83 replies to this topic

[thetruth24]

Here's a little tidbit about androgens and ppars

http://www.medscape.com/viewarticle/460988_5

Sebocyte Glands

Activation of PPARgamma and PPARalpha by their respective specific ligands, thiazolidinedione, rosiglitazone and the fibrate, WY-14643, were found to stimulate lipid droplet accumulation in cultured immature sebocytes, but not in keratinocytes, as assessed histochemically using Oil Red O staining in cells cultured under high calcium conditions.[46,47] When dihydrotestosterone (DHT) was added with PPAR activators, an additive effect on lipid droplet formation in sebocytes was only seen with the combination of DHT and PPARgamma activator. This suggests that PPARgamma influences a step in sebocyte differentiation that is related but distinct from that influenced by androgen.[48]

Because increased sebum production is an important element in the pathogenesis of acne vulgaris, development of PPAR antagonists that can interfere selectively with sebum formation may have implications for the treatment of acne.

[jemini]

Yeah, the video pretty much summed up how they work in a nutshell.

"Since RXR forms heterodimers with both PPARalpha and PPARgamma blocking RXR may produce a phenotype that shares some similarities with PPARalpha deletion and others with PPARgamma deletion. Since therapeutic candidates that target PPAR may confer most benefit in the context of diabetes and obesity if they activate PPARalpha and/or block PPARgamma it is conceivable that RXRalpha antagonists may be of use if they are selective for RXR:PPARgamma heterodimers and fail to impede RXR:PPARalpha mediated effects. This is supported in part by recent research showing that the dual antagonism of RXR and PPARgamma decreases triglyceride content, potentiates leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating diet-induced obesity and insulin resistance. Molecules that block RXR:PPARgamma and stimulate RXR:PPARalpha dimers may represent an even better approach."

Looks like PPARs and RXRs go hand in hand. Isotretinoin binds to RXR and does not allow PPARs to form dimers?

So basically we need to upregulate PPAR alpha? What are the roles of delta and gamma?

Yes, basically isotretinoin (or much more likely its metabolites since isotretinoin actually has a low affinity for the rxr receptor) binds very tightly to rxr, thus preventing other molecules to stimulate/activate ppar alpha and gamma. My HYPOTHESIS on accutane is as follows. I feel that among other things, acne for many people is caused by overactivation of ppar gamma, or an increased transcription of the dna ppar gamma activates due to seemingly "normal" levels of natural ligands in the body (could be a genetic factor here). Anecdotal reports say that Sesamin, a known ppar alpha activator used as a weight loss supplement seemingly clears acne. How exactly is anyones guess. A few possibilities include that binding a ligand binding with ppar alpha (presumably by also forming a dimer with rxr maybe?) prevents the "bad" over activation of ppar gamma. Perhaps some of the transcription products of ppar alpha counter the negative effects of ppar gamma. Whatever the case may be, it is my best guess that tilting the ratio of in favor of ppar alpha versus gamma is probably a good thing, at least for acne. My belief is that when accutane binds to rxr and shuts off both ppar gamma and alpha in the skin, these receptors overtime become downregulated (body produces less receptors). This might be why the effects of accutane and other retinoids persist, even after treatment has stopped.

What I can tell you from personal experience is that sesamin definitely made me oiler, though acne remained approximately the same. My guess is that ppar's have some overlapping functions, sebum function being one of them. Maybe if i stuck with it long enough, over time it might have corrected the imbalance between ppar alpha and gamma. This could take months to see results, or it could not work at all if a) the activating effects of sesamin (or fish oil) aren't powerful enough to "override" the genetic programming in the expression of ppar gamma, or b) I'm completely wrong. Judging from accutanes effects, it could take months or longer to get this downregulation to finally occur.

