Alzheimer’s Disease: Is A Dysfunctional Mevalonate Biosynthetic Pathway The Master-Inducer Of Delete

[LeeLemonoil]

https://www.researchgate.net/public...cer_of_Deleterious_Changes_in_Cell_Physiology

There is a growing awareness that the proteins—amyloid-beta (Aβ) and tau—do not cause Alzheimer’s disease (AD) but are produced as a result of it. Similarly, doubt reigns over the degree of causality of high plasma cholesterol and prenylation in AD. This review proposes a fresh and important perspective, in addition to the current line of thinking. It emerges from comparative analysis, in evolutionary retrospect, of the characteristics of the mevalonate biosynthetic pathways in insects versus vertebrates, and of the drastic effects of the absence of farnesol and its esters with juvenile hormone (JH) activity. A dysfunctional mevalonate biosynthetic pathway, with farnesol at its very heart, can disturb “Golgicrine” activity, reduce mitochondrial multiplication, alter Ca2+ homeostasis, and cause massive apoptosis in specific tissues. These effects were observed in insects in the 1960–70s. It became undeniably established that the absence of endogenous sesquiterpenoids farnesol and its JH esters is the direct inducer of complete metamorphosis. Such effects are remarkably similar in metamorphosing insects and in the brain with AD. In insects, the administration of farnesol/JH temporarily prevents all mentioned changes. The absence of farnesol/JH was not observed in insects with incomplete metamorphosis; hence, there is no massive apoptosis. Neither do vertebrates have a period in their development in which the mevalonate biosynthetic pathway—that synthesizes farnesyl pyrophosphate, farnesol, and cholesterol—comes to a complete halt. Hence, there exists a difficulty in uncovering the other functions of farnesol, besides being an intermediate in the mevalonate pathway. A major breakthrough was achieved in 1999 with the discovery that farnesol in rodent and human brains potently blocks N-type Ca2+ channels. It was proved that the mevalonate pathway and farnesol play key roles in Ca2+ homeostasis. This paper highlights the major consequences of this chemical/pathway in AD research.

 

[GAF]

Farnesol - Wikipedia

Among other interesting tidbits in the article, this one caught my eyeball.

"In a 1994 report released by five top cigarette companies, farnesol was listed as one of 599 additives to cigarettes.[1] It is a flavoring ingredient."

Seems like I remember reading that smokers rarely get AD. Is that correct?

 

[GAF]

Mode of Action of Farnesol, the “Noble Unknown” in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect

 

[GAF]

Farnesol - an overview | ScienceDirect Topics

 

[GAF]

Farnesol, a Sesquiterpene Alcohol in Herbal Plants, Exerts Anti-Inflammatory and Antiallergic Effects on Ovalbumin-Sensitized and -Challenged Asthmatic Mice

5. Conclusions
Our results showed that actual farnesol supplementation at the indicated high dose of 151 mg/kg BW/day for 5 weeks had no toxic effect on the experimental mice. Farnesol supplementation decreased IL-6/IL-10 level ratios in BALF, suggesting an anti-inflammatory effect of farnesol on the lungs and airways. Farnesol supplementation significantly restored the secretion ability of peritoneal macrophages and slightly decreased TNF-α/IL-10 cytokine secretion ratios, indicating farnesol might enhance systemic immunity but inhibit inflammation in the lungs and airways in asthmatic mice. Farnesol supplementation slightly decreased IL-4 but significantly increased IL-2 levels secreted by the splenocytes in the presence of OVA, implying that farnesol supplementation might have a systemic antiallergic effect on allergic asthmatic mice. Furthermore, farnesol supplementation significantly increased IL-10 levels secreted by the splenocytes in the presence of OVA, suggesting that farnesol supplementation might also have an anti-inflammatory potential to allergic asthmatic mice.

 

[GAF]

https://www.researchgate.net/public...matory_and_Anti-Cancer_Properties_of_Farnesol

4. Conclusions and Future Perspectives
Overall, several studies have demonstrated the potential pro/anti-inflammatory and anti-cancer
effects of farnesol in various diseases and cancers. Although farnesol displayed a more
pro-inflammatory effect under in vitro settings, in vivo findings showed that it is likely to act in
an anti-inflammatory fashion in various chronic inflammation-induced diseases such as asthma.
This could be attributed to inflammation being a process that is dependent on the extracellular milieu,
where various types of immune cells also contribute to a pro- or anti-inflammatory environment.
Therefore, it is necessary to further investigate the in-depth mechanism of action of farnesol in
modulating inflammation.

