Sederma Executive Summary:
The attack on Teprenone/Renovage by Dr. John is centered on four main arguments:
HSP70, telomere length, fibroblast senescence and drug claims (safety)
With respect to HSP, we show that not only is the attack based on an apparently biased selection of articles that neglects all the articles and arguments in favor of HSP70 stimulation (see attached some literature references, from of a much larger body of studies showing benefits).
Dr. John's argument goes as follows:
Teprenone stimulates HSP70 synthesis
true; but he does not cite any of the articles that show this fact and which indicate the high use levels necessary to obtain this effect, nor the type of cells (lung, stomach) on which this occurs. There is NO evidence that Teprenone induces HSP in skin cells.
Then he takes another article (from Experim. Dermatol.) that pretends to show that extracellular HSP70 is a "danger signal” and "may be related to skin diseases".
But the article does not mention Teprenone at all! Furthermore, the article mentions that there is no difference in HSP70 release between healthy and Lupus diseased skin cells; and beyond that, the Sederma brochure shows that Teprenone reduces HSP release in stressed cells, just like the good antioxidant it is. There is nothing to show that cells in contact with Teprenone increase HSP70 or release it into the extracellular environment, and there is no reason they should.
This whole argument falls totally flat.
With respect to telomere influence on skin condition; abundant literature (and a recent review by Dr. Blackburn, Nobel Prize winner for the discovery of telomere importance) speak for the correlation between increased telomere length and a healthy body. New Sederma data shows that Teprenone significantly reduces the telomere shortening in stressed and non-stressed replicating human skin cells, that is: Teprenone maintains telomere length.
The nine month study on fibroblast senescence, detailed in the technical brochure on RENOVAGE demonstrates that fibroblasts in culture remain in replicative states longer (for three months!) when incubated with Teprenone, compared to control cells in identical conditions without Teprenone. The arguments of Dr. John that many things contribute to fibroblast senescence are correct, but beside the point inasmuch the culture conditions (in triplicate) were identical for the two experimental groups.
The inference that telomere length played a role in this prolonged life span, tentative at the outset and based on genomic studies (detailed also in the Sederma brochure), is now borne out by the two new studies (detailed below). And as Dr. John correctly says, a good antioxidant will help fibroblasts live longer; but he forget or does not know that Teprenone IS a good antioxidant which furthermore stimulates the genes of the cells to increase their own anti-oxidant response.
A six month clinical trial on a panel of 24 women with minor skin lesions (dry skin, redness, …) showed significant improvement of several skin parameters (moisture, TEWL, cutaneous blood flow, firmness, skin roughness profile…).
Given the in vitro and ex vivo data of Teprenone activity, it is likely that RENOVAGE, the solution that contains Teprenone, participates in the improvement of skin conditions; no claim is being made that the observed effects are specifically or exclusively due to telomere length or DNA repair or similar shortcut messages.
As to the safety and legality of the product: Teprenone is not a drug in any country (other than Japan where it therefore cannot be incorporated into a cosmetic), therefore it is not prohibited for use in cosmetics anywhere else. Its theoretical maximum exposure level for systemic effects through skin absorption is 500 to 10.000 times lower than published data on Teprenone prescription levels or efficacy studies on ulcers in mice, thus far removed from drug effects.
Sederma has of course a full, toxicologist certified dossier on the skin and eye irritation, sensitization and mutagenicity profile of RENOVAGE for cosmetic usage that is available to any professional formulating person using the product. There is, however, no legal requirement to publish these safety (or efficacy) data.
Rebuttal of Dr. John's attack on RENOVAGE, an oily preparation containing Teprenone (geranylgeranlyacetone).
In response to the request about the attacks on the ingredient called RENOVAGE, we would like to address the following items:
• the question of "drug" vs. cosmetics, including the action by FDA
• The role of HSP70
• The role of Telomers, telomere length
• RENOVAGE and Teprenone tests on safety and efficacy
a) On these discussion forums, there is never the place (nor the time) to discuss issues in detail; mini facts, taken out of context, half (incomplete) truths are professed, which, by the time it takes to fight them, to correct them, have done their damage. A real scientist (like a truly objective journalist) would first contact the person or company he (or she) intends to criticize to get a statement, to start a discussion, to learn about the real facts. Only if that approach fails, does not suffice to convince a scientist trained and expert in the specific field, AND if there is real cause for concern, is it acceptable and maybe even desirable to go public.
b) The present accusations against Renovage, Teprenone, and your Serum containing it and against Sederma are gratuitous, biased, unjustified and based on assumptions Dr. John has no right to make ("absence of data" on efficacy and safety"). Had he contacted Sederma (through you or directly), he might have written either nothing or a quite more positive comment.
