How to hack your health – knowing how your body reacts to the environment

View
Eggplant and apple cider vinegar for skin cancer
View
DMSO, hydrogen peroxide and Vit C fight cancer cells
View
Can Gout be cured permanently?
View
Non pasteurized beers have more health benefits
View
Signs of the preactive/ active phase of dying and medications for terminally ill
View
Philippines Coconut Wine -Tuba
View
Nitric Oxide Dump Exercise with nose breathing to lower blood pressure and thin blood
View
Foods to eat and avoid when you have Gout and leg pains
View
Parkinson and Exercises
View
What’s a good analogy to explain the immune system?
View
Best posts on knowing and healing your body
View
MEDICATIONS TO AVOID that worse PD (Parkinson’s disease)
View
Home page / Archives
View
Apple cider vinegar kills parasites, cleansing to the liver and prevents stroke
View
Can balsamic vinegar help with gout?
View
Inflammation to colitis to Alzheimer’s disease
View
Blood Deficiency, parasites, iron,metabolic disease
View
Roman Coriander, Fennel flower or Black Cumin Seed Oil as an anti-tumor, anti-gastritis and anti-convulsant oil
View
Parasites and their effects on your immune system
View
Alcohol causes gut damage allowing bacteria to escape from your gut into the blood stream
View
2
Fatigue and Red (bloodshot) eyes from WebMD
View
2
Chlorine rich foods are cleansing (avocado, coconut, onions, parsnips)
View
2
FOXO3, a gene linked to intelligence and involved in insulin signalling that might trigger apoptosis
View
2
What are the benefits of eating chicken soup during pregnancy?
View
2
What will happen if a person accidentally drinks kerosene/petrol/diesel?
View
2
Comments from We the People demands Trump’ tax returns
View
2
Increase the body’s oxygen carrying capacity with exercise, EPO and whole foods
View
2
Disease prediction with HELO wearable, own a piece of the market
View
2
What long-term impact has 2 months of use of atypical antipsychotic (AP) drugs on dopamine (DA) receptors and cells?
View
1
Caring for parents by gen X
View
1
Boron fights radiation by Dr Mercola
View
1
Detox your lungs from air pollution and metal toxins and for early lung cancer
View
1
Avoid chronic bronchitis with green apple, onions, garlic, vinegar and rest
View
1
Rheumatoid Arthritis by Dr Mercola
View
1
Stronger immune system, less Alzheimer’s symptoms
View
1
Anti-aging and Parkinson/Alzheimer’s prevention: Enzymes and apple cider vinegar
View
1
Negative emotions, cortisol, immune system and neurological disorders
View
1
Menu for the healthy plus kitchen tips
View
1
Hypocretin, Insomia or Sleep Disturbances, Narcolepsy, Depression and Parkinson’s
View
1
Herbal oil for Lice, Scabies and skin issues
View
1
Crisis in Retirement Planning by Robert Merton
View
1
Fight VIRUS with Enzymes from pineapple and papaya, baking soda, alkaline food, calcium and magnesium from whole foods
View
1
Restore your vision naturally y Dr. Mercola
View
1
IRS-1 protein in blood, indicative of Alzheimer
View
1
Stop aging of your face with DIY Vitamin C serum by wellnessmama
View
1
Browning or caramelized sugar is a carcinogen
View
1
Neck pain and MTHFR gene , folate , methionine
View
1
Your complete DNA sequence will help shape the future of medicine
View
1
Nitric Oxide for strong blood vessels’ cells , up with exercise, melons, cucumber, Vit C, E, amino acid – L-arginine, L-citrulline
View
1
Top 10 Poisons that are the legacy of Monsanto
View
1
Chemicals Banned 40 Years Ago Linked to Increased Autism Risk Today
View
1
Whole foods prevent inflammation
View
1
Disease condition and odor symptom
View
1
How the brain helps us to learn and make decisions, attention and learning
View
1
Fasting, sun bathing ,Vit C, Lysine, turmeric, green tea, carrots and raw food diet to reduce tumor size
View
1
Leaky gut, leaky brain, eat your garlic and pickles by C Guthrie
View
1
Brain food , sources of GABA and for brain cell growth
View
1
Excess Salt May Hurt Your Brain
View
1
Lung Cancer deaths from 55-70
View
1
How to fight toxic build up in the brain
View
1
Anxiety with Dementia decreased by calcium and magnesium nutrients
View
1
Shark oil for your skin, wound healing and overall health
View
1
How does a CBC test for a leukemia patient usually look like?
View
1
Inclined Bed Therapy
View
1
Acetylcholine/Choline Deficiency in Chronic Illness – eat soft boiled eggs
View
1
Benign prostatic hyperplasia (BPH), estrogen and phytoestrogens
View
1
Hemochromatosis patients should be on a low-iron diet
View
1
Teeth marks on the side of the tongue and liver inflammation
View
1
Dr Mercola’s Diverticulitis diet
View
1
Growth hormone DHEA increases libido/anti-aging
View
1
Iodine prevents cancer growth; up avocado and reduce caffeine intake to prevent Thyroid cancer
View
1
Reduce the stress hormone cortisol
View
1
MSM powder benefits – Alzheimer is a sulfur deficiency
View
1
Are fitness trackers like Jawbone and Fitbit useful?
View
1
Soda and Heart Attack
View
1
Intestinal disorders , herbs and nutrition
View
1
Police then Funeral Homes before body is removed from the house
View
1
NAC, activated charcoal , sleep and parasites
View
1
Physical inactivity, dopamine, lactate , glucose and aging
View
1
Save our students, schools and teachers from unqualified Betsy DeVos
View
1
Our congresswomen heroes protecting our education from DeVos policies and budget
View
1
Bernie Sanders: Overturn Citizens United
View
1
The Half Life of Caffeine
View
1
Make your own alkaline water to kill any virus growth
View
1
Blood magnesium levels , dementia and alcohol
View
1
Eat protein-rich food when drinking alcohol to protect your stomach
View
1
A balance of dopamine and serotonin for your brain function
View
1
Shape of microbes matter in phagocytosis

