Showing posts with label cancer. Show all posts
Showing posts with label cancer. Show all posts

Thursday, 7 February 2019

Pterostilbene for Neuromodulation – worth a look?

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A common criticism of this blog is that it is mainly about prescription drugs rather than OTC supplements.
Today’s post is about a supplement that is highly regarded by our reader Ling.
Pterostilbene is like a super potent version of resveratrol.  

Resveratrol is quite well known and has long been put forward as having some potentially highly beneficial health effects, but in practise it is just too poorly absorbed to have much effect in humans.
Pterostilbene is found in blueberries.  Also found in blueberries is Anthocyanin, which is worth a mention in this post, it is what gives blueberries their colour; very often it is the colour in a food that underlies part of its health benefit. This is why eating a mixed colour diet is a wise idea.
Aronia is extremely rich in anthocyanins and Aronia juice is very common where I live. We even have a bottle of the dark coloured juice in the kitchen.
The purple colour in beetroot is betanin, a so-called betacyanin and may well have anti-Alzheimer’s effects, inhibiting plaque formation.
Anthocyanin is put forward as one reason certain Japanese who eat large amounts of purple sweet potato do not suffer much cancer or dementia and live a very long time.

Today we are mainly looking at pterostilbene, but if you want Anthocyanins, to avoid dementia, just eat blue and purple coloured fruit and vegetables on a very regular basis.
Ling has proposed pterostilbene as a PDE4 inhibitor, but as is often the case, it has numerous other effects, so it would be hard to know which is the main reason it might be therapeutic.  

Known biological effects of Pterostilbene                                                                                   
Here is an excellent graphic that highlights many of the effects of Pterostilbene, other than on PDE4.

The regular readers of this blog will note that the great majority of the above signalling molecules are implicated in autism.

The proposed effects on the brain are highlighted in the next graphic

The source paper is here: -  


Based on the evidence presented, PTE (Pterostilbene) is more bioavailable and better at evoking molecular and functional events than RES (Resveratrol) in vivo

Although clinical trials are underway to assess the effects of RES in diseases such as dementia and AD, pre-clinical and clinical studies on PTE have yet to be conducted. Furthermore, the biological effects of many of the structural analogues of RES and PTE are unknown, and no studies have identified the metabolites of RES or PTE in brain tissues. There is a need for future studies to identify means of enhancing the efficacy and bioavailability of these compounds and to analyse the metabolites of these compounds in thebrain. Altogether, the evidence from a variety of studies strongly suggests the potential of RES and PTE as promising bioactive agents to improve brain health and prevent neurodegeneration

Most research, but not all, concerns aging and dementia. 

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.

Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer's disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

Low-dose pterostilbene, but not resveratrol, is apotent neuromodulator in aging and Alzheimer's disease.

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene                                                                                                        

Effect of resveratrol and pterostilbene on aging and longevity.

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms.

One area of autism research concerns targeting mTOR signalling. This is covered in the paper below

and was the subject of this blog post from 2015

Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.

And finally, PDE4
Inhibiting PDE4 has some very useful anti-inflammatory benefits. It may also improve myelination and indeed cognition.  PDE4 inhibitors are currently used to treat severe asthma and in clinical trials for Multiple Sclerosis (MS) and cognitive enhancement.
There are different sub-types of PDE4.
Inhibiting one of the subtypes has the tendency to make you want to vomit.  This is currently the drawback that limits the use of PDE4 inhibiting drugs.
A selective PDE4 inhibitor is required.
As Ling has found, research does indeed show that pterostilbene is a PDE4 inhibitor.

The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.

The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2',3,5',5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.

Based on Ling’s recommendation, I have ordered some Pterostilbene and I am curious to see its effects. It is another substance that might be helpful for older adults, if not for your case of autism.
It is clear that in most cases resveratrol is a substance whose effect is limited to the test tube rather than humans. As a “super-resveratrol” we should take a closer look at Pterostilbene.
Eating large amounts of fruits, vegetables and berries with anthocyanins and betacyanins is going to do you no harm and does look a way to possibly secure a long healthy future, like those Japanese centenarians in Okinawa.