Now let us get on to the more technical arguments:
a) Drug vs. Cosmetic:
While it is true that the molecule Teprenone is a registered API (Active Pharmaceutical Ingredient) in Japan (to treat ulcers), which in Japanese regulations prevents it from being used in any cosmetic product, this is not the case in the US where Teprenone is not listed in the US Pharmacopea, thus not automatically prohibited; there is no law in Europe, for instance, that forbids the use of a substance that is registered as a drug in one or another form, in a cosmetic formula; e.g. you can use acetyl-salicylic acid (aspirin) in a cosmetic cream. In Germany, for instance, Panthenol is sold at 4% concentration in a cosmetic formula and at 2% in a registered drug; Minoxidil, ketoconazole and others are similar examples…
The fact that Teprenone is not an FDA approved substance as a drug may have many causes totally unrelated to questions of its safety on the skin or elsewhere:
Insufficient efficacy for its intended use (ulcer treatment), incomplete registration files, withdrawal by the registrant, side effects considered more prudently than the Japanese? Who knows. But the MHW (Ministry of Health and Welfare) in Japan is certainly not lagging behind FDA in severity of registration requirements and safety evaluation.
Furthermore, one needs to compare things that are comparable:
Teprenone is prescribed for oral absorption; 3 capsules of 50mg a day, i.e. 150mg.
RENOVAGE contains 2% of Teprenone; if used at 2% in a cream, that makes 0.04% Teprenone in the cream, i.e. 400mg/kg of product, thus 400 micrograms per gram, or 400 nanograms/mg. Normal usage on the skin is, say, 2mg of cream/cm2 , thus 800 nanograms per cm2; if you use it on your entire face, say, 200cm2, you would apply 160 micrograms; twice a day: 320 micrograms. Even assuming 100% of this amount penetrates into the skin (highly unlikely); you would absorb 500 times less Teprenone than with a daily oral use.
Conclusion: the very low amount of Teprenone in the cream removes it very far from any claim of being a drug, of presenting systemic effects or risks.
b) "peer reviewed" publications
Dr. John laments and accuses the fact that no "peer reviewed" studies of Teprenone activity on the skin are published, forgetting that except for retinoic acid (an active drug, an API) and retinol and its derivatives (quite as "active" but NOT registered as a drug, and thus allowed in cosmetics) – and a very few other ingredients (peptides…) there are hardly any peer reviewed publications for cosmetic activity. The reasons for this are several: for commercial and competitive reasons companies do not want to publish too much of their data; academic laboratories are hardly interested in doing these studies on their own…
But the absence of publications does not mean absence of data (see below)!
c) now to HSP 70
Dr. John writes that Teprenone induces HSP 70 increase, but does not mention under which conditions, in which cells or organs. The number of articles on Teprenone and HSP70 increase is small; they do not include any studies on skin cells, but show only that in rats with artificially induced gastric ulcer the amount of HSP70 increases when the rats are treated with Teprenone, and this leads to improvement of the ulcers! (Lü et al. Zhonghua Yi Xue Za Zhi. 2008 Jan 22;88(4):220-4). But this is with a dosage of 50-200mg/kg, i.e. 3-12 grams (!) of Teprenone when calculated for a woman of 60kg. Thus ten thousand times higher amounts than theoretically absorbed from the Serum discussed!
Two other studies, one done on humans (Itoh Youko et al. Japanese Journal of Hyperthermic Oncology 21, 209-220(2005), the other done on mice (Fujibayahsi et al., BMC Pulm Med. 2009; 9: 45), show that on one hand, even 600mg of Teprenone given orally to sportsmen does NOT increase HSP70 levels, but given to stressed mice protected them against drug-induced lung injury/fibrosis, presumably due to the HSP70 induction.
And so on… It is simply unacceptable to take ONE publication with a racy headline, then take another publication where HSP70 is called "a danger signal", and let the reader draw the connections. The "danger signal" is mentioned for extracellular release of HSP70, but the article cited by Dr. John says:
" No difference with regard to HSP70 release or uptake was observable between keratinocytes from healthy donors or patients with cutaneous Lupus erythematosus (LE)"!
