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What is better/cheaper between Calcitriol, Calcipotrio, and Lithium Chloride ?Comment
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Hi Elder , How are u ?Thanks for the nice post .For Number 3 : topical Tretinoin 0.01% I think you mean 0.001% , Since I have read your other posts in the past.
And Also for Valproic Acid you put that in Both Categories of Topical PGE2 and also An
Androgen Receptor blocker, So it works both ways?
ThanksComment
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Tretinoin- it's 0.01% maximum and there ARE 0.01% premade generic creams around. you have to be VERY carefully using this by using only the lowest dose possible
Mechanism of action[edit]
Although the mechanism of action of valproate is not fully understood,[39] it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[50] In addition, its anticonvulsant effect has been attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[39] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[39] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.[39] It also possesses histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.[51][52]
Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence a non-steroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[53] It was concluded that these actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[53]
Its upregulates CD34
Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells.
De Felice L1, Tatarelli C, Mascolo MG, Gregorj C, Agostini F, Fiorini R, Gelmetti V, Pascale S, Padula F, Petrucci MT, Arcese W, Nervi C.
Author information
Abstract
Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine ****tails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune–deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.Comment
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Experimental small molecule pharmalogical solutions for AGA by topical/oral route administration in order of descending preference(would be updated from time to time):
1):
All affected genes indicated in the Scoliosis study:
TATA <= Topical Calcitirol/Calcipotriol
HNF4 <= Topical Carbamazepine(direct activator of SHBG for disactivating circulating sex hormones with highest affinity for DHT=>increased bone resorption in the balding skull. Has sides), Topical Valproic acid(Androgen Receptor Blocker, Wnt/B-catenin agonist, CD34 upregulator and several other pro-hair growth properties. Has sides if taken orally), Topical RU58841(Androgen Receptor Blocker- less systemic side effects), topical CB(Androgen Receptor Blocker), topical/oral Dutasteride(5A Redutase Inhibitor to decrease circulating DHT. Used carefully- will dramatically slow down, but not stop- AGA and increase 'free' Testosterone levels for the muscles), topical/oral Finasteride(5A Redutase Inhibitor to decrease circulating DHT- almost the same profile as Dutasteride but with less potency), oral Spironolactone(Androgen Receptor Blocker, Aldosterone Inhibitor=> Less sodium reabsorption in kidneys=>less vasoconstriction=>increased blood supply to hair follicles. Has feminizing sides.)
RAR <= Ultra low dose topical Tretinoin (0.01%-0.0005%. Ultra low doses of it induces hair shaft differentation at a stabilised rate with stem cells as the fuel while increasing dosages depletes stem cells rapidly and leads to apoptosis instead. Is also toxic when used in dosages above a certain threshold- and this 'threshold' is very low.)
RXRA <= Topical Calcitriol/Calcipotirol(Calcitriol-binded VDR is needed for full transcription of PPAR Alpha, Beta and Gamma. VDR-null cells on the scalp diverts pluripotent stem cells to the sebocyte(sebum) and sudoriferous(sweat) lineage).
STAT <= Topical Calcitriol/Calcipotriol(Calcitriol acts as a modulator of this central inflammation pathway- the JAK-STAT pathway.), topical/oral Sulfasalazine(via inhibiting TH1 cytokines)
BATF <= Topical Calcitirol/Calcipotriol(Calcitriol acts as a modulator of this TH17 cytokines regulatory gene), topical/oral Sulfasalazine(via inhibiting TH17 cytokines).
COMP <= Topical Calcitirol/Calcipotriol, topical Valproic acid(Both Calcitriol and Valproic acid increase expression of this gene- and it is upregulated only in haired-scalp.)
VDR <= Topical Calcitirol/Calcipotriol(Calcitriol's own receptor. It is a receptor that regulates, modulates and thus- controls hundreds of genes(900+ genes) involved with Immunity, Calcium homeostasis, Bone formation/resorption(in synergy with BMPs) and many, many more in the human body.)
HDAC2 <= Topical Valproic acid(inhibitor of HDAC2- which inhibits AGA-afflicted hair follicles stem cell renewal's function)
CART1 <= Topical Calcitriol/Calcipotriol
FOXA <= FOXA2 inhibits pre-adipocyte differentiation. topical Sirt 1 activators like Resveratrol inhibits Foxa2 expression.
FOXP1 <= Topical Valproic acid, Ultra low dose topical Tretinoin(0.01% - 0.0005%)(FOXP1 regulates stem cells levels in the hair)
GATA <= Topical Calcitriol/Calcipotriol, Oral Montelukast, Oral Zafirlukast(GATA3 is the master regulator TH2 cytokines profileration and differentiation.)