Genetic Marker for Stroke and Cardiovascular Disease – Folate and Vit B12 pathways

Researchers Discover Underlying Genetic Marker for Stroke and Cardiovascular Disease

NIH-funded findings point to new potential strategies for disease prevention and treatment.

Scientists studying the genomes of nearly 5,000 people have pinpointed a genetic variant tied to an increased risk for stroke, and have also uncovered new details about an important metabolic pathway that plays a major role in several common diseases. Together, their findings may provide new clues to underlying genetic and biochemical influences in the development of stroke and cardiovascular disease, and may also help lead to new treatment strategies.

“Our findings have the potential to identify new targets in the prevention and treatment of stroke, cardiovascular disease and many other common diseases,” said Stephen R. Williams, Ph.D., a postdoctoral fellow at the University of Virginia Cardiovascular Research Center and the University of Virginia Center for Public Health Genomics, Charlottesville.

Dr. Williams, Michele Sale, Ph.D., associate professor of medicine, Brad Worrall, M.D., professor of neurology and public health sciences, all at the University of Virginia, and their team reported their findings March 20, 2014 in PLoS Genetics. The investigators were supported by the National Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program.

This image shows a group of people with GTCA written above them.

Researchers supported by NHGRI’s Genomics and Randomized Trials Network (GARNET) program, who have been studying the genomes of nearly 5,000 people, have pinpointed a genetic variant tied to increased risk for stoke and cardiovascular disease. Credit Jonathan Bailey, NHGRI.

Stroke is the fourth leading cause of death and a major cause of adult disability in this country, yet its underlying genetics have been difficult to understand. Numerous genetic and environmental factors can contribute to a person having a stroke. “Our goals were to break down the risk factors for stroke,” Dr. Williams said.

The researchers focused on one particular biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. They knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia. Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when.

But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels – and methionine metabolism gone awry – are not well defined.

Dr. Williams and his colleagues conducted genome-wide association studies of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism – the ability to convert methionine to homocysteine – in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.

In a genome-wide association study, researchers scan the genome to identify specific genomic variants associated with a disease. In this case, the scientists were trying to identify variants associated with a trait – the ability to metabolize methionine into homocysteine.

Investigators identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine. They found that among the five genes, one – the ALDH1L1 gene – was also strongly associated with stroke in the Framingham study. When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death, and cancer cell survival.

They also made important discoveries about the methionine-homocysteine process. “GNMT produces a protein that converts methionine to homocysteine. Of the five genes that we identified, it was the one most significantly associated with this process,” Dr. Williams said. “The analyses suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.”