There is also some anecodotal evidence that ppar gamma antagonism might work as well. I know of 2 examples, which hint at this correlation. First, there is Zileuton, a 5-lox inhibitor. It is used as an asthma medication, but was believed to be the next breakthrough in acne treatment. 5-lox produces inflammatory ligands which among other things, bind to ppar gamma. One study showed it dried up oil as much as low dose accutane (google it if you don't believe me). The actual clinical trial was less than breakthrough. After a few months (I think 3) the level of acne between placebo group and medicated group was about the same. However, the full study revealed that in the medicated group, the level of imflammatory acne decreased. What does this mean? Obviously, further testing is required but perhaps if the trial was run for longer the results would have been better. Also, Zileuton isn't the best 5-lox inhibitor since it has to be taken I think 4 times a day since it gets metabolized so fast (it was designed with asthma in mind). So perhaps a better drug based on this principle would have been better. Also, ppar gamma ligands may be produced by other pathways as well. The point is that inhibiting ppar gamma ligands did have a beneficial effect on acne. Perhaps a drug which targeted ppar gamma directly and efficiently would yield much better results.
Green tea extract which seems to be popular on this board is also known to be a 5-lox inhibitor among other things. And for some people, it seems to take the imflammation out of acne.

I'm not saying ppars are the only factor in acne formation. i'm willing to bet that many of the nuclear receptors have some sort of moderating effect on each other, this may explain why androgen and thyroid disorders may cause acne as well.

I am currently on my second course of accutane at 30 mg's a day for 8 months. I am about 2 months in and still suffering from the IB. Knowing my past history, I should see a turn around in a few weeks. I might consider a little self experimentation. I would continue my accutane course until clear, maybe at even a lower dosage. Accutane has the ability to clear acne at low dosages around 5-10mg a day, but is prescribed higher due to a better chance of remission. I am 22, almost 23 and my gut instinct is that accutane this time around won't clear me for good, just buy me more time. I am considering taking accutane until clear, then dropping the accutane and picking up the sesamin and fish oil again. Perhaps, once my ppar's are "reset" so to speak, these supplements might be able to maintain IF my theory is right. If the acne returns, then I'll just hop back on the accutrain.

I apologize for rambling, hijacking the thread, telling my life story and once again being an asshole in general.

[thetruth24]

Jemini,

Thats some real interesting thinking!

What exactly are the metabolites of isotretinoin? Would taking something with a higher affinity for the RXR receptors have the saem effect as accutane?

It's interesting that you mention weight loss, because alot of bodybuilders who obviously have high amounts of testosterone have no acne. I know they take supplements to shed the fat, and maybe that plays a role in acne as well? I mean maybe fat loss regimens affect lipogensis?

Perhaps you are correct about, sticking to it longer. Some people on accutane get oiler for a couple weeks and then they get dry. Keep in mind that this is megadosing on 13 cis retinoic acid. The effects of "regular" supplementing with sesamin. Kinda like B5. It looks like you need to mega dose on something to see results.

Off topic, women usually start to break out during period, when hormones are in flux. There must be something going on when there are hormonal shifts. Whether it be with the PPARs or the ARs themselves.

If you read the study I posted early on in this thread, there was a study that showed 95% of people have significant success with topical resveratrol. Resveratrol is a 5 lipoxygenase inhibtor. If memory serves correct (there are so many things, I get confused), 4 Lipoxygenase is responsible for anachinodic acid, which in turn makes leukotrines, which can stimulate the sebaceous glands. Resveratrol also inhibits CYP1A1, an enzyme that could break down retinoic acid quicker than it can be used. Just things to think about.

My mom has hypthyroidism. I'm not sure if I have it because:
1) I don't have any of the symptoms for it
2) I have alot of my dad's genes. I look like him, built like him and everything.

Check out the studies about the chlorophyll too! Its very interesting that its derivatives affect PPARs. Like Autonomous said, look at all the green around, the algae which has survived for 2.5 billion years, and is abundant in chlorophyll. As an added benefits, its very effective in cleansing the entire body. Always a plus if you're acne is produced by toxins that may affect the up/downregulation of certain PPARs

[Listener]

Anyone tried chlorophyll for a decent amount of time? Any results to speak of?