Tuesday, 1 January 2019

Apple Cider Vinegar (ACV), Phloretin, Phloridzin, Chlorogenic Acid, OAT3, Autism and Colon Cancer

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 2,2diphenyl1picrylhydrazyl and 2,2′azinobis3ethylbenzthiazoline6sulphonic 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, quercetin3Ogalactoside 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.


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.

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. 

Thursday, 2 August 2018

Turmeric/Curcumin – clinically effective in humans after all? SLC6A15 Amino Acid Transporter

Turmeric powder, only in food, modified the SLC6A15 gene

I know that most readers of this blog want to treat autism with supplements and/or diet.
Many supplements and herbal medicines do show promise in the laboratory, when tests are conducted in vitro, but very often when tests are made in humans the results are much weaker, or just not present.  Turmeric/Curcumin is a perfect example; in the test tube it has a wide range of potent benefits, but due to low absorption into humans (bioavailability) it does not show such conclusive results in human studies.
One researcher a while back did send me a study that reviewed all the turmeric/curcumin trials and it concluded that curcumin has no beneficial effect in humans.
In modern medicine anecdotal evidence does not count. Some anecdotes are genuine, but some are coincidence and some are placebo. 

Mini trial of Turmeric at three UK Universities
There is a remarkably good medical program produced by the BBC in the UK, called Trust me I’m a Doctor, where the doctor presenters team up with universities to test practical medical hypotheses.
In one study they took 100 people to assess whether turmeric has any measurable medical benefit. They teamed up with Newcastle University, Leeds University and a clever genetic researcher at University College London (UCL).

They showed that eating turmeric in your food modified a specific gene (SLC6A15) associated with certain cancers, asthma/eczema and depression.
Taking turmeric as a supplement pill or taking a placebo pill had no effect on the gene.
The researcher at UCL was measuring the epigenetic tags attached to the genes. He showed that methylation of this gene was increased by dietary turmeric. Changing the methylation of this gene will change when it turns on/off.
Anecdotally, we know that people who eat a lot of turmeric tend to have less cancer, less asthma and less eczema.
Given that this gene is also associated with depression, you might expect big eaters of turmeric to have either less, or more, depression. Probably nobody has researched this.  

SLC6 Gene Family
It is true that asthma and eczema (atopic dermatitis) are common in people with autism, but variations in the broader SLC6 family of genes are known to affect people with ADHD, Fragile X, Tourette’s and broad autism.
SLC transporters encompass approximately 350 transporters organized into 55 families. The SLC6 family is among the largest SLC families, containing 20 genes that encode a group of highly similar transporter proteins. These proteins perform transport of amino acids and amino acid derivatives into cells. 

In humans, the SLC6 family of transporters defines one of the most clinically relevant protein groups with links to orthostatic intolerance, attention deficit hyperactivity disorder (ADHD), addiction, osmotic imbalance, X-linked mental retardation , Hartnup disorder, hyperekplexia, Tourette syndrome, schizophrenia, Parkinson disease (PD), autism  and mood disorders such as depression, anxiety, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).
This review will focus on the structure-function aspects of the mammalian SLC6 transporters, their regulation by both classical as well as emerging epigenetic/transgenerational mechanisms and what impact these properties may have on disease and the use of biomarkers to detect these proteins in disease states  

The functional impact of SLC6 transporter genetic variation.

Solute carrier 6 (SLC6) is a gene family of ion-coupled plasma membrane cotransporters, including transporters of neurotransmitters, amino acids, and osmolytes that mediate the movement of their substrates into cells to facilitate or regulate synaptic transmission, neurotransmitter recycling, metabolic function, and fluid homeostasis. Polymorphisms in transporter genes may influence expression and activity of transporters and contribute to behavior, traits, and disease. Determining the relationship between the monoamine transporters and complex psychiatric disorders has been a particular challenge that is being met by evolving approaches. Elucidating the functional consequences of and interactions among polymorphic sites is advancing our understanding of this relationship. Examining the influence of environmental influences, especially early-life events, has helped bridge the gap between genotype and phenotype. Refining phenotypes, through assessment of endophenotypes, specific behavioral tasks, medication response, and brain network properties has also improved detection of the impact of genetic variation on complex behavior and disease. 