“It’s striking that the genes are in the same pathway, so we know that the genomic variants affecting that pathway contribute to the variability in disease and risk that we’re seeing,” he said. “We may have found how genetic information controls the regulation of GNMT.”

The group determined that the five genes accounted for 6 percent of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13 percent of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk. In many complex diseases, genomic variants often account for less than 5 percent of such differences.

“This is a great example of the kinds of successful research efforts coming out of the GARNET program,” said program director Ebony Madden, Ph.D. “GARNET scientists aim to identify variants that affect treatment response by doing association studies in randomized trials. These results show that variants in genes are associated with the differences in homocysteine levels in individuals.”

The association of the ALDH1L1 gene variant with stroke is just one example of how the findings may potentially lead to new prevention efforts, and help develop new targets for treating stroke and heart disease, Dr. Williams said.

“As genome sequencing becomes more widespread, clinicians may be able to determine if a person’s risk for abnormally high levels of homocysteine is elevated,” he said. “Changes could be made to an individual’s diet because of a greater risk for stroke and cardiovascular disease.”

The investigators plan to study the other four genes in the pathway to try to better understand their potential roles in stroke and cardiovascular disease risk.

NOTES ABOUT THIS GENETICS RESEARCH

In addition to NHGRI, the research was supported by funds from the National Heart, Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging and the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine.

The National Human Genome Research Institute is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research and training and career development at sites nationwide.

Contact: Press Office – National Human Genome Research Institute/NIH
Source:National Human Genome Research Institute/NIH press release.


 

Methionine

Although mammals cannot synthesize methionine, they can still use it in a variety of biochemical pathways:

Catabolism

Methionine is converted to S-adenosylmethionine (SAM) by (1) methionine adenosyltransferase.

SAM serves as a methyl-donor in many (2) methyltransferase reactions, and is converted to S-adenosylhomocysteine (SAH).

(3) Adenosylhomocysteinase converts SAH to homocysteine.

There are two fates of homocysteine: it can be used to regenerate methionine, or to form cysteine.

Regeneration

Methionine can be regenerated from homocysteine via (4) methionine synthase in a reaction that requires Vitamin B12 as a cofactor.

Homocysteine can also be remethylated using glycine betaine (NNN-trimethyl glycine, TMG) to methionine via the enzyme betaine-homocysteine methyltransferase (E.C.2.1.1.5, BHMT). BHMT makes up to 1.5% of all the soluble protein of the liver, and recent evidence suggests that it may have a greater influence on methionine and homocysteine homeostasis than methionine synthase.

Reverse-transulfurylation pathway: conversion to cysteine[edit]

Homocysteine can be converted to cysteine.

Ethylene synthesis

This amino acid is also used by plants for synthesis of ethylene. The process is known as the Yang Cycle or the methionine cycle.

The Yang cycle

Chemical synthesis

Racemic methionine can be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation.[17]

Human nutrition

Requirements

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For methionine combined with cysteine, for adults 19 years and older, 19 mg/kg body weight/day.[18]

Dietary sources

Food sources of Methionine[19]
Food g/100g
Egg, white, dried, powder, glucose reduced 3.204
Sesame seeds flour (low fat) 1.656
Egg, whole, dried 1.477
Cheese, Parmesan, shredded 1.114
Brazil nuts 1.008
Soy protein concentrate 0.814
Chicken, broilers or fryers, roasted 0.801
Fish, tuna, light, canned in water, drained solids 0.755
Beef, cured, dried 0.749
Bacon 0.593
Beef, ground, 95% lean meat / 5% fat, raw 0.565
Pork, ground, 96% lean / 4% fat, raw 0.564
Wheat germ 0.456
Oat 0.312
Peanuts 0.309
Chickpea 0.253
Corn, yellow 0.197
Almonds 0.151
Beans, pinto, cooked 0.117
Lentils, cooked 0.077
Rice, brown, medium-grain, cooked 0.052

High levels of methionine can be found in eggs, sesame seeds, Brazil nuts, fish, meats and some other plant seeds; methionine is also found in cereal grains. Most fruits and vegetables contain very little of it. Most legumes are also low in methionine. However, it is the combination of methionine and lysine which is considered for completeness of a protein.[20] Racemic methionine is sometimes added as an ingredient to pet foods.[21]

Restriction

There is scientific evidence that restricting methionine consumption can increase lifespans in fruit flies.[22]

A 2005 study showed methionine restriction without energy restriction extends mouse lifespan.[23]