So if healthy skin and Lupus skin both have the same amount of HSP70 release in their keratinocytes, one does not see why HSP70 is singled out as dangerous or reflecting a danger situation.
And the proposed connection of this "extracellular" HSP 70 to various skin diseases is just that, a conjecture that would need further confirmation, as the conclusion of that same article states.
Hence, the choice of this article, the words of "danger signal" taken out of context, clearly show a biased attitude toward the subject.
If one does a more extensive literature search on HSP70 and its activity, one finds many MORE articles showing its potential benefits, not "dangers" imagined or real (references attached). There are papers on cosmetic ingredients that positively look for and claim the increase of HPS70 and show the benefits in vitro and in vivo.
All in all, the arguments brought by Dr. John against HSP70 in this context don't hold water (but see also below, the data on RENOVAGE).
d) The telomere story:
It is correct to say that at the time RENOVAGE was developed, Sederma did not have the technology to measure telomere length; it was not readily available. The company did not claim to prolong telomeres, nor did it claim to stimulate telomerase; it only demonstrated that genes related to telomere maintenance were activated by incubation of skin cells with low levels of Teprenone. The DNA array genomic study on whole human gene genome turned up a complex network of interactions from which a credible conjecture about involvement of Teprenone in telomere protection emerged.
A conference by Nobel Prize Dr. Blackburn at the recently held AAD in San Diego underlined once again the clear correlation between telomere length and integrity with overall health and skin condition. Protecting telomeres is a valid strategy to maintain a healthy skin, she said.
Any interpretation or simplification of the results and data proposed by Sederma beyond what is written in the Technical Brochure is beyond the responsibility of Sederma.
e) old and new results on RENOVAGE/Teprenone
Two results of which Dr. John could not be aware, for not having contacted SEDERMA, need to be mentioned here:
i) HSP70: the Technical Brochure of RENOVAGE from Sederma explains an experiment on human skin biopsies where the expression of HSP27 (a chaperone protein) and HSP70 was measured, both at the basal level and after UV irradiation.
UVB irradiation increases both HSP proteins significantly (HSP27 more than HSP70). Treatment with either Trolox® or Teprenone at 100M dramatically reduces the amount of both HSP proteins!
This can be explained by the anti-oxidant activity of both substances, which preempt the need for HSP synthesis.
Therefore, the entire HSP attack by Dr. John is beside the point as no increase with Teprenone is observed. Remember, this is done in a 3D skin sample, not in a culture dish, and at the very low recommended use levels.
ii) Telomere length: It does turn out, however, that in the meantime, the method to measure telomere length had been developed and adopted at Sederma laboratories.
GGA (geranylgeranylacetone=Teprenone) was tested on human skin fibroblasts that had arrived at pre-senescent state.
iii) The results are the following: in three cell division passages (15th to 18th), the average length of telomers shortens by 630 bases in the control group, and by only 200 bases in the Teprenone treated group of cells.
iv) Furthermore, the number of cell divisions during these 3 weeks was higher in the Teprenone group.
v) An almost identical substance, geranylgeranylpropanol, had also been tested for this activity in the meantime. In a similar experiment, a difference of +1400 bases in telomere length was found for the treated cell culture compared to the control cells.
vi) Teprenone has excellent anti-oxidant activity, compared to Trolox®, a vitamin E derivative, and stimulates genes that activate the cells own anti-oxidant systems. This anti-oxidant activity, reducing "stress" levels in the cells, may alone be the cause for the decrease in telomere shortening.
f) a phrase by phrase response to some affirmations in Dr. John's attack on Teprenone/RENOVAGE:
One of our favorite product review (selling) sites is currently recommending a product (Osmotics Renovage Cellular Longevity Serum, $150) whose active ingredient is Teprenone. Their “scientific” review claims that the product “stabilizes telomeres”. Very interesting, because when you go to the Sederma site and track down the (unpublished) studies to support this claim you find nada, nothing
Here are a few publications that DO help support the claim of Teprenone skin care benefits:
PhD thesis on Teprenone by Muriel ISSOIR of 2006, done under the supervision of Dr. Benderitter, a stem cell specialist doing research in wound healing.
http://www.irsn.fr/FR/Larecherche/F...soutenues/DRPH/Documents/2006-these-isoir.pdf
Issoir M. Et al. (2005) Geranylgeranylacetone treatment accelerates cutaneous wound healing after ionising exposure, 35th Annual ESDR Congress, 22-24 September, Munich.