[AutonomousOne1980]

Anyone tried chlorophyll for a decent amount of time? Any results to speak of?

i was doing green smoothies for about three weeks and saw some change, but i fell out of the habit and im gonna try again, the change wasnt anything too amazing but with the science being there and all i at least have to give it a chance for a full twelve weeks.

The amount of sugar from fruit i was using was negatively affecting me i think i need to find a good balance of fruit and greens or just eat spinach salads. spinach i think has the highest concentration of the green pigment chlorophyll.

just make green smoothies or find a way to eat a big salad everyday, oh and im pretty sure you need lots of fat to absorb cholorphyll, not absolutly sure though.

[Listener]

I've been looking around for some chlorophyll extract actually. Was the active ingredient in it, phytanic acid or something? I wonder if that can be got separately.

[thetruth24]

Today was the third time I took Chlorophyll. (Chloro Combo)

I mix it with orange juice and drink 1 cup in the morning and 1 cup at night. It really helps with bowel movements and it feels like everything comes out.

There are alot of benefits with cholorphyll, aside from the possibility it may upregulate ppar alpha.

As for phytanic acid, no I don't think they have that as a supplement. The chlorophyll you buy in stores is actually chlorophyllins, and theyre suppose be have more benefits that chlorophyll itself.

I know my previous post was for Jemini, but does anyone else have any thoughts?

Thanks!

[AutonomousOne1980]

I've been looking around for some chlorophyll extract actually. Was the active ingredient in it, phytanic acid or something? I wonder if that can be got separately.

your body makes phytanic acid out of chlorophyll i think, have to check for sure though.

[jemini]

What exactly are the metabolites of isotretinoin? Would taking something with a higher affinity for the RXR receptors have the saem effect as accutane?

"Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin)." There is some debate whether it is actually one or a combination of these metabolites which actually bind to the rxr receptor since isotretinoin actually has a LOW affinity on its own.

It's interesting that you mention weight loss, because alot of bodybuilders who obviously have high amounts of testosterone have no acne. I know they take supplements to shed the fat, and maybe that plays a role in acne as well? I mean maybe fat loss regimens affect lipogensis?

Actually, a lot of bodybuilders DO have acne, or at least the ones who use steroids and other prohormone substances. Though, many have professional bodybuilders have good photographers, fake tans and lots of makeup. Though, there are plenty of people who lift and don't abuse these substances with no acne. So there is some sort of threshold at least in some people. the weight loss substance I was referring to, Sesamin, is relatively new to the market and is not completely studied. Most weight loss aids bodybuilders use were usually stimulants like caffiene or ephedrine and the like. If anything, these also probably aggravate acne as they can overstimulate the adrenals and be equivalent to heavy stress. So if you know that stress breaks you out, then these supplements aren't for you. Sesamin isn't a stimulant and works in a completely different manner, at least in theory.

Perhaps you are correct about, sticking to it longer. Some people on accutane get oiler for a couple weeks and then they get dry. Keep in mind that this is megadosing on 13 cis retinoic acid. The effects of "regular" supplementing with sesamin. Kinda like B5. It looks like you need to mega dose on something to see results.

Im kind of lost on your correlation here. You are generally not "megadosing" on accutane, even at high doses. Accutane just has a high affinity for the receptors. Think of the drug and the receptor as two magnets. Normal vitamin A is like a crappy fridge magnet, while accutane is like a super magnet. The receptor is a metal surface I guess. It doesn't take much of the super magnet to get a strong "Stick." B5 is definately megadosing. Unfortunately I don't think anyone could tell you how it works yet. Personally, I think accutane is the much safer and more practical choice. Less pills, and doctors supervision. We don't even know what the side effects of taking 10 grams of b5 a day are.

Off topic, women usually start to break out during period, when hormones are in flux. There must be something going on when there are hormonal shifts. Whether it be with the PPARs or the ARs themselves.

Your guess is as good as mine. I have my speculations, but I will just keep them to myself since my guess really is as good as yours in this area.