A study published in Nature showed adding just the essential amino acid methionine to the diet of fruit fliesunder dietary restriction, including restriction of essential amino acids (EAAs), restored fertility without reducing the longer lifespans that are typical of dietary restriction, leading the researchers to determine that methionine “acts in combination with one or more other EAAs to shorten lifespan.”[22][24][25] Restoring methionine to the diet of mice on a dietary restriction regimen blocks many acute benefits of dietary restriction, a process that may be mediated by increased production of hydrogen sulfide.[26]

Several studies showed that methionine restriction also inhibits aging-related disease processes in mice[27][28] and inhibits colon carcinogenesis in rats.[29] In humans, methionine restriction through dietary modification could be achieved through a vegan diet. Veganism being a completely plant based diet is typically very low in methionine, however certain nuts and legumes may provide higher levels.[30]

A 2009 study on rats showed “methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its hepatotoxicity“.[31]

However, since methionine is an essential amino acid, it cannot be entirely removed from animals’ diets without disease or death occurring over time[citation needed]. For example, rats fed a diet without methionine and choline developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks. Administration of methionine ameliorated the pathological consequences of methionine deprivation.[32] Short-term removal of only methionine from the diet can reverse diet-induced obesity and promotes insulin sensitivity in mice.[33]

Methionine might also be essential to reversing damaging methylation of glucocorticoid receptors caused by repeated stress exposures, with implications for depression.[34]

Health

Loss of methionine has been linked to senile greying of hair. Its lack leads to a buildup of hydrogen peroxide in hair follicles, a reduction in tyrosinase effectiveness, and a gradual loss of hair color.[35]

Methionine is an intermediate in the biosynthesis of cysteinecarnitinetaurinelecithinphosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis.[

Melatonin counteract estrogen’s tendency to stimulate cell growth

Oct 10, 2013  Melatonin is a powerful antioxidant that helps protect you against heart disease, diabetes, migraine headaches, Alzheimer’s disease, and cancer. … When this hormone latches onto a breast cancer cell, it has been found to counteract estrogen’s tendency to stimulate cell growth. In fact, melatonin has a …
https://articles.mercola.com/…/alzheimers-dementia-treatment.aspx
Jun 13, 2013  A study reveals that vitamins B6, B12, and folic acid, as well as cinnamon, may help slow the progression of Alzheimer’s disease.
Sep 12, 2013  When used at extreme levels, copper can be very toxic and can increase your risk of Alzheimer’s disease.
Nov 8, 2008  Eating the wrong diet could increase your risk of developing Alzheimer’s disease. Scientists have found a link between the degenerative brain disease and raised levels of an omega-6 fatty acid. Researchers compared the brains of mice bred with a condition that mimics Alzheimer’s to those of normal mice.
https://articles.mercola.com/…/estrogen-levels-and-cognitive-decline.aspx
Jan 2, 2008  Another nail in the coffin for postmenopausal estrogen therapy. Last year, NEJM published a study that suggested that estrogen helps prevent Alzheimers disease in women. This information provided another false justification for traditional medicine to prescribe it. If you have not purchased Dr. Lee’s book, …
Apr 27, 2017  Mounting research also suggests Alzheimer’s disease is intricately connected to insulin resistance; even mild elevation of blood sugar is associated with an elevated risk for dementia. Diabetes and heart disease are also known to elevate your risk, and both are rooted in insulin resistance.
Feb 11, 2010  Copper pipes have no place in your home. Learn why installing special filters can help you avoid heart disease, Alzheimer’s disease and diabetes.
Aug 4, 2013  Not only heart disease and stroke, but I’m thinking cancer, Alzheimer’s, multiple sclerosis, or any illness that requires good oxygenation to the tissues. … One of the mechanisms that causes this increased risk is that synthetic estrogens and progesterones increase blood viscosity, i.e., they decrease the zeta …
Feb 16, 2010  Alzheimer’s disease is not the only reason to ditch your aluminum-containing antiperspirant and deodorant, as this metal has also been linked to cancer. A 2006 study found that aluminum salts can mimic the hormone estrogen, and chemicals that imitate that hormone are known to increase breast cancer …
Nov 6, 2014  A six-year study reveals that those with vitamin D deficiency are more than twice as likely to develop dementia and Alzheimer’s disease.

How I have lucid dreams and restful sleep with deep breathing and AgeLOC Youth

I have been experimenting and trying new ways to have restful sleep or uninterrupted sleep at night.