Lintner K. et al. (2007) Teprenone (geranylgeranylacetone=GGA), a novel isoprene analog of geranylgeranylphosphate prolongs cell survival and improves skin condition, IFSCC Conference, Amsterdam. P301.
Lintner K. et al. (2009) The study of cellular senescence in vitro: models protocols and mechanisms and ways to delay the onset of senescence in vitro, Journal of Cosmetic Science, 60, 68-69.
Dr. J: Instead what you find is a study in which fibroblasts in culture given Teprenone lived longer (as a colony) than untreated fibroblasts. From which they infer that it has something to do with telomeres (the basis of a popular theory about aging). The problem (and there are many) is that they didn’t bother to actually look at telomeres. They just built an assumption upon an assumption, then added some more assumptions. Then they built a marketing message on top of that.
Sederma: It was not a question of "not bothering to look at telomeres" : at the time, SEDERMA did not have the technology to measure telomere lengths. The conjecture about protecting and maintaining telomeres was based, nevertheless, on a detailed and complex study of genetic activity modulated by Teprenone, where clear indications of telomere maintenance (and anti-oxidant protection) emerged. In the meantime, it has become possible to do these experiments, they have been done and the results have been given in the paragraphs above.
SEDERMA did not observe and did not claim an increase in the telomerase enzyme.
Dr. J: In culture (in vitro, in the lab) there are a lot of things that influence the life span of fibroblast cells:
Sederma: Yes, of course, no one doubts that.
Dr. J: Donor characteristics, sampling site, culture conditions, media used, temperature, etc., etc. There are literally hundreds of things you can do to a fibroblast culture to make it “live longer”. Add chemicals that slow down metabolism.
Lower the temperature of the incubator. Change the oxygen concentration. Add an antioxidant. Many, many things.
Sederma: Yes, true; but the study in question was done under identical conditions for cells WITHOUT Teprenone; when you compare studies where only ONE parameter is changed (in this case, the presence or absence of Teprenone in the culture dishes), then you can reasonably conclude that any observed effects have a causal relationship to the tested substance, all other conditions (temperature, oxygen, nutrients…) being equal.
Dr .J: All of this means nothing in terms of life span of cells in in your body (in vivo)
Sederma: This is NOT correct, a great number of scientific articles show that these parameters (temperature, oxygen levels, nutrition) greatly influence the cell life in vivo and thus in the entire body.
Dr. J: Why? Because in your body, fibroblasts are “never required to make as many divisions as they do in vitro” (from Littlefield*, a classic textbook out of Harvard). And why is that? Because new fibroblasts are made (from stem cells) to replace them long before they reach their limit
Sederma: The book cited (Litterfield 1976) may be a "classic", but in the 36 years since its publication, much has happened in telomere and senescence research…
Indeed, fibroblasts may be replaced before reaching their limit, but may also (during wound healing) be generated from neighboring fibroblasts.
If the cells remain always young, as implied by the reference to Littlefield, then 1) why does the body age nevertheless? 2) why are cells harvested from older individuals less capable of multiplication? and 3) why are these older cells less able to synthesize the required macromolecules of connective tissue? One has to conclude that, unfortunately, stem cells do NOT replace all cells before they reach their limits…
Dr. J: And why would the body do that? Kill off perfectly good cells before they have exhausted their ability to replicate? Because the longer cells have been around, the more prone they are to DNA mutations (e.g. cancer). It’s a good strategy.
Had the reviewer in question looked more closely, she might have discovered that Teprenone (the active ingredient) is a trade name for geranylgeranylacetone – a drug approved in Japan to treat gastric ulcers. It was rejected by the FDA in this country and remains unapproved
Sederma: We have found no evidence that the substance Teprenone was "rejected". All the websites on Trepenone and skin care simply repeat this in circular ways from each other; without referring to any source of information; reasons for "not being FDA approved" can be multiple; was it ever even filed as an NDA? There are many drugs that are approved by the FDA and not approved in Europe, and vice versa.
The fact that it is not an FDA/Pharmacopea drug in the US means absolutely NOTHING, nada, unless one clearly knows the reasons for a reject if there ever was one.
