Quote from hillcountry on January 23, 2020, 3:45 am

@bludicka - haven't seen you post in awhile, hope you're OK. Did you listen to this interview about Dr. Gominak's Parkinson's patients? There's a Pantothenic Acid and Acetylcholine aspect to this, as well as Dopamine according to her hypothesis, based upon a lot of clinical experience. 

Interview One : March 2018 : The Sleep Disorder that Causes Parkinson’s Disease

Interview Two: April 2018: How to Repair the Sleep Disorders of Parkinson’s Disease

Quote from ggenereux on January 23, 2020, 7:24 am

Here's a related paper that I had referenced in P4P.

13-cis-Retinoic acid alters intracellular serotonin, increases 5-HT1A receptor, and serotonin reuptake transporter levels in vitro.

"In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13-cis-retinoic acid, isotretinoin) treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13-cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT(1A) receptor and the serotonin reuptake transporter (SERT).

…

Treatment with 13-cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. " 

Source: Volume: 232 issue: 9, page(s): 1195-1203
Issue published: October 1, 2007
https://doi.org/10.3181/0703-RM-83
Kally C. O’Reilly, Simon Trent, Sarah J. Bailey, 1, Michelle A. Lane, 1, 2
Institute of Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712; Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY UK; and Department of Human Ecology, Division of Nutritional Sciences, The University of Texas at Austin

I find it troubling that so many of these researches have jumped to the same conclusion that: "RA regulates" or "RA modulates" some important biological function when at the same time they know that it's a poison.

 

 

 

Quote from hillcountry on January 23, 2020, 8:02 pm

Hi Grant - it is troubling, especially when we see papers stating RA is affecting over 6,000 genes in one experiment. The mind reels. Yours led me to look for others along that line and here's one from Japanese researchers a year later.

Eur J Neurosci.

2008 May

13-cis-retinoic acid alters the cellular morphology of slice-cultured serotonergic neurons in the rat.

Ishikawa J¹, Sutoh C, Ishikawa A, Kagechika H, Hirano H, Nakamura S.

Author information

Department of Neuroscience, Yamaguchi University Graduate School of Medicine

Abstract

Retinoids influence cellular processes such as differentiation, proliferation and apoptosis via retinoic acid receptor (RAR) and retinoid X receptor (RXR), and have therapeutic applications in several cancers and dermatologic diseases. Recent reports indicate that depression occasionally occurs in patients using the acne drug Accutane, the active component of which is 13-cis-retinoic acid (13-cis-RA). Although impairment of serotonin (5-HT)-expressing neurons, including morphologic changes, is thought to be associated with depressive symptoms, the effects of 13-cis-RA on 5-HT neurons have not been examined.

The present study demonstrated that 13-cis-RA alters the morphology of 5-HT neurons in cultured rat midbrain slices. The 13-cis-RA-induced changes were partially blocked by RXR and RAR antagonists.

Furthermore, cotreatment with RAR and RXR agonists altered the morphology of 5-HT neurons to a greater extent than the individual application of each agonist. The morphologic changes were completely blocked by RXR antagonist, whereas RAR antagonist partially blocked the effects. These results suggest that 13-cis-RA exerts its action on slice-cultured 5-HT neurons, at least in part, through specific retinoid receptors. Moreover, RXR has a greater influence on the morphology of 5-HT neurons than RAR. The receptor-mediated actions of 13-cis-RA presented here may provide a clue for further research on depression associated with the use of 13-cis-RA.

PMID:18445226

 

And this one

Prog Neuropsychopharmacol Biol Psychiatry.

2008 Feb

The neurobiology of retinoic acid in affective disorders.

Bremner JD, McCaffery P.

Department of Psychiatry, Emory University School of Medicine, Atlanta, GA

Institute of Medical Science, University of Aberdeen, Foresterhill, Aberdeen, UK

Abstract

Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood.

Until now retinoids have not been considered as possible contributors to affective disorders.

Retinoids represent a family of compounds derived from vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS.

More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus.

Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression.