If you read the study I posted early on in this thread, there was a study that showed 95% of people have significant success with topical resveratrol. Resveratrol is a 5 lipoxygenase inhibtor. If memory serves correct (there are so many things, I get confused), 4 Lipoxygenase is responsible for anachinodic acid, which in turn makes leukotrines, which can stimulate the sebaceous glands. Resveratrol also inhibits CYP1A1, an enzyme that could break down retinoic acid quicker than it can be used. Just things to think about.

I didn't read the study. But if what you say is true then resveratrol could have its place in acne treatment. To what degree, I don't know. I would be suspicious of 95% had significant success though.

[AutonomousOne1980]

I didn't read the study. But if what you say is true then resveratrol could have its place in acne treatment. To what degree, I don't know. I would be suspicious of 95% had significant success though.

it all depends on how success is defined by the study i guess.

but there are still good reasons to believe topical resveratrol could have some benefit for acne.

[thetruth24]

Jemini,

Thanks for clearing that up for me.

Actually, I am into lifting weights, and I see alot of guys who juice with clear skin. It makes sense though, that stimulating any kind of hormones may aggravate acne.I don't have any known "sensitivities" to stress though. I think I will experiment with it.

Well no, you're not megadosing on Accutane, but I've read that its like megadosing on Vitamin A. A theory is that some people have an overactive enzyme that breaks down retinoic acid before it can be used. So basically you're flooding youre body with Vitamin fast enough that not all of it gets broken down to be used.

I still would like to hear you're opinion though, on the fluxing of hormones though! If you don't mind.

It's interesting that you talk about thyroid receptors. My mom has hypthyroidism. I mentioned earlier that, I take after my dad in more ways than one though.

Glad to hear you're thoughts Jemini.

[Listener]

Not sure if this has been mentioned already, but in the same vain as flax lignans and sesamin, it is purported that Resveratrol too may be estrogenic:

'While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen.[62] [63] However, other studies have found that resveratrol actually fights breast cancer.[64][65] Citing the evidence that resveratrol is estrogenic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under 18, as no studies have shown how it effects their natural development."[66]'

From wiki

[jemini]

Well no, you're not megadosing on Accutane, but I've read that its like megadosing on Vitamin A. A theory is that some people have an overactive enzyme that breaks down retinoic acid before it can be used. So basically you're flooding youre body with Vitamin fast enough that not all of it gets broken down to be used.

Yes, megadosing on vitamin a will have accutane like effects, though it is much more dangerous. I can only imagine the strain it puts on your liver and kidneys, among other things. While some people have proposed that the enzyme responsible for breaking down endogenous retinoic acid is overactive in acne patients, I tend not to believe that for most cases. First off, retinoic acid is metabolized by one of the cyp450 enzymes, a family of degradation enzymes which breakdown many natural compounds and drugs. I can't remember which one specifically is responsible for metabolizing retinoic acid. But those enzymes are very well studied. If an extremely overactive cyp450 enzyme was responsible for acne in most cases, someone would have connected the dots years ago. While there is variance among the cyp450 genes between people in how fast they metabolize products, its usually not a huge difference. Also, if that enzyme was really that overactive where retinoic acid couldn't accumulate in the skin at a normal rate, it would have other side effects on the body besides acne most likely. Those enzymes are generally multipurpose.

I still would like to hear you're opinion though, on the fluxing of hormones though! If you don't mind.

It is my belief that hormones, specifically male hormones might have some sort of positive regulation on ppars. In that, more testosterone binding to the AR receptor makes it easier for dimers to form possibly. Or something along those lines. Although this is my hypothesis and I have nothing to back it up really.

It's interesting that you talk about thyroid receptors. My mom has hypthyroidism. I mentioned earlier that, I take after my dad in more ways than one though.

Google the symptoms of hypo and hyperthyroidism. I remember in some instances, though its pretty rare, one of those diseases may cause acne. But if you had it, you would have other symptoms as well. All i figure is like I have been saying all along, I think all the nuclear hormone receptors are interrelated to a degree. Possibly over or understimulating one receptor might have effects on the other receptors, or their pathways.

