The American Heart Association alters the natural history of bipolar disorder

l Individuals with bipolar disorder

Mania and periods of hypomania could have become rarer with the recommendations of the American Heart Association to avoid long chain saturated fats. With the decrease in intakes of long-chain saturated fats periods of depression in bipolar disorder lengthen. Individuals with bipolar disorder are now mainly depressed or rapidly cycling. What was bipolar disorder historically is now no longer bipolar disorder. .

Dysregulation of TET enzymes contributes to transgenerational epigenetic inheritance in mice.

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Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate (DEHP) in liver

Yi Wen  1 Saniya Rattan  2 Jodi A Flaws  2 Joseph Irudayaraj  3

Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous industrial pollutant, is a known endocrine disrupter implicated in metabolic diseases. Prenatal DEHP exposure promotes epigenetic multi- and transgenerational inheritance of adult onset disease in subsequent generations (F1-F3). However, the epigenetic toxicity is less understood in the liver. In this study, CD-1 mice were prenatally exposed to 20 μg/kg/day, 200 μg/kg/day, 500 mg/kg/day, or 750 mg/kg/day DEHP from gestational day (GD) 10.5 until birth of pups. Following prenatal exposure, the multigenerational and transgenerational effects of mRNA expression of epigenetic regulators were evaluated in F1, F2, and F3 generation mouse livers at postnatal days (PNDs) 8 and 60. Results showed that DEHP exposed mice livers exhibited significant changes in global DNA methylation levels in all three generations, with the effect being different in F2 after high dosage exposure. Histopathology indicated that DEHP exposure could induce mild damage in F1 livers. The expression levels of DNA methyltransferase 1 (Dnmt1) were significantly changed in both the F1 and F2 generations at PND 8, suggesting that maintenance Dnmt1 plays a major role in the multigenerational effect that occur in the early developmental stages. Additionally, DEHP exposure caused significant changes in ten-eleven translocation methylcytosine (Tet) dioxygenases encoding Tet1 expression in all three generations and Tet2 expression in F3 at PND 60, implicating their contributions in inducing both multi- and transgenerational effects after DEHP exposure in mouse liver. Overall, our results establish that prenatal and ancestral DEHP exposure are critical for epigenetic regulation of DNA methylation in female mouse livers.

The case for autism being biochemically similar to schizophrenia and Alzheimer’s disease

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Aconitase activity was significantly decreased in cerebellums of individuals who had autism. Glutathione levels were decreased in individuals with autism. Glutathione peroxidase activity is decreased in individuals with autism. Homocysteine levels are increased in children with autism. Vitamin D levels are decreased in individuals with autism. Individuals with autism have reduced bone mineral density. Taurine levels are low in a subset of individuals with autism. There are low levels of biotin in patients with autism. Iron deficiency is very common in autism.

See my papers Treatment-resistant schizophrenia: focus on the transsulfuration pathway. and A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway as to how similar biochemical abnormalities are also present in schizophrenia and Alzheimer’s disease. Other posts on this blog are also relevant to biochemical abnormalities found in schizophrenia.

Autism, schizophrenia and Alzheimer’s disease are epigenetic illnesses. Despite various biochemical commonalities between autism, schizophrenia and Alzheimer’s disease there are epigenenetic differences with these epigenetic differences channeling the illnesses in divergent directions. However, with autism, schizophrenia and Alzheimer’s disease being fundamentally similar treatments for autism, schizophrenia and Alzheimer’s disease could be very similar. As there are now no biological treatments for autism treatments currently used in autism and which are partially effective can not now be clearly hooked up to a treatment for schizophrenia.

Social skills interventions is individuals with autism aged 6-21 have shown limited and equivocal effectiveness. Biological treatments for autism are needed.

Opioids can result in euphoria so opioid antagonists would be perfect for individuals with schizophrenia

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Samidorphan is an opioid antagonist. Samidorphan supposedly reduces weight gain that very frequently occurs with olanzapine. ALKERMES INC, a pharmaceutical corporation, concluded that individuals with schizophrenia could benefit from less than normal opioid agonism, which fits right in with the history of the treatment of schizophrenia. Some terrible treatment is somehow or other a boon to individuals with schizophrenia. Olanzapine/samidorphan, with olanzapine being the antipsychotic and samidorphan being the opioid antagonist, combines two pleasure killing drugs in one pill so, of course, olanzapine/samidorphan is a treatment advance for individuals with schizophrenia. Metabolic parameters did not vary between olanzapine and olanzapine/samidorphan and individuals on olanzapine/samidorphan still gain weight. Also a meta-analysis indicates that olanzapine/samidorphan is not effective in reducing weight gain due to olanzapine. LYBALVI, an olanzapine/samidorphan combination, was recently approved by the FDA for the treatment of schizophrenia and bipolar 1 disorder.

The horrors of innocuous biotin

Biotin is synthesized by microorganisms in the gut. Supposedly no one has a deficiency of biotin. I have been arguing that the the sodium-dependent multivitamin transporter (SMVT) which transports biotin is dysregulated.

Given a biotin deficiency the difficulty should be very easy to fix. Biotin is a widely marketed supplement. The RDA for biotin is 30 micrograms per day. Biotin is very frequently sold in 5000 and 10,000 supplemental forms. Taking one of the biotin tablets daily should fix everything. But I do not think this is the case. Fixing a biotin deficiency that has gone on a long time is not easy to fix at all. .

