Heparin Nanofibers Loaded with VEGF and FGF Mimic Stem Cells
In previous articles, I have emphasized the mediation of extracellular signaling by heparan sulfate proteoglycans (HSPGs, polysaccharides attached to proteins) and heparin (HS fragments, oligosaccharides) and the sensitivity of HSPG expression and HS degradation by inflammation. I return to that subject, spurred on by reading two articles that together show both the significance of heparin-mediated growth factors in general and in the specific case of symptom development in rosacea.
FGF Receptor Inhibitors Cause Symptoms Like Rosacea
Fibroblast growth factors stimulate the development of cancers, and antibodies against FGF receptors block cancer growth (see ref.) FGF receptor inhibiting antibodies are now being used to stop cancers. Unfortunately, FGFR antibodies (e.g. cetuximab, panitumumab) also cause symptoms in the skin (telangiectasia, acneiform eruption) similar to the facial inflammation of rosacea. Similarly, in knock-out mice, that lack the ability to produce FGFR, there are related symptoms. It appears that lack of some FGF signaling may produce the symptoms of visible blood vessels and pus-filled (though lacking bacteria) follicles of rosacea.
FGF Mediated by HSPG
FGF binds to the heparan sulfate of membrane bound HSPG in pairs and these FGF dimer/heparan sulfate complexes activate a pair of FGF receptors. The result is activation of protein phosphorylation activity (tyrosine kinase) and normal skin development. HSPG synthesis is modified by inflammation and heparanase activity is increased. This suggests that inflammation will decrease FGF signaling and could lead to symptoms of rosacea.
Growth Factors (VEGF, FGF) Bind to Heparin Nanofibers that Mimic Stem Cells
Stem cells produce lots of different growth factors and when stem cells are introduced into damaged cardiovascular tissue, more healing results (see ref.) To determine if the growth factors produced by the transplanted stem cells was sufficient for the improved healing, fibers made of heparin were dipped into stem cell cultures and the resulting growth factor-coated fibers were injected into damaged tissue. The heparin-binding growth factors were just as effective at enhancing healing as were the stem cells in previous experiments. This demonstrated that heparin-binding growth factors were the key to normal repair/revascularization and function.
Rosacea Results from Inflammation and Aberrant Vascularization
Rosacea is poorly understood and is probably numerous diseases that have related symptoms and complex development. As I indicated in previous articles, neurotransmitters from stimulated facial nerves, enzymes (kallikrein) and cytokines from intestinal interactions with gut flora, mast cell products (heparin, protease) and modified antimicrobial peptides (cathelicidins), as well as cryptic bacteria in facial tissues, may all be involved. Inflammation in the skin of the face and in the intestines is involved. Vitamin D, omega-3 fatty acids and anti-oxidants have a variety of responses (sometimes paradoxical) that differ from individual to individual and at different stages in the development of the disease. Facial inflammation leads to abnormal development of blood vessels (telangiectasia) and in accumulation of lymphocytes and neutrophils (papulopustular rosacea).
Facial Inflammation May Depress HSPG Production and Disrupt FGF Function
One of the key ramifications of persistent facial inflammation may be the depletion of of HSPGs that normally coat cells. HSPGs are continually produced, reabsorbed and degraded. The half-life for HSPGs, even those that surround the cells that produce cartilage in connective tissue, is six hours. HSPGs are also the source of heparin, that is produced as a counter ion bound to histamine and proteases in the secretory granules released by activated mast cells. Thus, inflammation-based depression of HSPG production, which is also accompanied by heparanase activation, will remove the HSPG coating of cells. This HSPG coating is needed for normal growth factor function. Lack of an HSPG matrix on the surface of cells will also result in the migration of growth factors away from where they are normally functional and into adjacent tissue where they may stimulate aberrant development of blood vessels. This may explain telangiectasia.
Is Topical Heparin a Rosacea Treatment?
Topical heparin does penetrate the skin. It would appear to be a logical treatment, if HSPG depletion is contributing to symptom development in rosacea. The length of the heparin fragments may be important. I am unaware if anyone has tried the heparin lotions that are available for treatment of wounds to minimize scarring, on rosacea. Heparin may be useful in combination with vitamin D3 and remediation of gut flora in a general scheme to treat rosacea.
refs:
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005 Sep;16(9):1425-33. Epub 2005 Jul 12.
