDL down to dangerously low levels. Pharmaceutical company advertising has made it appear as if

the only cause of CAD is excess LDL and cholesterol; however over a thousand scientific peer reviewed research

studies show this conclusion to be completely false…

Beginning in 1979, medical researcher scientists made discoveries which clearly indicated that CAD was the result

of the oxidation of LDL that results in the formation of blocked arteries and arterial damage.4,5   Thousands of peer

reviewed studies now reveal how oxidized LDL creates CAD from start to finish.

There are doctors who argue that CAD is all about inflammation and they are correct but what they failed to

realize is that oxidized cholesterol mainly LDL injures endothelial cells and causes this massive inflammation of the

coronary arteries.6-12

Oxidized LDL causes endothelial cells to secrete ultra-sticky adhesion molecules that allow white blood cells to

penetrate the inner lining of the artery. This is where initial fatty streaks congeal and atherosclerotic plaques

develop in thickening layers.13

Oxidized LDL turns on white blood cell gene expression that enable them to convert into foam cells, which results

in continuous accumulation of oxidized LDL and thick plaque in the coronary arteries.14

Oxidized LDL initiates an inflammatory process by causing foam cells to make molecules that attract

proinflammatory cells and cytotoxins that further inflame the artery linings.15

Oxidized LDL enhances the process whereby immune cells, foam cells, smooth muscle cells, and the lining of

coronary arteries called endothelial cells, degrade collagen, which leads to the rupture of the fibrous plaque. The

extreme heat from the inflammation can cause even small amounts of cholesterol to blow up 40 times their normal

size and clot up an entire coronary artery, thus recently the Harvard study group called this phenomenon Popcorn

Cholesterol. This finally explains why 53% of all fatal heart attacks occur in people with rather low cholesterol,

something until recently which has greatly confused cardiac medical researchers.16

Forty years ago coronary artery disease was the #1 cause of death in America roughly 600,000 people died each

year from CAD. Today despite doctors handing out statin drugs like candy CAD is still the #1 cause of death each

year at roughly 630,000 deaths per year. We have the highest rate of cardiac disease in the entire world despite all

of the most so called state of the art drugs…in fact statin drugs have led some 200,000 people to develop

irreversible muscle wasting syndrome which is always fatal; and statins have also been linked to advanced liver

and kidney disease.

THE SOLUTION

In reality the solution to this problem of oxidized LDL is very simple if you understand plant based biochemistry.

Dr. Pritikin thought the reversal of plaque and CAD was due to the very low intake of fats in the diet he created. In

fact that had little to do with anything, it was the antioxidants from a huge assortment of fruits and vegetables

which prevented LDL from oxidizing in the coronary arteries and thus stopped inflammation and the whole above

described process of oxidized LDL leading to CAD.

The problem with the Pritikin program is it is so very restrictive in calories that most folks simply cannot make a

lifelong commitment to it. We also now know about antioxidants in the form of nutraceutical plant based

supplements 1000’s of times more powerful then eating the fruits and veggies on the Pritikin diet.

We should all breathe easier knowing that when it comes to INHIBITING LDL oxidation we can now stop it cold with

natural biochemicals such as UBIQUINOL CoQ10…. With the exception of Alpha Lipoic Acid and the active

biochemical in Pomegranate (Proanthocyandids, and Polyphenols) nothing is effective as CoQ10, we can actually

now improve the inhibition of oxidized LDL cholesterol by 130%… far greater protection then the Pritikin diet.17

Yet we can go even far greater in reversing CAD by taking Nutraceutical quality Omega 3 oils every day. Omega 3

fish oil, Krill oil and Green Lipid muscle oil are extraordinarily powerful inhibitors of inflammation. The above are

such powerful High Density Lipids the good HDL’s, they can virtually assure that hard LDL cannot clump together,

in fact Eskimos and the arctic circle indigenous peoples account for five million people. They eat huge amounts of

cholesterol from seal blubber and whale blubber yet we have never found even one upon autopsy who had CAD.

Think about that, although they eat a diet 80% pure cholesterol they are completely protected by the 18% of their

diet which is cold water fish oil in the form of wild salmon.18-22

Stacking Powerful Antioxidants… The Sosna Protocol to cure advanced CAD

I have created a unique program by stacking the most powerfully effective antioxidants to reverse CAD for even

the most advanced CAD patient. Besides the above mentioned powerful antioxidants the stacking of nutraceutical

antioxidants also includes:

SAMe, Folic acid, isoflavones, Epigallate-Catchen-3 Galate, Resveratrol, Tocotrienols, Vit. E, Lutein, Lycopenes,

Ascorbyl Palmitate, Gingerols, Silymarin, Bromelain, Calcium D-Glucarate, Punicalagins, Hesperidin, Canthaxathin

and several others if need be. All of these super antioxidants are found only in the bio-diversity of plant based

molecular biochemistry in nature and in scientifically fresh cold pressed ocean based omega 3 fatty acids.

President Clinton is receiving with stellar results a similar protocol to mine…He will not need any more balloon

angioplasty or any other invasive treatments again so long as he stays on this treatment protocol for life.

In addition we have discovered plant extracted sterols can lower LDL by 38% in a very unique manner. They trick

the production of harmful LDL from entering the blood stream and instead send them a signal to enter the large

intestines where they are excreted via normal bowel movements.

In conclusion we have had for a long time the most effective all natural treatment protocol for reversing

cardiovascular disease. All the natural biochemicals I have mentioned are derived from plants, fruits, and marine

life, extracted and highly concentrated by a leading biotechnology company which is ISO 9001 and ISO 17025

While one may be tempted with this information to do it yourself without expert guidance, I strongly urge you to

consider the following. Eighty percent of all stores bought cold water fish oil sold as omega 3 HDL is already rancid

when purchased! Rancid oils have enormous amounts of free radical oxidants which cause CAD.  Unless you are

positive you are obtaining your nutraceutical supplements from a true ISO certified biotechnology laboratory be

very careful. The quality and purity of store the supplements will be no more than 20% pure due to their poor

quality extraction methodology, the other 80% may include large amounts of biological fragments, fillers, and

environmental toxins to the point where one is actually consuming enormous amounts of free radical oxidants

which seriously damage the heart, and other organs! Why? Because market competition is so fierce in the

supplement industry over 90% of the drug store and health store brands buy their raw materials from China; where

raw materials for making supplements are extremely inexpensive. The problem is China is the most polluted

industrial toxic country and raw organic material from China to make supplements will have high levels of toxins.

Any supplements made in the USA but sourced from China may be highly toxic. They will never be made by ISO

9001 ISO 17025 biotechnology companies; you simply cannot find this highest quality in health food stores and if

they claim they carry such a high standard ask the manager for a certified copy of ISO 9001 ISO 17025 for the item

you desire to purchase. They cannot produce the above mentioned certifications because there are only several

biotechnology companies worldwide, that have both ISO certifications and they only sell to doctors, dentists,

naturopathic doctors and nutritionists with a PhD.

Peer Reviewed research and footnotes.

1. Roberts CK, Chen AK Bernard JR Effects of short term diet and exercise intervention in youth on atherosclerotic

disease risk factors. Atherosclerosis. 2007 mar; 191 (1) : 98-106

2. Roberts CK, won D, pruthi S, et al. Effects of short term diet and exercise intervention on oxidative stress,

inflammation, MM-9, and monocyte chemotactic activity in men with metabolic syndrome factors. J Appl

Physiol. 2006 may; 100(5): 1657-65.

3. Roberts CK, Vaziri ND, Bernard RJ. Effects of diet and exercise intervention on blood pressure, insulin,

oxidative stress, and nitric oxide availability. Circulation. 2002 Nov 12;106(20):2530-2.

4. Anderson JW, Konz EC, Jenkins DJ. Health advantages and disadvantages of weight-reducing diets: a computer

analysis and critical review. J Am Coll Nutr. 2000 oct;19(5):587-90

5. Henriksen T Mahoney EM Steinberg D. Enhanced macrophage degradation of low density lipoproteins previously

incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins.

Proc Natl acad Sci USA. 1981 Oct;78(10):6499-503.

6. Hessler JR, morel DW, Lewis LJ, Chisolm GM. Lipoprotein oxidation and lipoprotein-induced cytotoxicity.

Arteriosclerosis. 1983 May;3(3):215-22.

7. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential

role in recruitment and retention of monocyte/macrophages during athero-genesis. Proc Natl Acad Sci USA.

1987 may;84(9):2995-8.

8. Ross R. Atherosclerosis—an inflammatory disease. N Engl J med. 1999 Jan 14;340(2):115-26.

9. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med. 1986 Feb 20;314(8):488-500.

10. Yla-herttuala S, Palinski W Rosenfeld ME, et al. Evidence for the presence of oxidatively modified LDL in

atherosclerotic lesions of rabbit and man. J Clin invest. 1989 Oct;84(4):1086-95.

11. Steinberg d, Carew TE, khoo JC, witztum JL. Beyond cholesterol. Modifications of LDL that increase its

atherogenicity. N Engl J Med. 1989 Apr 6,320(14):915-24.

12. Berliner JA, navab m, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation. Inflammation, and

genetics. Circulation. 1995 May 1;91(9):2488-96.

13. Suits AG, Chait A Aviram M, Heinke JW. Phagocytosis of aggregated lipoprotein receptor-dependent foam cell

formation. Proc Natl acad sci USA. 1989 Apr;86(8):2713-7.

14. Zhang WZ, Vernardos K Finch S, kaye DM. detrimental effect of oxidized LDL on endothelial arginine

metabolism and transportation. Int J Biochem Cell Biol. 2008;40(5):920-8

15. Faloon W. A lethal misconception of epidemic proportion. Life Extension. 2007 May; 13(5):7-14.

Danesh j, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major

Read More

Glycomics, One of the 10 emerging technologies that will change the world.

