Retinoic Acid Might Cure Milk Allergies

[LeeLemonoil]

Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope


The major cow’s milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of −7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.

 

[LeeLemonoil]

@Travis

any significance towards why said RA-isoform might be helpful with acne?
Also a very interesting publication given that some Peaters experience problems with milk.

 

[Wagner83]

@Travis

any significance towards why said RA-isoform might be helpful with acne?
Also a very interesting publication given that some Peaters experience problems with milk.

See here (there are others):

As a side-note, the study on vitamin A proved that isotretinoin (a.k.a. 13-cis retinoic acid; Accutane™) was a major metabolite of vitamin A.

View attachment 8121 ​

 

[Travis]

See here (there are others):

Nice find, I was looking for that. I think this makes sense because when retinoids are considered individually, only 13‐cis has these effects; isotretinoin alone reduces sebum and no other. I think this is why it takes potentially liver‐damaging doses of retinol to achieve acne results.

@Travis

any significance towards why said RA-isoform might be helpful with acne?
Also a very interesting publication given that some Peaters experience problems with milk.

I read a review article on isotretinoin and acne (13‐cis), and nobody knows how it works. What is interesting is that the most active one (13‐cis) binds the least to the classic retinoic acid receptors RXR and RAR. So the search is still on (for anyone wanting to Linus Pauling the ***t out this problem!)

I had a few targets in mind: the farnesol X receptor (FXR), peroxisome proliferator‐activated receptor alpha (PPARα), or the liver X receptor (LXR). Since it works for acne, a person might be tempted to assume that it antagonizes the androgen receptor (AR); however, there is more evidence that it downregulates the androgen receptor than blocks it directly. It could then be worth then knowing how this receptor is transcribed.. .

'...and administration of isotretinoin to animals reduced androgen receptor levels (17), no data on the effect of isotretinoin treatment on human androgen receptor are available. This study was designed to investigate the effect of isotretinoin...' ―Boudou

'In accordance with recent findings, no change in serum testosterone and significant decreases in 5α-dihydrotestosterone, 5α-androstanediol glucosiduronate, and androsterone glucosiduronate levels were observed after treatment. Androgen receptor status was investigated in back skin biopsies obtained in acne areas before and after 3 months of isotretinoin treatment. The treatment did not modify the binding affinity constant of skin androgen receptor, but it did induce a 2.6-fold decrease in its binding capacity constant, as assessed by Scatchard plot and confirmed immunologically by Western blot analysis. These data clearly showed that skin androgen receptor was sensitive to oral isotretinoin administration in acneic patients. The decrease in skin androgen receptor levels (this study) and the recently reported suppression of skin 5α-dihydrotestosterone production by isotretinoin treatment appeared consistent with the involvement of androgen receptor and 5α-dihydrotestosterone in the pathogenesis of acne. Indeed, sebum production is under androgen control, and an abnormal response of the pilosebaceous unit to androgens appears to be implicated in the pathogenesis of acne. These observations were consistent with the absence of sebum in complete androgen-insensitive patients and normal sebum production in male...' ―Boudou​

But after reading the following study, I think we can exonerate the LXRα receptor as its not found in epithelial cells:

'Using reverse transcription– polymerase chain reaction (PCR) we examined RNA expression patterns for PPARα, PPARβ, PPARγ, retinoid X receptor a (RXRα), liver X receptor a (LXRα), pregnane X receptor (PXR) and FXR in freshly isolated and 7-day maintained human sebaceous glands.' ―Downie

'Furthermore, PPARα ligands have been shown to enhance lipid metabolism in a skin equivalent model.' ―Downie

'In normal human keratinocytes, PPARα, PPARβ and PPARγ protein were strongly expressed whereas LXRα was not detectable.' ―Downie​

But both PPARα and FXR ligands reduced sebum synthesis, although nothing had been said about the androgen receptor. For that, perhaps having a look at fibrates could be enlightening. These are somewhat common drugs that should have enough safety studies to see if they (1) either downregualate or overexpress the androgen receptor or (2) reduce/exacerbate acne:

Zhao, Hu. "Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP." Biochemical and biophysical research communications (2013)​

The Chinaman unwittingly drops a veritable bombshell in isotretinoin–acne etiology. We all knew that China had a nuclear weapons program but nobody could see this coming. What Dr. Hu Zhao had shown was a dose‐dependent reduction in androgen receptor with PPARα ligand fenofibrate:

Isotretinoin also downregulates the androgen receptor, so perhaps its working through PPARα? a receptor known to bind fatty acids and molecules with six‐membered rings (fibrates); isotrentinoin has both of these, but its 'tail' is also reminiscent of the farnesyl isoprenoid chain.. . (Wherever it's working, it's not working through RAR or RXR; that much is certain.)

Lookingbill, D.P. "Effect of isotretinoin on serum levels of precursor and peripherally derived androgens in patients with acne." Archives of dermatology (1988)
Boudou, P. H. "Effect of oral isotretinoin treatment on skin androgen receptor levels in male acneic patients." The Journal of Clinical Endocrinology & Metabolism (1995)
Downie, M. M. "Peroxisome proliferator‐activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro." British Journal of Dermatology (2004)
Zhao, Hu. "Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP." Biochemical and biophysical research communications (2013)​

 

[Terma]

@Travis the very recent articles blame p53 for isotretinoin problems (and the androgen downregulation):
p53: key conductor of all anti-acne therapies
Overexpression of p53 explains isotretinoin's teratogenicity. - PubMed - NCBI

It's an extension of the 2010-ish FoxO1 ideas:
Isotretinoin and FoxO1: A scientific hypothesis

This was originally lower-level than what you're looking at, but p53 (IIRC) is pretty major.