Dr. J: Geranylgeranylacetone is a very potent chemical that induces naturally made molecules inside cells (from bacteria to human) called heat shock proteins (HSP’s).
Sederma: Well, yes, that is why it is interesting! Can't expect skin care benefits without some activity…
Dr. J: It effects several classes of these, including HSP 70 and 90 families. The stress-inducible chaperone heat shock protein (HSP) 70 is considered a danger signal if released into the extracellular environment.
Sederma: To choose this particular publication and to use the words "danger signal" in the context of a layman's blog is to show extreme bias. The article quoted says that no difference in HSP70 release exists between healthy and diseased keratinocytes.
Sederma's data on Teprenone show actually that the molecule decreases HSP70 synthesis; but also show that HSP70 was never found in the culture medium (in extracellular space). No publication indicates that Teprenone favors HSP70 release into extracellular space!
Dr. J: It has been proposed to play a role in the pathogenesis of skin diseases such as psoriasis and lupus erythematosus (Exp Dermatol. 2011 Aug;20
637-41). Hsp70 has been found to act as a recognition structure for natural killer (NK) cells in the body. (Int J Hyperthermia. 2009 May;25(3):169-75.). Cells transformed by Hsp70 are tagged as senescent and targeted for destruction by our indwelling immune system assassins, killer T cells.
Sederma: This is the same article, there is no evidence but just a conjecture of causality, yet unproven; and it is actually unlikely, given the absence of difference in HSP70 levels cited above. Correlations don't always mean causality.
Dr. J: Geranylgeranylacetone induces apoptosis (programmed cell death) and cell cycle arrest as well as cell growth inhibition (Oncogene. 2001 May 24;20(23):2927-36)
Sederma: This sentence again shows Dr. John's uncritical bias, as the article does not speak of Teprenone AT ALL, but indole-3-carbinol, a molecule that can in no way be confused with Teprenone!
On the contrary, Teprenone shows (in Sederma's own studies and in recent published articles) that that it has protective and apoptose preventing activity.
Geranylgeranylacetone suppresses hydrogen peroxide-induced apoptosis of osteoarthritic chondrocytes; J Orthop Sci. 2011; 16; Yoda M et al.,
A non-toxic heat shock protein 70 inducer, geranylgeranylacetone, suppresses apoptosis of cultured rat hepatocytes caused by hydrogen peroxide and ethanol. ; J Hepatol. 2001 35; Ikeyama S,
Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model; BMC Pulm Med. 2009 16; Fujibayashi T,
Oral administration of geranylgeranylacetone improves survival rate in a rat endotoxin shock model: administration timing and heat shock protein 70 induction.; Shock. 2005; 24; Nakada J.
Neuroprotective effect of geranylgeranylacetone against ischemia-induced retinal injury.; Mol Vis. 2007 13, Harada C
Geranylgeranylacetone enhances expression of thioredoxin and suppresses ethanol-induced cytotoxicity in cultured hepatocytes.; Biochem Biophys Res Commun. 2000; 275; Hirota K,
Dr. J: This is quite likely why it slows down fibroblasts in culture (prolonging their life, by making them a lot less active). This drug may have anti-cancer effects for these very reasons. But as an anti-aging strategy, it lacks logic. Even if it does make fibroblasts in the skin live longer, it slows down the production of matrix proteins (like collagen) which would accelerate the signs of aging.
Sederma: Dr. John contradicts himself here: even IF Teprenone were to induce apoptosis (as he claimed with the wrongly cited article of Oncogene), then it would NOT prolong cell life because apoptosis means cell death! It is either one or the other!
As to apoptosis: even vitamin C is able to induce apoptosis (An S.H., BMB Rep., 2011 ; Shinozaki K., J. Radiat. Res., 2011), but also can prolong cell life under different conditions. Studies in vitro have the annoying possibility to show one thing in one protocol and another thing in a different protocol, both having reasons and explanations. It is just not acceptable to take one isolated study and draw general conclusions (and attacks with commercial impact!) from them, without PRIOR discussion with the parties concerned.
Dr. J: Heat shock proteins are of great interest to cell biologists, and clearly can have a protective effect against cell damage (e.g. gastric epithelial cells). But the particular HSP’s that Teprenone induce are not the ones that are likely to benefit skin.
