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Microsoft word - hair growth factors

Hair Growth Factors

A Nanogen Briefing for the Scientific Community
by Toby Cobbledick
Emerging research in proteomics and the systems biology approach to molecular biology have significantly increased our understanding of cellular development, and the processes involved in controlling cellular cycling. From this research the importance of the role of cytokines has been established. VEGF in particular has a significant role throughout the development and “life” of a hair follicle, not just to begin growth but to determine differentiation, structure, and the duration of growth. Useful applications of VEGF for hair loss treatment are considered, as well as a method to overcome safety and viability concerns of cytokine therapy. Introduction
required by the hair as an organ later to maintain the cycle, however it is also possible that VEGF may have proliferative Throughout the history of medicine, we have focussed upon effects in certain cells other than endothelial cells. discovering external chemical molecules or elements, and applying them to the body to make a physiological change. An additional consideration is the control of LEF-1 expression, proliferation is controlled via a variety of pathways including the It is only very recently that advances in molecular biology, and MAPKinase pathway. The MAPKinase pathway is stimulated via a particularly proteomics, have fully described the use of calcium dependent signal by VEGF[4]. It is therefore also possible intercellular signals. We now know that many cellular functions that VEGF indirectly acts as a check on uncontrolled proliferation. from mitosis and differentiation, right through to apoptosis, are largely controlled by a group of signalling molecules - cytokines. What is surprising about cytokines is not their existence which Proliferation of cells without organisation and migration will not has been known to medicine for a long time, but the intensity and form a hair, or any other organ. A hair shaft is a complex breadth of their modes of action. The effect of cytokines or, structure, and keratinocyte migration to form the differentiated “growth factors” as they are commonly known, is so significant layered lineages of the hair shaft, as well as the hair bulb and that they would have great utility if they could be isolated and applied correctly as a therapeutic agent. A second pathway for VEGF action is commonly known, and Cytokine treatment will be specific with the allergic reactions and upregulates the Akt/PKB genes to prevent apoptosis. However unforeseen side effects very unlikely. Any unintended effect the other function of this pathway upregulates eNOS, producing would clearly be described by the signal’s action and could be nitric oxide[5]. This signal causes vasodilation and membrane anticipated. Also as cytokines are large and locally acting permeability, and is thought to allow cellular migration and molecules, they can target small areas effectively. intracellular communication via other cytokines. In a variety of cel s, VEGF also influences cellular migration by stimulating actin reorganisation and focal adhesion turnover[6]. VEGF and the Hair Growth Cycle
This reorganisation of the cytoskeleton is vital for any cell migration. A similar pathway is stimulated by Wnt11 in other In order to form a hair organ from the dormant dermal papilla cells, and also utilises the MAPKinase pathway upregulated by VEGF to increase the gene transcription necessary for migration[7]. Cells of the papilla and secondary hair germ must multiply rapidly. First, the epithelial finger forms into the dermis, the Without doubt the key to maintaining hair shaft growth is a multiplication then reverses direction outwards towards the sufficient supply of oxygen and essential amino acids. This epidermis. Once formed, stem cells from an as-yet undetermined requires blood. As has been shown by repeated experiments, source proliferate and differentiate into hair matrix cells- increasing blood flow and blood vessel formation to hair follicles identifiable by their high levels of LEF-1 expression[1,2]. improves and maintains hair growth, without this hair growth will cease. The role of VEGF in Anagen is not known, experimentation has shown that dermal papilla cells express high levels of VEGF VEGF is the cytokine solely responsible for blood vessel mRNA in Anagen[3]. This may begin the angiogenic processes formation. Via the VEGFR2 receptor, VEGF stimulates vascular 2010 Copyright Nanogen Hair Research. Al rights reserved. This paper is for internal and professional use only and should not be shared with or acted upon by consumers cells to proliferate to extend the blood vessel, migrate and make the VEGF signal more efficient and increase the organise to form the vessel organ. This rapidly extends new vessels into areas that require blood supply. VEGF also stimulates eNOS to create nitric