Two things helped me during the last 3 nights giving me lucid dreams and restful sleep:

AgeLOC Young supplement and deep breathing (breathing in through your nose and slowly exhaling through your mouth.

https://www.nuskin.com/content/nuskin/en_US/products/shop/px_categories.html

is where you can order AGELOC Youth and add other supplements here like Lifepak. This red colored capsule is slowly changing my hair color to black and my dreams are more lucid, giving me restful sleep. My brain is getting younger.  Join me to share this with others and enter the sponsor code: USW9578356 at

http://www.nuskin.com

During the day, I drink more and drink less at night.

Last week, there are other supplements that I take every other day such as melatonin, Vitamin B complex, probiotic, digestive enzymes, Omega 3, Vitamin D and few times a week – Activated charcoal.

I went back to my 30-min cross fit gym after being absent due to my Philippine vacation and flu. I use rest, lemon, honey, ginger, garlic and onions for my flu.

 

This slideshow requires JavaScript.

 

AgeLOC Youth for Cognitive Health

What is cognitive reserve?


Image: Bigstock

An important concept that is crucial to the understanding of cognitive health is known as cognitive reserve. You can think of cognitive reserve as your brain’s ability to improvise and find alternate ways of getting a job done. Just like a powerful car that enables you to engage another gear and suddenly accelerate to avoid an obstacle, your brain can change the way it operates and thus make added recourses available to cope with challenges. Cognitive reserve is developed by a lifetime of education and curiosity to help your brain better cope with any failures or declines it faces.

Thymosin beta 4 and Skin Repair

 Thymosin beta 4 and Skin Repair

By Carmia Borek, Ph.D.

IMAGE TAG

The promise of repairing sun parched aging skin is alluring, especially if damage control may be attained by applying a substance that is abundant in our body. Thymosin beta 4 (Tb4), a molecule that accelerates wound healing in animals and cultured cells, “may be valuable in repairing skin damage caused by sun or even by the wear and tear of aging?”

This hopeful message of Tb4’s potential to restore damaged human skin was voiced at the 5th International Symposium on Aging Skin, in California (May 2001), by Dr. Allan Goldstein, Chairman of the Biochemistry Department at George Washington University and founder of RegeneRX Biopharmaceuticals. RegeneRX is carrying out preclinical research on Tb4 as a wound healer, in collaboration with scientists at the National Institutes of Health.

Skin is the largest organ of the body, which makes up 16% of total body weight. It is also the largest organ that provides immune protection and plays a role in inflammation. Composed of specialized epithelial and connective tissue cells, skin is our major interface with the environment, a shield from the outside world and a means of interacting with it. As such, the skin is subjected to insults and injuries: burns from the sun’s ultraviolet radiation that elicit inflammatory reactions, damage from environmental pollutants and wear and tear that comes with aging.

Image with Caption

An effective healer, Tb4 can be
administered topically on the
surface of cells and systemically,
through injection. Besides
healing skin wounds, Tb4 has
been shown to promote repair
in the cornea of the eye, in rats,
thus preventing loss of vision.

There are several layers in the skin; the outer epidermis and beneath it the dermis and the subcutaneous layer. Cells in the epidermis include keratinocytes, its major cell type, that move continuously from the lower basal layer where they are formed by cell division. Other cells in the epidermis are the melanocytes that synthesize pigment and transfer it to the keratinocytes, giving our skin its color, and a wide variety of immune cells that maintain immune surveillance and secrete substances called cytokines, like interleukin 1 and 2, which are active in inflammation. The dermis contains connective tissue, mainly collagen, blood vessels, various types of immune white cells and fibroblasts.

The structure that provides the cell with form is the cytoskeleton, whose protein actin, a housekeeping molecule in cells, comprises 10% of the cell protein. Actin is essential for cell division, cell movement, phagocytosis (engulfing foreign bodies in immunoprotection) and differentiation.

Cells on the surface of the skin are constantly being replaced by regeneration from below. The repair of a wound is a scaling up of this normal process, with additional complex interactions among cells, formation of new blood vessels, collagen, more extensive cell division and cell migration, as well as strict control of inflammatory cells and the cytokines they release to resolve the inflammation.

