Today’s post is only marginally related to autism, but does again show how some common food products have potential medical benefits.
Where I currently live people have been using apple cider vinegar (ACV) as a home remedy for generations. It is the apple part, rather than the vinegar part that is most interesting. I think they should continue with this home remedy, just be careful not to dissolve the enamel on their teeth.
Rather surprisingly we can link ACV to improving Bumetanide effectiveness in autism and the chemoprotective effect of statins.
I have read so much research about statins, I do take Atorvastatin myself. The only downside is that research shows it does increase fasting glucose levels by about 0.4 mmol/L, exactly why nobody is quite sure.
If you want to further boost the chemoprotective power of statins it seems you may need a little help from something called Phloretin. Phloretin is a phenol that occurs in apples and the leaves of apple trees. Apple cider vinegar (ACV) is rich in Phloretin.
Viability of HCT 116 colon cancer cells 48 hours after treatment with:-
PT = Phloretin
ATST = Atorvastatin
PT+ATST = Phloretin + Atorvastatin
The closer to zero the better the result.
If you want to improve insulin sensitivity and reduce fasting glucose levels it looks like it is the Phloridzin, a close relative of Phloretin, in apple cider vinegar that is useful.
If you want to improve the pharmacokinetics (how a drug is absorbed, distributed, metabolized, and excreted) of bumetanide you may also be able to use apple cider vinegar (ACV). ACV also contains Chlorogenic acid which we we saw in an earlier post inhibits excretion of bumetanide through OAT3 (Organic acid transporter 3). Chlorogenic acid is also found in coffee.
In theory ACV will cause the level of bumetanide in blood to be higher, which might increase the amount that crosses the blood brain barrier and so make bumetanide a more potent autism drug.
One odd proposed benefit of ACV is on GERD/reflux. You might have thought taking an acid would be the last thing that would help.
You would have thought that strong alcohol (also low pH, so very acidic) would also upset people with GERD/esophagitis, but some people I know swear that it is very beneficial.
In the case of GERD/esophagitis rather bizarrely I think it is the acetic acid (low pH) that is the reason why ACV seems to help some people. I think it may help via feedback loops to trick the body into reducing its own acid production.
The drawbacks of Apple Cider Vinegar (ACV)
The acetic acid in apple cider vinegar can damage your teeth and your esophagus. People avoid these problems by diluting ACV in a glass of water and rinsing their mouth with clean water afterwards.
ACV can lower potassium levels and it will lower blood glucose levels, which is good thing for most people, but diabetics would need to take care. Low potassium seems to worsen behaviour and increase sound sensitivity.
The Phloridzin in ACV is likely to reduce appetite, which for most people is a good thing, but for those few who struggle to gain weight it might be an issue.
ACV should lower triglycerides significantly, which might be bad for somebody.
The results of the present study demonstrated that the antitumor efficacy of ATST could be enhanced at a relatively low dosage through the synergistic action with PT, which suggested the potential interaction of statins with other compounds in the food matrix. This interaction affects the efficacy of statins, and may explain the controversial results obtained in prior studies regarding the associations between statin use and the risk of colon cancer-associated mortality (27,28). As the dietary composition is different for each individual, this can result in varying statin efficacy. Conversely, different statins have different antitumor effects. In six colorectal cancer cell lines, including DLD1, HT29, SW620, HCT116, LoVo and colo320, simvastatin and fluvastatin showed strong growth suppressive effects. Atorvastatin demonstrated a relatively weak growth suppressive effect, whereas no growth suppressive effect was observed with pravastatin (29). This may be another reason for the paradoxical results regarding the antitumor effects of statins.
Therefore, the p21 gene may be the potential regulatory target underlying the G2/M phase arrest following the synergistic action of ATST and PT; more in depth future investigations are warranted.