MIT said the field of Glycomics, is “One of the 10 emerging technologies that will change the

world.” Notice, they did not say, one of the 10 medical technologies but one out of ALL

technologies that will change our world. It is as important as DNA and the Genome because the

8 major fundamentals of Glycobiology control both DNA and RNA. We even have the

Glyconome! Glycobiology controls our hormones and how they function…If you cannot get

enough of these 8 essentials life sustaining Glyconutrient’s, no matter how much HGH you take

it will have no effect or a neg. effect I am one of the few true experts in this exploding field. The

value to this more ramped up scientific language is so unique in this article that Google will

get in on these words I am using, KEY in on them and our standing in Google will go up

and up because no other competitor knows the scientific language of this anti-aging

breakthrough.. but Google’s algorithm’s and scrubbers places a very high value when you

write what others cannot or have not. When it is singular, as mine is and only on our

website blog Google loves that! That is why I want to write several articles on this topic so

germane to regeneration and living heathier for much longer. AND, there is big money in

this field selling sugars that heal. Please let me know what you think.

HELP DEFEAT ILLNESS AND GREATLY EXTEND YOU’RE LIFESPAN

Seminal Research by Larry Sosna N.D. PhD HHP

GLYCOBIOLOGY OF LIFE

See and hear what the true great university scientists are saying. “This is the future

today”, declares Dr. Gerald Hart of John Hopkins University…The number one rated

medical/scientific teaching hospital in the entire USA. “We won’t understand

Immunology, Neurology, Developmental Biology or Pathology until we get a handle on

Glycobiology.” ….. “If you ask, what is the Glycome for a single cell type it will be many

thousands of times more complex than the genetic Genome,” says Ajit Varki past

director of the Glycobiology Research and Training Center at Cal Tech. Professor

Raymond Dwek, head of the University of Oxford’s Glycobiology Institute, who

coined the term Glycobiology in 1988 says, “ As recent advances in genetics have

unfolded, the importance of sugars which heal has become ever more apparent.”…..

Varki said, “It’s like we just discovered the continent of North America. Now we have to

send out scouting parties to find out how big it is…..”

New Scientist Magazine, October 2002

I’m certain you have been told many times, sugar is one of the main enemies in life

causing all kinds of disease states and folks that can indeed be true. There are harmful

sugars and there are sugars so vitally important to vigorous good health that without

them we would all have suffered and died a long time ago. In fact, without these

miraculous special sugars we never would have made it out of infancy.

Glyco means sweet, there are bad sugars and ones we cannot live without, they are the

healthy Glyconutrients. If you are on one of those fad diets that does not allow the life

enhancing complex carbohydrates then you cannot make Glycoproteins which are

molecules that combine sugars with proteins as well as glycolipids, which are

combinations of healing complex sugars with fats. The term for these life giving

combinations are called glycoconjugates. These glycoconjugates have brought together

the world’s most brilliant medical scientists to comprehend a field so sophisticated the

combinations of glycoconjugates are infinite in how they arrange themselves to yield a

healthy body free from disease if you have them in high enough blood levels.

It will be useful to provide one with a high level of education concerning the immense

healing powers of a strong personal Glycobiology. Let’s shine some light on what

healthy levels of Glycoconjugates can do for the human body to improve both structure

and function.

Immune System Modulation:

Glyconutrients are necessary for healthy immune cells and a body wide capable

immune system function. They have been shown to:

Play a key role in many aspects of cell and tissue regeneration and repair, as well as

cell survival. They have strong positive effects on asthma and allergies in general.

Glyconutrients are one of the very few methods of preventing and or slowing down even

rheumatoid arthritis, lupus, and improves the symptoms of periodontal disease, canker

sores and herpes simplex 1 of the lips.

They have a favorable outcome in suppressing skin reactions and contact dermatitis as

well as inhibiting bronchitis. Many studies show they can prevent arthritis, substantially

reducing pain and increasing joint mobility in osteoarthritis, the most common form of

arthritis.

CANCER RESEARCH:

Glyconutrients and glycoconjugates help to inhibit growth and or tumor cell metastasis

in certain types of cancer. They do this by instructing white blood cells called Natural

Killer Cells to mobilize and seek out and destroy cancer cells. Today there is an entire

field of Glycobiology devoted to cancer research and the NIH and CDC have received

hundreds of millions in government funds to further enhance the field of Glycobiology

and cancer control.

Stress

An adequate supply of dietary glyconutritional healing sugars is vitally important during

periods of body wide stress, since glycoconjugates synthesized from eight key sugars

play key roles in many aspects of tissue healing and repair as well as cell survival

during extremely stressful periods. Corticotropin-releasing factor receptor is hormone

glycoprotein that regulates responses to emotional and other types of stress by

coordinating the endocrine, behavioral and immune responses to stress through

hormonal actions in the brain.

The Heart and Glycobiology

Glycolipid Conjugates are responsible for correct Low Density Lipid receptor site

instruction…These Low Density Lipids are the kind of cholesterol that can cause a

blocked artery and thus a heart attack…. But regulation of the dreaded LDL’s by

Glycolipid Conjugation makes the likelihood of artery blockage by LDL’s a very unlikely

event.

Most of us have heard that cold water fish oil is protective to the arteries of the heart.

When we all have high levels of Glycolipids the Omega 3 fatty acids become like a

super biological Teflon…coating the linings of the arteries so the bad types of LDL

cholesterol cannot aggregate and build up on the artery linings from both sides of the

coronary arteries thus in the scientific review of many research cardiologists who have

researched Glycolipid conjugation they have published findings that are very highly

suggestive that proper amounts of Glycolipids in the blood protects against a buildup of

bad LDL aggregation, such that the arteries seem to be fully protected from a heart

attack. The problem is a mass of Americans do not have adequate blood levels of

Glycolipid Conjugates especially, Galactose which is of great importance for normal

heart and brain health.

Glyconutritional high levels of galactose, mannose, galactosamine and sialic acid binds

vitamin B12 to make B12 bioavailable to the cells. In other without the above mentioned

healing sugar combinations you can inject all the B12 in the world and it will not work.

The same combination of Glucoconjugates helps people from drug and alcohol cravings

all of which are injurious to the heart and liver.

AND the exact same above described combination, seriously reduces HUNGER

Hormone Function

Gonadotropin hormones are glycoproteins derived from the pituitary gland which

controls the release of many other hormones throughout the body including human

growth hormone (hgh).

Glycosylation of gonadotrophin hormones affects their size, circulatory life span, ease

of movement through cells, storage and secretion, clearance, immunoreactivity and

hormone bioactivity within the entire human body.

Glycosylation of IGF receptors contributes to their tissue regeneration and tissue

differences, which affects their biological activity. If an individual does not have

adequate blood levels of Glycoconjugates (the healing 8 combined sugars) all hormone

activity no matter how much one takes will be seriously insufficient to do their job in the

human body and that can be a health crisis.

Glycoconjugation which does not occur in its proper sequence will lead to a disruption

of insulin formation and correct synthesis and can be causal in some types of diabetes.

The sugars I am about to share with you are so incredible they actually have a

language all of their own. I call them the great hidden code of human life itself. They are

every bit as important as DNA. Amazingly, when these life giving sugars are combined

they can even change mistakes in DNA expression. Mistakes… that can lead to cancer

and every other nightmare type of nightmare illness. However, I am going to show you

how to take a true and certain quantum leap in your ability to regenerate, fight off

virtually all illness, protecting you’re cells, tissues and all of the organs, collectively in all

of our bodies.

You may be thinking this is absurd, sugar is bad for us, correct? Not so simple, just the

sugar D-Ribose is so vital to life that without it we cannot make Messenger RNA and

without messenger RNA you may as well not even make DNA because both are

needed for correct structure and proper functioning of each and every cell, tissue and

organ our bodies. You might even remember from high school biology in the 9th grade

that RNA stands for Ribo Nucleic Acid…and it’s very back bone comes from our good

friend, the amazing D-Ribose SUGAR.

I am very excited to share this science with you. Unfortunately this is a science within

the medical field that is so complex it was not until the 1960’s to 1980’s that we got our

arms around this field of Molecular Glyco-Synthesis. And just like the field of DNA it took

the most brilliant hand full of scientists in molecular bio-science to advance this new

field and show how massively important it is. The field is so important to every phase of

our life cycle; I still study it weekly even though it has been a 20 years endeavor. That is

how important this field is and it is an honor to share this life enhancing information with

you, our family of friends here at AAI …. Though the field to this day is not being brought

to the public with much attention or consistency.

We have given you a small taste of the importance of the 5 carbon sugar D-Ribose now

let’s really delve into the Art and Science of the other life giving sugars.

There are eight Essential Sugars called Saccharides required for Glycoprotein

Synthesis…They are as follows Xylose, Fucose, Mannose, Galactose, Glucose, N-

Acetylglucosamine, N-Acetylgalactosamine, and N-Acetylineuraminic Acid.

What does this mean? It means no expression of protein’s abilities to build up the cells

into tissues and then into organs can occur. No Protein, no big muscles no matter how

hard you work. Actually, no protein , means death That means that without these eight

amazing sugars which create Glycoprotein Synthesis we would not have a body to even

take care of. That is why you must learn how to obtain these super regenerative eight

sugars…if you want to be in a perfected state of excellent health.

Guess what else? We cannot make any HORMONES or even utilize them efficiently

without these super eight sugars but wait there is more good news. Since the early

1990’s Gluco-Scientists found 200 other super sugars from plant based sources,

funding to scientifically evaluate all 200 found so far has several years ago reached the

many hundreds of millions of dollars so are discovering the roles of all 200 sugars.

Mother Nature’s vast array of biochemistry, including these 200 sugars has a specific

purpose. The overwhelming majority of them will be to create an even more complex

language to further healing, cell regeneration and repair. So please don’t be stuck on

eating (sucrose white ultra-refined table sugar) as sucrose in that form is BAD for

human consumption.

Speaking of Hormones, about 10 years ago I learned from Dr. David Wesser M.D.

DDS, a very close friend and teacher, taught if you combine a significant dose of D-

Ribose with Galactose, the human body will regenerate all hormones that have reached

the end of their life cycle, bringing them right back to the top of their life cycle. If you

want to feel like a Greek God, put this into you’re program.