Sederma: Not likely? What is the basis of this statement? Above are a number of articles that indeed show the potential BENEFITS of HSP70 stimulation. But once again, Teprenone at the recommended use levels does not even induce HSP70 in skin cells!
Dr. J: There are, in fact, other unrelated compounds under investigation that prevent and reverse DNA damage due to solar irradiation (the principle kind of stress that skin has to deal with). We will be talking about that good news in a post coming soon.
Sederma: Ah yes? No commercial bias here? Attacking Teprenone to sell Dr. John's products?
Dr. J: Summary: the company that sells Teprenone as an active for skin care wants you to think it does good things for DNA and telomeres (the ends of DNA strands that have to do with programmed cell death). This claim is bogus. It appears they never even measured telomeres.
Sederma: See the results above in the new studies by Sederma.
Dr. J: What Teprenone actually does is induce heat shock proteins.
Sederma: NO, it does not always! The article on ulcers in mice shows that it does so, at VERY HIGH USE LEVELS; but it does NOT induce HSPs in skin cells, at cosmetic use levels, in an entirely different protocol.
Dr. J: These are powerful natural cellular messaging chemicals. Released under the wrong circumstances, these signals could be harmful, accelerating rather than retarding the visible signs of aging over time.
Sederma: What are these "wrong circumstances"? This is pure speculation, interested bias.
Documents referred to in the text:
BMC Pulm Med. 2009; 9: 45.
Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model
Takayoshi Fujibayashi,#1 Naozumi Hashimoto,#2 Mayumi Jijiwa,3Yoshinori Hasegawa,2 Toshihisa Kojima, 1 and Naoki Ishiguro
We used a bleomycin (BLM)-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration.
We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice.
Cell Stress Chaperones. 2005 Autumn;10(3):197-203.
Ectoine from halophilic microorganisms induces the expression of hsp70 and hsp70B' in human keratinocytes modulating the proinflammatory response.
Buommino E, Schiraldi C, Baroni A, Paoletti I, Lamberti M, De Rosa M, Tufano MA.
Source
Department of Experimental Medicine, Microbiology and Clinical Microbiology Section, Second University of Naples, Napoli 80138, Italy.
Abstract
The heat shock proteins (Hsps) have an important role in the cytoprotection and repair of cells and tissues. One potential mechanism of protection is the ability of Hsp to inhibit genetic expression of proinflammatory cytokines, the transcription of which is dependent on nuclear factor-kappa B (NF-kappaB) activation. In this study, we evaluated the ability of ectoine, a novel natural biomolecule produced by halophilic microorganisms, to activate the hsp70 and hsp70B'. By reverse transcriptase-polymerase chain reaction and Western blot analysis, we demonstrated increased hsp70B' gene expression in human keratinocytes treated with ectoine and heat stressed. In contrast, in the absence of heat shock, ectoine was unable to induce hsp70B' but had the ability to induce another member of the Hsp family, the hsp70. The latter is not only elevated in response to stress but is also present at basal level in unstressed cells. In addition, ectoine had no effect on proinflammatory cytokines interleukin (IL)-1alpha, IL-6, IL-8, and tumor necrosis factor-alpha and on NF-kappaB and IkappaB-alpha pathway, whereas it downregulated the expression of cited proinflammatory cytokines, in lipopolysaccharides-treated keratinocytes. These results highlighted the ability of ectoine to protect cells from stress conditions and to prevent cell damage by maintaining an elevated level of the Hsp70. Overall, these data might suggest the use of this compatible solute in cosmetic and even pharmaceutical preparations aiming to activate a cytoprotective heat shock response in human cells.
ECTOINE is a popular cosmetic ingredient, sold my Merck under the name of RONACARE™.
THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 8, pp. 5848–5858, February 19, 2010
Prevention of UVB Radiation-induced Epidermal Damage by Expression of Heat Shock Protein 70
Minoru Matsuda et al.