Webber MJ, Han X, Prasanna Murthy SN, Rajangam K, Stupp SI, Lomasney JW. Capturing the stem cell paracrine effect using heparin-presenting nanofibres to treat cardiovascular diseases. J Tissue Eng Regen Med. 2010 Mar 10. [Epub ahead of print]
37 comments:
"FGF binds to the heparan sulfate of membrane bound HSPG in pairs and these FGF dimer/heparan sulfate complexes activate a pair of FGF receptors. The result is activation of protein phosphorylation activity (tyrosine kinase) and normal skin development. HSPG synthesis is modified by inflammation and heparanase activity is increased."
I have NO Idea what you said. Wish I did, it would be so much more informative.
Anon,
Ouch. I guess I failed at communicating my major points. I was excited about putting some pieces of the rosacea puzzle together, but I guess that I just succeeded in phrasing for myself.
The main point is that the two articles that I cite show that the normal development of skin can be disrupted by inflammation. Continual inflammation of the face from many different causes can result in the symptoms of rosacea. Normal heparin synthesis in the face is needed for normal development and inflammation compromises heparin synthesis.
The bottom line is that once rosacea occurs, one treatment may be to add back missing heparin and restore normal skin development. Topical heparin treatment may permit an attack on multiple sources of inflammation in the facial skin and in the gut using vitamin D, an anti-inflammatory diet, exercise, perhaps even antibiotics etc.
Thanks for your comments. I am just trying to explain rosacea to provide a little relief for those who suffer from it.
Anon,
I also put in a link to one of my other articles that shows a little video clip that I made to explain the essential role of the heparan sulfate (HS) in the binding of growth factor hormones to protein receptors on the surface of cells. Without the HS, the hormones don't work and the symptoms of rosacea appear.
Hi Dr. Ayers,
Interesting post. It appears that topical heparin isn't available for rosacea and I know my health care provider wouldn't prescribe it off-label - do you have any other recommendations for restoring heparin synthesis?
I've been following a fairly orthodox paleo diet for about the last year with great results, but the rosacea remains.
Thanks!
Anon,
From listening to rosacea sufferers, it appears that vitamin D3 supplements may improve rosacea. The secret appears to be to slowly increase the amount of vitamin D3 so that the face is permitted to recover and never gets very inflamed.
There are other reports that keeping the gut flora moving through the intestines is important to minimizing symptoms, so I would encourage the use of pectin and inulin rich foods in an anti-inflammatory diet. Since you are already on a mostly paleo diet, that should be relatively easy.
Thanks for the comments/questions.
RE: I have NO Idea what you said. Wish I did, it would be so much more informative.
OK Dr. Ayres Here's my view.
You come across as a genuine intelligent, concerned, researcher. I thank you for that. I try to read everything that you write but though I have a science background (physics, electronics), I don't know much about the human body processes (still learning). I don't want you to "Dumb down" your ideas, just your explanation to those of us who may not have had the years of experience that you have had. I highly respect your efforts. My specific concern is Psoriasis and WTF is it?
Keep up the good fight.
Thank You
Anon,
I have written about psoriasis in a couple of articles that can be found by using the search in the upper left or the lengthy index on the lower right.
It is appropriate to ask what psoriasis is, because it seems to me that the biggest problem with the medical industry is that few are concerned with the molecular/cellular basis of disease. Cure and treatment will come from a simple explanation of what a disease is. That explanation for dozens of diseases is my goal.
Psoriasis appears to be an inflammation of the skin that disrupts normal development of the shedding outer layers of keratinocytes. This also disrupts the function of the skin as a boundary layer to prevent dehydration and infection. So, psoriasis probably shares some signaling problems with rosacea, but it doesn't have the localization to the face, that comes with the nerve-signaling aspect of rosacea. Psoriasis appears to involve the autoinflammatory aspect related to basic antimicrobial peptides, cathelicidins, binding to DNA from damaged host cells to trigger inflammation and would probably also respond to topical heparin.
Thanks for your comments and persist in asking for clarification.
Dr. Ayers,
Thanks for your work continuing to shed some light on Rosacea. It seems like most Rosacea treatments these days are aimed at suppressing inflammation instead of getting at the root cause(s) of the inflammation. For Rosacea sufferers, to even begin to truly understand the disease would be extremely helpful and comforting.
