Abscisic Acid - Fruit Ripening Agent, Hypothalamic Regulator In Animals, Anti-cancer Agent

Terma

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I'm just going to leave these two studies here, they speak for themselves.

Antidepressant Effects of Abscisic Acid Mediated by the Downregulation of Corticotrophin-Releasing Hormone Gene Expression in Rats
Antidepressant Effects of Abscisic Acid Mediated by the Downregulation of Corticotrophin-Releasing Hormone Gene Expression in Rats

Abstract
Background:
Corticotrophin-releasing hormone (CRH) is considered to be the central driving force of the hypothalamic-pituitary-adrenal axis, which plays a key role in the stress response and depression. Clinical reports have suggested that excess retinoic acid (RA) is associated with depression. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share a similar molecular structure. Here, we proposed that ABA also plays a role in the regulation of CRH activity sharing with the RA signaling pathway.

Methods:
[3H]-ABA radioimmunoassay demonstrated that the hypothalamus of rats shows the highest concentration of ABA compared with the cortex and the hippocampus under basal conditions.

Results:
Under acute stress, ABA concentrations increased in the serum, but decreased in the hypothalamus and were accompanied by increased corticosterone in the serum and c-fos expression in the hypothalamus. Moreover, chronic ABA administration increased sucrose intake and decreased the mRNA expression of CRH and retinoic acid receptor alpha (RARα) in the hypothalamus of rats. Furthermore, ABA improved the symptom of chronic unpredictable mild stress in model rats, as indicated by increased sucrose intake, increased swimming in the forced swim test, and reduced mRNA expression of CRH and RARα in the rat hypothalamus. In vitro, CRH expression decreased after ABA treatment across different neural cells. In BE(2)-C cells, ABA inhibited a series of retinoid receptor expression, including RARα, a receptor that could facilitate CRH expression directly.

Conclusions:
These results suggest that ABA may play a role in the pathogenesis of depression by downregulating CRH mRNA expression shared with the RA signaling pathway.

[...]

These results indicate that ABA inhibits HPA axis activity under physiological conditions. In addition, it suggests that RA and ABA may act as a pair of regulators in the balance of CRH activity.


Roles of Abscisic Acid in Fruit Ripening | SETHA | Walailak Journal of Science and Technology (WJST)
Roles of Abscisic Acid in Fruit Ripening
Sutthiwal SETHA

Abstract

Abscisic acid (ABA) is a plant growth regulator, and it plays a variety of important roles throughout a plant’s life cycle. These roles include seed development and dormancy, plant response to environmental stresses, and fruit ripening. ABA concentration is very low in unripe fruit, but it increases as a fruit ripens, so it is therefore believed that ABA plays an important role in regulating the rate of fruit ripening. This article reviews the effect of ABA on ripening and quality of climacteric and non-climacteric fruits. The effects of ABA application on fruit ripening are subsequently discussed. Moreover, it is found that during fruit ripening, ABA also contributes to other functions, such as ethylene and respiratory metabolism, pigment and color changes, phenolic metabolism and nutritional contents, cell wall metabolism and fruit softening, and sugar and acid metabolism. These processes are all discussed as part of the relationship between ABA and fruit ripening, and the possibilities for its commercial application and use are highlighted.
 

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Terma

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The way I interpreted this, stretching it a bit, when combined when some other studies on fruit ripening (I haven't read that many), such as Implication of Abscisic Acid on Ripening and Quality in Sweet Cherries: Differential Effects during Pre- and Post-harvest, is that ABA might act as a seasonal or environmental cue to animals' HPA axis, increasing insulin for food storage and higher levels inhibiting catabolic signals.

ABA curiously appears to direct fruit and plant growth a little bit like retinoic acid would in animals. According to some articles it appears ABA promote ripening on the branch but tends to increase and act when plants are under stress. In that article on cherries, it increases while the fruit is ripening on the vine, until it's picked. However, if the fruit is subjected to cold after picking, the ABA content shoots right back up.

Maple Syrup got some press about this a few years back: Research reveals maple syrup and maple water contain abscisic acid
And of course this comes from a cold environment.