Amino acids are very important and it is not just that you need them, but you need them in the right place at the right time.
It appears that one of the many effects of defective amino acid/derivative transport into cells is on behaviour.
Improving amino acid transmission is therefore a potential therapy to correct aberrant behaviour, including depression but likely much more. 

Modern clinical trials are often hugely expensive, but as the BBC keeps showing with its TV series, you can carry out very meaningful research without breaking the bank.
You would think that cancer researchers would now look at the modified versions of turmeric that claim higher bioavailability and see if these pills can also modify this cancer gene, since they can easily repeat the UCL laboratory analysis. I doubt this will happen any time soon.
It has long been known that turmeric is not well absorbed, but just one teaspoon a day added to food was enough to modify the gene.
Indians have a low incidence of cancer and a high consumption of turmeric. Turmeric should particularly limit breast cancer.


The above chart, where blue is best, shows India does well, as do some other turmeric eating countries (South Asia and the Middle East). Clearly longevity and quality of healthcare also matter, so beware Africa. Europe, Russia, Argentina, Uraguay, Oz, NZ and North American might want to up their turmeric intake.

We can say that turmeric is a potential epigenetic therapy for at least one important gene (SLC6A15) and possibly more, because turmeric does not just affect methylation. It has several other better documented epigenetic properties. 

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.
Only a few reports have so far investigated the effect of curcumin on DNA methylation. Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of DNMT1 to exert its inhibitory effect on DNA methylation. However, a more recent study showed no curcumin-dependent demethylation, which suggested that curcumin has little or no pharmacologically relevant activity as a DNMT inhibitor. To clarify these contradictions, more research is urgently needed.
Given that 5-azacitidine and decitabine, two FDA-approved hypomethylating agents for treating myelodysplastic syndrome, have a demonstrated ability to sensitize cancer cells to chemotherapeutic agents, it would be worthwhile to explore whether the hypomethylation effect of curcumin can also induce cancer cell chemosensitization. Interestingly, a phase 1 trial with curcumin administered several days before docetaxel in patients with metastatic breast cancer resulted in 5 partial remissions and stable disease in 3 of 8 patients. This unexpected high response might have resulted from the clever sequential delivery of these two agents, which capitalized on and maximized curcumin’s epigenetic activity for cancer treatment.

Docetaxel is a 20 year old chemotherapy drug produced using extracts from the leaves of the European yew tree, perhaps best taken with root (rhizome) of the Asian Curcuma Longa plant. 
The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly. It exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.

Thursday, 12 April 2018

HDAC Inhibitors for which Cancer/Autism?

Most types of autism can be viewed as the miss-expression of a few hundred genes, in some cases this has been caused by an initial defect in just one gene.  These single gene autisms are the ones that are usually studied.

Epigenetics has been covered previously in this blog and can either be made to look ultra-complex, which is the reality, or quite simple. The simple view is that in some people genes are miss-expressed because they have been tagged with heritable and removable markers; these can be wiped away. One type of epigenetic marker can be modified by an HDAC inhibitor or HDI.  
Some medical conditions featured genes turned off when they should be on. For example tumor suppressor gene (and autism gene) PTEN is turned off in the prostate of many males with prostate cancer; a neat therapy would be to switch it back on.  Deacetylation of PTEN by SIRT1 deacetylase and, by HDAC1, can stimulate its activity, so probably a good thing for people with this kind of common cancer.
In some types of autism there is a deficiency of a single protein because one of the two copies of the gene that encodes it does not work (Haploinsufficiency) and a neat therapy would be to make the remaining copy of that gene work harder. When I originally looked at epigenetics I thought it would not be possible to epigenetically tag the good copy of the specific gene, to switch it on. However it seems that we do not need to tag a specific gene, just provide the “post-it” notes and let the body do the tagging.
All this leads to the use of HDIs to treat cancer, leaving the body to figure out the hard part of which genes.  In reality an HDI will change the expression of numerous genes, not just the one(s) you wanted.

