The other day I looked back at an entry posted a couple of months after my first rather miraculous and large fisetin dose of three grams mixed in olive oil. I had been suffering for months with an allergic chronic cough, likely histamine induced. Eventually, went to the doctors and was immediately admitted, quite a feat in the UK, dispensed anti-histamines and inhalers which offered some relief, but not solving the problem. Three grams mixed with olive oil and it was an overnight success - though confounded with taurine and NMN, but these would only likely have been causative synergistically. Anyhow, it was subsequently pointed out in the thread that fisetin suppresses mast cell activation.
I'd forgotten, though, that the waking apnea went too, and red wine had stopped making me cough, which it had done regularly for at least 15 years. It may have occurred since but not so that it has been recollected.
I had noticed too over the last couple of years not experiencing too much trouble with candida. This was especially surprising since although I have taken coconut oil and caprylic acid acid from time to time, I hadn't done so prolonged or intensely. Poor diet and alcohol intake has increased signifcantly over the past couple of years, with next to no fasting, yet there has been no signifcant resurgence. So I wondered, perhaps if fisetin had something to do with it.
Well, I found a couple of studies linking candida to poor outcomes in obstructive sleep apnea (I used to have a problem here too and, noting the study, poor dental health) and COPD mortality and reccurrence.
Is there a link between candida and mast cell activation?
Well,
https://www.ncbi.nlm...les/PMC5812373/
"Overall, these studies indicate that mast cells can influence innate immune responses against bacterial and fungal infections via multiple mechanisms. Importantly, the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, hence highlighting the complexity of mast cell biology in the context of innate immune responses.
As for the red wine, it has been recommended to avoid alcohol while trying to eliminate candida, though I haven't been able to find something substantial and specific to the red.
The following post-fisetin day with the coughing 90% abated, I decided to test for said vin rouge, which always set it off. The inebriation was cough-free and cannot recall an incident since, there has perhaps been the occasional sign of candida and the kind of brain fog I used to experience seems to have staved off considerably. But I supplemement intermittently more with zinc, magnesium and iron now, while the former has been shown to regulate histamine. One interesting study, and I appreciate this probably needs its own thread, but since it is quiet, shows that when deprived of zinc the candida cells become stressed and form goliath cells. ZInc is dumped in order to fight off the infection, so supplementing, one assumes would be a bad idea with candida overgrowth, though initially perhaps it might make our zinc depleted selves feel good.
Anyhow, on to the interesting stuff - this a fabulous entry on the anti-fungal mechanisms of flavanoids. The flavanoid modes of fungal attack are quite impressive:
- Inhibition of efflux pumps - Efflux pumps are transporters present in most living cells, including fungi; they have the noteworthy function of removing toxic substances from the fungal body. This transporter can detoxify a fungal cell through the removal of a drug being accumulated. The high efflux pump’s expression can lead to drug-resistance. Hence, inhibiting the efflux pumps is a crucial aim for reducing drug resistance.
- Inhibition of cell division - The inhibition of cell division generally causes inhibition of microtubule polymerization, which inhibits the mitotic spindle formation.
- Inhibition of RNA/DNA division or protean synthesis - The antifungal agent generally enters into the cell through active transport that reaches into the nucleus, and thus inhibits DNA, RNA, and protein synthesis. The inhibition of protein synthesis is well-recognized as an antifungal target............ Carvacrol, a chalcone extracted from Lavandula multifida L. that inhibits the nucleic acid synthesis and disrupts the cellular cytoplasmic membrane, eventually causes apoptosis in various candida species
- Plasma membran disruption - The ergosterols are a vital component for the manufacturing of cell membranes. Antifungal drugs normally inhibit the ergosterol biosynthesis, and the cell membrane’s integrity is perhaps disrupted, leading to leakage of intracellular components. This inadequate formation or disruption of the plasma membrane leads to a lesion or membrane permeability changes
- Mitochondrial disfunction - Inhibition of the mitochondrial electron transport chain (ETC) leads to diminishing membrane potential. This inhibition generally takes place in the ETC by inhibition of proton pumps, which reduces ATP synthesis, and thus, cell death......quercetin, resveratrol, and curcumin modulate mitochondrial functions by inhibiting oxidative phosphorylation through various mitochondrial enzymes, or by changing the generation of ROS in mitochondria and by modulating the activity of transcription factors which control mitochondrial proteins’ expression. All these compounds exhibit pro-apoptotic functions, mediated by the ability to discharge of cytochrome c from mitochondria, or indirectly by upregulating pro-apoptotic proteins of Bcl-2 expressions and downregulating anti-apoptotic proteins
- Inhibition of cell wall formation - The cell walls of fungi are primarily composed of β-glucans and chitin. The antifungal mechanism has been based on cell wall deformation which is caused by the inhibition of the synthesis of those compounds....... The antifungal process is achieved based on the cell wall deformation which includes the remarkable decreasing of cell size and increasing membrane permeability. Similarly, glabridin treatment enhances the expression of various genes in C. glabrata which participate in the fragmentation of DNA (chromatin condensation) resulting in apoptosis.
So I am rather forced to conclude, that the high dose of fisetin likely killed off candida overgrowth, which in turn was causing a chronic hsitamine response and many zinc deficiency symptoms I appear to have developed over the years.
Fisetin, quercitin and curcumin are three flavanoids which we know to be senolytics and so the sciency lay question that follows in light of reading the flavanoids' impressive antifungal assault range is, are some, any of these, the potential mechanisms through which fisetin et al act as a senolytic? Are the flavanoid senolytic mechanisms known? It would seem pretty likely, Unity's DME drug, for example, removes sensescent cells through blocking proteins. It would make sense that some of the mechanisms known to attack fungus, would be triggering apoptosis in sensecent cells - given it is already known some flavanoids are deleterious to those cells.
It would seem too reasonable to assume those mechanisms that would work against senescent cells can be used synergistically with other compounds/drugs - I'm assuming the inhibiting cell division line of attack would be one to rule out ! It might seem quite reasonable, I'd have thought, that some of these flavanoids which may not be effective at triggering apoptosis on their own, could be used in combination with other flavanoids or drugs. There would seem to be considerable grounds for experimentation with the flavanoids. If I recall correctly Dastanib + Quercitin were shown to be synergistic.
nb I did experience significant candida symptoms with the Turnbuckle's Alzheimers Protocol, which should be done with real care, with the likely breaking up of candida plaques, which may have contributed to some of the remission; however, the symptom relief from fisetin was instantaneous and independent.
Edited by ambivalent, 22 September 2022 - 06:21 PM.
.){kind=link}