I sincerely hope you keep looking into this. [this post went through fine]

 

[Travis]

Notice that it needs to be isomerized first because isotretinoin does not bind to the retinoic acid receptor (RAR) in its cis form? I think more or less means that any retinoic acid, or even high‐dose retinol could do the same thing.

 

[Terma]

[thought was fixed for a second... nope] A lot articles I skimmed believed 13-cis was only prodrug for ATRA. Was skeptical but now seems plausible.

Best I could remember the overload depends on plasma levels of ATRA (Plasma Delivery of Retinoic Acid to Tissues in the Rat) and the cellular retinol->RA enzymes [but less so in adults?] (https://sci-hub.la/http://www.sciencedirect.com/science/article/pii/S1359610100000022 - very dense, linked Liver Craving/Vitamin A Observation, note I haven't read concrete link between that and p53 idea yet, might never)

For retinol this bit may be relevant (Plasma Delivery of Retinoic Acid to Tissues in the Rat):

A small fraction of dietary retinoid is converted to retinoic acid in the intestine (or may arrive as such in the diet) and is absorbed via the portal system as retinoic acid bound to albumin

For 13-cis I think I read somewhere it could potentially be more effective as a prodrug for ATRA than ATRA itself, but I might have imagined that.

Beyond that, information overload.

 

[Travis]

[thought was fixed for a second... nope] A lot articles I skimmed believed 13-cis was only prodrug for ATRA. Was skeptical but now seems plausible.

Best I could remember the overload depends on plasma levels of ATRA (Plasma Delivery of Retinoic Acid to Tissues in the Rat) and the cellular retinol->RA enzymes [but less so in adults?] (https://sci-hub.la/http://www.sciencedirect.com/science/article/pii/S1359610100000022 - very dense, linked Liver Craving/Vitamin A Observation, note I haven't read concrete link between that and p53 idea yet, might never)

For retinol this bit may be relevant (Plasma Delivery of Retinoic Acid to Tissues in the Rat):


For 13-cis I think I read somewhere it could potentially be more effective as a prodrug for ATRA than ATRA itself, but I might have imagined that.

Beyond that, information overload.

I'll have to do some reading on this tomorrow, because I know that retinoic acid transcribes for the acetylcholine receptor (among many other things). But the liver provides a 'ballast' for retinol and the retinoic acid levels normally stay within a very tight range, meaning that supplementation probably does little unless you take enough to exceed the storage capacity making it 'spill over.' I think when compared to the other lipid hormones such as vitamin D, the steroids, and the eicosanoids, the retinoids seems relatively resistant to dietary modification. Nonetheless, they are important enough to spend some time reading about and p53 is a very interesting corepressor/transcription factor in the nucleus. The way I see it: The p53 protein sits inactive in its binding protein with a redox‐sensitive disulfide bridge domain. Upon oxidative stress: the disulfide bridges are electronically reduced, an event which 'springs' apart the corepressor exposing an internal transcription factor domain. This then goes on to initiate a caspase apoptosis cascade by transcribing DNA, an entire process initiated by extreme redox conditions. I see p53 almost as a cellular 'kill switch.'

 

[GorillaHead]

I'll have to do some reading on this tomorrow, because I know that retinoic acid transcribes for the acetylcholine receptor (among many other things). But the liver provides a 'ballast' for retinol and the retinoic acid levels normally stay within a very tight range, meaning that supplementation probably does little unless you take enough to exceed the storage capacity making it 'spill over.' I think when compared to the other lipid hormones such as vitamin D, the steroids, and the eicosanoids, the retinoids seems relatively resistant to dietary modification. Nonetheless, they are important enough to spend some time reading about and p53 is a very interesting corepressor/transcription factor in the nucleus. The way I see it: The p53 protein sits inactive in its binding protein with a redox‐sensitive disulfide bridge domain. Upon oxidative stress: the disulfide bridges are electronically reduced, an event which 'springs' apart the corepressor exposing an internal transcription factor domain. This then goes on to initiate a caspase apoptosis cascade by transcribing DNA, an entire process initiated by extreme redox conditions. I see p53 almost as a cellular 'kill switch.'

God damn i wish this guy could come back to life.

 

[Nomane Euger]

God damn i wish this guy could come back to life.

hi dude,why do you wish it?

 

[GorillaHead]

hi dude,why do you wish it?

Travis was a genius.

 

[Nomane Euger]

Travis was a genius.

why do you consider him a genius?

 

[GorillaHead]

why do you consider him a genius?

He just understood more of the science behind our bodies and was close to helping solve issues for us here

 

[Nomane Euger]

He just understood more of the science behind our bodies and was close to helping solve issues for us here

which criterias do you gauge to estimate if someone has a good understanding of the science behind our bodies?can you explicit on him being close to helping solve issues for some of us here?

 

[tfcjesse]

God damn i wish this guy could come back to life.

Same…he was focused on all the right topics and was making good progress

 

[Dr. B]

Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope


The major cow’s milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of −7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.

wouldnt this be present in whole milk with its natural vitamin A anyway?