Different Colours of Tags
Just as those useful Post-It notes come in multiple colours, epigenetic markers come in different varieties.  This has been well studied in the cancer research.
HDAC1 inhibitors only affect part of the epigenome; there are other modifiers that are required to affect other genes.
In autism, as in cancer, you need to know which genes are miss-expressed and then you can see if an epigenetic therapy exists that covers them.  Put more simply if HDAC1 inhibitors affect only yellow post-its, which cancers/autisms would become treatable?
The more complex explanation regarding different colours of post-its:

“Important epigenetic modifications known to regulate gene expression. a DNA methylation of CpG islands in promoter regions by DNA methyltransferases (DNMT) represses gene activity. Posttranslational covalent histone modifications of lysine (K), arginine (R) or serine (S) residues in the “histone tail” also influence gene expression in different ways. b Histone acetylation (Ac) catalysed by histone acetyltransferases (HAT) is usually correlated to increased gene activity, whereas histone deacetylation caused by histone deacetylases (HDAC) is considered to decrease gene expression, even though histone hyperacetylation not always matches regions of increased gene activity. c Histone methylation (Me) and demethylation by histone methyltransferases (HMT) and histone demethylases (HDM) at lysine or arginine residues show different effects on gene activity depending on number and position of methyl groups. d Histone ubiquitinylation (Ub) at lysine residues alters histone structure and allows access of enzymes involved in transcription. e Histone phosphorylation (P) at distinct serine residues is known to be associated with increased gene expression, and it is also involved in DNA damage response and chromatin remodelling. Phosphorylation at linker histone (LH) H1 is considered to be a signal for the release of histone H1 from chromatin. In general, epigenetic regulation depends on the addition of epigenetic marks by writer enzymes (e.g. DNMT, HMT, HAT) and the removal of these marks by epigenetic eraser enzymes (e.g. HDAC and HDM) as well as epigenetic reader enzymes (not shown in this figure)”

Treating cancer is always going to be more difficult than treating autism because by the time it has been identified a whole cascade of changes is already underway and whereas autism is not degenerative, cancer by definition is. So even a very partially effective cancer drug might be potent enough for autism, or just a tiny dose of an effective cancer drug.

This post is about HDAC1&2 / yellow Post-its 

1.  The Grant Application 

The goal of this study is to discover novel, mechanism-based pharmacological intervention for autism, a devastating neurodevelopmental disorder with no treatment currently. Genetic sequencing has revealed extensive overlap in risk genes for autism and for cancer, many of which are chromatin remodeling factors important for transcriptional regulation, suggesting the possibility of repurposing the anti-cancer drugs targeting epigenetic enzymes for autism treatment. ASDDR LLC and Yan Lab at SUNY-Buffalo propose to jointly investigate the hypothesis that histone deacetylase (HDAC) inhibitors are able to restore the expression of key autism risk factors and induce long-lasting rescue of autism-like behavioral and synaptic deficits. Combined behavioral, biochemical and electrophysiological approaches will be used to address two specific aims. 

Aim 1. To discover HDAC inhibitors that can alleviate autism-like behavioral deficits in autism mouse models. Yan lab screened a number of drugs and found that a brief treatment with the highly potent and class I-specific HDAC inhibitor, romidepsin (Istodax, an FDA-approved anti-cancer agent) at the very low dose, led to dramatic and prolonged rescue of the social deficits in the Shank3-deficient mouse model of autism. To determine whether this pharmacological agent can serve as a tool compound for autism drug development, its therapeutic efficacy and safety will be examined in two different models of autism, Shank3-deficient mice and BTBR mice.