H6 family homeobox 2 <= ? (Has got more to do with inner ear functions than to hair on the balding scalp)
IRF <= Topical Calcitriol/Calcipotriol
PAX5 <= Topical Calcitriol/Calcipotriol(PAX5 is the master regulator of B cells profileration and differentiation.).
P300 <= Topical Calcitriol/Calcipotriol
2):
Top 5 upregulated genes in haired-scalp and Top 5 downregulated genes in haired-scalp as indicated by Dr Cotsarelis's patent in order of descending preference:
Upregulated in haired-scalp:
GPRC5D <= Ultra low dose topical Tretinoin(0.01% - 0.0005% )
CDT6<= Topical Calcitriol/Calcipotriol
LY6G6D<= Closest that could be found for small molecules addressing this extremely-rarely-described gene is Valproic acid(seeing how Valproic acid has an overwhelming pro-hair growth effect when used topically, this means it probably upregulates it to a certain degree.).
S100A3<= Topical Calcitriol/Calcipotriol
COMP<= Topical Calcitriol/Calcipotriol, topical Valproic acid
3):
Downregulated in haired-scalp:
CCL19<= Topical Calcitriol/Calcipotriol
FOSB<= Topical Valproic acid
c-FOS<= Topical Valproic acid(via inhibiting Protein Kinase C), Topical/oral Verapamil(Calicum channel blocker with lower half-life), topical Cilnidipine(Calcium cahnnel blocker with half-life of 24hrs), topical D609(research chemical).
PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant(Newest CRTH2 inhibitor in trials, topical/oral Ramatroban(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral OC(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.)
CORIN<= Topical Curcumin(Upregulates Serpina1- another gene upregulated by 5.721 folds in haired-scalp which in turns inhibits the production of Corin that equautes to 1-32BNP(pro-hairgrowth) production instead of 4-32 BNP production- via trypsin inhibition. it is also a GSK3B inhibitor.), Oral Spironolactone(indirectly by antagonising Aldosterone=> CORIN downregulation=> FURIN-Cleaved proBNP=> 1-32 BNP(the pro-hair growth form of BNP) => hair pigmentation + keratinization)
4):
Three 'endpoint' genes indicated by Dr Cotsarelis's patent that are significantly-upregulated in haired-scalp:
CD200<== Topical Cacitirol/Calcipotriol(Calcitriol increases both CD200's expression in the balding scalp and balding skull. In the latter's case, without adequate CD200's expression- bone resorption is severely-impaired that leads to ever-increasing bone formation in the balding skull.)
CD34<== Topical Valproic acid(via existing cell self-renewal), Topical 16,16-Dimethly-PGE2(via homing from bone marrow), Topical PGE2(PGE2=>EP2 Receptor=>Survivin=>CD34. Also- PGE2=>EP4 Receptor=>BMP-2=>SMAD1/5/8=>SMAD4=>DLX3=>RUNX2=>Hair shaft differentiation), Topical Butaprost(This is a selective EP2 receptor and EP4 receptor agonist. An PGE2 analog), topical/oral Sulfasalazine(Upregulates PGE2 while inhibiting COX-2), Minoxidil sulfate(via mPGE2).
Intergrin A6<= Ultra low dose topical Tretinoin(0.01%-0.0005%. Tretinoin is the only small molecule that could be found to upregulate IntergrinA6(CD49F) with the other being the Parathyroid hormone-related protein(not a small molecule))
*Dietary adjustments*
IMO adjusting your diet will never have much of an impact on AGA. The only thing to look out for would be anything that will cause vasocontriction. 1)Caffeine antagonises the Adenosine receptors and 2)Calcium will not only cause vasocontriction- it also is used as fuel to form our ever growing bones in the balding skull and also as mineral deposits on our fibrosising balding-scalp. Keep it at not more than 1 cup of coffee a day(I know it's hard to not drink coffee-including myself) and /or best of all- avoid milk/cheese consumption.
END
Ok now that i have consolidated a list of the items to address each gene mentioned in the scoliosis study and Dr Cotsarelis patent- i will post the contacts again for the last time
I have to stress yet again that
1)i do not gain anything at all from posting these contacts(my own) other then having the pleasure of knowing I have helped a fellow AGA researcher in conducting his own experiments.
2)i do not know the contacts and nor do I deal with them pertaining to a Business-Business relationship, other than being a Consumer myself in sourcing supplies for my research.