[thetruth24]

Listener,

Hmmm, thats strange. On Testosterone's website, it says it does the opposite. Its suppose to support testosterone. I've been taking it for a 4 days now, nothing to report. Ill continue taking it though for the health benefits!

[thetruth24]

Jemini,

Haha, damn, do you have a degree in this field of something?! All you're rationales are very logical and are things I would have never thought about. I'll be going to college in the fall, and I am definitely going to take a class in Nuclear Biology.

It is more than likely that all these NR, as you said, are intertwined. When people grow out of acne, I am wondering if its the stabilization of androgens that makes the difference and/or change of gene expression. Is there any study that says gene expression can change with time? Without any stimulation? (Naturally)

I looked up the symptoms of hypothyroidism. None of them fit me, so thats a good things!

On a side note, while I was looking up different topicals and RXR and such, and came across a medication called Targretin (Bexarotene). It is "subclass of retinoids that selectively activate retinoid X receptors (RXRs)."

http://www.rxlist.com/cgi/generic/bexarotene.htm

I wonder if this can be used for acne treatment as well, since it specifically targets the RXR receptors, same as isotretinoin.

[Listener]

Listener,

Hmmm, thats strange. On Testosterone's website, it says it does the opposite. Its suppose to support testosterone. I've been taking it for a 4 days now, nothing to report. Ill continue taking it though for the health benefits!

It's good to hear you're testing it out. Let us know your progress.
I am currently testing out 10 grams omega 3 per day along with 1800mg chromium picolinate since 10th august.

[thetruth24]

Sounds Good Listener! Ill keep you updated!

Damn, 10 grams?! How many pills is that?

[AutonomousOne1980]

While some people have proposed that the enzyme responsible for breaking down endogenous retinoic acid is overactive in acne patients, I tend not to believe that for most cases. First off, retinoic acid is metabolized by one of the cyp450 enzymes, a family of degradation enzymes which breakdown many natural compounds and drugs. I can't remember which one specifically is responsible for metabolizing retinoic acid. But those enzymes are very well studied. If an extremely overactive cyp450 enzyme was responsible for acne in most cases, someone would have connected the dots years ago. While there is variance among the cyp450 genes between people in how fast they metabolize products, its usually not a huge difference. Also, if that enzyme was really that overactive where retinoic acid couldn't accumulate in the skin at a normal rate, it would have other side effects on the body besides acne most likely. Those enzymes are generally multipurpose.

Jemini,
very good point about the cyp enzyme theory and how the enzymes overactivity would be apparent in other systems in the body, although i dont know what is known about the cyp enzymes and how well they are known, or even how they work!! it seems to be a decent enough reason to question this theory of the enzymes.

but a point i would like too add about acne is that there is a big connection to altered fat metabolism, so however fat metabolism would be connected to acne that may point to the key, ppar alpha may be this key. But even accutane has been shown to correct altered fat metabolism as well so there is a very weird and close relationship between rxr and ppar it seems.

[AutonomousOne1980]

It is more than likely that all these NR, as you said, are intertwined. When people grow out of acne, I am wondering if its the stabilization of androgens that makes the difference and/or change of gene expression. Is there any study that says gene expression can change with time? Without any stimulation? (Naturally)

well if you look into nutrigenomics, or how the internal dietary environment interacts with with genes you will see that alot is possible and genes do change in response to certain phytochemicals and such, this is a new science all together the arose from mapping the human genome, its pretty exciting stuff.

the goal of this type of research is to prevent disease and read peoples genetic profile and tell them what diseases they are susceptible to and tell them what foods to eat more of or less of to maximize their genetic potential and avoid disease as long as possible.

[jemini]

Well, I was persuing a degree in Pharmacy for a few years, but decided to switch out. I'm now a microbiology major. The education is the pharmacy school was awsome, but the idea of working at a CVS or Walgreens for the rest of my life and being a corporate whore finally got to me. I'd rather be in the lab and take a hit in the paycheck instead.