oxide, stimulating blood vessel and cell An interesting corollary to the possibility of minoxidil acting with membrane permeability for the efficient transfer of nutrients. or via VEGF is the fact that minoxidil upregulates VEGF expression VEGF is particularly useful because VEGF upregulation and many in Anagen dermal papilla cells. This upregulation ensures related pathways are stimulated by hypoxia, so it acts where it is adequate vascularisation of the follicle through the Anagen phase, and is likely at least part of the mode of action of minoxidil[12]. Dihydrotestosterone has long been studied as a major cause of hair loss. It is a hormonal signal which penetrates the follicle, and Prostaglandins have been another widely researched treatment causes downregulation of Bcl-2 leading to apoptosis. Bcl-2 option. Research suggests that prostaglandins are active in the interacts with Bax and Bad genes to prevent apoptosis, and so very early stages of Anagen, possibly even at the initiation step lowering the concentration of Bcl-2 allows Bax and Bad to as suggested by the new eyelash growth in several clinical promote apoptosis through the same pathway[9]. trials[13]. The prostaglandin system is complex, made from a large number of different prostaglandins, and still not fully researched. VEGF blocks Bad conversion, maintaining the pre-apoptotic state[10]. This means that Bcl-2 only has Bax to interact with, and VEGF has been shown to induce prostaglandin I(2) production in so prevents apoptosis at lower concentrations. VEGF also leads to epithelial cells. Prostaglandin I(2) is unlikely to stimulate new hair the downregulation of caspase 9[10], reducing a different growth, however prostaglandin I(2) receptors have been found to apoptotic pathway. VEGF has a clear role in preventing early be specifically expressed in hair cuticle layer, suggesting an apoptosis via these two pathways, and the prevention of hypoxia important role for hair matrix cell differentiation to form the outer and oxidative stress. This will lead to the maintenance of Anagen hair cuticle[14]. This outer layer is essential for terminal hair This may also help explain the necessity for VEGF upregulation in the early anagen stage discussed earlier. Treatment Correlations
Widely regarded as the most successful treatment for alopecia Minoxidil is the medicine of choice for most physicians when areata, diphencyprone is another treatment with no definite treating hair loss. It is surprising then that several modes of mechanism. As a potent allergen, topical application of action have been theorised, but none of them proven. diphencyprone as an immunotherapeutic agent stimulates a response and leads to normalisation of hair growth[15]. The principle mode of action for minoxidil is thought to be the donation of nitric oxide. This gaseous signalling molecule is well Recent work shows this “response” is threefold. Firstly, the ratio known to cause vasodilation and improve circulation. Nitric oxide of CD4/CD8 cells is known to differ significantly in alopecia signals are degraded rapidly by free radicals, therefore many areata patients. Diphencyprone stimulates a normalisation of this treatment utilise antioxidants to prolong the signal life. A notable ratio to one approaching normal scalp tissue. Diphencyprone also antioxidant is superoxide dismutase, as an enzyme with a high upregulates the expression of survivin. This helps to preventing turnover rate superoxide dismutase removes may reactive the premature apoptosis symptomatic of alopecia areata patients. oxygen species, and effectively reduces nitric oxide breakdown. Lastly, it upregulates the expression of VEGF in hair follicle keratinocytes, maintaining nutrient and oxygen supply[16]. VEGF A very credible newer theory is that minoxidil’s effects opening also has an anti-apoptotic role, downregulating Casp9 and Bad the Na+/K+ATPase channel promote hair growth; this has been genes which are key to follicle apoptosis[10]. shown by the classification of two channel subtypes in the follicle, one of which is opened by minoxidil. When opened by a Whilst alopecia areata pathenogenesis is still unknown, VEGF different specific channel opener hair growth was improved, explains part of the success of the most successful treatment to when a channel inhibitor was used the growth effect was In summary, it is well known that minoxidil and anti-
The Na+/K+ATPase channel has another function, regulating Ca2+ dihydrotestosterone treatments are effective against
ion levels. Permanently opening the channels would cause the androgenetic alopecia, and diphencyprone is a useful
levels of Ca2+ ions to stabilise. As the proliferative and eNOS treatment for alopecia areata. Cytokines and particularly
stimulating effects of VEGF are Ca2+ mediated, there is evidence VEGF provide an alternative to these treatments, or
that maintenance of Ca2+ ion levels is necessary for VEGFR2 supporting role to all of these known therapeutic options.