PMID:17707566 Free PMC Article

(hillcountry: not too many paragraphs into the full article leads one to think that the word "modulate" is actually a euphemism for the word "cause", no matter what dose they're talking about. I haven't seen one study in over a year of reading that calls for research into what the lowest-dose of retinoic acid is that will cause similar effects. Doesn't that seem like a very logical thing to do, once you know you have serious toxic-effects at higher levels?  At least we see an indictment of Accutane here, in no uncertain terms. The bit about "similar neuropsychiatric effects with other retinoids in its class (e.g., Vitamin A)" is an interesting way to phrase it.)

In the embryo, RA is essential to guide growth, development, and patterning in many organ systems, while exposure to abnormal concentrations of RA, for instance through treatment of acne with isotretinoin (13-cis RA), results in multiple malformations, including abnormalities in the developing brain (Coberly et al 1996; Lammer and Armstrong 1992; McCaffery et al 2003).

The role of RA in regulating CNS development has been extensively investigated (as reviewed by Maden (Maden 2001)) but, until recently, it was scarcely considered that RA may also influence neuronal function in the adult brain.

Accumulating evidence has shown, however, that RA signaling occurs in the brain of the adult (Krezel et al 1999; Luo et al 2004a; Sakai et al 2004; Thompson Haskell et al 2002; Zetterstrom et al 1999; Zetterstrom et al 1994), suggesting that the adult brain, like the embryo, may be sensitive to exposure to excess RA.

(hillcountry: it's starting to read a bit like a Monty Python skit – “scarcely considered” – “may be sensitive” - we're talking about a known systemic poison here.)

As we describe below, retinoids like all-trans-RA (the active form of vitamin A), an isomeric variant of 13-cis-RA, have psychiatric effects at high doses, and when deficient can lead to impairment of learning and memory. Studies in both humans and animals show that 13-cis-RA can induce depressive behaviors. Clinical evidence for an association between 13-cis-RA and depression in humans comes from similar neuropsychiatric effects with other retinoids in its class (e.g., Vitamin A),…

This report proposes RA as a previously under-recognized neurochemical system that is involved in the pathophysiology of depression. Section 2 of this review describes the general neurobiology of RA, while section 3 discusses the behavioral effects of exposure to retinoids in animal studies as well as the clinical literature on 13-cis-RA and depression. Finally, in section 4, retinoids are described as novel neurosignalling molecules that can modulate, at least in part, symptoms of affective disorders.

(hillcountry: how is a molecule, Retinoic Acid, a "neurochemical system"? Am I being too picky about the use of language? Does it even matter, when in the next breath they use "modulate" instead of "cause"?)

 

Quote from hillcountry on January 24, 2020, 5:18 am

@Grant - isn't it interesting to see papers where retinoic acid is clearly indicted, yet the language used tends to obscure the facts that the researchers themselves just documented. There must be a lot of self-censor-conditioning as part of the training. For instance, in those papers we've found where researchers are actually surprised to find a toxicity-angle they didn't expect, and then seem compelled to wrap the discovery in technical or vague jargon that tends to minimize it. I sometimes wonder if there's any hard-core, double-E's on the front-lines, gritting-their-teeth as the abstracts are written by committee. One problem I see after 14-months of reading papers is that there's such a wide-spectrum of information, of such vast quantity, that even thinking about anyone ever trying to disprove retinoic acid's involvement in morphology is a waste of time, especially when there's bigger fish to fry. It wouldn't be possible in any case. I doubt they have it all wrong, not that it matters what I think about that. There are just too many papers like the one copied below and there's 910 other hits on a query of "retinoic acid and regeneration" at PubMed. I'm interested in getting to the root of why there aren't more clear warnings from the establishment about the dangers of the known-toxicity, sub-clinical or otherwise, and about the ongoing epidemic of a hidden-form of hypervitaminosis-a as described in the University of Wisconsin critique. Nobody I talk to has a clue. Maybe pediatricians are up-to-speed; but VA-supplements are still flying off the shelves, isotretinoin in large-doses is still being prescribed, body-care products with Retin-A like molecules are multiplying by the day, and the VA-content of foods is disappearing from labels. This is where a words like 'public-outrage' are applicable. Where are the protectors of the flock? Is this just about feeding people into the insatiable maws of specialty-medicine once they succumb? Is it simply an expression of collective ignorance? And now, thinking about hormone-D deficiency, and the potential that it is intertwined with all of this VA-toxicity, then many of us would be facing a double-barreled shotgun. Here's to hoping we figure it all out. 