Remember the eight super sugars are a code containing an extensive language. Each

sugar is like a 1000 page book in terms of its ability to communicate instructions

throughout the entire body. Each page in any of the eight books can code and give

hundreds of millions of directions throughout the body. So, we are talking about a code

of life capable of issuing Trillions of life enhancing instructions from the molecular level

to the cells, tissues and organs and even the brain itself gets its instructions to develop

into a brain, as well as sustain you’re brain.

For Illustrative purposes, these molecular communication codes are like precisely

shaped words that protrude from the cells surface and are recognized and understood

by neighboring cells, we call this Glycoform Cellular Communication. It is these eight

amazing Glycoforms that determine your blood type. Imagine that, a sugar

molecule called a Glycoform, N-Acetylgalactosamine will make your blood type A … and

type B blood types are determined by the sugar Galactose. How IMPORTANT are these

eight sugars? You cannot make blood without them, need I say more. Yes indeed there

is so much more but to go further I would need to speak in the language of advanced

biochemistry.

The important factor really is on a practical level which asks the question where do I get

these eight super regenerative sugars? Simply call us at AAI and you can learn how to

obtain the Super Eight!

Mechanisms of the Sialidase and Trans-sialidase Activities of Bacterial Sialyltransferases from

Glycosyltransferase Family 80 (GT80).

Mehr K, Withers SG.

Glycobiology. 2015 Nov 17. pii: cwv105. [Epub ahead of print]

PMID:

 

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Select item 265786732.

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Adherent-Invasive Escherichia coli Bacteria Associated with Crohn’s Disease.

Sivignon A, Yan X, Alvarez Dorta D, Bonnet R, Bouckaert J, Fleury E, Bernard J, Gouin SG,

Darfeuille-Michaud A, Barnich N.

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Select item 265625464.

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pyrophosphorylases.

Daligaux P, Bernadat G, Tran L, Cavé C, Loiseau PM, Pomel S, Ha-Duong T.

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Select item 265585155.

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and their zwitterionic analogues.

Fusari M, Fallarini S, Lombardi G, Lay L.

Bioorg Med Chem. 2015 Oct 30. pii: S0968-0896(15)30121-8. doi: 10.1016/j.bmc.2015.10.043. [Epub ahead of print]

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Select item 265540936.

Imaging. RNA catch and release.

Larochelle S.

Nat Methods. 2015 Sep;12(9):813. No abstract available.

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Select item 265532867.

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André S, Kaltner H, Kayser K, Murphy PV, Gabius HJ.

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26569224

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Select item 265432578.

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Davis RA, Fettinger JC, Gervay-Hague J.

Tetrahedron Lett. 2015 Jun 3;56(23):3690-3694. Epub 2015 May 8.

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Select item 265419749.

Enhanced Cross-Linking of Diazirine-Modified Sialylated Glycoproteins Enabled through

Profiling of Sialidase Specificities.

McCombs JE, Zou C, Parker RB, Cairo CW, Kohler JJ.

ACS Chem Biol. 2015 Nov 16. [Epub ahead of print]

PMID:

 

Select item 2653133610.

Glycoconjugates distribution during developing mouse Spinal Cord motor organizer.

Fazel A, Vojoudi E, Ebrahimi V, Ebrahimzadeh A.

Int J Dev Neurosci. 2015 Dec;47(Pt A):2-3. doi: 10.1016/j.ijdevneu.2015.04.016. No abstract available.

PMID:

 

Select item 2652635411.

Identification and functional analysis of two Golgi-localized UDP-galactofuranose

transporters with overlapping functions in Aspergillus niger.

Park J, Tefsen B, Heemskerk MJ, Lagendijk EL, van den Hondel CA, van Die I, Ram

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BMC Microbiol. 2015 Nov 2;15(1):253. doi: 10.1186/s12866-015-0541-2.

PMID:

 

Select item 2652540212.

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Sfihi-Loualia G, Hurtaux T, Fabre E, Fradin C, Mée A, Pourcelot M, Maes E, Bouckaert

J, Mallet JM, Poulain D, Delplace F, Guérardel Y.

Glycobiology. 2015 Nov 1. pii: cwv094. [Epub ahead of print]

PMID:

 

Select item 2652448113.

26543257

26541974

26526354

26525402

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Gervay-Hague J.

Acc Chem Res. 2015 Nov 2. [Epub ahead of print]

PMID:

 

26524481

 

15.

HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study.

Haase CL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R.

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PMID:

 

25972569

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Strate I, Tessadori F, Bakkers J.

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Arsov Z, Švajger U, Mravljak J, Pajk S, Kotar A, Urbančič I, Štrancar J, Anderluh M.

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PMID:

 

26406919

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Pinheiro LP, Linden R, Mariante RM.

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PMID:

 

26298321

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Lee SK, Kim SD, Kook M, Lee HY, Ghim J, Choi Y, Zabel BA, Ryu SH, Bae YS.

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26282875

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Villanueva-Cabello TM, Mollicone R, Cruz-Muñoz ME, López-Guerrero DV, Martínez-Duncker I.

Glycobiology. 2015 Dec;25(12):1454-64. doi: 10.1093/glycob/cwv062. Epub 2015 Aug 11.

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[CONTEMPORARY CONCEPTION OF IMMUNE RESPONSE ACTIVATION MECHA- NISM BY

CONJUGATED POLYSACCHARIDE VACCINES].

Kolesnikov AV, Kozyr AV, Schemyakin IG, Dyatlov IA.

Zh Mikrobiol Epidemiol Immunobiol. 2015 May-Jun;(3):97-106. Review. Russian.

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[The significance of fucosylated glycoconjugates of human milk in nutrition of newborns and

infants].

Lis-Kuberka J, Orczyk-Pawiłowicz M.

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HUMAN MICROBIOTA. Small molecules from the human microbiota.

Donia MS, Fischbach MA.

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Regrowth of Neurons

by: Dr. Larry Sosna

Regrowth of neurons… also called Neuro-Regeneration is one of the most complicated

issues in the field of medical/science. The subject matter concerns the repair and

regrowth of nerve cells called neurons. The long body of the neuron is called the Axon.

This issue is divided into two imperative groups…. Peripheral Nervous System (PNS)

and the Central Nervous System (CNS) characterized by the brain and spinal cord.

When I took High School Biology the teacher made a clear and emphatic

statement. Central Nervous System neurons NEVER heal. He went on to state, that

Peripheral Neurons do heal but slowly. In Biology and Biochemistry at undergraduate

work in college both professors made the exact same statement my high school biology

teach made almost by rote. Never one to fully agree with such absolute matters in

science my questions were so penetrating and complex as to be unanswerable which

gained respect by one Professor and benign neglect from the second Professor

PNS has a method of regeneration to the injured neurons followed by the quick release

of white blood cells to fight infection. Schwann cells release neurotropic factors which

enhance regrowth of PNS neurons in several ways. The Schwann cells, prevent to

much cytotoxicity which is generally part of the healing process but illicit’s far to much

inflammation for regeneration to proceed normally. Schwann cells, also set up tubes

along side the damaged neuron. These tubes are even connected to the injured

degraded PNS neuron and a host of healing biochemicals are release by the tube to

stop neural degradation and provide healing repair to the affected injured neuron.

There are a host of outside interventions that can make this process go faster but I will

save them for Regeneration of the brain and spinal cord, which please remember is

still thought in many universities even taught to this day that CNS neurons cannot

Regeneration and Repair of the Central Nervous System (Brain and Spinal Cord. There

are two types of cells meant to serve and protect CNS neurons from injury. They are

called Astrocytes and Gllial cells. It may be hard to believe but there are many more

astrocytes in the brain then there are brain Neurons and there are some 15 to 18 billion

brain neurons. Normally, after injury to brain neurons…astrocytes support neurons by

providing antioxidant protection.

The Good the Bad and the Ugly

While the Astrocytes bring in many antioxidants to prevent free radical oxidative toxic

damage to the brain neurons…they also over-react and allow for too much inflammation

and cytotoxins from white blood cell production of Interleukin-2 and 6… this is called up-

regulation of immune cell activity. It can destroy brain neurons faster then the initial

injury to a brain or spinal neurons. This process

brings about even more inflammation to try and carry away all of the dead cells,

including neurons and astrocytes as well as white blood cell waste deposits.

Unfortunately the brain is limited in size and to much inflammation causes intracranial

pressure to the point where brain infarct is possible without making a surgical opening in

the cranium to release the pressure….that is the bad and the ugly.

How do we solve the above dire situation and bring about brain cell neuron

In some cases like bacterial or viral Encephalitis of the brain and spinal cord

many neurons can be killed or injured due to massive white blood cell

proliferation. The white blood cells kill the bacteria and virus that causes

Encephalitis but the situation is so dramatic that in order for the brain to survive

the infection killing neurons…the message which signals the white blood cells to

enter the brain becomes so up-regulated that cannot down-regulate to a normal

response thus further killing both infected neurons and the infected brain cells

both. Many people die from this berserk super up-regulated immune response

stuck on full throttle. It is a vicious repetitive cycle.

We can stop this deathly cycle by giving the patient large intravenous doses of

Gamma Globulin. Gamma Globulin consists of every type of antibody the human

body can make. Scientists are not exactly certain how and why this has such a

profound normalizing effect immunologically but it does. It is called Immuno-

modulation to the normal set point.

In both Stroke patients and infection based Encephalitis of the brain… Immuno-

Modulation to a normal set point is a must in order for neuron cell death to stop and for

Certain biochemical factors play a vital role to decrease astrocytes!  Cyclin Kinase

decreases astrocyte proliferation, increasing neuron function and recovery. Caffeic acid,

alpha- melanocyte stimulating hormone and cliostazol are all highly beneficial. They are

considered essential to a improved condition by reducing astrocyte production…this

treatment shows a decrease in neuron injury, the decrease in astrocyte high levels of

production is associated with a more positive and improved outcome moving toward

In 1984, I experienced a life/death illness called Herpetic Viral Encephalitis. It was

misdiagnosed my Manhattans most elite doctors…virtually always fatal, I lived and due

to the fact the death rate is so nearly complete I spent 3 years in bed and several more

in a wheel chair. There was no internet, no smart phones, just a nearly destroyed brain

with pain so blinding it felt as if two ice picks were being run through both eyes… and

trying to escape by pushing through the back of my skull. Luckily for me the feelers I

sent out daily… resulted in a call from Nobel prize winning doctor and scientist, Dr. Rita

Levi Montalcini who won the Nobel Prize for the discovery of Embryonic Fetal Nerve

Growth Factor in 1986. I was the first human to ever get shots of Fetal Nerve Growth

Factor in 1988 to grow back and regenerate my damaged brain neurons. Then this

magnificent woman became my mentor….I still live speaking to her shadow everyday as

she passed over at the age of almost 104.