There is nothing worse than having a hundred different possible triggers/causes in your mind when reflecting on a very visible chronic inflammatory skin condition. Is it stress? Is it humidity? Is it temperature fluctuations? Is it too much turmeric/garlic/boswellia/quercetin/ginger/milk thistle/etc... (natural 5-LOX inhibitors) suppressing my body's ability to fight off a chronic infection? It it those starches or simple carbs I indulged in last weekend? Is it the gut flora? Is it SIBO? Is it too much UVA exposure? Is it die off from cryptic bacteria due to higher D3 blood serum levels? Is it leaky gut? Is it paradoxical inflammation from agus nerve stimulation or more omega-3s? The list of questions goes on and on seemingly ad infinitum....
Personally, I've been following your anti-inflammatory diet, as well as eating natto, kimchi, homemade yogurt, plenty of omega3s, reuteri pearls, vitamin K2, plenty of vitamin D, exercise.
Now, I'm just wondering about what you said concerning pectin. I do have some apple pectin powder, when have you heard is a good time for people to take it? An hour before a meal? With a meal? After a meal?
Also, Do you think high enough blood serum levels of vitamin D (90-100ng/ml) are enough to take out the cryptic bacteria in facial skin? What about biofilms in the face not just in the gut? Can D3 help the immune system get to those chronic infections?
Eric
Eric,
It is amazing to me to hear reports of rosaceans with extremely different abilities to tolerate different treatments and foods.
You seem to have a high tolerance for many anti-inflammatory treatments and diet components. That suggests that your gut is in fairly good shape compared to many rosaceans who have gut flora heavily compromised by chronic use of antibiotics.
It would be interesting to know what your serum vit.D level is. I would expect it to still be around 30. Raising the level to closer to 100 should eliminate most of your symptoms, but I haven't heard of any rosacean who has been cured.
Lack of a cure suggests a chronic form of an infectious agent. In other diseases it is viral, but I think that it is bacterial in rosacea. It is probably one of the bacterial forms that lacks walls and probably resides intracellularly (or as a biofilm?) The intracellular form is indistinguishable from the molecular machinery of the mitochondria, e.g. both use prokaryotic ribosomes, DNA replication, transcription, and therefore relatively unapproachable by antibiotics.
Part of the action of vitamin D is to act as a hormone that turns on the production of the antimicrobial peptide, cathelicidin, that attacks extracellular bacteria. High vitD should then attack all of the bacteria that are not intracellular, but leave the chronic intracellular forms. That would eliminate most symptoms, but not produce a cure.
That is how it looks to me. I hope this is useful.
Thanks for your comments.
Art, I would guess I consider myself a 'cured' Rosacean - in as much as I don't use my Rozex anymore and haven't for nearly a year. It's possible I've just outgrown the disease I suppose (I was diagnosed at 34 and am now 46) but it had improved steadily as I shifted my diet first to low-carb, then increasingly towards 'paleo' (but I still eat dairy) or perhaps a more accurate description might Kwasniewski-like 'optimal' diet. What are the main changes over the last year? I started taking Vit. D in gel caps at a much higher dose (4800 IU per day) and my serum D3 in September last year was 74 ng/ml. Also, I pretty much gave up wheat.
Jacqueline,
It's great that your rosacea responded to low carb/high sat. fat, no grain and high vitD3. As you may know, some more severe cases respond to similar treatment with flareups. They also cannot tolerate fish oil.
It is also good that your longterm use of the broad spectrum/anaerobic antibiotic Metronidazole didn't cause more permanent damage to your gut flora.
I still am perplexed at how to proceed in cases that appear to have complex inflammatory interactions with large tissue loads of bacteria in both face and gut.
Some people have found success with vitD and suppression of the die-off inflammation by pretreating with aspirin.
I appreciate your personal experience and hope that it also helps others.
Dr Art,
Do you have any hope for eczema suffers? A couple of friends have bad cases and the only real relief,
temporary at best, are the steroid creams.
After reading your rosacea post, I suspect these friends have gut flora problems also.
I have suggested high VitD3, elimination of gluten, coconut oil,
no frankenoils, only O3 fish oil...basically a paleo diet...all without any success.
What is it that the body is exposed to...that eczema suffers are expelling through their skin? And what is irritating the skin to cause the need to scratch the skin all the time?