Mech Dev.

2018 Oct

Exogenous Vitamin D signaling alters skeletal patterning, differentiation, and tissue integration during limb regeneration in the axolotl.

Department of Biology, University of Massachusetts Boston, Boston, MA, USA.

Urodele amphibians such as the axolotl regenerate complete limbs as adults, and understanding how the "blueprint", or pattern, of the regenerate is established and manipulated are areas of intense interest. Nutrient signaling plays an important role in pattern formation during regeneration.

Retinoic acid signaling is the most characterized pathway during this process.

Exogenous retinoic acid (RA) reprograms the pattern information in regenerating cells to a more posterior, ventral, and proximal identity. Vitamin D signaling shares several molecular similarities with RA and has been shown to alter pattern formation during zebrafish pectoral fin regeneration. To determine if exogenous Vitamin D signaling is capable of reprograming pattern in the axolotl limb blastema, we treated regenerating limbs with a potent Vitamin D agonist.

Under the studied conditions, exogenous Vitamin D did not act in a manner similar to RA and failed to proximalize the pattern of the resulting regenerates. The Vitamin D treatment did result in several skeletal defects during regeneration, including carpal fusions along the A/P axis; failure to integrate the newly regenerated tissue with the existing tissue, formation of ectopic nodules of cartilage at the site of amputation, and altered bone morphology in uninjured skeletal tissue.

PMID:30096415   Free PMC Article

Quote from lil chick on January 24, 2020, 6:25 am

I'll give you a question for an answer:  Why do we still have fluoride in the water? 

Quote from tim on January 24, 2020, 7:36 am

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Quote from ggenereux on January 24, 2020, 9:12 am

Hi @hillcountry

RE: Isn't it interesting to see papers where retinoic acid is clearly indicted, yet the language used tends to obscure the facts that the researchers themselves just documented.

Yeah, you sure have to wonder what’s really going on. I totally agree about the obfuscation and diversionary jargon used in so many papers. And, it’s almost like the peer review process is not there to ensure the integrity of the science at all; rather it’s a gate-keeper process to try to make sure nothing too damaging leaks out.

If you have not read this one yet, it’s a paper showing the plasma concentrations of all three RAs increases post meals with either vA, B-Carotene and of course retinyl palmitate too.

Circulating Endogenous Retinoic Acid Concentrations among Participants Enrolled in a Randomized
Placebo-Controlled Clinical Trial of Retinyl Palmitate

Rebecca L. Sedjo,1 James Ranger-Moore,1,2 Janet Foote,3 Neal E. Craft,4 David S. Alberts,1 Min-Jian Xu,1 and Anna R. Giuliano1,2
1Arizona Cancer Center and 2Arizona College of Public Health, University of Arizona, Tucson, Arizona; 3Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii; and 4Craft Technologies, Inc., Wilson, North Carolina

So, we have this direct chain of evidence that:

RA ⇒ Causes depression and anxiety 

Vitamin A (in its various forms) naturally ⇒ Causes increased RA serum levels

In addition to the record rates of adult suicides in North America,  we now have record rates of child suicides too. There’s an average of more than 5,000 US students in grades 7-12 who attempt to take their lives each day. source

And 7,213,599 kids on psychiatric drugs source

Are these drugs cheering kids up so much that they are deciding to kill themselves at record numbers? What am I missing here?  

Could it be that pharma and their pals in government who have promoted and supplemented our food with vA and retinyl palmitate know exactly what's going on and are now in cover-up mode to hide what they’ve caused?