Rita Levi-Montalcini’s discovery of a protein called ‘fetal nerve growth factor,”

which fosters the growth of nerve fibers and also plays a role in the brain and the immune

system, is one of the most important steps taken so far toward understanding how the

fantastically complex system of nerves is laid down and linked to the tissues in a developing

embryo. Her account of the adventures leading to this discovery, for which she won a Nobel

Prize in Physiology and Medicine in 1986, has a special contemporary interest. We now

know her discovery is how the brain grows all of it’s neurons when one is an embryo inside

one’s mothers womb until birth and sustains, protects and regenerates brain neurons if one

is fortunate to be born with a large amount of FNGF .  Thank goodness she was able to scale

it up through a deal with a large cutting edge biotechnology lab. in Montreal. They are the

ONLY Lab. in the world to this day that makes Dr. Rita’s original formulations.

We at AA,I are indeed incredibly fortunate to be able to have access to her formulations at

I combined her fetal nerve growth factors with very youthful blood levels of HGH (human

growth hormone…levels that would be normal for the average healthy 16 year old. Eighteen

months later, I was completely better in every way… brain regeneration wise… and in every

other health manner. The addition of HGH was my inspiration as it has been known for

many decades that it is HGH which mobilizes all of the fetal tissue growth factors such as

cardiac tissue growth factor…to do protein synthesis and thus regeneration of the heart

AND all other tissues contained within the human body. Without youthful blood levels of

HGH(say blood levels normal for a healthy 26 year old to 30 year old) and credible levels of

fetal nerve growth factor… regrowth of Neurons is unlikely in the extreme BUT with these

safe and effective blood levels of both Regrowth of every type of Neuron is probable in and

that brings amazing hope. The only Regrowth we cannot master yet is CNS spinal cord cut

in half…but the army medical scientists are getting very close.

Imagine how old we would all look, if we did not have adequate cell levels of

epithelial (skin tissue growth factor) to regenerate our SKIN? So, just like

hormones, as we age we lose our tissue growth factors…and if they cannot be

replaced to the optimal level from exogenous sources we will all be subject to

the ravages of age related illness.

Gratefully, here at AAI we have all critical tissue growth factors available to

you, our beloved family of clients.

Kindly, Larry Sosna PhD HHP

1. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB,

Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V,

Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian

D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T,

Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Heart disease and stroke statistics–2010

update: a report from the American Heart

Association.Circulation. 2010;121:e46–e215. [PubMed]

2. Blakeley JO, Llinas RH. Thrombolytic therapy for acute ischemic stroke. J. Neurol.

Sci. 2007;261:55–62.[PubMed]

3. Marder VJ, Jahan R, Gruber T, Goyal A, Arora V. Thrombolysis with plasmin: implications

for stroke treatment. Stroke. 2010;41:S45–S49. [PMC free article] [PubMed]

4. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment

of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J.

Med.2002;346:557–563. [PubMed]

5. Howells DW, Porritt MJ, Rewell SS, O’Collins V, Sena ES, van der Worp HB, Traystman RJ,

Macleod MR. Different strokes for different folks: the rich diversity of animal models of focal

cerebral ischemia. J. Cereb. Blood Flow Metab. 30:1412–1431. [PMC free article] [PubMed]

6. Kettenmann H, Ramson BR. Neuroglia. New York: Oxford University Press; 1995.

7. Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional

architecture of the brain. Trends Neurosci. 2003;26:523–530. [PubMed]

8. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta

Neuropathol. 2010;119:7–35.[PMC free article] [PubMed]

9. Goldberg MP, Choi DW. Combined oxygen and glucose deprivation in cortical cell culture:

calcium-dependent and calcium-independent mechanisms of neuronal injury. J.

Neurosci. 1993;13:3510–3524.[PubMed]

10. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal

death. Curr. Mol. Med. 2004;4:193–205. [PubMed]

11. Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol.

Chem. 2003;384:505–516. [PubMed]

12. Wilson JX. Antioxidant defense of the brain: a role for astrocytes. Can. J. Physiol.

Pharmacol.1997;75:1149–1163. [PubMed]

13. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain

ischemia. Nat. Neurosci.2007;10:1377–1386. [PubMed]

14. Nedergaard M, Dirnagl U. Role of glial cells in cerebral

ischemia. Glia. 2005;50:281–286. [PubMed]

15. Ouyang YB, Voloboueva LA, Xu LJ, Giffard RG. Selective dysfunction of hippocampal

CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J.

Neurosci.2007;27:4253–4260. [PMC free article] [PubMed]

16. Xu L, Emery JF, Ouyang YB, Voloboueva LA, Giffard RG. Astrocyte targeted

overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain

ischemia. Glia. 2010;58:1042–1049.[PMC free article] [PubMed]

17. Anderson MF, Blomstrand F, Blomstrand C, Eriksson PS, Nilsson M. Astrocytes and stroke:

networking for survival? Neurochem. Res. 2003;28:293–305. [PubMed]

18. Giffard RG, Swanson RA. Ischemia-induced programmed cell death in

astrocytes. Glia. 2005;50:299–306. [PubMed]

19. Almeida A, Delgado-Esteban M, Bolanos JP, Medina JM. Oxygen and glucose deprivation

induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in

primary culture. J. Neurochem. 2002;81:207–217. [PubMed]

20. Xu L, Sapolsky RM, Giffard RG. Differential sensitivity of murine astrocytes and neurons

from different brain regions to injury. Exp. Neurol. 2001;169:416–424. [PubMed]

21. Zhao G, Flavin MP. Differential sensitivity of rat hippocampal and cortical astrocytes to

oxygen-glucose deprivation injury. Neurosci. Lett. 2000;285:177–180. [PubMed]

22. Lukaszevicz AC, Sampaio N, Guegan C, Benchoua A, Couriaud C, Chevalier E, Sola B,

Lacombe P, Onteniente B. High sensitivity of protoplasmic cortical astroglia to focal ischemia. J.

Cereb. Blood Flow Metab. 2002;22:289–298. [PubMed]

23. Bondarenko A, Chesler M. Rapid astrocyte death induced by transient hypoxia, acidosis, and

extracellular ion shifts. Glia. 2001;34:134–142. [PubMed]

24. Giffard RG, Monyer H, Choi DW. Selective vulnerability of cultured cortical glia to injury

by extracellular acidosis. Brain Res. 1990;530:138–141. [PubMed]

25. Swanson RA, Farrell K, Stein BA. Astrocyte energetics, function, and death under conditions

of incomplete ischemia: a mechanism of glial death in the

penumbra. Glia. 1997;21:142–153. [PubMed]

26. Tombaugh GC, Sapolsky RM. Mechanistic distinctions between excitotoxic and acidotic

hippocampal damage in an in vitro model of ischemia. J. Cereb. Blood Flow

Metab. 1990;10:527–535. [PubMed]

27. Chen Y, Swanson RA. Astrocytes and brain injury. J. Cereb. Blood Flow

Metab. 2003;23:137–149.[PubMed]

28. Lee MH, Kim H, Kim SS, Lee TH, Lim BV, Chang HK, Jang MH, Shin MC, Shin MS, Kim

CJ. Treadmill exercise suppresses ischemia-induced increment in apoptosis and cell proliferation

in hippocampal dentate gyrus of gerbils. Life Sci. 2003;73:2455–2465. [PubMed]

29. Li Y, Chopp M, Zhang ZG, Zhang RL. Expression of glial fibrillary acidic protein in areas of

focal cerebral ischemia accompanies neuronal expression of 72-kDa heat shock protein. J.

Neurol. Sci.1995;128:134–142. [PubMed]

30. Schroeter M, Schiene K, Kraemer M, Hagemann G, Weigel H, Eysel UT, Witte OW, Stoll G.

Astroglial responses in photochemically induced focal ischemia of the rat cortex. Exp Brain

Res. 1995;106:1–6.[PubMed]

31. Van Beek J, Chan P, Bernaudin M, Petit E, MacKenzie ET, Fontaine M. Glial responses,

clusterin, and complement in permanent focal cerebral ischemia in the

mouse. Glia. 2000;31:39–50. [PubMed]

32. Yamashita K, Vogel P, Fritze K, Back T, Hossmann KA, Wiessner C. Monitoring the

temporal and spatial activation pattern of astrocytes in focal cerebral ischemia using in situ

hybridization to GFAP mRNA: comparison with sgp-2 and hsp70 mRNA and the effect of

glutamate receptor antagonists. Brain Res.1996;735:285–297. [PubMed]

33. Liu D, Smith CL, Barone FC, Ellison JA, Lysko PG, Li K, Simpson IA. Astrocytic demise

precedes delayed neuronal death in focal ischemic rat brain. Brain Res. Mol. Brain

Res. 1999;68:29–41. [PubMed]

34. Dugan LL, Bruno VM, Amagasu SM, Giffard RG. Glia modulate the response of murine

cortical neurons to excitotoxicity: glia exacerbate AMPA neurotoxicity. J.

Neurosci. 1995;15:4545–4555. [PubMed]

35. Rosenberg PA, Aizenman E. Hundred-fold increase in neuronal vulnerability to glutamate

toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci.