Skin damage and aging are induced to a large extent by free radicals from the sun and environmental pollutants and from oxidants produced during infection and inflammation. Lipid peroxidation of membranes and increased inflammatory substances, such as thromboxanes and leukotriens, add insult to injury. While skin damage accumulates with age, repair processes slow down. Thus, any boost by a molecule that would reduce free radicals and accelerate molecular events in healing has the potential to hasten skin repair. Tb4 has such healing qualities.

The nature of Tb4

Image with Caption

The promise of repairing sun
parched aging skin is alluring,
especially if damage control
may be attained by applying
a substance that is abundant
in our body.

Thymosin beta 4 is a small 43 amino acid protein (a peptide) that was originally identified in calf thymus, an organ that is central in the development of immunity. Tb4 was later found in all cells except red blood cells. It is highest in blood platelets that are the first to enter injured areas, in wound healing. Tb4 is also detected outside cells, in blood plasma and in wound and blister fluids.

Its unique potential as a healing substance lies in that it interacts with cellular actin and regulates its activity. Tb4 prevents actin from assembling (polymerizing) to form filaments but supplies a pool of actin monomers (unpolymerized actin) when a cell needs filaments for its activity. A cell cannot divide if actin is polymerized. Tb4 therefore serves in vivo to maintain a reservoir of unpolymerized actin that will be put to use when cells divide, move and differentiate.

Tb4 has other effects that are needed in healing and repair of damaged tissue. It is a chemo-attractant for cells, stimulates new blood vessel growth (angiogenesis), downregulates cytokines and reduces inflammation, thus protecting newly formed tissue from damaging inflammatory events. Tb4 has been shown to reduce free radical levels (with similar efficiency as superoxide dismutase), decrease lipid peroxidation, inhibit interleukin 1 and other cytokines, and decrease inflammatory thromboxane (TxB2) and prostaglandin (PGF2 alpha).

An effective healer, Tb4 can be administered topically on the surface of cells and systemically, through injection. Besides healing skin wounds, Tb4 has been shown to promote repair in the cornea of the eye, in rats, thus preventing loss of vision.

Wound healing

A critical step in wound healing is angiogenesis. New vessels are needed to supply nutrients and oxygen to the cells involved in repair, to remove toxic materials and debris of dead cells and generate optimal conditions for new tissue formation. Another important step is the directional migration of cells into the injured area, joining up to repair the wound. This requires an attractant that will direct the cells to the wound and propel them to the site. These critical steps in wound healing are regulated by beta 4, as seen in the following experiments.

Endothelial cells

Cells that line blood vessels (endothelial cells), taken from human umbilical chord veins, were grown in culture and the layer of cells subjected to a scratch wound. Cultures were then treated with Tb4 or kept in growth medium without Tb4. When examined four hours later, Tb4 treatment attracted cells to migrate into the wound and accelerated their movement, showing it is a chemoattractant. Cell migration was four to six times faster in the presence of Tb4 compared to the migration of untreated cells. Tb4 also hastened wound closure and increased the production of enzymes, called metalloproteases, that could pave the way for angiogenesis by breaking down barrier membranes and facilitating the invasion of new cells to the needy area, to form new vessels. Other experiments showed Tb4 acts in vivo. When endothelial cells were implanted under the skin in a gel supplemented with Tb4, the cells formed vessel-like structures containing red blood cells, indicating the ability to stimulate angiogenesis in the animals.

Skin repair

Thymosin beta 4 accelerated skin wound healing in a rat model of a full thickness wound where the epithelial layer was destroyed. When Tb4 was applied topically to the wound or injected into the animal, epithelial layer restoration in the wound was increased 42% by day four and 61% by day seven, after treatment, compared to untreated. Furthermore, Tb4 stimulated collagen deposition in the wound and angiogenesis. Tb4 accelerated keratinocyte migration, resulting in the wound contracting by more than 11%, compared to untreated wounds, to close the skin gap in the wound. An analysis of skin sections (histological observations) showed that the Tb4 treated wounds healed faster than the untreated. Proof of accelerated cell migration was also seen in vitro, where Tb4 increased keratinocyte migration two to three fold, within four to five hours after treatment, compared to untreated keratinocytes.

Repair of the cornea

IMAGE TAG

The cornea is the outer thin layer of epithelial cells protecting the eye. After wounding, timely resurfacing of the cornea with new cells is critical, to prevent loss of normal function and loss of vision. Corneal epithelial healing occurs in stages, with cells migrating, dividing and differentiating. Therapies for corneal injury are limited. Therefore, the recent finding that Tb4 promotes corneal wound repair in animal models offers hope for a therapeutic product that will improve the clinical outcome of patients with injured corneas.