Additionally, studies have also revealed farnesol to be efficacious as a potential anti-cancer agent
as it can exert cytotoxic effects against various neoplastic cell lines and it can significantly inhibit tumor
growth in vivo. Farnesol can also regulate various pathways to exert its anti-cancer effects in tumor
cells, which include the PC biosynthesis, MEK/ERK, UPR, JAK/STAT3, and PI3K/Akt signaling
cascades. Since in most cancers multiple oncogenic pathways would be deregulated to contribute to
the progression of the disease, farnesol could be beneficial as it can target different signal transduction
pathways, making it a promising anti-cancer therapeutic. However, more research needs to be carried
out to determine the safety and efficacy of farnesol for cancer treatment, which includes testing it in
clinical trials, as its effectiveness, has not yet been exactly determined in cancer patients

 

[GAF]

Farnesol induces cell detachment from established S. epidermidis biofilms | The Journal of Antibiotics

Farnesol induces cell detachment from established S. epidermidis biofilms

• The Journal of Antibiotics volume 66, pages255–258(2013)Cite this article
  
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Abstract
Antibiotic resistance is a serious problem in Staphylococcus epidermidis infections as many clinical isolates of this organism are resistant to up to eight different antibiotics. The increased resistance to conventional antibiotic therapy has lead to the search for new antimicrobial therapeutic agents. Farnesol, an essential oil found in many plants, has been shown to be active against S. epidermidis. Using a type control strain we recently described that although farnesol was not efficient at killing biofilm bacteria, a strong reduction on biofilm biomass was detected, and we hypothesize that farnesol could, somehow, induce biofilm detachment. In this report, to test our hypothesis we used 36 representative clinical strains of S. epidermidis from different geographic locations and characterized them in terms of genetic variability by multilocus sequence typing and staphylococcal chromosome cassette mec. Strains were tested for biofilm formation, and the presence of ica, bhp and aap genes was determined. Stronger biofilms had always the presence of ica operon but often co-harbored bhp and aap genes. Farnesol was then used in biofilm-forming strains, and biofilm detachment was detected in half of the strains tested. Furthermore, we also showed that farnesol inability to kill biofilm bacteria was not the result of the biofilm structure but was related to high cell density. Our results demonstrate, for the first time, that the biomass reduction previously found by us, and many other groups, is the result not of cell killing but instead is the result of biofilm detachment.

 

[GAF]

Farnesol-containing facial masks may improve UVB-exposed skin

Farnesol, an alcohol found in essential oils including ambrette seed and citronella, could be a beneficial component of facial masks, according to a study published June 27 in the Journal of Cosmetic Dermatology. Researchers in Taiwan report facial masks containing 0.3 and 0.8 mM farnesol improved skin smoothness and enhanced collagen content and arrangement in a study of rats’ skin, when the mask was applied with and after UVB exposure.

Farnesol is a fungal quorum-sensing molecule and natural sesquiterpene produced by many organisms, according to the study. It can be found in peaches, tomatoes, lemongrass and chamomile, the authors write.

ses·qui·ter·pene (noun)
a terpene with the formula C15H24, or a simple derivative of such a compound.

This colorless liquid with a delicate odor is widely used in cosmetic and personal care products, according to CosmeticsInfo.org.

The researchers studied facial mask formulations they prepared with 0.3 mM or 0.8 mM farnesol, 0.1% hyaluronan and 2% hydroxypropyl methylcellulose. They examined the effects of the facial masks on collagen production in vitro. And they conducted in vivo research using mask administration interspersed with UVB exposure and mask administration post UVB exposure to study collagen synthesis, skin smoothness and skin inflammation.