Lett. 1989;103:162–168. [PubMed]

36. Voloboueva LA, Suh SW, Swanson RA, Giffard RG. Inhibition of mitochondrial function in

astrocytes: implications for neuroprotection. J. Neurochem. 2007;102:1383–1394. [PMC free

37. Chen JC, Hsu-Chou H, Lu JL, Chiang YC, Huang HM, Wang HL, Wu T, Liao JJ, Yeh TS.

Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and

its modulation by a group III metabotropic glutamate receptor antagonist following transient

global forebrain ischemia. Neuro-pharmacology. 2005;49:703–714. [PubMed]

38. Yeh TH, Hwang HM, Chen JJ, Wu T, Li AH, Wang HL. Glutamate transporter function of

rat hippocampal astrocytes is impaired following the global ischemia. Neurobiol.

Dis. 2005;18:476–483.[PubMed]

39. Ito U, Hakamata Y, Kawakami E, Oyanagi K. Degeneration of astrocytic processes and their

mitochondria in cerebral cortical regions peripheral to the cortical infarction: heterogeneity of

their disintegration is closely associated with disseminated selective neuronal necrosis and

maturation of injury.Stroke. 2009;40:2173–2181. [PubMed]

40. Ito U, Hakamata Y, Kawakami E, Oyanagi K. Temporary focal cerebral ischemia results in

swollen astrocytic end-feet that compress microvessels and lead to focal cortical infarction. J.

Cereb. Blood Flow Metab. 2010 [PMC free article] [PubMed]

41. Vangeison G, Rempe DA. The Janus-faced effects of hypoxia on astrocyte

function. Neuroscientist.2009;15:579–588. [PMC free article] [PubMed]

42. Bidmon HJ, Jancsik V, Schleicher A, Hagemann G, Witte OW, Woodhams P, Zilles K.

Structural alterations and changes in cytoskeletal proteins and proteoglycans after focal cortical

ischemia. Neuroscience.1998;82:397–420. [PubMed]

43. Yasuda Y, Tateishi N, Shimoda T, Satoh S, Ogitani E, Fu-jita S. Relationship between

S100beta and GFAP expression in astrocytes during infarction and glial scar formation after mild

transient ischemia. Brain Res. 2004;1021:20–31. [PubMed]

44. Smith GM, Strunz C. Growth factor and cytokine regulation of chondroitin sulfate

proteoglycans by astrocytes. Glia. 2005;52:209–218. [PubMed]

45. Gris P, Tighe A, Levin D, Sharma R, Brown A. Transcriptional regulation of scar gene

expression in primary astrocytes. Glia. 2007;55:1145–1155. [PubMed]

46. Martinez AD, Saez JC. Regulation of astrocyte gap junctions by hypoxia-

reoxygenation. Brain Res. Brain Res. Rev. 2000;32:250–258. [PubMed]

47. Lin JH, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ, Hansen TW, Goldman S,

Nedergaard M. Gap-junction-mediated propagation and amplification of cell injury. Nat.

Neurosci. 1998;1:494–500.[PubMed]

48. Wang W, Redecker C, Yu ZY, Xie MJ, Tian DS, Zhang L, Bu BT, Witte OW. Rat focal

cerebral ischemia induced astrocyte proliferation and delayed neuronal death are attenuated by

cyclin-dependent kinase inhibition. J. Clin. Neurosci. 2008;15:278–285. [PubMed]

49. Forslin Aronsson S, Spulber S, Popescu LM, Winblad B, Post C, Oprica M, Schultzberg M.

alpha-Melanocyte-stimulating hormone is neuroprotective in rat global cerebral

ischemia. Neuropeptides.2006;40:65–75. [PubMed]

50. Fang SH, Wei EQ, Zhou Y, Wang ML, Zhang WP, Yu GL, Chu LS, Chen Z. Increased

expression of cysteinyl leukotriene receptor-1 in the brain mediates neuronal damage and

astrogliosis after focal cerebral ischemia in rats. Neuroscience. 2006;140:969–979. [PubMed]

51. Ye YL, Shi WZ, Zhang WP, Wang ML, Zhou Y, Fang SH, Liu LY, Zhang Q, Yu YP, Wei

EQ. Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic

brain injuries. Eur. J. Pharmacol. 2007;557:23–31. [PubMed]

52. Zhou Y, Fang SH, Ye YL, Chu LS, Zhang WP, Wang ML, Wei EQ. Caffeic acid ameliorates

early and delayed brain injuries after focal cerebral ischemia in rats. Acta Pharmacol.

Sin. 2006;27:1103–1110.[PubMed]

53. Chung JH, Lee EY, Jang MH, Kim CJ, Kim J, Ha E, Park HK, Choi S, Lee H, Park SH,

Leem KH, Kim EH. Acupuncture decreases ischemia-induced apoptosis and cell proliferation in

dentate gyrus of gerbils. Neurol. Res. 2007;29 Suppl 1:S23–S27. [PubMed]

54. del Zoppo GJ. Inflammation and the neurovascular unit in the setting of focal cerebral

ischemia.Neuroscience. 2009;158:972–982. [PMC free article] [PubMed]

55. Kaur C, Ling EA. Blood brain barrier in hypoxic-ischemic conditions. Curr. Neurovasc.

Res. 2008;5:71–81. [PubMed]

56. Nawashiro H, Brenner M, Fukui S, Shima K, Hallenbeck JM. High susceptibility to cerebral

ischemia in GFAP-null mice. J. Cereb. Blood Flow Metab. 2000;20:1040–1044. [PubMed]

57. Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, Nodin C, Stahlberg

A, Aprico K, Larsson K, Yabe T, Moons L, Fotheringham A, Davies I, Carmeliet P, Schwartz

JP, Pekna M, Kubista M, Blomstrand F, Mara-gakis N, Nilsson M, Pekny M. Protective role of

reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 2008;28:468–481. [PubMed]

58. Kinoshita A, Yamada K, Kohmura E, Hayakawa T. Effect of astrocyte-derived factors on

ischemic brain edema induced by rat MCA occlusion. APMIS. 1990;98:851–857. [PubMed]

59. Buchhold B, Mogoanta L, Suofu Y, Hamm A, Walker L, Kessler C, Popa-Wagner A.

Environmental enrichment improves functional and neuropathological indices following stroke

in young and aged rats.Restor. Neurol. Neurosci. 2007;25:467–484. [PubMed]

60. Keiner S, Wurm F, Kunze A, Witte OW, Redecker C. Rehabilitative therapies differentially

alter proliferation and survival of glial cell populations in the perilesional zone of cortical

infarcts. Glia.2008;56:516–527. [PubMed]

61. Popa-Wagner A, Badan I, Walker L, Groppa S, Patrana N, Kessler C. Accelerated infarct

development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats. Acta

Neuropathol.2007;113:277–293. [PubMed]

62. Li Y, Chen J, Zhang CL, Wang L, Lu D, Katakowski M, Gao Q, Shen LH, Zhang J, Lu M,

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Stroke is the third leading cause of death in the United States

1. INTRODUCTION

Stroke is the third leading cause of death in the United States and results in substantial health-

care expenditures; the mean lifetime cost resulting from an ischemic stroke is estimated at

$140,048 per patient, and this estimation is higher for people over 45 years. Nationwide in 2010,

the estimated direct and indirect costs of stroke totaled $73.7 billion [1]. Although many clinical

trials have been completed in stroke patients, none of these have demonstrated protective

efficacy except for thrombolysis [2, 3]. In the case of cardiac arrest and resuscitation only

hypothermia has been shown to have clinical utility [4]. In some sense the two therapies that

have been effective thus far clinically have broad targets, and do not only affect a single injury

mechanism. In contrast, of the failed trials, many targeted neuron-specific injury mechanisms

[5]. This may reflect too narrow a view of what is needed for brain preservation. A large body of

work has shown that astrocytes play key roles both in normal and pathological central nervous

system functioning [6]. Astrocytes are the most abundant brain cell type, and in addition to their

multiple important homeostatic roles, they organize the structural architecture of the brain, help

organize communication pathways, and modulate neuronal plasticity (for recent review see

[7, 8]). Thus, astrocytes are now thought to be important potential targets for manipulation.

Ischemic stroke is caused by an interruption of cerebral blood flow that leads to stress, cell death,

and inflammation. Neurons are more susceptible to injury than astrocytes when studied under

some in vitroconditions [9, 10]. Neurons have less endogenous antioxidants and are susceptible

to excito-toxicity [10]. Both normally and after ischemia, astrocytes support neurons by

providing antioxidant protection [11, 12], substrates for neuronal metabolism [13], and glutamate

clearance REF. Although astrocytes are sometimes more resilient than neurons, injury can result

in impaired astrocyte function even when astrocytes do not die. Impaired astrocyte function can

amplify neuronal death [14]. Therefore, many recent efforts have focused on the astrocyte-

neuron interaction and how astrocyte function can be improved after stroke to enhance neuronal

support and survival [10, 15, 16]. A growing body of data demonstrates that astrocytes play a

multifaceted and complex role in the response to ischemia, with potential to both enhance and

impair neuronal survival and regeneration [17]. Many recent studies focus on the astrocyte-

neuron interaction and several investigate ways in which astrocyte function can be improved

after stroke to enhance neuronal survival.

This review provides a brief overview of the pathophysiological events underlying ischemic

brain damage, and considers how these events affect astrocyte-mediated support of neurons. In

addition, we discuss some experimental approaches to enhance the neuronal supportive role of

astrocytes as a novel strategy against stroke. Finally, we explore how these approaches may

eventually be applied in the clinical setting to improve stroke outcome for patients.

2. ASTROCYTE VIABILITY AFTER ISCHEMIA

2.1. In Vitro Studies

In vitro studies have provided substantial insight into the mechanisms governing the survival of

astrocytes following simulated ischemia. These investigations have shown that astrocytes are

generally more resistant than neurons to oxygen-glucose deprivation (OGD) performed in media

at physiologically normal pH, an in vitro model of ischemia [10, 18]. Most neurons in astrocyte-

neuronal co-cultures will die after 60–90 min of OGD, while astrocyte cultures only suffer a

similar extent of injury after 4–6 hours [9, 18, 19]. Different astrocyte populations exist and

astrocytes isolated from different brain regions such as cortex, striatum, and hippocampus differ

in their sensitivity to OGD [15, 20, 21]. Furthermore, Lukaszevicz and colleagues [22] reported

that protoplasmic astrocytes lose their integrity faster than fibrous astrocytes, which may explain

the regional differences in susceptibility to ischemia between white matter astrocytes which are

fibrous and grey matter astrocytes that are protoplasmic. Although less susceptible to OGD-

induced damaged in vitro studies have highlighted certain elements that are highly toxic to

astrocytes. For example, acidosis has been found to be very effective in killing astrocytes

[23–26], in contrast to neurons, which are protected in acidic conditions [24, 26].