Irradiation with UV light, especially UVB, causes epidermal damage via the induction of apoptosis, inflammatory responses, and DNA damage. Various stressors, including UV light, induce heat shock proteins (HSPs) and the induction, particularly that of HSP70, provides cellular resistance to such stressors. The anti-inflammatory activity of HSP70, such as its inhibition of nuclear factor kappa B (NF-B), was recently revealed. These in vitro results suggest that HSP70 protects against UVB-induced epidermal damage. Here we tested this idea by using transgenic mice expressing HSP70 and cultured keratinocytes. Irradiation of wild-type mice with UVB caused epidermal damage such as induction of apoptosis, which was suppressed in transgenic mice expressing HSP70. UVB-induced apoptosis in cultured keratinocytes was suppressed by overexpression of HSP70. Irradiation of wild-type mice with UVB decreased the cutaneous level of IB-(an inhibitor of NF-B) and increased the infiltration of leukocytes and levels of pro-inflammatory cytokines and chemokines in the epidermis. These inflammatory responses were suppressed in transgenic mice expressing HSP70. In vitro, the overexpression of HSP70 suppressed the expression of pro-inflammatory cytokines and chemokines and increased the level of IB-in keratinocytes irradiated with UVB. UVB induced an increase in cutaneous levels of cyclobutane pyrimidine dimers and 8-hydroxy-2-deoxyguanosine, both of which were suppressed in transgenic mice expressing HSP70. This study provides genetic evidence that HSP70 protects the epidermis from UVB-induced radiation damage. The findings here also suggest that the protective action of HSP70 is mediated by anti-apoptotic, anti-inflammatory, and anti-DNA damage effects.
J Biomed Opt. 2011 Jul;16(7):078002.
Pulse duration determines levels of Hsp70 induction in tissues following laser irradiation.
Mackanos MA, Contag CH.
Source
Stanford University School of Medicine, Department of Pediatrics, Clark Center E-150, 318 Campus Drive, Stanford, California 94305-5427, USA.
Abstract
Induction of heat shock protein (Hsp) expression correlates with cytoprotection, reduced tissue damage, and accelerated healing in animal models. Since Hsps are transcriptionally activated in response to stress, they can act as stress indicators in burn injury or surgical procedures that produce heat and thermal change. A fast in vivo readout for induction of Hsp transcription in tissues would allow for the study of these proteins as therapeutic effect mediators and reporters of thermal stress∕damage. We used a transgenic reporter mouse in which a luciferase expression is controlled by the regulatory region of the inducible 70 kilodalton (kDa) Hsp as a rapid readout of cellular responses to laser-mediated thermal stress∕injury in mouse skin. We assessed the pulse duration dependence of the Hsp70 expression after irradiation with a CO(2) laser at 10.6 μm in wavelength over a range of 1000 to 1 ms. Hsp70 induction varied with changes in laser pulse durations and radiant exposures, which defined the ranges at which thermal activation of Hsp70 can be used to protect cells from subsequent stress, and reveals the window of thermal stress that tissues can endure.
Personal CARE Magazine; June 2011
… Heat Shock Proteins were first reported to be induced by heat shock (temperatures above 42°C) and are believed to represent a mechanism of cellular stress response that protects intracellular proteins from damaging events and subsequent challenges.(1,2,3) The HSP group of proteins is a conserved set of molecular chaperones involved in folding and protein transport. HSPs are expressed intracellularly in all cells and organisms from prokaryotes to humans, showing high evolutionary conservation, which implies that HSPs are necessary for survival under hostile environmental conditions.(1,5) HSPs are expressed both constitutively (cognate proteins) and under stressful conditions (inducible forms). Consequently, they present both constitutive and inducible chaperone functions … binding to several proteins and taking part in proteins conformational changes during folding, activation/inactivation, disaggregation, renaturation and intracellular transport. They are also known to directly participate in different aspects of protein maturation, especially in the early stages where the protein is still unfolded. Moreover, they might allow translocation, folding or assembly of new proteins.