Is it food or the envionment suffers are exposed to?
It seems to be a disease that is not life threatening...but suffers are truly living a life of misery.
Dextery,
I should probably do some more thinking and a lit. search on eczema. My initial impression is that there are multiple forms of eczema and some of them are like rosacea. Others are autoimmune and related to celiac (sisters of Hashimoto's thyroiditis).
The difficult cases are probably like the tough cases of rosacea and involve gut inflammation. I would suspect that they would respond to a total bowel irrigation, indicating pathogenic gut biofilms. A history of antibiotic use would be a giveaway. The gut would need to be rejuvenated with probiotics, pectin and inulin, and an absence of antibiotics. Normal bowel function would be a prerequisite before an anti-inflammatory diet would be expected to work.
High vitD3, fish oil supplements, in the absence of grain, and omega-6 vegetable oils. Remember to include saturated fats or the omega-3s might backfire.
Some things that would be interesting to try on surrounding uninvolved skin would be castor oil and Vick's. Vagal stimulation exercises might also be effective.
A new idea would be to try topical application of heparin in the form of Lipactin, a cold sore treatment.
Tell me what happens.
For many, eczema is related to the same gene that causes asthma and hay fever. I am an eczema suffer and i can tell you that i have found no cure through diet or supplements. It is seasonal: no humidity in the air and eczema arises; when it is humid once again, the eczema recedes and frequently disappears until winter comes back. It has a genetic basis as my teenager has inherited it from me. The normal skin barrier that retains moisture in the skin is deficient in eczema suffers leaving us with the best remedy: moisturize topically, and resort to topical steroids as a last resort.
Hope you find something better Dr Ayers!
Steve,
The seasonality you mentioned sparked my interest....ie. the return of the eczema in the winter.
We know that there is a higher incidence of disease in folks that live in northern areas of the US and these folks are chronically deficient in Vit D3.
Could it be that lack of natural sunshine and chronically deficient
serum Vit D3 plays a factor.
Have you ever checked your D3 level to see if you are in the reference range of 30 to 100ng/nl
http://www.grassrootshealth.net/ one can get an in-home blood splot
kit to mail in.
Vit D Council wants in the mid 60s or higher.
Dextery: I have supplemented with D3 for sometime and my blood level of 25(oh)is between 62-72 on 8,000 to 10,000 units per day. It is the humidity,and not the lack of D that affects the eczema. you will generally see it in families with history of airborne allergies/asthma. A non inflammatory diet does not seem to help and in my case with age it seems to worsen, probably due to the skin drying out with age. Good thought on the D!
Hi Steve,
Thanks for the follow up post on eczema.
From all I can read, it is an inherited condition that can be only be controlled.
In addition to my two friends, see
this blog of this lady and her children.
http://onemomagainsteczema.blogspot.com/
...A constant battle...of which, I am sure you have fought.
Perhaps Dr Ayers will find the magic bullet and become famous.
Thanks Dextery: Unfortunately, as much as we would like to otherwise believe, many diseases are genetically based. Best to follow anti-inflammation diet, but it cannpt always do the trick for every issue out there.
We know Dr. Ayers is trying and does a superb, greatly appreciated job!
Steve and Dextery,
I still think that the evidence for particular genes leading to atopic dermatitis is unconvincing. There are very few diseases in which genetics dominates the outcome. Several large studies with many prominent diseases have concluded that the contribution of genetics to the disease course is minor compared to the dominant factors: diet and lifestyle.
Allergies and autoimmune diseases have a big dietary history component, by which I mean, once chronic dietary inflammation has produced symptoms, it is very hard to repair the damaged immune system. This seems to be the case with all of the high IgE/allergy and autoimmune diseases, yet most of these can be at least temporarily reversed by helminth therapy. This shows that the problem may be a major disruption of immune system cell development in the gut.
So, I persist in thinking that most of what is seen as familial and genetic is just shared diet history and gut flora. I will continue to try to explain the molecular biology and identify simple interventions.
Thanks for the fun discussion.
thanks Dr. Art
do you think that a course of probiotics (non dairy) might be helpful for the eczema and if so what ones to buy.
Steve,
It is hard to judge the amounts of probiotics, because the bacteria multiply extravagantly. I always recommend a full fat yogurt with live bacterial cultures, because the saturated fats are helpful to support fish oil. Pectin (apples, tomatoes) and inulin (leeks) are helpful prebiotics to support the probiotics.