Among their other findings: Masks containing 0.8 mM farnesol had the greatest impact on the production and arrangement of collagen, as well as improvement in skin smoothness. They saw histopathologically that covering skin with facial masks containing 0.8 mM farnesol resulted in decreased inflammation and interleukin (IL)-6 compared to uncovered skin. These experimental studies suggest the facial mask containing 0.8 mM farnesol has preventive and reparative effects on sunburnt skin.

“Based on the findings of the current study, farnesol is a potential skin quality improving component applicable in facial masks designed for skin reparative and smoothness-improving skincare purposes for the skin frequently exposed to UV,” the authors write.

Notably, farnesol is associated with allergies and contact dermatitis, according to the Environmental Working Group.

 

[yerrag]

Farnesol - Wikipedia

Among other interesting tidbits in the article, this one caught my eyeball.

"In a 1994 report released by five top cigarette companies, farnesol was listed as one of 599 additives to cigarettes.[1] It is a flavoring ingredient."

Seems like I remember reading that smokers rarely get AD. Is that correct?

https://www.researchgate.net/public...cer_of_Deleterious_Changes_in_Cell_Physiology

There is a growing awareness that the proteins—amyloid-beta (Aβ) and tau—do not cause Alzheimer’s disease (AD) but are produced as a result of it. Similarly, doubt reigns over the degree of causality of high plasma cholesterol and prenylation in AD. This review proposes a fresh and important perspective, in addition to the current line of thinking. It emerges from comparative analysis, in evolutionary retrospect, of the characteristics of the mevalonate biosynthetic pathways in insects versus vertebrates, and of the drastic effects of the absence of and its esters with juvenile hormone (JH) activity. A dysfunctional mevalonate biosynthetic pathway, with farnesol at its very heart, can disturb “Golgicrine” activity, reduce mitochondrial multiplication, alter Ca2+ homeostasis, and cause massive apoptosis in specific tissues. These effects were observed in insects in the 1960–70s. It became undeniably established that the absence of endogenous sesquiterpenoids farnesol and its JH esters is the direct inducer of complete metamorphosis. Such effects are remarkably similar in metamorphosing insects and in the brain with AD. In insects, the administration of farnesol/JH temporarily prevents all mentioned changes. The absence of farnesol/JH was not observed in insects with incomplete metamorphosis; hence, there is no massive apoptosis. Neither do vertebrates have a period in their development in which the mevalonate biosynthetic pathway—that synthesizes farnesyl pyrophosphate, farnesol, and cholesterol—comes to a complete halt. Hence, there exists a difficulty in uncovering the other functions of farnesol, besides being an intermediate in the mevalonate pathway. A major breakthrough was achieved in 1999 with the discovery that farnesol in rodent and human brains potently blocks N-type Ca2+ channels. It was proved that the mevalonate pathway and farnesol play key roles in Ca2+ homeostasis. This paper highlights the major consequences of this chemical/pathway in AD research.

So farnesol is detrimental to the complete metamorphosis of insects, so does the study say it is also causative to Alzheimer's? The abstract was rather vague, requiring me to read the article. Since TL-DNR except for the conclusion, the language is rather hard to decrypt. It's confusing because farnesol kills larvae by stopping full development from larvae to a mature insect, by apoptosis caused by inhibition of Ca2+ influx into the cell. And the study invites the thinking that farnesol could have a similar mechanism in the etiology of AD.

But if farsenol is associated with the mevalonate pathway, and my take is that it is produced in the mevalonate pathway, would inhibition of the mevalonate pathway be good, as in taking statin drugs? I don't exactly know where this study is leading but it seems it is inviting more studies to affirm the suppression of the mevalonate pathway. But I thought inhibition of the mevalonate pathway is not good, because it inhibits cholesterol production as well as the production of CoQ10.

I'm very leery of this study, and feel it muddies up the water regarding the etiology of Alzheimer's Disease, with the aim of maybe justifying the use of statin drugs, because of the putative added benefit of arresting the development of Alzheimer's Disease.

 

[yerrag]

Farnesol-containing facial masks may improve UVB-exposed skin

Farnesol, an alcohol found in essential oils including ambrette seed and citronella, could be a beneficial component of facial masks, according to a study published June 27 in the Journal of Cosmetic Dermatology. Researchers in Taiwan report facial masks containing 0.3 and 0.8 mM farnesol improved skin smoothness and enhanced collagen content and arrangement in a study of rats’ skin, when the mask was applied with and after UVB exposure.