(2,4) These abilities let them take part in normal cell life and proteotoxic stress response, and to protect skin cells from further stress exposure (tolerance). HSPs are classified into families according to their molecular weights. HSP70 family includes two major HSPs that are found both in the cytosol and the nucleus of the cells: Hsp73, which is constitutively expressed in all cells and tissues, and Hsp72 (also named Hsp70), which is the inducible form of HSP70 family. Hsp72 has been reported to help skin cells recover from cellular stress and prevent further damage when exposed to different stressful situations. (4 ) Under stress conditions, Hsp72 expression is greatly enhanced, and despite being HSP70 inducible form, its role in keratinocytes is so important that it also presents basal expression. Hsp72 is expressed throughout all layers of the epidermis including other structures like hair follicles and sweat glands and is considered the major HSP responsible for the protective function in human skin.(1,6) However, there is an agerelated reduction in Hsp72 expression after heat stress: protection afforded by Hsp72 induction may be impaired with ageing rendering the cell more vulnerable to environmental attacks. Daily, skin faces challenging situations such as UV exposure, high temperatures, desiccation, cold and pollution and heavy metals exposure. Low humidity levels result in osmotic stress and, consequently, loss of cellular water and denaturation of intracellular proteins. It has been suggested that Hsp72 could take part in protein stabilisation in epidermal keratinocytes after massive water loss.(1,7) Stress proteins have recently become of interest in the investigation of ageing molecular mechanisms due to their role in protein refolding, stabilisation and degradation. These proteins are presumed to increase the ability of cells to recover from toxic effects of physiological stress.(1,4,6). A boost in Hsp72 skin levels may create a protective shield providing stress tolerance against everyday challenges and stressful situations. A new molecular cosmetic peptide has been developed to confer stress tolerance to the skin. …
References:
1 Jonak C, Klosner G, Trautinger F. Heat shock proteins in the skin. Int J Cosmet Sci 2006; 28 (4): 233-41. 2 Laplante AF, Moulin V, Auger FA, Landry J, Li H, Morrow G, Tanguay RM, Germain L. Expression of heat shock proteins in mouse skin during wound healing. J Histochem Cytochem 1998; 46 (11): 1291-301. 3 Maytin EV. Differential effects of heat shock and UVB light upon stress protein expression in epidermal keratinocytes. J Biol Chem 1992; 267 (32): 23189-96. 4 Diez C, Cascales M. Proteínas del estrés y hepatotoxicidad. Madrid: Facultad de Farmacia, Instituto de Bioquímica (CSIC–UCM), 1997. 5 Bivik C, Rosdahl I, Öllinger K. Hsp70 protects against UVB induced apoptosis by preventing release of cathepsins and cytochrome c in human melanocytes. Carcinogenesis 2007; 28 (3): 537-44. 6 Fargnoli J, Kunisada T, Fornace AJ, Schneider EL, Holbrook NJ. Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats, Proc Natl Acad Sci USA 1990; 87 (2): 846-50. 7 Garmyn M, Mammone T, Pupe A, Gan D, Declercq L, Maes D. Human keratinocytes respond to osmotic stress by p38 map kinase regulated induction of HSP70 and HSP72. J Invest Dermatol. 2001; 117 (5): 1290-5.
HSP70 inducers from Chinese herbs and their effect on melanin production
Yasuhiro Yamashita et al.
Skin hyperpigmentation disorders as a result of abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and a cosmetic problem. This melanin production is mediated by tyrosinase whose expression is positively regulated by microphthalmia-associated transcription factor (MITF). We recently found that expression of heat shock protein 70 (HSP70) inhibits melanin production. In this study, we searched for HSP70 inducers from Chinese herbs and selected an ethanol extract of Eupatorium lindleyanum(E. lindleyanum). Not only melanin production but also the activity and expression of tyrosinase were significantly suppressed in cells treated with E. lindleyanum extract as well as in HSP70-overexpressing cells. The expression of MITF was clearly suppressed in cells treated with E. lindleyanum extract but not in HSP70-overexpressing cells. These results suggest that E. lindleyanum extract suppresses the expression of tyrosinase and melanin production through both HSP70-dependent and HSP70-independent mechanisms.
CUCUMEL K ET AL: "Artemia extract induces Hsp70 in human cells and enhances cell protection from stress." JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 117, no. 2, août 2001 (2001-0, page 454 XP002218532 62nd Annual Meeting of the Society for Investigative Dermatology;Washington, DC, USA; May 09-12, 2001 ISSN: 0022-202X
Смотреть далее Так вот,когда я подарила маме Шанель №5,купленные в Иль Де Ботэ ,она сказала,что они лишь отдаленно напоминают те,которые ей привозил брат,есть общие нотки,не более... Вобщем,полное разочарование. 
Хистори только ухудшил состояние,иссушил кожу и резче обозначил проблему. Хистори для лица я не поняла,кожа как кожа,не лучше,чем от других средств. Сульвасу вокруг глаз сначала показался замечательным,позже выяснилось,что это было самовнушение.Мама-мой честный критик,никаких улучшений не заметила. Часть Хистори и Сульвасу я подарила ей, но она не особо ими пользуется.