2.2. Focal Cerebral Ischemia

Much of the information about the recovery of astrocytes in vivo has been provided by studies

using immunohistological markers for astrocyte specific proteins, such as glial fibrillary acidic

protein (GFAP) and glutamine synthetase GS; Fig. 1. Using these markers as tools, several

investigations suggest that astrocytes are better preserved than neurons in animal models of

stroke outside the core where all cells die [27–29]. Though neuronal markers are decreased as

soon as 1 hour after MCAO, GFAP expression is preserved over the first 3 hours of reperfusion

after 2 hour MCAO [29] and GS is increased 3 hours following a 3 hour MCAO [28]. At later

reperfusion periods, GFAP increases in the peri-infarct area that later develops into the glial scar

[29–32]. In contrast, Liu and colleagues [33] reported the deterioration of some astrocyte

markers prior to that of neuronal markers. Discrepancy in findings may be due to differences in

detection (i.e., protein vs. mRNA) and injury paradigms.

Fig. (1)

Expression of different astrocytic proteins following stroke. Increased expression of GFAP is a

hallmark of astrocytes activation, as is induction/re-expression of vimentin. Astrocytes normally

express glutamine synthetase (GS) and S100β, genes …

2.3. Forebrain Ischemia

Excitotoxic neuronal injury is a common mechanism in both acute and chronic

neurodegenerative diseases. It has long been appreciated that inhibition of astrocyte glutamate

uptake [34, 35], and more recently inhibition of astrocyte mitochondrial function [36], impairs

neuronal survival from excitotoxic injury. Brief forebrain ischemia is a model of the delayed

hippocampal neuronal loss seen in patients following cardiac arrest and resuscitation, and in part

involves excitotoxicity. Increased generation of reactive oxygen species (ROS) and

mitochondrial dysfunction in CA1 astrocytes contributes to ischemia-induced loss of GLT-1 and

ultimately to delayed death of CA1 neurons [15]. Our studies and those of other laboratories

have demonstrated that selective dysfunction of hippocampal CA1 subregion astrocytes, with

loss of glutamate transport activity and immunoreactivity for glutamate transporter 1 (GLT-1),

occurs at early reperfusion times, hours to days before the death of CA1 neurons [15, 37, 38].

The heterogeneous degeneration of astrocytic processes and mitochondria was tightly associated

with the appearance of disseminated selective neuronal necrosis and its maturation after

temporary ischemia [39]. By electronmicroscopy the same investigators [40] found that focal

infarction is exacerbated by temporary microvascular obstruction due to compression by swollen

astrocytic end-feet. However, hypoxia has multiple effects on astrocytes and their ability to

support neuronal viability [41]. For example, hypoxia induces astrocyte-dependent protection of

neurons following hypoxic preconditioning. Yet, hypoxia induces processes in astrocytes that

augment neuronal death in other situations, such as the coincidence of hypoxia with

inflammatory signaling.

3. REACTIVE ASTROGLIA: GOOD OR BAD AFTER STROKE?

The astrocyte response to ischemia has traditionally been viewed as detrimental to recovery, as

the astrocyte-rich glial scar has both physical and chemical inhibitory properties [42, 43]. As

components of the glial scar, astrocytes exhibit hypertrophied, interdigitated processes that form

a physical barrier. Astrocytes produce inhibitory molecules including chondroitin sulfate

proteoglycans (CSPGs) that contribute to chemical inhibition [44, 45]. In the acute setting,

astrocytic gap junctions may remain open following ischemia [46], allowing substances such as

proapoptotic factors to spread through the syncytium, thereby expanding the size of the infarct

[47]. As discussed below, astrocytes can also produce a variety of pro-inflammatory cytokines.

Many studies have shown that decreased astrogliosis often correlates with decreased infarct size.

Nonspecific inhibition of cell proliferation following ischemia using a cyclin kinase inhibitor

decreases astrocyte proliferation and results in improved functional recovery [48]. In addition,

treatment with alpha-melanocyte stimulating hormone [49], cysteinyl leukotriene receptor

antagonist [50], cliostazol [51], and caffeic acid [52] result in reduced infarct size accompanied

by a decrease in astrogliosis. Treadmill exercise [28] and acupuncture [53] are similarly

associated with improved outcome and reduced astrogliosis. Thus, results from several studies

suggest that treatments that decrease infarct size are often accompanied by attenuated astrocyte

response. Despite the frequent association of decreased astrogliosis with improved outcome, it is

difficult to determine cause and effect, since the extent of astrogliosis likely reflects the severity

of the injury, as well as influencing it.

In addition to their role in glial scar formation, astrocytes also respond to ischemia with functions

important for neuroprotection and repair. These include protecting spared tissue from further

damage [14], taking up excess glutamate as discussed above, rebuilding the blood brain barrier

[54, 55], and producing neurotrophic factors [10]. GFAP knockout mice exhibit larger lesions

than their wild-type littermates following focal ischemia [56], and mice lacking both GFAP and

vimentin have impaired astrocyte activation, decreased glutamate uptake abilities, and attenuated

PAI-1 expression after ischemia [57]. Application of astrocyte-conditioned media after transient

MCAO results in decreased infarct volume and regained blood-brain barrier function [58],

suggesting that factors released by astrocytes following ischemia are important for

neuroprotection.

Although few studies other than the use of animals lacking vimentin and GFAP have specifically

targeted astrocyte activation after ischemia, there is correlational evidence suggesting that

astrogliosis may be beneficial. Environmental enrichment, which results in reduced infarct size

and improved recovery following ischemia, also leads to increased astrocyte proliferation

[59, 60]. After focal ischemia, aged rats exhibit increased tissue damage and increased astrocyte

hypertrophy, but have decreased astrocyte proliferation compared to young rats [61]. Systemic

infusion of bone marrow stromal cells following MCAO increases gliogenesis and decreases

lesion size [62, 63]. In addition, administration of transforming growth factor α (TGFα), a known

mitogen for astrocytes [64], following MCAO leads to reduced infarct size and improved

functional recovery [65]. Furthermore, ischemic preconditioning that produces a neuroprotective

state leads to prolonged astrocyte expression of Hsp27 [66]. Finally, mice lacking connexin 43,

the gap junction connecting astrocyte networks that is needed for proper neurotransmitter and

potassium regulation, have increased infarcts following MCAO [67]. Thus, astrocytes have the

potential to be both detrimental and beneficial following ischemic insult, making them promising

targets for manipulation to improve outcome.

4. ASTROCYTE-MEDIATED INFLAMMATION AFTER STROKE: A DOUBLE-EDGED

SWORD

Inflammation plays both detrimental and beneficial roles in brain ischemia, depending upon the

timing and severity of the inflammation. Within minutes after injury, injured neurons in the core

and penumbra of the lesion and glial cells in the core produce pro-inflammatory mediators,

cytokines, and reactive oxygen species, which activate both astrocytes and microglia [68].

Activated astrocytes can produce the proinflammatory cytokines IL-6, TNFα, IL-1α and β,

interferon γ, and others [68–70]. High levels of these cytokines can be detrimental to ischemic

recovery [71–75] by directly inducing apoptosis of neuronal cells and/or increasing toxic nitric

oxide levels [76] and inhibiting neurogenesis [77]. Indeed, inactivation of astrocyte NfκB

signaling, shown to induce astrocyte production of pro-inflammatory cytokines [78], decreases

cytokine production and protects neurons after ischemic injury [79]. Hsp72 overexpression is

associated with lower NfκB activation and lower TNFα [80]. In addition to cytokines, reactive

astrocytes also produce chemokines following ischemia [81]. Chemokines upregulate adhesion

molecules in vascular endothelial cells, resulting in attraction of immune cells, which may

worsen ischemia-induced damage [82]. Overall, some aspects of the local inflammatory response

contribute to secondary injury to potentially viable tissue and lead to apoptotic and necrotic

neuronal cell death hours to days after injury [83], while other aspects are beneficial.

Although the potential benefits of inflammation after stroke have received relatively little

attention so far, indirect evidence suggests that some specific inflammatory reactions are

neuroprotective and neuroregenerative [84–91]. In addition to providing defense against the

invasion of pathogens, inflammation is also involved in clearing damaged tissue, and in

angiogenesis, tissue remodeling, and regeneration [89]. This is probably best studied in wound

healing, which is severely compromised if inflammation is inhibited [89, 91]. There is also

evidence suggesting that specific inflammatory factors can be protective in some circumstances.

IL-6, produced by astrocytes acutely after MCAO [69], is likely neuroprotective early after

ischemia [84]. Interestingly, ischemic preconditioning resulting in protection appears to be

dependent on TLR-4 signaling, and is accompanied by increased TNFα, NFκB, and COX-2

expression [90]. Indeed, in vitro work has shown that administration of TNFα in combination

with Hsp70 results in decreased expression of pro-apoptotic proteins following hypoxia [88].

Thus, it is important to consider these factors, along with timing, when trying to determine the

best strategy to reduce damage and improve recovery and regeneration.

5. ASTROCYTE SUPPORT OF NEURONS AFTER STROKE

5.1. Antioxidant Production

One hallmark of the cellular response to ischemia is a rapid, dramatic increase in damaging free

radicals, including nitric oxide (NO), superoxide, and peroxynitrite [92]. Nitric oxide synthetase

levels increase as soon as 10 minutes after induction of MCAO [93], followed by NO production

that persists for at least one week after MCAO [94]. Nitric oxide can cause cell death by

inducing the release of cytochrome-c from mitochondria, leading to apoptosis [95]. Nitric oxide

can also induce necrotic death [96]. Furthermore, the production of nitric oxide and other free

radicals can modify oxidative metabolism and impair ATP production [13, 19]. Changes in

mitochondrial properties can further limit oxidative metabolism [97]. Not surprisingly, several

studies have shown that antioxidant treatment enhances neuroprotection and recovery after

stroke [98–101].