In summary, the present study demonstrated that PT and ATST produce a powerful synergistic interaction in suppressing colon cancer cell growth. This process was accomplished via the synergistic induction of apoptosis and the arrest of the cell cycle at the G2/M checkpoint, which resulted from downregulated cdc2 activation following combined treatment.
Vinegars contain several bioactive compounds that are characterized according to the type of the raw material, such as grape vinegars and apple vinegars. Liquid chromatography coupled to diode array detection and electrospray ionization tandem mass spectrometry was used for identification and quantification of phenolic compounds. Antioxidant properties of vinegars were determined by 2,2‐diphenyl‐1‐picrylhydrazyl and 2,2′‐azino‐bis‐3‐ethylbenzthiazoline‐6‐sulphonic acid assays. Antimicrobial activities of vinegars were examined with an agar disc diffusion method with Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Gallic acid and chlorogenic acid were found to be the major phenolic acids accounting for the largest proportion of the total phenolic acid contents in grape vinegars and apple vinegars. Within the flavonols, quercetin‐3‐O‐galactoside and quercetin were detected as the major compounds in grape vinegars. Apple vinegars were characterized by phloridzin, phloretin and high chlorogenic acid content. Antimicrobial activity results indicated that grape vinegars exhibited higher antimicrobial activity against tested bacterial strains correlated with their higher antioxidant capacity.
In conclusion, gallic acid, tyrosol, protocatechuic acid, caftaric acid, catechin, epicatechin and syringic acid constituted the highest proportion of the total phenolic contents in GV. Chlorogenic acid, phloridzin and phloretin were found to be the major phenolic compounds in AV. With respect to antimicrobial and antioxidant activity results, GV showed higher antimicrobial and antioxidant activity than AV. With regard to phenolic composition of vinegars with their antioxidant capacities, two separate groups were obtained and characterized the vinegars with PCA based on the type of raw material. The results we obtained in this study extend our knowledge about the composition of vinegars obtained from different raw materials consumed in Turkey and allow the consumer to compare vinegar brands with the highest contents of beneficial compounds.
Coffee = chlorogenic acids = 1,3- and 1,5-dicaffeoylquinic acid
Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions
3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids
Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus pmol mg 10 , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.
Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats.
Abstract
Phloridzin is the specific and competitive inhibition of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products. The effect of phloridzin orally doses 5, 10, 20 and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic, urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.
Harvard Medical School vs the BBC?
You might expect when it comes to investigating health claims about apple cider vinegar (ACV) that Harvard would give you the science and the BBC would be just superficial.
While neither actually bother to use google to find what the active constituents of ACV might be, the BBC do actually make a trial in humans and measure the results in a lab.
It looks like if you have high triglycerides, or indeed high blood glucose, ACV is a potentially interesting non-drug therapy.
The guys at Harvard should watch the BBC and try a little harder next time.
Conclusion
Apple cider vinegar (ACV) is one home remedy that now has some science to support it. It is cheap and easy to access.
It is perhaps not relevant to many people with autism, but does show how medicine turns a blind eye to some old treatments that were stumbled upon as being effective hundreds of years ago.
When it comes to chemoprevention, the majority of cancers in males (prostate, colon, esophagus, bladder etc) have been shown in the research to be inhibited by statins. Some people know they have a familial risk of one or more of these cancers, would it not make sense that they be informed about chemoprevention? It is much better to avoid cancer than to have to try to treat it. In colon cancer it appears that phloretin from ACV might even be helpful.
We also saw that people with type 2 diabetes often find the beta cells in their pancreas die and so they stop making insulin, and yet a cheap calcium channel blocker can protect those insulin-producing cells and put off the day that insulin injections are required.
I did actually borrow my “polypill” name for my son’s autism therapy from another polypill that was designed to extend the healthy life expectancy of older people. Their pill has not been a huge success.
What is needed is a personalized polypill, whether it is for people with autism or typical adults from the age of 50.