It tends to concentrate more in peels and seeds. Although there are exceptions.

In other articles ABA is praised as being anti-diabetic in mammals by increasing insulin (sensitivity) and activating PPARgamma (T cell PPAR γ is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD). In other terms, it promotes storage. Which would be crucial for animals finding cold fruit on the ground in fall.

It has an interesting possible interplay with retinoic acid on CRH. Maybe it's supposed to be in balance with RA for some reason (this is what the top article suggests).

So an anti-depressant anti-CRH action is clearly desirable on one hand, and it may be a missing link in RA or glucocorticoid effects; but on the other, ABA resembles or basically is a plant stress hormone and might be a signal for stressful environment, so I'm not convinced it's pro-metabolic.

I'm interested if anyone has more knowledge on plants and this substance who might have a better informed opinion. Because this is making generalizations based on a few types of fruit only. To know if this is worth pursuing.
 

burtlancast

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Virginia Livingston patented abscisic acid as a regulator of cancer growth, by opposing the growth stimulating effect of HCG-like hormone secreted by the cancer-causing microbe, progenitor cryptocydes.
She used it extensively and successfully in her cancer clinic.

" The Production of HCG In Vitro by Progenitor Cryptocides. Its Neutralization by Abscissic Acid In Vitro and In Vivo.

Abscisic acid (dormin), a plant hormone occurring naturally in certain parts of plants of many varieties, is known to produce a state of dormancy in roots and seeds as well as to cause leaf abscission and ripening of fruits, has been synthesized by Hoffman La Roche. This action of A.A. in inducing dormancy of plants, roots and seeds opposes the growth promoting action of the gibberlins and auxins.
The microbe, Progenitor Cryptocides a member ofthe Order Actinomycetales previously described at length, produces in vitro a hormone immunologically identical to the human growth hormone, chorionic gonadotropin. However, in vivo the microbic hormone does not produce genital hyperplasia in mice and rats as does the human hormone.
Since fungi and some related microbes produce hormones similar to those of plants, it was proposed by the applicant (VWCL) that the microbic choriogonadotropin, a growth factor, might be opposed or neutralized by a growth retardant, A.A. Both the crude plant extract containing only 30% of the ‘A.A., and the pure synthesized A.A. from Hoffman La'Roche did prove to inhibit the production of microbic HCG in vitro."
Patent US3958025 - Abscisic acid tablets and process


This research has been confirmed in later patents: Abscisic acid against cancer

"Since Dr. Livingston's works, which were crystallized in researches, books and inventions, nobody else had studied and mentioned ABA in relation to cancer until 2005 and following years. During the year 2006, the invention number (CN 1748674A) published by The Chengdui Biological Institute Academy of Sciences, titled “New Use of Natural Abscisic Acid (ABA) in Developing Differentiation Inducer Drugs of Tumor Cells”, experimentally determined that ABA is able to: make proliferating tumor cells stagnate in S-phase and stop cell division, become cancer cells in normal cells, produce apoptosis and inhibit angiogenesis in a variety of tumor cells. In addition, on 2006 and re-examining the Livingston-Wheeler contentions, Marianne Ehrhorn Kruse, then in the Department of Biochemistry and Molecular Biology of the University of Southern Denmark, elaborated a master thesis titled “The Importance of Abscisic Acid as Possible New Drug in Cancer Treatment and its Role on Human Chorionic Gonadotropin Pathways”. She found that, ABA caused a tumor growth reduction, reduced cell proliferation rate, changed cell cycle progression, and produced induction of apoptosis, in four human cancer cell lines (HELA, DU145, HCT116 AND K562). In addition, ABA has also been proven in hepatocarcinoma cells and oral cancer."


One of the easiest ways of getting abscisic acid is to drink carrot juice; the Vitamin A will be converted in abscisic aid by your liver. If your liver is struggling, one can still get abscisic acid from carrot juice by adding a teaspoon of beef liver powder to the juice.
 
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Terma

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Hah, a patent for everything. It's quite informative though, thanks.