There are five biotin dependent enzymes methylcrotonyl CoA carboxylase which is involved degradation of branched-chain amino acids, propionyl-CoA carboxylase which is also involved in degradation of branched-chain amino acids, acetyl-CoA carboxylase alpha and acetyl-CoA carboxylase beta both of which are involved in the synthesis of fatty acids and pyruvate carboxylase.

The difficulty that arises is that with long term deficiencies of biotin due to dysregulation of the SMVT is that genes for biotin-dependent enzymes can become hypermethylated,. Supplementing with biotin alone no longer fixes the difficulty. A difficulty that should be dirt simple to fix, just go to the grocery store purchase some biotin and take one tablet a day, is no longer easy to fix. The SMVT besides transporting biotin also transports pantothenic acid. Pantothenic acid would have to be supplemented. Branched-chain amino acids would also have to be supplemented.

But the difficulties are even more extreme. Histones at the SMVT locus can become biotinylated which reduces transport by the SMVT. Supplementing with biotin could reduce transport of pantothenic acid by the SMVT via biotinylation of histones at the SMVT locus. How long does biotinylation last? I don’t know. The SMVT also transports iodide. Supplementing with biotin could reduce transport of iodide resulting in hard to diagnose thyroid difficulties.

I think a lot of individuals could have deficiencies of biotin but I am not recommending that individuals start supplementing with biotin. Given individuals are supplementing with biotin 5000 micrograms of biotin would be better than 10,000 micrograms. Very importantly biotin would only be taken once day. Sublingual biotin is avoided. Supplements as an almost invariable rule must be bioavailable in the gastrointestinal tract..

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Increasing magnesium levels in the gut by supplementing with magnesium oxide could increase calcium absorption in the gut

TRPM7

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that increases intracellular calcium levels. TRPM7 is inhibited by magnesium, however, when TRP7 complexes with transient receptor potential melastatin 6 (TRPM6) TRPM7 is insensitive to inhibition by magnesium. A magnesium-enriched diet upregulates messenger RNA of TRPM6 in the colon. Even though TRPM7 in inhibited by magnesium a magnesium enriched diet would not decrease absorption of calcium from the gut as TRPPM6 and TRPM6/7 complexes are not inhibited by magnesium. TRPM6 is highly expressed in the gut. Mutations in TRPM6 are associated with hypomagnesia with secondary hypocalcemia

Magnesium in the gut could have a large effect on calcium absorption in the gut. . Rather than calcium supplementation magnesium oxide supplementation could be the way to address osteoporosis with a mineral. Calcium supplements available in the gut taken with magnesium oxide could result in hypercalcemia marked by spaced out feelings. Supplementing with too much magnesium oxide even when taken without supplemental calcium could also result in spaced-out feelings .That a goal of magnesium supplementation is to increase calcium absorption in the gut once again underlines that minerals to be effective must be bioavailable in the gut. Chelated magnesium supplements, for example, magnesium glycinate, are avoided.

That magnesium can affect calcium absorption is not news, however, calcium is now still very frequently the ‘go to’ ,mineral given a mineral is supplemented for the prevention and/or treatment of osteoporosis. .A search of PubMed using “calcium supplementation” and “‘osteoporosis” turned up 725 hits while a search of “magnesium supplementation” and “osteoporosis” turned up 20 hits. Taurine, vitamin D3 and vitamin K2 MK-7 would also be required to prevent and/or treat osteoporosis..

Mental illnesses – gut-body-brain illnesses

The gut is a staging area, The vagus nerve sends signals to liver and the brain that prep the liver and the brain for soon to be there nutrients. Without the prepping via the gut other parts of the body cannot use nutrients that are delivered. Supplements and/or drinks that are formulated to bypass the gut and/or decrease use of nutrients by the gut upset homeostasis and utilization of key nutrients throughout the body and/or starve the gut of nutrients..

Individuals until very recently in history were tied to the nutrients found in immediate environments in which such individuals lived. Individuals were constrained by environments. Supplement formulations that bypass the gut or drinks that affect absorption of nutrients can apparently but only apparently free individuals from environmental constraints. Soft drinks are sold on the basis of soft drinks imparting a bounce to individuals. Chelated minerals can give a bounce. That bounce is paid for with deleterious effects on long term health and with deterioration in immediate functioning.

Paternal age as a risk factor for schizophrenia points to epigenetics as being involved in inheritance of schizophrenia

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Paternal age is a risk factor for schizophrenia. There is no evidence of deleterious genetic loci in schizophrenia except for some very rare high impact alleles. Genetic loci associated with schizophrenia are common variants which points to such genetic loci conferring increased fitness leading to such genetic loci being conserved. .

Besides there being no evidence of deleterious genetic loci in schizophrenia except for some very rare high impact alleles.there is not enough time in spermatogenesis to accumulate a lot of mutations. For humans, the entire process of spermatogenesis is variously estimated as taking 74 days[8][9] (according to tritium-labelled biopsies) and approximately 120 days[10] (according to DNA clock measurements).

DNA methylation and histone methylation occurs in spermatogenesis. Dysregulation of epigenetic mechanisms could have occurred over time in aged dads resulting is dysregulation of spermatogenesis. This does not answer the question of how methyl marks are not stripped from embryos, however, the circumstantial evidence points to epigenetic dysregulations rather than genetic mutations as being the factor in paternal age which increases the risk for schizophrenia in offspring.