Thanks for the comments.
I will put forth some wild speculation about eczema. I would say it is not necessarily genetic, but it the lack of certain gut bacteria. This could also explain why it gets passed on from parent to child - not through genetics but through gut bacteria from other to child.
I would say it is possible that by adding in certain missing gut bacteria (bifidobacterium in particular) that you could treat eczema:
http://smilinggreenmom.com/2009/10/ethan/
Matt,
As you can see from my other posts, I think that gut flora and their interactions with the gut/immune system, are an integral component of health. Even the primitive attempts to alter gut flora by adding lactobacilli, have significant positive impacts on altering gut flora and minimizing numerous diseases.
We are in the very early days of analyzing gut flora, relating gut flora to disease and altering gut flora to support health. Hopefully this will be an area of rapid development in healthcare. The difficulty will be in developing healthcare business models that exploit gut health.
I enjoy your blog. Thanks for your comments.
Dear Dr. Ayers,
I have a question about the genetic aspect of asthma. It was mentioned on a health program on the TV yesterday that Ireland has the highest incidence of asthma in Europe. As I am from Romania and I married an Irishman I'm interested in how genetics might affect my children.
Almost 1 in 5 people have it. My husband says it's genetic but I don't agree and think that Irish people's celiac, eczema and asthma incidence is caused by their consumption of wheat, food that might have been introduced here very late, compared to warmer areas.
I was told that certain African populations, have high incidence of sickle cell anemia, which points to a genetic defect. (or the Ashkenazi jews's case)
What do you think?
This posting at paleohacks has a discussion regarding nightshades.
The are two anecdotal reports by commenters that avoiding nightshade vegs eliminated or helped one rosacea sufferer and one eczema sufferer.
http://paleohacks.com/questions/342/has-anyone-seen-benefits-of-avoiding-nighshades
Lightcan,
I should be an advocate for genes causing disease. I am a molecular biologist who teaches genetics, so I know that genotype produces phenotype and that suggests that genes determine susceptibility to disease. Several diseases result directly from genetic mutations, but the genetic contribution to disease is very limited. Diet is much more important.
A major study of genetic predisposition to gastric cancer, for example, found several mutations that contributed to gastric cancer. It was expected that these mutations would involve pathogenesis by Helicobacter pylori, the causal agent in stomach cancer. The cancer-associated genes were involved in inflammatory cytokine signalling. The inflammatory response during bacterial infection of the stomach controlled the progression to cancer. Diet, however, determined if predisposed people got cancer. I think that individual genetically predisposed to cancer, in all but the extreme cases, would avoid the disease with an anti-inflammatory diet.
I think that the same is true of genetic predisposition to asthma. Asthma is more indirect in its relationship to inflammation, because the initial allergic component developed from earlier chronic inflammation. Asthma also involves changes in the development of the respiratory system. To reverse asthma requires altering the immune system to produce tolerance. Since tolerance is based on the immune system that resides in the gut, then asthma cures also require a reshaping of the gut flora and gut. There is a minor genetic contribution to the development of asthma, but I think that initiation of the process was via a chronic source of inflammation, such as diet.
Thanks for your comments.
Dextery
You pose a complex, as yet unanswered question -- how do nightshade alkaloids produce an immune reaction? I don't know, but that provides lots of room for speculation.
I have noticed that the variable region of antibodies, the region involved in antigen recognition, frequently contains numerous tryptophans. The reason this is significant, is because tryptophan amino acids are typically used to stabilize folding intermediates or are involved in binding to ligands, since hydrophobic binding to the face of the tryptophan is more than ten times stronger than other typical weak bonds, e.g. hydrogen or ionic bonds.
I mention tryptophans, because they are typically involved in binding to carbohydrates, basic amino acids or aromatic phytochemicals, e.g. alkaloids. Alkaloids can't typically stimulate antibody production, because they can't participate in presentation, but alkaloids can mimic parts of proteins that have stimulated antibody production.
So, I think that alkaloids from nightshades trigger inflammatory and immune responses by virtue of binding to IgEs that have been elaborated in response to a different antigen. Avoiding nightshade alkaloids simply removes the trigger, as with other allergic reactions. A cure for alkaloid sensitivity (in rosacea or eczema) would involve both a removal of the original sources of chronic inflammation at the base of the allergy production and restructuring the gut and its flora to revive immunological tolerance. (An alternative would be helminth therapy.)