I imagine, in 50 years time, when your family doctor has your genome on file, you probably will have a personalized little pill to help you minimize the risk of developing preventable disease.
Dear Peter, I have recently stumbled upon the fact that there is a neurotransmitter I have never heard of - Substance P. I have spent just about half an hour so far reading about it, but the buzzwords surrounding it ring so familiar: gut, serotonin, pain sensitivity, microglial activation, glutamate etc. I have never read about any one thing that had so many lets call them ‘google word links’ with autism. As that when you read about the two things, the same words pop up. I will dedicate a lot more time to looking into it, just wondered what your take on it is. I cant recall that you ever mentioned it here.
ReplyDeleteSubstance P receptor antagonists should in theory give pain relief. A lot of money was spent to develop some, but they did not "work" and it looks like researchers just moved on to other work.
DeleteAlso, I have been trying for a few days now to post a comment and it never went through so lets try now: We did an EEG with a local neurologist, an expert on TMS in depression and epilepsy. He wanted ti get a baseline to see whether he would feel comfortable to do TMS for my kid, and he does not have experience with it in the area of autism. The EEG showed what he said was subclinical epileptic signs, but which could as well be signs of a brain maturing as she is just 6.We got 20 mins asleep and 20 mins awake and the results showed ‘sharpened theta waves mostly anterior’ in both states and ‘K complex of irregular morphology’ in asleep state. He advised to repeat the same in 6 months since with this subcli. epi stuff he doesnt feel comfortable doing TMS. If anyone has anything smart to say, please do.
ReplyDeleteSpoiler: acetaldehyde (both endogenous and exogenous metabolite of alcohol metabolism through ADH induction and downstream detoxification through ALDH2 which is also a target of sulforaphane etc etc) is a VTA dopamine potentiator. Now acetaldehyde affects DNA methylation and alter SAM-E/SAH/homocysteine ratios.
ReplyDeleteWhat you see in kids with asd/autism and even myself is that they often eat foods that arent very good for them (think: their food preference feed histamine/candida etc).
http://acetaldehydetoxicity.com/food-products/
https://mthfr-genetics.co.uk/onewebmedia/SAMPLE%20REPORT.pdf <= very detailed graphs how methylation pathways (methionine which is often low in autism and affects mTOR signalling).
Also shows how acetaldehyde affects neurotransmitters and such. In fact asians which often have low ALDH2 genes have more mGluR1 activity.
The effect of ethanol and its metabolites upon methionine synthase activity in vitro.
https://www.ncbi.nlm.nih.gov/pubmed/9590515
"The reported inhibition by acetaldehyde was found to become irreversible over time. Acetaldehyde-induced inhibition of liver methionine synthase activity is thus proposed as the most likely explanation of the reported in vivo effect of ethanol upon methionine synthase."
Also alcohol is an mTOR INHIBITOR!
The actual detoxification effect of the whole SAM-E/SAH/homocysteine/adenosine is what drives glutathione and neurotransmitters synthesis and breakdown.
It doesnt just end there, the whole SAM-E cycle also generates polyamines (through ornithine/putrescine/spermine/spermidine pathways, which are NMDA modulators)
Also SAM-E/SAH ratios alter H3K4 and H3K9 ratios, which affect fyn kinase which obviously control NR2B signalling and is implicated in autism, individuals with deficient fyn kinase signalling was shown to not have amygdala kindling!
Now as if stated before a hangover makes me feel normal (as it feeds all these critical - yet toxic pathways) and this is also the reason why it doesnt induce convulsions in me, my fyn kinase (which are normally surpressed) get activated and nr2b activity in the amygdala comes online and this brings back emotions.
Together with the fact that dehydration from alcohol (and dehydration in genera, yes this also applies to bumetanide), increases nr1/nr2b expression on OXTR and AVP neurons in the hypothalamus).
Im sure this is how bumetanide works and im very excited to see if some scientists will do an animal study of bumetanide on rats/mice their nr2b/oxtra/avp neurons in the brain after bumetanide administration.