The release of glutathione and SOD by astrocytes has been reported and is suggested to play an

important role in maintaining and enhancing neuronal survival, yet they are able to reduce

ascorbate for further neuronal antioxidant defense Fig. (2) [10, 102–106]. Interestingly, neurons

cocultured with astrocytes exhibit higher levels of glutathione compared with neurons cultured

alone [107]. Although astrocytes upregulate SOD after cerebral ischemia [108], they do not

appear to increase levels of glutathione in ischemic conditions [109]. It is unknown whether

ischemia alters astrocytic ascorbate levels, but osmotic swelling from ischemia results in

increased astrocyte release of ascorbate in vitro [110], suggesting that similar mechanisms may

occur in vivo.

Fig. (2)

Mechanisms of astrocyte support of neurons important in stroke. Antioxidant defense includes

release of glutathione and ascorbate. Regulation of extracellular levels of ions and neuro-

transmitters, especially K+ and glutamate, strongly influences neuronal …

Several treatments that attenuate ischemic injury result in increased glutathione levels [111, 112].

SOD converts superoxide into oxygen and hydrogen peroxide. Similar to glutathione, many

treatments that ameliorate stroke damage are accompanied by an increase in SOD [113, 114].

Furthermore, rodents overexpressing SOD1 have significantly smaller injuries after both focal

and global ischemia [115, 116], while mice with decreased SOD1 have larger infarcts [117].

Finally, ascorbate can also reduce oxidative stress [118]. Treatment with dehydroascorbic acid, a

blood-brain-barrier-permeable precursor to ascorbic acid, is protective after MCAO [119].

Dehydroascorbic acid is taken up by astrocytes and released as ascorbic acid [12], a process

increased by propofol [120], a treatment that can be protective after stroke [121]. In summary,

astrocytes are important producers of antioxidants in the normal CNS, and astrocyte production

of these molecules after stroke may enhance neuronal survival and protect astrocyte function.

5.2. Glutamate Regulation

Astrocytes are key players in the regulation of neuro-transmitters in the CNS. Astrocytes make

glutamine, the precursor for the neurotransmitters glutamate and GABA [122] Fig. (2). Astrocyte

production of neurotransmitter precursors is impaired after MCAO, and alterations in neuro-

transmitter levels occur throughout the brain following stroke, possibly contributing to neuronal

death [123, 124].

Astrocytes are primarily responsible for glutamate uptake in the normal brain using the astrocyte

specific glutamate transporters GLAST and GLT-1 (Fig. 2) [125–127], as excess glutamate leads

to cell death via excitotoxicity [128]. Glutamate transporter levels in astrocytes decrease acutely

following global ischemia [38, 129] and neonatal hypoxia-ischemia [130], most likely

exacerbating neuronal death as a result of glutamate-induced excitoxicity. Despite the therapeutic

potential of increasing astrocyte glutamate transport after stroke, few groups have explored this

possibility. Carnosine, shown to be protective after focal ischemia, may partially be effective

because it prevents loss of GLT-1 on astrocytes, resulting in attenuated excitotoxicity [131]. In a

more direct assessment of how post-ischemic astrocyte glutamate transporters contribute to

neuronal survival, our laboratory has shown that upregulation of GLT-1 on astrocytes using

ceftriaxone protects CA1 neurons after global ischemia [129], similar to its effects in focal

cerebral ischemia [132].

5.3. Potassium Uptake and Energy Metabolism

Astrocytes also regulate neuronal activation by extracellular potassium uptake [133] Fig. (2).

Neurons release potassium after activation, and increased extracellular potassium leads to

neuronal hyperexcitability [133], a phenomenon that occurs in ischemic conditions [134]. In

addition to regulating neuronal activation, proper maintenance of ion gradients, such as

potassium, is important in regulating cell volume in both normal and ischemic conditions

[135, 136]. Astrocytes increase potassium transporter activity in response to transient in

vitro ischemia [137]. Due to its effects on both neuronal activity and cell volume, increasing

astrocytic potassium uptake may be a possible therapeutic target for stroke.

Astrocytes are also integral to normal maintenance of neuronal metabolism. When astrocytes

take up extracellular glutamate as a result of neuronal activity, the Na+/ K+-ATPase, along with

AMPA signaling, triggers astrocyte uptake of glucose from the blood, as astrocytic endfeet

contact capillaries [138, 139]. This glucose is then made into lactate, a substrate for neuronal

energy, to further “fuel” active neurons [140] Fig. (2). As mentioned above, astrocytes produce

glutathione. In addition to its antioxidant properties, glutathione is needed for the conversion of

methylglyoxal, a toxic by-product of metabolism, into D-Lactate by glyoxalase 1 [141].

Although the role of astrocyte metabolism is relatively well-established in normal tissue, the

post-ischemic role of astrocyte metabolism maintenance is less clear [142]. After ischemia,

astrocytes upregulate glucose transporters in order to provide energy to stressed/dying neuronal

cells [143,144]. Ethyl pyruvate, a derivative of the energy substrate pyruvate, is neuroprotective

after stroke only when astrocytes are viable, suggesting that astrocytes are necessary for

improvement in post-ischemic energy metabolism [122].

6. NOVEL STRATEGIES TO IMPROVE THE NEURONAL SUPPORTIVE ROLE OF

ASTROCYTES

Although few studies have specifically targeted astrocytes for repair after stroke, there is some

evidence that this can be a successful strategy. Recent results indicate that induction of BDNF in

astrocytes by galectin-1 reduces neuronal apoptosis in ischemic boundary zone and improves

functional recovery [145]. In addition, protection by pyruvate against glutamate neurotoxicity is

mediated by astrocytes through a glutathione-dependent mechanism [146]. Our recent study

demonstrated that enhancing astrocyte resistance to ischemic stress by overexpressing protective

proteins or antioxidant enzyme results in improved survival of CA1 neurons following forebrain

ischemia Fig. (3) [16]. Two well-studied protective proteins, heat shock protein 72 (Hsp72) and

mitochondrial SOD, were genetically targeted for expression in astrocytes using the astrocyte-

specific human GFAP promoter. In both cases protection was accompanied by preservation of

the astrocytic glutamate transporter GLT-1, and reduced evidence of oxidative stress in the CA1

region [16]. Similarly, selective overexpression of excitatory amino acid transporter 2 (EAAT2)

in astrocytes enhances neuroprotection from moderate hypoxia-ischemia [147].

Fig. (3)

Targeted over-expression of Hsp72 in astrocytes reduces the vulnerability of CA1 neurons to

forebrain ischemia. Selective overexpression of Hsp72 in astrocytes by expressing it from the

astrocyte specific GFAP promoter was achieved by unilateral stereotaxic …

7. TRANSLATING INSIGHTS INTO PROTECTION INTO CLINICAL APPLICATIONS

Many factors have been identified that likely contribute to the failure in translation seen so far

with stroke therapies. Currently, the only approved stroke therapy is thrombolysis induced by

intravenous administration of recombinant tissue plasminogen activator [148]; however, because

of a short therapeutic time window, only a small fraction of patients benefit from this treatment.

Hypothermia is the only accepted acute treatment to reduce brain injury following cardiac arrest

and resuscitation [4]. Thus far many clinical trials have focused on treatments that would likely

be beneficial to neurons, with fewer studies focused on mechanisms that might benefit all cell

types or specifically targeting other cell types, such as astrocytes. Often the consequence of these

treatments on the astrocyte response is not considered. Several examples of past and ongoing

clinical trials are discussed below, with specific attention to how these treatments may alter

astrocyte response or viability.

Several clinical trials have targeted manipulation of the inflammatory response to ischemia, as

stroke patients with systemic inflammation exhibit poorer outcomes [149]. Although anti-

inflammatory therapy decreases infarct size and improves neurological sequelae in experimental

animal models of stroke [150], human trials with anti-neutrophil therapy have not shown a clear

benefit [151, 152]. In addition, recent clinical trials in which anti-CD11/18 antibodies were

administered to human subjects were unsuccessful [153]. Likewise, a double-blinded, placebo-

controlled clinical trial in which anti–ICAM-1 antibody was administered within 6 hours of

stroke symptoms showed disappointing results [151]. In understanding these results it is

important to recall that while experimental stroke is relatively homogeneous concerning size,

territory, and etiology, with more consistent inflammatory response, human stroke is extremely

heterogeneous [154], with different vascular territories and extents of injury. In addition, these

mediators are known to affect many organ systems beyond the central nervous system. Systemic

administration of anti-inflammatory agents may have exacerbated the relative state of

immunocompromise seen in stroke patients, thereby confounding the outcome. Furthermore,

inflammation and astrocyte response are likely closely connected. Although there is little

evidence for a direct relationship between neutrophils and astrocytes, it has been shown that

mice with a blunted inflammatory response exhibit increased loss of GFAP-positive astrocytes

after cortical stab injury [155]. Because astrocytic glial scar formation is important in protection

of spared tissue from further damage [156], it is possible that treatments that drastically attenuate

inflammation lead to a stunted astrocyte response that is deleterious to recovery.

Another drug that has advanced to clinical study is DP-b99, currently in phase III studies for

acute stroke. DP-b99 is a membrane active chelator derivative of the known calcium chelator,

BAPTA spell out [157]. A lipophilic chelator of calcium, zinc and copper ions, DP-b99

sequesters metal ions only within and in to cell membranes. This clinical trial is especially

attractive because sequestration of calcium, zinc, and copper are potentially beneficial not only

to neurons, but also to astrocytes. It has been shown in Alzheimer’s disease that beta amyloid

increases astrocyte calcium influx, which causes decreased glutathione levels [158]. Zinc

chloride is toxic to astrocytes as well as neurons in vitro [159]. Similarly, astrocytes exposed to

neocuprine exhibit increased copper influx and undergo apoptotic cell death [160]. Approaches

that benefit multiple cell types, including astrocytes, are more likely to be successful.