signal transmission to be effective. Therefore minoxidil may 2010 Copyright Nanogen Hair Research. Al rights reserved. This paper is for internal and professional use only and should not be shared with or acted upon by consumers Applications
product for medical treatment, with the exception of organ transplants. There are clearly diverse possibilities for VEGF, either as an independent treatment or to supplement minoxidil for A further consideration behind using human-derived growth androgenetic alopecia, or diphencyprone for alopecia areata. As factors is the danger presented by prion proteins. The dangers of the role in stimulating vascularisation is clear, it is also likely that these causing Creutzfeldt - Jakob disease have been widely a solution containing VEGF would help graft survival and improve publicised. The dangerous presence of prion proteins is possible in any tissue, and is the main reason behind the widespread ban on human-derived products. It is also conceivable that VEGF could be added alone, or with other growth factors to an autologous growth factor treatment One solution to the problem would be to use recombinant VEGF is quite a large molecule, and applied topically to normal bacteria such as E. coli to produce the desired growth factor. human epidermis, penetration would be low. Research into There are however, several drawbacks to bacterial systems. molecule penetration has shown that penetration via the hair shaft is possible. Penetration through the thinner epidermis Recombinant technology would utilise human DNA and around pores and hair shafts would be sufficient to allow a useful incorporate that, via a plasmid or viral vector, into a bacterial cell. The bacterial cell therefore contains human DNA, and even when purified the end product may still contain traces of this, making it As has been widely discussed, a way to ensure penetration of a human-derived product with many of the associated dangers any larger molecule through the scalp is to use a microneedle roller. The microneedle array creates quickly healing channels through the stratum corneum, allowing over 5 times penetration Bacteria are prokaryotes and as such lack many of the cell of many molecules, including proteins far larger than VEGF[17]. components of eukaryotic cells, notably those responsible for This will deliver effective levels of VEGF from solutions containing folding complex proteins. Therefore even a genetically perfect protein is often not assembled correctly, giving lower or no biological activity. Cytotoxins are commonly produced waste products of most Safe, Legal Growth Factors
prokaryotes. They are mostly small soluble glycoproteins and other molecules that do not harm the organism in small There are many safety and ethical concerns with cytokines, quantities; however they can have noticeable effects on humans. however these can be overcome with careful selection of sources Due to their nature, cytotoxins are not removed by purification processes, and therefore remain in the finished product. These can cause side-effects or prevent the cytokine from working These concerns have been widely explored by the media, ensuring that it is not just the physician’s position that is important. Patients will have their own opinions on the subject, and will judge their physician in light of these opinions. Unfortunately this is true even if the patient’s opinion has largely Fungi are the next most obvious source to make recombinant been formed by the media, and consequently the patient may not growth factors. They are eukaryotes and very similar to human have fully understood the evidence and rationale behind the cells, and so produce active proteins very similar to the human physician’s position. With this in mind the following There still remains the problem of small traces of human material, however, which mean many yeast products are only legal for research purposes. The most obvious source of human growth factors is human cells. These can be grown successfully from human embryos, Although less of a concern, yeast cells produce cytotoxins like stem cells can be used, or guided to differentiate into suitable bacterial systems. Like bacterial cytotoxins, these can cause cell lines. These can then be kept in conditions to produce side-effects and allergic-type reactions. growth factors which are then extracted and purified. Even the traces of fungal tissue in purified growth factor media Whist there are advantages to this method, it is costly. Also many have the potential to stimulate immune responses. This is people object to the use of embryos for research, and in fact an especially important as human epithelial tissues react strongly to international moratorium has been declared limited research with many varieties of fungi as an evolved response to fungal human cells. Apart from ethical considerations, it is also illegal in infection. The stimulation of background immune responses can many countries to use any human tissue or human-derived change or cancel out the effects of growth factor treatment. 2010 Copyright Nanogen Hair Research. Al rights reserved. This paper is for internal and professional use only and should not be shared with or acted upon by consumers References
Synthetic Human VEGF or sh-VEGF is not actually chemically 1. Chan E.F., et al., A common human skin tumor is caused by synthesised, it is produced for Nanogen utilising a unique plant activating mutations in β-catenin. Nature Genetics, 1999. 21: p.