In the experiments, an epithelial wound was made in the corneas of sedated rats. A Tb4 solution was applied at several concentrations to the injured eyes in one group of rats while another group was treated with a solution without Tb4. Following 12, 24 and 36 hours, the eyes were tested by microscopic observation for epithelial growth over the injured site. Investigators found the Tb4 accelerated corneal wound repair at doses of Tb4 similar to those found to repair skin wounds. When tested 24 hours after treatment, the rate of accelerated repair was proportional to the concentration of Tb4, with the highest dose (25 microgram) showing a threefold acceleration of epithelial cell migration, compared to untreated. Treatment with Tb4 showed anti-inflammatory effects, helping resolve the injury. An application to human cells in a model of human corneal cells in culture showed that Tb4 enhanced epithelial cell migration in vitro.

RegeRx and Tb4

Thymosin beta 4, developed by RegeneRx Biopharmaceuticals as a pharmaceutical for the healing of wounds, is a synthetic version of the natural peptide. As Dr. Allan Goldstein emphasizes, “Tb4 represents a new class of wound healing compounds. It is not a growth factor or cytokine, but rather exhibits a number of physiological properties which include the ability to sequester and regulate actin, its potent chemotactic properties. . . and its capability to downregulate a number of inflammatory cytokines that are present in chronic wounds.” When a wound heals there are many growth factors produced in the area so that additional factors, such as those currently on the market for wound healing, may help but are not necessarily lacking. Tb4 treatment, however, adds a new dimension to wound repair by providing cells with actin as needed, for cell migration, replication and differentiation.

RegeneRX Biopharmaceuticals is focusing on the commercialization of Tb4 “For the treatment of injured tissue and non-healing wounds, to enable more rapid repair and/or tissue regeneration.” Especially needy are diabetics who suffer from poor blood circulation and loss of sensation of pain that keeps their wounds unnoticed and unattended for days, leading to ulcers that may not heal. Other hard healing wounds are pressure ulcers in patients who are bed ridden and often receive skin grafts as treatment, or reconstructive surgery.

RegeneRx is continuing with pre-clinical research, in collaborative arrangements with the National Institutes of Health, accumulating data on the effects of Tb4 and aiming for an IND application (Investigational New drug App-lication) to proceed with clinical studies. Phase I clinical trials will determine the ability of Tb4 to repair ulcers in diabetic patients and to reduce inflammation and accelerate recovery from burns and abrasions to the cornea.

Aging skin

IMAGE TAG

The potential of Tb4 to repair sun damaged and aging skin is yet to be established by extensive studies. Many of the biological events that occur in wounding are involved in skin impaired by sun and aging. Ultraviolet radiation damage or other injuries to skin that are associated with aging may be in the future repairable with Tb4, similar to the success with wound repair. It is a hopeful prediction that this small anti-inflammatory molecule, which plays a vital role in regeneration, remodeling and healing of damaged tissues, would help rejuvenate aging skin. The effects of Tb4 in accelerating wound repair are important following surgery; Tb4 would then have practical applications following cosmetic surgery, a procedure growing in popularity in our society, in dealing with aging skin.

References

Goldstein AL. Thymosin In: McGraw Hill Yearbook of Science & Technology, McGraw Hill Publishers, New York PP371-373.

Low T, Goldstein AL. Chemical characterization of thymosin beta 4, J Biol Chem 1982; 257:1000-1006.

Malinda KM, Goldstein AL. Kleinman HK Thymosine beta 4 stimulates directional migration of human umbilical vein endothelial cells. FASEB J 1997; 11: 474-481.

Malinda M et al. Thymosin beta 4 accelerates wound healing J Inves Dermatol 1999; 113: 364-368.

Nachmias VT et al. Thymosin beta 4 (Tbeta4)in activated platelets Eur J. Cell Biol 1993; 61:314-320.

Sanders MC, Goldstein AL, Wang YL. Thymosin beta 4 (Fx peptide) is a potent regulator of actin polymerization in living cells Proc Nat Acad Sci 1992;89:4678-4682.

Sosne G et al. Thymosin beta 4 promotes wound healing and modulates inflammatory mediators in vivo Exp Eye Res 2001; 72:605-609.

Young JD et al. Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids Nat.Med 1999;5:1424-1427.