Aim 2. To identify the molecular targets of HDAC inhibitors as benchmarks for the treatment of autism. For the discovery of effective drugs to treat autism, the molecular pathways on which HDAC inhibitors act to alleviate the autism-like behavioral deficits in Shank3-deficient mice need to be understood. We will reveal the potential benchmark, such as actin regulators and NMDARs, as molecular targets of romidepsin. This phase I preclinical study will provide great promise for the discovery of new and effective pharmacological agents to treat the social interaction deficits, a core symptom of autism.

Public Health Relevance

This project is to discover novel, mechanism-based therapeutic strategies for autism. The corporate and academic partners propose to jointly investigate the hypothesis that histone deacetylase (HDAC) inhibitors are able to restore the expression of key autism risk factors and induce long-lasting rescue of autism-like behavioral and synaptic deficits.

2. Study Press Release 

Using an epigenetic mechanism, romidepsin restored gene expression and alleviated social deficits in animal model of autism 
 “The advantage of being able to adjust a set of genes identified as key autism risk factors may explain the strong and long-lasting efficacy of this therapeutic agent for autism.”
BUFFALO, N.Y. — Of all the challenges that come with a diagnosis of autism spectrum disorder (ASD), the social difficulties are among the most devastating. Currently, there is no treatment for this primary symptom of ASD. New research at the University at Buffalo reveals the first evidence that it may be possible to use a single compound to alleviate the behavioral symptoms by targeting sets of genes involved in the disease.

The research, published today in Nature Neuroscience, demonstrated that brief treatment with a very low dose of romidepsin, a Food and Drug Administration-approved anti-cancer drug, restored social deficits in animal models of autism in a sustained fashion.

The three-day treatment reversed social deficits in mice deficient in a gene called Shank 3, an important risk factor for ASD. This effect lasted for three weeks, spanning the juvenile to late adolescent period, a critical developmental stage for social and communication skills. That is equivalent to several years in humans, suggesting the effects of a similar treatment could potentially be long-lasting, the researchers say.
Profound, prolonged effect
“We have discovered a small molecule compound that shows a profound and prolonged effect on autism-like social deficits without obvious side effects, while many currently used compounds for treating a variety of psychiatric diseases have failed to exhibit the therapeutic efficacy for this core symptom of autism,” said Zhen Yan, PhD, professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB, and senior author on the paper.

The study builds on her previous research from 2015. That work revealed how the loss of Shank 3 disrupts neuronal communications by affecting the function of the NMDA (n-methyl-D-aspartate) receptor, a critical player in regulating cognition and emotion, leading to deficits in social preference that are common in ASD.
In the new research, the UB scientists found they could reverse those social deficits with a very low dose of romidepsin, which, they found, restores gene expression and function using an epigenetic mechanism, where gene changes are caused by influences other than DNA sequences. Yan noted that human genetics studies have suggested that epigenetic abnormalities likely play a major role in ASD.
To pursue these promising findings, Yan has founded a startup company called ASDDR, which was awarded a Small Business Technology Transfer grant from the National Institutes of Health last summer for more than $770,000.
Epigenetics in ASD
Many of the mutations in ASD, Yan explained, result from chromatin remodeling factors, which are involved in dynamically changing the structure of chromatin, the complex of genetic material in the cell nucleus that condenses into chromosomes.
“The extensive overlap in risk genes for autism and cancer, many of which are chromatin remodeling factors, supports the idea of repurposing epigenetic drugs used in cancer treatment as targeted treatments for autism,” said Yan.
She and her colleagues knew that chromatin regulators — which control how genetic material gains access to a cell’s transcriptional machinery — were key to treating the social deficits in ASD, but the challenge was to know how to affect key risk factors at once.
“Autism involves the loss of so many genes,” Yan explained. “To rescue the social deficits, a compound has to affect a number of genes that are involved in neuronal communication.”
To do so, the team turned to a type of chromatin remodeler called histone modifiers. They modify proteins called histones that help organize genetic material in the nucleus so gene expression can be regulated. Since many genes are altered in autism, the UB scientists knew a histone modifier might be effective.
Loosening up chromatin
In particular, they were interested in histone deacetylase (HDAC), a family of histone modifiers that are critically involved in the remodeling of chromatin structure and the transcriptional regulation of targeted genes.
“In the autism model, HDAC2 is abnormally high, which makes the chromatin in the nucleus very tight, preventing genetic material from accessing the transcriptional machinery it needs to be expressed,” said Yan. “Once HDAC2 is upregulated, it diminishes genes that should not be suppressed, and leads to behavioral changes, such as the autism-like social deficits.”
But the anti-cancer drug romidepsin, a highly potent HDAC inhibitor, turned down the effects of HDAC2, allowing genes involved in neuronal signaling to be expressed normally.
 “The HDAC inhibitor loosens up the densely packed chromatin so that the transcriptional machinery gains access to the promoter area of the genes; thus they can be expressed,” Yan said.
The rescue effect on gene expression was widespread. When Yan and her co-authors conducted genome-wide screening at the Genomics and Bioinformatics Core at UB’s New York State Center of Excellence in Bioinformatics and Life Sciences, they found that romidepsin restored the majority of the more than 200 genes that were suppressed in the autism animal model they used.
“The advantage of being able to adjust a set of genes identified as key autism risk factors may explain the strong and long-lasting efficacy of this therapeutic agent for autism,” Yan explained. She and her colleagues will continue their focus on discovering and developing better therapeutic agents for autism.  