2. Gat U., et al., De novo hair follicle morphogenesis and hair tumors in First, the human gene is immobilised and sequenced, the mice expressing a truncated β-catenin in skin. Cell, 1998 95: p.
sequence is the de-novo synthesised, and replicated by PCR. This creates only newly synthesised genes without even a 3. Yano K., Brown L.F., Detmar M., Control of hair growth and follicle size by VEGF-mediated angiogenesis. Clinical Investigation, 2001. The PCR copied genes are purified and transfected into Hordeum 107(4): p. 409-417.
vulgare plant seeds. The plants are then grown hydroponically to 4. Doanes A.M., et al., VEGF Stimulates MAPK through a Pathway That ensure conditions are perfect for VEGF production, and prevent Is Unique for Receptor Tyrosine Kinases. Biochemical and the modified genes from spreading to the environment. The high- Biophysical Research Communications, 1999. 255(2): p. 545-548.
yield H. vulgare is then harvested and the VEGF purified. 5. Boo Y., et al., Shear Stress Stimulates Phosphorylation of Endothelial Nitric-oxide Synthase at Ser1179 by Akt-independent Mechanisms. As a plant is also a eukaryote, the identical VEGF protein is The Journal of Biological Chemistry, 2002. 277: p. 3388-3396.
produced and folded correctly, and so has homology with the 6. Cross M.J., et al., VEGF-receptor signal transduction. Trends in original human protein, and high activity. Biochemical Sciences, 2003. 28:488-94.
7. Witzel S. et al., Wnt11 controls cell contact persistence by local H. vulgare does not produce cytotoxins like bacteria and yeast, accumulation of Frizzled 7 at the plasma membrane. Journal of Cell and does not stimulate an immune response. This prevents side- Biology, 2006. 175(5): p. 791-802.
effects and reactions, ensuring patient safety and results. 8. Hoeben A., et al., Vascular endothelial growth factor and angiogenesis. Pharmacology Review, 2004. 56: p. 549-80.
9. Winiarska A., et al., Effect of 5alpha-dihydrotestosterone and Nanogen sh-VEGF Complex™
testosterone on apoptosis in human dermal papilla cells. Skin
pharmacology and physiology, 2006. 19(6): p. 311-21.
Safe, plant derived sh-VEGF has been exclusively developed with 10. Manning B.D., Cantley L.C., AKT/PKB Signaling: Navigating Nanogen as a research partner. Al Nanogen treatment products Downstream. Cell, 2007. 129(7): p. 1261–1274.
contain the patent pending Nanogen sh-VEGF Complex™, a 11. Shorter K., et al., Human hair follicles contain two forms of ATP- complex of sh-VEGF and ciclopirox olamine. Ciclopirox olamine sensitive potassium channels, only one of which is sensitive to supports the action of VEGF, upregulating VEGF expression in minoxidil. FASEB Journal, 2008. 22(6): p. 1725-36.
hypoxic cells where VEGF is needed most[19]. Additionally, 12. Lachgar, et al., Minoxidil upregulates the expression of vascular ciclopirox olamine may maintain the Ca2+ ion levels in the cel , endothelial growth factor in human hair dermal papilla cells. British ensuring signal transmission from the VEGFR2 receptor Journal of Dermatology, 1998. 138(3): p. 407–411.
13. Johnstone M.A., Albert D.M., Prostaglandin-induced hair growth. Survey of Ophthalmology, 2002. 47(1): p. S185-202.
14. Colombe L., Michelet J.F., Bernard B.A., Prostanoid receptors in anagen human hair follicles. Experimental Dermatology, 2008. 17(1): p. 63-72.
Happle R., Diphencyprone for the Treatment of Alopecia Areata- More Data and New Aspects. Archives of Dermatolology, 2002. 138:
16. Simonetti O., et al., Expression of vascular endothelial growth factor, apoptosis inhibitors (survivin and p16) and CCL27 in alopecia areata before and after diphencyprone treatment: an immunohistochemical study. British Journal of Dermatology, 2004. 150(5): p. 940–948.
17. Verbaan, F.J., et al., Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. Journal of Controlled Release, 2007. 117(2): p. 238-245.
18. Venneti S., Prion diseases. Clinics in Laboratory Medicine, 2010. 30(1): p . 293-309.
19. Linden T., et al., The antimycotic ciclopirox olamine induces HIF-1a stability, VEGF expression, and angiogenesis. FASEB Journal, 2003. 2010 Copyright Nanogen Hair Research. Al rights reserved. This paper is for internal and professional use only and should not be shared with or acted upon by consumers



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