 

Quote from tim on January 24, 2020, 3:52 pm

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Quote from hillcountry on January 25, 2020, 5:25 am

I find that I have to keep reminding myself what's what. The situation (and so many elements thereof) is so staggering and even in-our-face that it must be normalcy-bias and the slow-pace of change that keeps it from generating panic on the part of the general population. @ggenereux2014 - That study you posted is a bombshell, plan to copy it on PM Research. Lately, been thinking about a project of going through all past posts and archiving the studies that are sort of buried on various threads, and copy them over to PubMed Research. 

So, a cancer center in Tampa is telling us that a chemo-therapeutic agent, i.e. 13-cis retinoic acid, is generated (significantly) by the same molecule our foods are fortified with, Retinyl Palmitate. We knew that, but seeing it in print is important, especially for those who are sitting on the fence. You know, like, at what concentration is it no longer chemotherapy? How about a billboard campaign - "Stop Putting Chemo In Our Milk" - with a bald-headed child sitting on a hospital bed.

There's 1337 hits at PubMed on a query of "13 cis retinoic acid and cancer" and just reading the titles makes you shake your head.

Dig this one from the first page of those. They're obviously not bashful about what's going on. They're studying poisons and how much the human body can take, particularly the liver. Can you imagine the statistics that are not published? There are a couple of glaring incongruencies in the excerpt below that makes one wonder if they have any shame at all, or simply look at humans as lab-animals. It was your indignation that resonated when I read about the study your kidney doctor was involved in and how amoral or immoral his reaction to the deaths was. There's no doubt in my mind that we're dealing with a lot of psychopaths in the world of medicine. 

Retinoids.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD):

National Institute of Diabetes and Digestive and Kidney Diseases; 2012-2018 May 1.

Excerpt

Retinoids are both natural and synthetic derivatives of vitamin A, several of which have been developed for medical uses, largely to replace vitamin A which in high, therapeutic doses is associated with considerable toxicity. Retinoids have multiple actions and play important roles in regulation of cell proliferation and differentiation, vision, bone growth, tumor suppression and immunity. The effects of retinoids are thought to be mediated (wait a minute, you guys don't really know?) by their binding to and activation of the retinoic acid and retinoid X receptors which regulate gene expression, important in normal growth and differentiation. Vitamin A in doses that have medical effects was found to be toxic, particularly when given long term. Modification of the vitamin A structure led to retinoid molecules that had many of its beneficial, but fewer of its adverse effects. Oral retinoids in use in the United States include acitretin for psoriasis and isotretinoin for severe nodular acne. Tretinoin is used topically and several other retinoids have been developed for therapy of uncommon forms of cancer (alitretinoin, bexarotene). The commonly used retinoids have many of the side effects of vitamin A including dry skin, cheilosis and nosebleeds and hair loss, but are not stored in the liver and do not cause the typical form of chronic liver disease associated with excessive vitamin A intake.

Both acitretin and isotretinoin are teratogenic and embryotoxic and are contraindicated in women who are or intend to become pregnant. Retinoids have been implicated in causing mild-to-moderate elevations in routine liver tests, but these elevations are usually asymptomatic and transient, resolving spontaneously even with continued therapy. Marked elevations in serum aminotransferase levels during retinoid therapy are uncommon, and dose adjustment or drug discontinuation are rarely required for liver test abnormalities. Nevertheless, laboratory monitoring is recommended with routine liver tests at baseline and one month later, and testing thereafter only if abnormalities were found or symptoms arise. Several retinoids (acitretin, etretinate, retinal acetate) have been associated with a clinically apparent acute liver injury which typically arises during the first 3 months of therapy, has many features of hypersensitivity and can be severe and even fatal.

Interestingly, isotretinoin often causes mild serum aminotransferase elevations and is commonly listed as having frequent adverse effects on the liver, but it has not been convincingly linked to instances of severe clinically apparent, acute liver injury with jaundice. Two retinoids used in dermatology, acitretin and isotretinoin, are discussed in this record and their combined references of retinoids are provided at the end of this introductory section. The hepatotoxicity of vitamin A is discussed separately in another record.   PMID:31643883 (full paper is linked)