Thanks for the provocative comment.
Dr Ayers,
Thanks very much for your response on nightshades. I take it that
the nightshades stimulate whatever is non optimal in the gut to produce the overt manifestation of
skin problems.
Does the GI track look as inflammed internally as the skin?
Thanks again.
Would you have time to participate in the PaleoHack forum periodically?
Dr Kurt Harris shows up now and then.
It would be great to have your
Molecular, Cellular and Developmental Biology background
in attendance.
Most of us do not have any training in these sciences, so a posting pretty much has to be in laymen's terms.
Consider it.
Thnks
Many people assume that rosacea is simply a sunburn or complexion problem that will eventually go away, and fail to realize they have a chronic condition that may get worse without medical treatment and lifestyle modifications,” said Dr. Jonathan Wilkin, chairman of the NRS medical advisory board of student aid. He noted that the steady growth and aging of the population over the past decade have significantly raised the incidence of this widespread but poorly understood disorder, and its effects are now in full force among the massive numbers in the baby boom generation. The NRS had previously estimated the number of rosacea sufferers in the United States at 14 million, and recent epidemiological studies have also found the incidence may be much higher. Despite its prevalence, however, most Americans Politics are unaware of its signs and symptoms, and medical data suggest that only a small percentage of rosacea sufferers are being treated.
http://www.theheart.org/article/1072875.do
Congressional investigation slams FDA over heparin contamination that came from China.
Thought might like the article. Couldn't find a direct email to you.
Dexter
I wants to know what the difference between Rosacea and acne is. It is a same thing or not. Please suggest me what is the best treatment for Rosacea.
Hi Art,
I follow your blog with great interest.
Have you spoken to anyone who has tried heparin for rosacea with success?
Do you think this cream would work:
http://www.pharmacyexpress.com/hirudoid-cream-40g.html
Thank you.
Preben
Hello Dr. Ayers. I have been reading your blog to learn more about autoimmunity. I did a search on your site for "borax" and found no hits. Do you have an opinion on using this as a supplement for killing candida?
http://www.health-science-spirit.com/borax.htm
Thank you very much for your time.
Dear Dr. Ayers,
Like the commenter before me, I, too, would like to know whether Ted's borax treatment as described on earthclinic's website is effective for Candida? I would also like to know if there are multiple species of Candida albicans? Additionally, I would am wondering if 1 tablespoon of psyllium husk dissolved in a glass of water will help destroy biofilms in the gut, and whether or not it will have any negative consequences to my efforts to kill Candida albicans?
I am currently trying Ted's borax treatment, but I have only recently began this treatment. It consists of using 1/4th teaspoon of borax to 1 liter of water (male dosage) or 1/8th teaspoon of borax to 1 liter of water (female dosage). To this, I add 2 teaspoons (10 grams) of baking soda and 12 drops of 3% hydrogen peroxide. The one liter of water is consumed over the course of a day. I am also using 12 drops of grapefruit seed extract every few hours. I have a very serious ragweed allergy which I am trying to cure by killing Candida albicans. The grapefruit seed extract and bilberry tea seem to relieve my ragweed allergy from three to six hours. When I start sneezing again, then I see this as a sign that I need to hit the Candida albicans with more grapefruit seed extract and elderberry tea.
Thanks, hope to hear back!
Zoe
Hi, I am suffering from rosacea after a derm here gave me a cream she compounded which contained Betaderm (a strong steroid). I was told to use it for 90 days straight on my face. I now have severe dermal and subcutaneous atrophy and rosacea.I am hoping to find a way to cure/treat all of this. Fat grafting (for the stem cells) and fibroblast injections have both been suggested. I also have Hashimoto's and am mainly gluten-free and take fish oil, Vit D, and probiotics daily. Do you have any suggestions? Thank you so much, Jennie
Thanks for sharing such an informative and useful post. we also offer most effective Rosacea Treatment in Abu Dhabi, where we provide best services of laser Skin treatments.
The insulin-like growth factors (IGF) is a group of polypeptides with growth-promoting effects. The secretory cells are widely distributed in tissues such as liver, Insulin Like Growth Factors Fragments
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