Other current ongoing clinical trials focus on neuroprotective agents for the purpose of aiding

neurological recovery after stroke. Minocycline (Phase I), edavarone (Phase IV), propanolol (a

β-blocker; phase II and III), and more recently arundic acid have been previously shown to be

protective and enhance neuronal survival in stroke [161–165], though by targeting different

mechanisms. Some additional completed and ongoing trials are summarized in Table 1.

Preclinical research needs to consider these clinical results, and assess effects on astrocytes as

well as neurons.

Table 1

Overview of Some Completed and Ongoing Clinical Trials for Stroke

Although anti-inflammatory strategies to diminish ischemic brain injury have failed thus far,

continued elucidation of the complex interactions involved in modulating the inflammatory

response may still enable novel therapeutic approaches that translate successfully into clinical

efficacy.

CONCLUSIONS

Traditionally, stroke research has focused on neurons and often ignored effects on glial cells. It is

increasingly evident that glia are vital to both normal CNS functioning and also play important

roles in neuropathological conditions. Although astrocytes form an inhibitory glial scar following

ischemia, they also perform functions necessary for neuronal survival and well-being, such as

maintaining low extracellular glutamate levels and providing antioxidant protection. Because

they have a great many functions, astrocytes are attractive candidates as therapeutic targets. By

striving to shift astrocytes towards a pro-reparative, neuronal-supportive phenotype following

stroke, future clinical therapies may well be more successful in protecting neurons from ischemic

damage and promoting repair.

ACKNOWLEDGEMENTS

This work was supported by NIH grants CM49831, N5053898, and NS014543 to RGG.

REFERENCES

1. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K,

Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D,

Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL,

Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J.

Heart disease and stroke statistics–2010 update: a report from the American Heart

Association.Circulation. 2010;121:e46–e215. [PubMed]

2. Blakeley JO, Llinas RH. Thrombolytic therapy for acute ischemic stroke. J. Neurol.

Sci. 2007;261:55–62.[PubMed]

3. Marder VJ, Jahan R, Gruber T, Goyal A, Arora V. Thrombolysis with plasmin: implications for stroke

treatment. Stroke. 2010;41:S45–S49. [PMC free article] [PubMed]

4. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose

survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J.

Med.2002;346:557–563. [PubMed]

5. Howells DW, Porritt MJ, Rewell SS, O’Collins V, Sena ES, van der Worp HB, Traystman RJ, Macleod MR.

Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J.

Cereb. Blood Flow Metab. 30:1412–1431. [PMC free article] [PubMed]

6. Kettenmann H, Ramson BR. Neuroglia. New York: Oxford University Press; 1995.

7. Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional

architecture of the brain. Trends Neurosci. 2003;26:523–530. [PubMed]

8. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta

Neuropathol. 2010;119:7–35.[PMC free article] [PubMed]

9. Goldberg MP, Choi DW. Combined oxygen and glucose deprivation in cortical cell culture: calcium-

dependent and calcium-independent mechanisms of neuronal injury. J.

Neurosci. 1993;13:3510–3524.[PubMed]

10. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr. Mol.

Med. 2004;4:193–205. [PubMed]

11. Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol. Chem. 2003;384:505–516. [PubMed]

12. Wilson JX. Antioxidant defense of the brain: a role for astrocytes. Can. J. Physiol.

Pharmacol.1997;75:1149–1163. [PubMed]

13. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat.

Neurosci.2007;10:1377–1386. [PubMed]

14. Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia. 2005;50:281–286. [PubMed]

15. Ouyang YB, Voloboueva LA, Xu LJ, Giffard RG. Selective dysfunction of hippocampal CA1 astrocytes

contributes to delayed neuronal damage after transient forebrain ischemia. J.

Neurosci.2007;27:4253–4260. [PMC free article] [PubMed]

16. Xu L, Emery JF, Ouyang YB, Voloboueva LA, Giffard RG. Astrocyte targeted overexpression of Hsp72

or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia. 2010;58:1042–1049.[PMC free

article] [PubMed]

17. Anderson MF, Blomstrand F, Blomstrand C, Eriksson PS, Nilsson M. Astrocytes and stroke:

networking for survival? Neurochem. Res. 2003;28:293–305. [PubMed]

18. Giffard RG, Swanson RA. Ischemia-induced programmed cell death in

astrocytes. Glia. 2005;50:299–306. [PubMed]

19. Almeida A, Delgado-Esteban M, Bolanos JP, Medina JM. Oxygen and glucose deprivation induces

mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture. J.

Neurochem. 2002;81:207–217. [PubMed]

20. Xu L, Sapolsky RM, Giffard RG. Differential sensitivity of murine astrocytes and neurons from

different brain regions to injury. Exp. Neurol. 2001;169:416–424. [PubMed]

21. Zhao G, Flavin MP. Differential sensitivity of rat hippocampal and cortical astrocytes to oxygen-

glucose deprivation injury. Neurosci. Lett. 2000;285:177–180. [PubMed]

22. Lukaszevicz AC, Sampaio N, Guegan C, Benchoua A, Couriaud C, Chevalier E, Sola B, Lacombe P,

Onteniente B. High sensitivity of protoplasmic cortical astroglia to focal ischemia. J. Cereb. Blood Flow

Metab. 2002;22:289–298. [PubMed]

23. Bondarenko A, Chesler M. Rapid astrocyte death induced by transient hypoxia, acidosis, and

extracellular ion shifts. Glia. 2001;34:134–142. [PubMed]

24. Giffard RG, Monyer H, Choi DW. Selective vulnerability of cultured cortical glia to injury by

extracellular acidosis. Brain Res. 1990;530:138–141. [PubMed]

25. Swanson RA, Farrell K, Stein BA. Astrocyte energetics, function, and death under conditions of

incomplete ischemia: a mechanism of glial death in the penumbra. Glia. 1997;21:142–153. [PubMed]

26. Tombaugh GC, Sapolsky RM. Mechanistic distinctions between excitotoxic and acidotic hippocampal

damage in an in vitro model of ischemia. J. Cereb. Blood Flow Metab. 1990;10:527–535. [PubMed]

27. Chen Y, Swanson RA. Astrocytes and brain injury. J. Cereb. Blood Flow

Metab. 2003;23:137–149.[PubMed]

28. Lee MH, Kim H, Kim SS, Lee TH, Lim BV, Chang HK, Jang MH, Shin MC, Shin MS, Kim CJ. Treadmill

exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal

dentate gyrus of gerbils. Life Sci. 2003;73:2455–2465. [PubMed]

29. Li Y, Chopp M, Zhang ZG, Zhang RL. Expression of glial fibrillary acidic protein in areas of focal

cerebral ischemia accompanies neuronal expression of 72-kDa heat shock protein. J. Neurol.

Sci.1995;128:134–142. [PubMed]

30. Schroeter M, Schiene K, Kraemer M, Hagemann G, Weigel H, Eysel UT, Witte OW, Stoll G. Astroglial

responses in photochemically induced focal ischemia of the rat cortex. Exp Brain

Res. 1995;106:1–6.[PubMed]

31. Van Beek J, Chan P, Bernaudin M, Petit E, MacKenzie ET, Fontaine M. Glial responses, clusterin, and

complement in permanent focal cerebral ischemia in the mouse. Glia. 2000;31:39–50. [PubMed]

32. Yamashita K, Vogel P, Fritze K, Back T, Hossmann KA, Wiessner C. Monitoring the temporal and

spatial activation pattern of astrocytes in focal cerebral ischemia using in situ hybridization to GFAP

mRNA: comparison with sgp-2 and hsp70 mRNA and the effect of glutamate receptor antagonists. Brain

Res.1996;735:285–297. [PubMed]

33. Liu D, Smith CL, Barone FC, Ellison JA, Lysko PG, Li K, Simpson IA. Astrocytic demise precedes delayed

neuronal death in focal ischemic rat brain. Brain Res. Mol. Brain Res. 1999;68:29–41. [PubMed]

34. Dugan LL, Bruno VM, Amagasu SM, Giffard RG. Glia modulate the response of murine cortical

neurons to excitotoxicity: glia exacerbate AMPA neurotoxicity. J.

Neurosci. 1995;15:4545–4555. [PubMed]

35. Rosenberg PA, Aizenman E. Hundred-fold increase in neuronal vulnerability to glutamate toxicity in

astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 1989;103:162–168. [PubMed]

36. Voloboueva LA, Suh SW, Swanson RA, Giffard RG. Inhibition of mitochondrial function in astrocytes:

implications for neuroprotection. J. Neurochem. 2007;102:1383–1394. [PMC free article] [PubMed]

37. Chen JC, Hsu-Chou H, Lu JL, Chiang YC, Huang HM, Wang HL, Wu T, Liao JJ, Yeh TS. Down-regulation

of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group

III metabotropic glutamate receptor antagonist following transient global forebrain ischemia. Neuro-

pharmacology. 2005;49:703–714. [PubMed]

38. Yeh TH, Hwang HM, Chen JJ, Wu T, Li AH, Wang HL. Glutamate transporter function of rat

hippocampal astrocytes is impaired following the global ischemia. Neurobiol.

Dis. 2005;18:476–483.[PubMed]

39. Ito U, Hakamata Y, Kawakami E, Oyanagi K. Degeneration of astrocytic processes and their

mitochondria in cerebral cortical regions peripheral to the cortical infarction: heterogeneity of their

disintegration is closely associated with disseminated selective neuronal necrosis and maturation of

injury.Stroke. 2009;40:2173–2181. [PubMed]

40. Ito U, Hakamata Y, Kawakami E, Oyanagi K. Temporary focal cerebral ischemia results in swollen

astrocytic end-feet that compress microvessels and lead to focal cortical infarction. J. Cereb. Blood Flow

Metab. 2010 [PMC free article] [PubMed]

41. Vangeison G, Rempe DA. The Janus-faced effects of hypoxia on astrocyte

function. Neuroscientist.2009;15:579–588. [PMC free article] [PubMed]

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