Farnesol is a fungal quorum-sensing molecule and natural sesquiterpene produced by many organisms, according to the study. It can be found in peaches, tomatoes, lemongrass and chamomile, the authors write.

ses·qui·ter·pene (noun)
a terpene with the formula C15H24, or a simple derivative of such a compound.

This colorless liquid with a delicate odor is widely used in cosmetic and personal care products, according to CosmeticsInfo.org.

The researchers studied facial mask formulations they prepared with 0.3 mM or 0.8 mM farnesol, 0.1% hyaluronan and 2% hydroxypropyl methylcellulose. They examined the effects of the facial masks on collagen production in vitro. And they conducted in vivo research using mask administration interspersed with UVB exposure and mask administration post UVB exposure to study collagen synthesis, skin smoothness and skin inflammation.

Among their other findings: Masks containing 0.8 mM farnesol had the greatest impact on the production and arrangement of collagen, as well as improvement in skin smoothness. They saw histopathologically that covering skin with facial masks containing 0.8 mM farnesol resulted in decreased inflammation and interleukin (IL)-6 compared to uncovered skin. These experimental studies suggest the facial mask containing 0.8 mM farnesol has preventive and reparative effects on sunburnt skin.

“Based on the findings of the current study, farnesol is a potential skin quality improving component applicable in facial masks designed for skin reparative and smoothness-improving skincare purposes for the skin frequently exposed to UV,” the authors write.

Notably, farnesol is associated with allergies and contact dermatitis, according to the Environmental Working Group.

Interesting. I'm going to try using citronella on my keloids. Maybe my keloids had its origins with staph infection on the skin that led to a biofilm growth, with the skin's defenses wrapping a matrix of collagen around it to keep it from spreading. Maybe applying farnesol would lead to biofilm detachment, if the farnesol in citronella oil would ably penetrate the keloid and penetrate the biofilm. Will be testing this for the next few weeks. Thanks.

 

[yerrag]

Farnesol - Wikipedia

Among other interesting tidbits in the article, this one caught my eyeball.

"In a 1994 report released by five top cigarette companies, farnesol was listed as one of 599 additives to cigarettes.[1] It is a flavoring ingredient."

Seems like I remember reading that smokers rarely get AD. Is that correct?

Farnesol, a Sesquiterpene Alcohol in Herbal Plants, Exerts Anti-Inflammatory and Antiallergic Effects on Ovalbumin-Sensitized and -Challenged Asthmatic Mice

5. Conclusions
Our results showed that actual farnesol supplementation at the indicated high dose of 151 mg/kg BW/day for 5 weeks had no toxic effect on the experimental mice. Farnesol supplementation decreased IL-6/IL-10 level ratios in BALF, suggesting an anti-inflammatory effect of farnesol on the lungs and airways. Farnesol supplementation significantly restored the secretion ability of peritoneal macrophages and slightly decreased TNF-α/IL-10 cytokine secretion ratios, indicating farnesol might enhance systemic immunity but inhibit inflammation in the lungs and airways in asthmatic mice. Farnesol supplementation slightly decreased IL-4 but significantly increased IL-2 levels secreted by the splenocytes in the presence of OVA, implying that farnesol supplementation might have a systemic antiallergic effect on allergic asthmatic mice. Furthermore, farnesol supplementation significantly increased IL-10 levels secreted by the splenocytes in the presence of OVA, suggesting that farnesol supplementation might also have an anti-inflammatory potential to allergic asthmatic mice.

Could explain why smokers are more immune to COVID-19? @Drareg

 

[GAF]

Could also explain why smokers live as long as they do.

I ordered a bottle of farsenol on Amazon.

I don't understand the studies either. It doesn't seem to me authors of the studies understand much either. The stuff appears to have positive impacts, but they have no idea how or why.

To me, it seems to be worth experimenting with.

I also wonder how much the tobacco companies know but have never shared.