Full study:-  

HDAC Inhibitors
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are being investigated as possible treatments for cancers, parasitic and inflammatory diseases. 
HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity.
“To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin, and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.[5][6][7] The open chromatin resulting from inhibition of histone deacetylases can result in either the up-regulation or the repression of genes.”

Pitt Hopkins Research
We saw that transcription factor TCF4 (the Pitt Hopkins gene) is also lacking in some MR/ID and schizophrenia. We saw in an earlier post that TCF4 can be upregulated by PKA (protein kinase A) and that this can be achieved using a PDE4 inhibitor as used to treat asthma and COPD. So in theory Daxas should help.
The lack of the TCF4 protein in Pitt Hopkins causes a cascade of other genes to be miss-expressed. The logical thing to do is to correct that miss-expression. 
The Shank3 research is not the first to suggest that HDAC inhibition as a potentially viable therapy. In 2016 the same idea was suggested for Pitt Hopkins and while this is a rare condition, milder dysfunctions of the same TCF4 gene are seen as common in MR/ID and indeed in schizophrenia. So HDAC inhibition may be a viable therapy for many people.

HDACi meds may reverse effects of Pitt Hopkins

In a paper published this week by the journal Cell Reports, Sweatt and his colleagues at the University of Alabama at Birmingham (UAB) report that mice deficient in Tcf4 exhibit impairments in social interaction, vocalization, learning and memory characteristic of PTHS.
The impairments were “normalized” when the mice were given small-molecule drugs called HDAC inhibitors, which alter Tcf4-associated gene expression in the brain. The finding suggests that “broadly acting, epigenetically targeted therapeutics … might be particularly beneficial in PTHS patients,” the researchers concluded.
“We are quite excited by these findings, said Sweatt, a Vanderbilt University-trained pharmacologist who formerly chaired the Department of Neurobiology and directed the McKnight Brain Institute, both at UAB.
“Pitt-Hopkins Syndrome is an orphan disease that has not been extensively studied,” he said. “Having identified one potential avenue for possible therapeutics is an important step forward.”

“Nearly one-quarter of the genes dysregulated in the Tcf4(+/−) mice are also regulated by HDAC inhibition. The strong negative correlation between Tcf4(+/−) and CI-994 DEGs (R2 = 0.72) suggests HDAC inhibition is a viable avenue for correcting a large percentage of transcriptional dysregulation associated with Tcf4 haploinsufficiency.”

Which HDAC Inhibitor?
It should be noted that Romidepsin inhibits both HDAC1 and HDAC2.
There are HDACs numbered 1 through 10.
HDAC inhibitors vary in potency. Below is a chart comparing different HDI drugs in the activation of HIV expression.