Some of those claims are completely alien to me, but despite the insulin-promoting effects I think an anti-cancer role is not contrary to what I've read so far:
Abscisic Acid Is an Endogenous Stimulator of Insulin Release from Human Pancreatic Islets with Cyclic ADP Ribose as Second Messenger
Indeed, most recent results indicate that ABA production occurs in human granulocytes stimulated with physical (temperature rise, latex beads) or chemical (phorbol myristate acetate) stimuli and that ABA activates several functional activities of granulocytes (including phagocytosis, migration, production of reactive oxygen species, and nitric oxide) involved in their defensive function (5). Thus, ABA behaves as an endogenous pro-inflammatory hormone in human granulocytes.

The remarkable conservation of the role of ABA as a stress signal from plants to humans is paralleled by the strikingly similar signal transduction pathway of the hormone in plants and animals. This pathway sequentially involves phosphorylation and activation of ADP-ribosyl cyclase (ADPRC), overproduction of the universal calcium mobilizer cyclic ADP-ribose (cADPR) (68), and increase of the intracellular Ca2+ concentration ([Ca2+]i) (2, 4, 9). In human granulocytes, ABA binding to the plasma membrane occurs through a pertussis toxin (PTX)-sensitive receptor-G protein complex, leading to a rapid increase of the [cAMP]i, activation of protein kinase A (PKA), phosphorylation of the ADPRC CD38 with cADPR overproduction, eventually leading to an increase of the [Ca2+]i (5).
I think it may have a quite different roles in the circulation versus the hypothalamus, and probably to cells types and organs. It's certainly got a lot of tricks up its sleeve.

Unrelated, this one it increases the sought-after GLP-1 for diabetes:
Abscisic Acid Stimulates Glucagon-Like Peptide-1 Secretion from L-Cells and Its Oral Administration Increases Plasma Glucagon-Like Peptide-1 Levels in Rats
 

Terma

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@burtlancast I forgot about this one: Inhibitory effect of maple syrup on the cell growth and invasion of human colorectal cancer cells
That's not to say there aren't other compounds in maple syrup, but coincidence.

One of the easiest ways of getting abscisic acid is to drink carrot juice; the Vitamin A will be converted in abscisic aid by your liver. If your liver is struggling, one can still get abscisic acid from carrot juice by adding a teaspoon of beef liver powder to the juice.
I kind of expected to see a statement like that, but it just makes me wonder what the conversion/amount rate is. I'm also having trouble finding a good list of food sources with real numbers. If you see any real book/study references on one... BioTherapeutics | Abscisic Acid (ABA)
 

Terma

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Damn, look at this:
LANCL2 - Wikipedia
The natural ligand of LANCL2, abscisic acid (ABA), has been identified as a new endogenous mammalian hormone implicated in glycemic control. [...]

Selective binding between LANCL2 and ABA or other ligands such as the benzimidazole NSC61610 and piperazine BT-11,[11] lead to elevation of intracellular cAMP, activation of PKA[12] and suppression of inflammation[12] in macrophages. In hepatocytes, LANCL2 regulates cell survival by phosphorylation of Akt through its interaction with the Akt kinase mTORC2.[13] Active mTORC2 causes translocation of GLUT4 to the plasma membrane and stimulates glucose uptake.[14]
So it can increase glucose uptake independently of insulin using Akt/mTORC2.

(This thread title could use more qualifiers! Can't edit it)
 

Terma

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This research has been confirmed in later patents: Abscisic acid against cancer [EDIT: quoted wrong link]
Your patent link has so many good tidbits I'll probably be looking at this for weeks:

Expression of Retinoic Acid Receptor Beta, PPAR Gamma, Involucrin Protein and Inhibition of Ki67 Cancer Marker

For long time, it has been recognized retinoic acid (RA) as a signaling molecule influencing developmental processes and cell differentiation. Since 1950, many investigations had proven its limited power as differentiation inducer drug. Nevertheless, it was reported by Khuri et al. 2006, during the largest retinoid chemoprevention trial that, retinoid (ISOTRETINOIN) was not effective against head and neck squamous cell carcinoma.