 

[not_James_Bond]

@GAF @yerrag
Please keep this thread updated with your findings farnesol and citronella

 

[LeeLemonoil]

Farnesoides are crucial hormones insects.
De Loof is an entomologist but also evolutionary theorist, he has some mind boggling papers out.
Farnesol seems to be his main point of theorizing, because farnesoids are the „juvenile hormones“ of insects. (Interestingly it was long thought that T3 is the Human equivalent to that.

Karel Slama, another entomologist, has recently postulated that ecdysteroids are actually Vitamin D types - juvenile hormones and ecdysteroids are the most important hormones in insects feedbacking and interlooping in action too.
Both are heavily involved in Ca+-influx in cells.
De Loof thinks that Ca+ was the most ubiquitous environmental pollutant on earth when life came into being. He thinks propagation can evolutionarily explained by organisms trying to get rid of excess calcium.

His papers are all very interesting, I’ve linked some up in 2 threads here already.

Farnesol is cheap and available, it’s often sold as a DIY deodorizing agent

 

[LeeLemonoil]

I wouldn’t use citronella oil excessively topically, there ain’t much farnesol in it

 

[LeeLemonoil]

Farnesol is a major part of that

Why flavored vape products may be attractive: Green apple tobacco flavor elicits reward-related behavior, upregulates nAChRs on VTA dopamine neurons, and alters midbrain dopamine and GABA neuron function - PubMed

 

[LeeLemonoil]

Two prior threads discussing farnesol, de Loof and ecdysteroids


Plants And Insects As A Source Of Steroids


Retinoids: Vertebrae Analouges To Juvenile Hormone Of Insects?

 

[yerrag]

Could also explain why smokers live as long as they do.

I ordered a bottle of farsenol on Amazon.

I don't understand the studies either. It doesn't seem to me authors of the studies understand much either. The stuff appears to have positive impacts, but they have no idea how or why.

To me, it seems to be worth experimenting with.

I also wonder how much the tobacco companies know but have never shared.

I'm just as perplexed as the study poses the question of whether a dysregulated mevalonate biosynth. pathway is the master-inducer of deleterious changes in cell physiology, and then goes on to give the impression (at least in me) that farnesol is implicated in the development of AD. As to whether farnesol is a product of a dysregulated mevalonate pathway or not I cannot glean from the study's conclusion. It appears a deliberate doublespeak on the part of the authors, when they aren't sure of what they're saying they express their ideas in very very ambiguous language.

 

[LeeLemonoil]

It’s not a study, it’s a publication. And yes, de Loof admits he doesn’t know farnesols exact role and action - only that he thinks it could be very important in human physiology too.

 

[Diokine]

This is interesting stuff, I like to frame some of this in the context of higher-order modulation of hydrophobic and hydrophilic interfaces in cells. Alcohols like retinol and isoprenoids (terpenes) are important in this context. There is a lot to learn about thyroid hormones, insulin, Ca2+, and modifiable water/lipid boundaries.

Insulin resistance is essentially cholinergic fatigue. At the most basic level, the system is trying to coordinate flux of calcium in an out of tissue. When the tissue is unable to repsond, the system presses harder to the point of fatigue. The tissue in your neck (thyroid and parathyroid) essentially form an electric circuit with your brain stem (sympathetic) and vagal (parasympathetic) centers to coordinate this action. Prolonged fatigue will manifest here.

The inability of tissue to respond to stimulation from nerves, in my opinion, is the prime reason for nearly all tissue degeneration and inability of the body to heal
Specifically, the endogenous cannabinoid system, in concert with the cholinergic nervous system, is involved in setting the range of neural output and directly controls the influence of nerves on tissue. I think chronic over activation of the cannabinoid system reduces the effect of acetylcholine on neural inputs. This is truly at the heart of nearly any metabolic dysfunction, including blood sugar regulation problems and autoimmune conditions. When the timing of the nerves themselves is disrupted the entire system becomes deranged and slowly loses the ability to communicate with itself.

I had experimented with falcarinol in the past due to it being a CB1 receptor inverse agonist. I wonder if farnesol would have similar effects. I suspect chronic activation of the endogenous cannabinoid system is partly responsible for the derangement of the cholinergic nervous system and is responsible for defects in phospholipid synthesis that is prevalent in many neurodegenerative diseases. I also suspect this is foundational to neurogenic digestive issues, along with pancreatic and liver problems.