In vitro activation of HIV expression by HDAC inhibitors in an in vitro latency model.

The role of diet
I know that many readers of this blog like dietary interventions and do not like drugs.
In cancer I think diet can be preventative rather than therapeutic or curative. Once cancer takes hold you need very potent therapies.
In dementia it looks like diet can be preventative and therapeutic.
In mild ADHD and mild autism it looks like dietary intervention can be sufficient.  
Many flavonoids have mild epigenetic properties. They are unlikely to be potent enough to halt the cascade of changes seen in a runaway cancer, but they may well be chemoprotective, i.e. they prevent cancer developing in the first place.
Since in some autism we only need a relatively mild  effect perhaps flavonoids do have some potential, depending on which genes are miss expressed.

Food containing high amounts of epigenetically active flavonoids

Ǿ mg/100 g
Sources of data
Grapefruit, raw (not specified as to colour) (Citrus paradisi)
aUSDA Database for the Flavonoid Content of Selected Foods: e.g. [193]



Onions, red, raw
aUSDA Database for the Flavonoid Content of Selected Foods: e.g. [193, 194, 195, 196]




Soybeans, mature seeds, raw (all sources)
bUSDA Database for the Isoflavone Content of Selected Foods: e.g. [197, 198, 199, 200, 201, 202]

Spices, parsley, dried (Petroselinum crispum)
aUSDA Database for the Flavonoid Content of Selected Foods: e.g. [196]

Strawberries (including frozen unsweetened strawberries)

aUSDA Database for the Flavonoid Content of Selected Foods: e.g. [204, 205]


Cacao beans
aUSDA Database for the aFlavonoid Content of Selected Foods: e.g. [206]
Tea, black, brewed, prepared with tap water
aUSDA Database for the Flavonoid Content of Selected Foods: e.g. [196, 207, 208, 209]

(−)-Epigallocatechin 3-gallate



Tea, green, brewed, decaffeinated
(−)-Epigallocatechin 3-gallate
aUSDA Database for the Flavonoid Content of Selected Foods:




A good example is EGCG 
In earlier posts on EGCG, being trialed in Spain on Down Syndrome and Fragile X; I was intrigued by the its long-lasting effects: 

For most of the tests (21 of 24) there were no differences between the groups. 
However, in three tests people who'd taken EGCG did better. This improvement lasted for six months after the study ended

Another example is Sulforaphane (sometimes)
It appears that some people taking sulforaphane experience disease changing results, which are likely caused by the epigenetic effects of inhibiting HDAC. 

Summarized Case Reports

A.    Three participants who took SF did not appear to improve during the study. Their parents reported lack of a noticeable effect and were not aware whether their young adults had been taking SF or placebo.

B.     One participant no longer uses SF. However, he improved dramatically while taking it during the study and remained “improved” after the study, suggesting to the study team a possible “epigenetic switch” might have been triggered.
“W is doing fantastic. He really turned into the most relaxed and fantastic child (on sulforaphane). Definitely something great. Helped him a lot. His friends, family, and members at his home all noticed a wonderful change. He is off the sulforaphane and has been since the end of his study in 2012.”
Perhaps Butyrate?  

As interest in the gut microbiome has grown in recent years, attention has turned to the impact of our diet on our brain. The benefits of a high fiber diet in the colon have been well documented in epidemiological studies, but its potential impact on the brain has largely been understudied. Here, we will review evidence that butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, can improve brain health. Butyrate has been extensively studied as a histone deacetylase (HDAC) inhibitor but also functions as a ligand for a subset of G protein-coupled receptors and as an energy metabolite. These diverse modes of action make it well suited for solving the wide array of imbalances frequently encountered in neurological disorders. In this review, we will integrate evidence from the disparate fields of gastroenterology and neuroscience to hypothesize that the metabolism of a high fiber diet in the gut can alter gene expression in the brain to prevent neurodegeneration and promote regeneration.