3)My conduct at contributing information about AGA to our community should prove that
These contacts are sourced from over the years while looking for research solutions for investigating AGA, Nootropics, Anabolics and even Myopia. My strategy for sourcing low-cost experimentals for my research is:
1)http://www.mims.com/India/drug/AdvancedSearch/ to look for any Generic drug I want. Then: (Source A)gksales4@guokang8286.com.cn <==China-based Biochemical factory-based manufacturer for research chemicals(some)/generic drugs in raw powder form. I find most of their prices to be the lowest but some are grossly expensive. They respond to my queries fast, though OR : (Source B)leehpl900@gmail.com <==India-based direct dropshipper from the low-cost Generics Pharmaceutical Industry in India in premade form(gels/ointments/capsules/tabs). Alldaychemist and Inhouse get their stocks from the very same India-based Generics Pharmaceutical Industry base as the 1 mentioned above(but the latter 2 marks up their prices by several folds). This source takes 1 whole day to reply- so don't expect an immediate response.
2)Santacruz Bio or Tocris website(these are commercial links and Im not gonna post them- so please google their homepage yourself) to look at a comprehensive search list of existing Research chemicals that i want . Then: (Source C)theKaneshop- and he gets his supplies/raw materials from the very same China-based Biochemicals Industry base as the other 2 listed here. Kane doesn't respond to queries sometimes. For all other research chemicals that thekaneshop do not have: (Source D)mail08@sciphar.com <==China-based Biochemical factory-based manufacturer. They provide recombinant products. The downside to this source is that they take a long time to reply, if they do- that is. If they don't', keep emailing them.
3)Make a list of the items that you want, drop them an email and negotiate with them for the total price(more items = lower prices). Dont' be afraid and ASK for ANYTHING that you want. Asking for quotes do not equate to commiting yourself into buying anything and cost you no $ for doing it. I have been ASKED alot of times whether these sources have this or that- I have provided contacts of these low-cost sources, so stop ASKING me whether they have this or that- ASK them(like i said- costs you next to nothing other then some finger work to type some sentences to send some emails and ASK them yourself).
Good luck conducting experiments for your research and please report back if you've got positive results with photos of your mouse samples.Comment
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LETS DO SCIENCE BITCHES
Where's the RV?Comment
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From Cotsarelis's patent:
Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data.
Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell migration necessary for hair growth. <==topical Valproic acid
Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B). <==oral Resveratol, topical Carbamazepine
GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==Topical Valproic acid, Topical Trichostatin A
The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular. <== Topical Calcitirol/Calcipotriol 0.005%
GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E). <== Topical Tretinoin(0.01%-0.0005%)
FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G). <== upregulated indirectly via FOXP1 by topical Valproic acid or topical Tretinoin(0.01%-0.0005%).
The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth.Comment
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From Cotsarelis's patent:
Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data.
Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell migration necessary for hair growth. <==topical Valproic acid
Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B). <==oral Resveratrol, topical Carbamazepine or any chemical that promotes Autophargy. PSI(Proteasome Inhibitor) works the same way as Serpina1.
GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==Topical Valproic acid, Topical Trichostatin A
The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular. <== Topical Calcitirol/Calcipotriol 0.005%
GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E). <== Topical Tretinoin(0.01%-0.0005%)
FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G). <== upregulated indirectly via FOXP1 by topical Valproic acid or topical Tretinoin(0.01%-0.0005%).
The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth.Comment
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Eldar,
I've only read part of this thread, but the curved spine and jaw cracking is exactly what i have. My right side throughout my body is bigger than the left...even my skull. My left arm and shoulder gets weak and numb especially when i'm stressed or don't get enough sleep.
Thanks for sharing your findings with us. I think you maybe onto something. It's such a coincidence that i was googling possible links between hairloss and scoliosis earlier today, and now i just saw your thread.Comment
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I'm thinning diffusely throughout the scalp, even back and sides.Comment
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then u might have a special case of DUPA- Diffused and Unpatterned Alopecia http://www.bernsteinmedical.com/hair...oss-treatment/Comment
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We have people who find the idea of Scoliosis being connected with AGA being 'outlandish'. These people(with their kind of narrow-minded thinking) are the reason why the true cause of AGA has not being discovered. I hope the scientish and researchers working to find out are not like them.Comment
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Hi Eldarmario,
Picking up on a post from you earlier about sensitivity of your scalp to ethanol, i also have similar issues with dandruff and very dry scalp. Further, i think my hair has lost ground due to the toxic effects of ethanol as definitely thinned a bit when using RU and CB.
I currently use 95% pure ethanol with DMI added so not more than 10% of total mix.
Further to the options you listed in your post, what other vehicles and options for sensitive scalps have you come across?
I've tried Jojoba and coconut oil with a bit of ethanol but it seems to un-dissolve the actives, and also it's too greasy to put on in the morning then go to work. Also, i've looked to stay clear of PG for obvious reasons.
Lastly, how long do you think would need to leave on with DMI to get say 50% of absorption?
Thanks a lot
CharlieComment
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