Oh yes, one last thing: a few days ago I used 400mg SAM-E it replicates the 'hangover effect' for me by 85-95%.
Once again its not just about feeding SAM-E, its the whole SAM-E/SAH/homocysteine ratios that are out of whack and science has proven that the ratios between these are critical.
For example SAH was shown to bi-directionally modulate KYNA synthesis.
Also SAH is DNMT inhibitor! while SAM-E does the exact oposite.
I will do a big post on the acetate (ketone)/vinegar subject later.
This will cover everything from how the antidepressant effect of sleep deprivation and alcohol hangover has connections with autism/asd.
The milk war between researchers of opposing opinions is definitely not over. Is milk a friend or foe - for whom and when?
ReplyDeleteWhile I won't dig deeper into the subject, I notice that there is an increasing amount of articles on epigenetic effects from milk consumption.
Just an example:
"Major miRNAs of milk, especially miRNA-125b, directly target TP53 and complex p53-dependent gene regulatory networks. TP53 regulates the expression of key genes involved in cell homeostasis such as FOXO1, PTEN, SESN1, SESN2, AR, IGF1R [..] The most abundant miRNA of milk and milk fat, miRNA-148a, directly targets DNMT1. Reduced DNMT1 expression further attenuates the activity of histone deacetylase 1 (HDAC1) [..] Therefore, bioactive miRNAs of commercial milk should be eliminated from the human food chain."
https://www.ncbi.nlm.nih.gov/pubmed/28814964
(This guy has at least three articles on Pubmed with similar anti-milk tendencies).
I am a big fan of milk myself, but I know there are some parents here with children that do better without it. For those of you, maybe take a look at these papers and see if they contain any useful information.
/Ling
Ling,
ReplyDeleteMilk and other foods contain opioid like peptides alter the reward system by influencing the endogenous opioid system.
DNMT is a hot target, Ive been looking into it. The whole methionine cycle is fascinating, it covers everything from mTOR, dnmt, hdac.
It also links to nmda and serotonin by other means, namely methionine directly affects the ratios of quinolinic acid/kynurenic acid/polyamines and the whole lot through the SAM-E cycle.
Now what you see on the rise is obesity and the whole folate cycle disorders (hence the recommendation of most doctors to mothers-to-be to take folate).
Look here, this could be one the reasons how reuteri atcc 6475 might also affect the brain, that is altering folate metabolism:
FolC2‐mediated folate metabolism contributes to suppression of inflammation by probiotic Lactobacillus reuteri
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061717/
What not many people also know is that l-methionine even at small doses can induce hallucinations in people, this shows what a profound impact methionine has on the human brain. On top of that methionine restriction is recommended for anti-aging and and anti-obesity.
2 common used cofactors of methionine metabolism into either throwing it back into recycling of SAM-E are magnesium and you guessed it p5p (requires atp). Now if you look back in history, magnesium and p5p are like the only 2 vitamin/mineral supplements that have an incredibly long history of use in ASD.
nearly all the ATP is magnesium bound, and ATP is needed for the recycle methionine into SAM-E (this happens through methionine adenosyltransferase), which 'steals' the adenosine molecule (yep anticonvulsant effect of keto diet THROUGH ADENOSINE and hdac regulation) of the ATP group AdenosineTriPhosphate - A T P, now in comes supplements such as taurine and sulforaphane, that can act by donating their sulfur molecule to connect the adenosine group to the methionine group.
Other than that exogenous taurine also keeps the glutathione pool high by putting less pressure on the enzymes needed to create it, which also happen downstream.
Now regarding opioid-ergic system, l-methionine also has a profound impact on degradation and synthesis of them. Are endogenous opioids a painkiller cause the methylation cycle fails when they are released? after all they are called for example MET-enkephalin, METhionine enkephalin.