According to Freemantle et al. 2006, in an article appeared in the editorials of the Journal of The National Cancer Institute vol 98, No 7, it has been discovered that, retinoic acid receptor beta (RARBETA) expression is frequently silenced in epithelial carcinogenesis. It has also led to the hypothesis that, RARBETA acts as a tumor suppressor and is partially responsible for the limited clinical activity of classical retinoids.

Herein, it is important to mention that, under a treatment with ABA, RARBETA is expressed and not silenced by cancer cell. The expression of this receptor has been confirmed by Zhao et al. 2007, in the Key Laboratory of Oral Biomedical Engineering of Ministry of Education, in Sichuan University. The research titled “Effect on Induction of Differentiation of TCA8113 Cells Affected by Abscisic Acid in Vitro”, confirms the expression of RARBETA, involucrin protein and caspase-3mRNA.

According to Donato and Noy 2005, presence of RA is not necessary for over expression of the cellular retinoic acid binding protein II (CRABP II), which is the key protein attaching to RARBETA. Also, they mention that the tumor suppression by RA regulates transcription of multiple genes.

Investigations mentioned above prove that, it is ABA and not RA, which induces and conducts efficiently a process of cell differentiation.

That is a crazy statement so I will have to look for sources on that. (it doesn't match the hypothalamus study where RARBETA was unchanged, but that may be organ-/cell-specific)
 
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burtlancast

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Virginia Livingston got better cancer treatment results than even Gerson; that's why everybody tried to bury her immunotherapy.
 

Terma

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Lemme know and I will edit it.
I was nonchalantly going to add ", anti-cancer agent, novel glucose uptake enhancer" (anti-diabetes doesn't quite do it justice it's so overused), but it may be too long.

This is looking like the real deal (despite the fact it reflects as a stress hormone, but so does RA):
Abscisic‐acid‐induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway [2016]
Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.
Abstract
Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway.
I don't have time to read all this but this one argues for RAR-α not beta.
 

Terma

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Thanks, um, I guess I would have put it in the tags then. If there are any.
 

Terma

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The opposing action of ABA to RA appears to extend to adipose tissue.

Whereas ABA increases PPARgamma for fat storage, RA increases PPARdelta in adipose tissue (this may be context-dependent) which leads to fat burning. [This is a simplification - PPARdelta is also involved in triggering differentiation of new adipocytes for storage, which requires PPARgamma - but again this hints at more complementary roles between ABA and RA]
Here was a study among a few that showed the RA and PPARdelta link (I already posted enough about ABA and PPARgamma):
Retinoic acid activation of peroxisome proliferation-activated receptor delta represses obesity and insulin resistance. - PubMed - NCBI ("RA implantation into obese mice has caused upregulation of levels of PPARdelta and consequent weight loss as well as increased expression of PPARdelta target genes")
(both PPARgamma and PPARdelta can have positive impacts on diabetes, but in different ways - however PPARgamma does it by increasing uptake and storage depots)

Specifically since ABA promotes insulin, GLP-1, LANCL2 at the same time as PPARgamma, it must be a pretty good promoter of uptake and fat storage while simultaneously benefitting diabetes state in the interim.

So in the above articles, we have RAR-receptor mediated ABA effects on hypothalamic and cancer cells and closely complementary actions on PPAR in adipose tissue. It's just other side of the coin to RA.

I still have no material idea how ABA effects will interact with systemic and local cortisol, because cortisol effects can be tissue-specific which is hard enough to follow as it is.
 
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Terma

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Some links about RA that show the stark contrast with ABA (and some obvious applications):

https://www.ncbi.nlm.nih.gov/pubmed/22396202
"The data also indicate that RA suppresses adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity."
Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription.
"Here we report that ectopic expression of either C/EBPalpha or C/EBPbeta induces PPARgamma expression and adipogenesis and that retinoic acid (RA) completely inhibits adipogenesis by either form of C/EBP."
Retinoic acid inhibits adipogenesis via activation of Wnt signaling pathway in 3T3-L1 preadipocytes
"We found that RA treatment resulted in a dramatic inhibition of adipogenesis"
 
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