In general, these data suggest that BT can enhance mitochondrial function in the context of physiological stress and/or mitochondrial dysfunction, and may be an important metabolite that can help rescue energy metabolism during disease states. Thus, insight into this metabolic modulator may have wide applications for both health and disease since BT has been implicated in a wide variety of conditions including ASD. However, future clinical studies in humans are needed to help define the practical implications of these physiological findings.

Clearly HDAC inhibitors are beneficial in some cancer and some autism.
In cancer the dose required is so high there almost inevitably will be some side effects, particularly in people already in poor health.
Hopefully when Dr Yan moves on to trial Romidepsin in her second mouse model, the BTBR model, she will be as successful as with the Shank3 model.
Ultimately, I assume she will trial her low dose Romidepsin as a single dose in humans. I am sure plenty of people will be interested in that, including all the Pitt Hopkins families. Hopefully someone will trial Daxas in Pitt Hopkins (upregulate PKA which then upregulates TCF4).
Dietary HDAC inhibitors include butyrate and sulforaphane. They are much weaker than Romidepsin. Would a very large dose of sulforaphane/butyrate have the potency of a small dose of Romidepsin?
To be effective in autism the HDAC inhibitor would have to freely cross the blood barrier, clearly drugs used to treat brain cancer tick this box.
Vorinostat/Zolinza also looks interesting.
We should not overlook Valproic acid, another HDAC inhibitor. This epilepsy drug can cause autism when taken during pregnancy, but is taken by some children with autism. Unlike Romidepsin and Vorinostat, which are hugely expensive, Valproic acid is cheap.
Continued use of Valproic acid can cause side effects, as seen in the comments section of this blog. A short sharp shock with valproic acid might be different.
I am sure Dr Yan chose Romidepsin for its potency. A small dose of Romidepsin is likely much more effective than a bucket load of broccoli sprouts (sulforophane).  
Just how low a dose is Dr Yan talking about? Recall that Professor Catterall’s  low dose of clonazepam (to modulate alpha3 subunits of GABAa receptors) was so low in humans it has none of the well-known drawbacks of benzodiazepine use (addiction, tolerance etc).
Dr Naviaux’s use of Suramin was long thought to be impractical in humans due to side effects, but now this appears not to be the case.
Back to Dr Yan:- 
Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition
Treatment with the HDAC inhibitor romidepsin lastingly relieves autism-like social deficits in Shank3-deficient mice. The level of global H3 acetylation (Fig. 1a) in the frontal cortex of Shank3+/ΔC mice was significantly lower than that from wild-type (WT) mice. 
 A systemic administration of low-dose romidepsin (0.25 mg/kg, intraperitoneally (i.p.), once daily for 3 d), a highly potent and brainpermeable class I-specific HDAC inhibitor (with nanomolar in vitro potency25) approved by the US Food and Drug Administration (FDA) for cancer treatment26–28, significantly elevated the level of acetylated H3 in Shank3+/ΔC mice, while it had little effect in WT mice. These data suggest that Shank3-deficient mice have an abnormally low level of histone acetylation, which can be restored by romidepsin treatment. 

This dose looks like about one tenth of the used in mice in cancer trials.
In humans, Romidepsin is for intravenous infusion only. Each 10 mg single-use vial of Romidepsin/Istodax costs about $2,800.
Vorinostat/Zolinza costs about $3,800 for 30 capsules.
If the autism effects of a potent HDAC1/2 inhibitor can last for several years in humans, as suggested by Dr Yan, and if the dose is a tenth of the cancer dose, the cost would not seem to be such a barrier.
The open question is the safety profile of Romidepsin at a single low dose in otherwise physically healthy children.

Risk vs Reward
While nobody wants side effects, one has to consider the risk versus the reward. In some single gene types of severe autism it is clear what the outcome with no intervention will be; perhaps that looming outcome warrants taking a bigger risk than someone with mild autism struggling with social difficulties? But then again, perhaps an HDAC1/2 inhibitor might improve social functioning so someone with Asperger’s, or indeed schizophrenia, does not commit suicide?