Juvenile treatment with mGluR2/3 agonist prevents schizophrenia:
ReplyDelete"We found that a medium dose of LY37 prevents learning deficits in MAM rats [model of SCZ]. These effects were mediated through postsynaptic mGluR2/3 via improving GluN2B-NMDAR function by inhibiting glycogen synthase kinase-3b (GSK3b). Furthermore, dendritic spine loss and learning and memory deficits observed in adult MAM rats were restored by juvenile LY37 treatment, which did not change prefrontal neuronal excitability and glutamatergic synaptic transmission in adult normal rats"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050107/
Anyone who knows any mGluR2/3 agonists?
/Ling
Ling, NAC does this.
ReplyDeleteNot suprisingly treatments that combine NAC with sarcosine are used a lot by people who are shizo and also effeciency is claimed for anhedonic symptoms.
mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine.
https://www.ncbi.nlm.nih.gov/pubmed/27558879
Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism.
https://www.ncbi.nlm.nih.gov/pubmed/24987341
The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice
https://www.ncbi.nlm.nih.gov/pubmed/20217053
Whats interesting Im having a lot of success with SAM-E which is also needed for the enzyme GNMT (this is responsible for the conversion of glycine into sarcosine).
Another article on the subject of mGluR2/3 agonists:
ReplyDelete"We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-d-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.
(..)
We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3."
https://www.ncbi.nlm.nih.gov/pubmed/26861891
I did not read the whole article, but it does sound promising with something that raises both GABAar and NMDAr. Olanzapine is probably the best antipsychotic for reelin enhancement, so it is interesting that they used it for comparison.
Another line of thought - could this be the reason why NAC doesn't work for some people? That it raises NMDAr, maybe after 8 weeks or so (as Bacopa does).
/Ling
I would Love to hear more on this subject,my 1 year old Great Grandson is showing signs of having autism,the first boy born into our family,I would Love to know of something that will help with his autism,Thank you..Deb
ReplyDeleteDeb, there are 500 posts in this blog all about doing something that will help autism. It is not a simple problem to solve, but the sooner you start the better the outcome will be.
DeleteHi Peter,
ReplyDeleteDr Chez has increased the dosage of Leucovorin to 20mg/day for my son who weighs 60 lb.
The only positive thing I have noticed is that he is able to
swallow pills.I could not teach him that for a very long time.
My son has severe ID.Probably 50-60 IQ along wit autism.So,most of the things that work for others don't work for him.
I will keep you posted.How long do you think I should continue the treatment?It has been 1.5 months
Thanks
SD
SD, in the current clinical trial the dosage used is:
Delete"Dosing will start at 10-20 mg/day, based on subject's weight, and increase to 30-50 mg/day over four weeks ..... participants between > 6.6 and < 12.5 years of age"
The only way to know the "correct" dosage would be to measure folate in spinal fluid, which only very few people actually do. The key thing is to avoid any side effects, like aggressive behavior.
It looks to me that your son is a responder to the low dosage. You might expect a better response at a higher dosage. If he was in the trial, he would be on 30 mg/day.
Did Dr Chez do the folate receptor antibody test?
I think almost everyone with severe autism has severe ID, it is just that often nobody has measured it.
Maybe on your next visit ask Dr Chez to raise the dosage again.
Dr Chez did not do the spinal tap test as the insurance will not cover it for diagnostic purpose. Moreover, he said it is very invasive.I will ask him to increase the dosage next time.Leucovorin is pretty expensive in USA for some reason.
ReplyDeleteI do have the liquid form from iHerb.I can try using that .
Thanks
SD
SD, the US has crazy drug prices. Just look at what diabetics pay for insulin. It is quite disgraceful.
Delete
ReplyDeleteHello
I have been using Verapamil for a week and the change in her mood has been incredible, she complained a lot of itching in her feet and this disappeared
Thanks
Melisa
Melisa, that is great news.
Delete