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Showing posts with label GSH. Show all posts
Showing posts with label GSH. Show all posts

Friday, 30 August 2019

Cesarian Delivery and Autism – another inconvenient truth?


Brasil is the C-section capital of the world, with rates in the public sector of 35–45%, and 80–90% in the private sector.

A recent study from the Karolinska Institute in Sweden, analysing 61 previous studies, has again shown a connection between birth by Cesarian Section and an increased risk of autism or indeed ADHD. 

C-sections account for just 16% of births in Sweden, but 32% in North America.

This of course prompted a reaction to reassure future mothers that they have nothing to fear, from experts in obstetrics who of course know nothing about the etiology of autism.  Mothers should be reassured, but trashing the study helps nobody.  Instead of a 1% risk of non-trivial autism, it rises to 1.3%. You still have more than a 98% chance of having a neurotypical child, all other factors being equal.  Without a medically necessary C-section, death is a real possibility.

It was a couple of years ago that the Karolinska Institute highlighted the fact that those with severe autism currently have a life expectancy of under 40 years.  Another inconvenient truth.


Association of Cesarean Delivery With Risk of Neurodevelopmental and Psychiatric Disorders in the Offspring 

Question  Is birth by cesarean delivery associated with an increased risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery?
Findings  In this systematic review and meta-analysis of 61 studies comprising more than 20 million deliveries, birth by cesarean delivery was significantly associated with autism spectrum disorder and attention-deficit/hyperactivity disorder.
Meaning  The findings suggest that understanding the potential mechanisms behind these associations is important, especially given the increase in cesarean delivery rates for nonmedical reasons.
Abstract
Importance  Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. 
Conclusions and Relevance  The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted. 
Very many things are known to slightly increase the odds of a person having autism and the more risk factors you have the more severely autistic you may be.  This ranges from maternal stress (anything from experiencing a hurricane, work stress, life trauma) to maternal/paternal age, obesity, gestational diabetes, alcohol/drug abuse, illness during pregnancy etc. This combines with whatever is in the parents’ DNA and random mutations that are bound to occur.    

A more rational reaction might be to investigate further why there might be a link and how you could counter any risk to children born by cesarian section.  You only have to read the existing research, or this blog.

There are 2 very good reasons why there should be a link between autism and C section, both have been covered in this blog.

1.     The microbiome comes from the mother. Science is only recently starting to understand the role of bacteria in health, but we know that it plays a key role in conditioning/calibrating the immune system of babies.  Once the immune system has been calibrated it is set for life.  Early exposure to bacteria is necessary and humans evolved to expect it.  If your immune system is over/under sensitive there will be consequences. Birth via C-section avoids exposure to bacteria in the birth canal, unless the newly arrived baby is “seeded” with bacteria from the mother. Mother’s milk is another key source of transferring the mother’s microbiome to the baby. 

2.     We saw that the birthing hormone Oxytocin plays a key role in triggering the “GABA switch” in new-borns. This is the process which transforms immature neurons with high chloride to mature neurons with low chloride shortly after birth.  During natural birth there is a surge in the hormone Oxytocin that is transferred to the baby, this causes the chloride transporter KCC2 to be further expressed and the “opposing” transporter NKCC1 to fade away.  In many people with severe autism their neurons remain in the immature state their entire life.  Just as you can replace the bacteria transfer lost in birth via C-section, there would be absolutely no reason why you could not replicate the surge in Oxytocin to "flip the GABA switch".

The recent study showed that elective C-sections (where the baby is in perfect health and not distressed) are associated with the elevated risk of both Autism and ASD.

Regular readers of this blog would probably be surprised if C-section did not increase autism prevalence.

The important thing is to acknowledge this likely connection and mitigate it, rather than try and fault the numerous studies that have shown the same effect.

The same of course applies to reducing the very small risk from vaccines, rather than construct new studies in a contrived way to show there is zero risk.   If you can safely and cheaply reduce the risk of a negative reaction to vaccines, why wouldn’t you?  Just follow Johns Hopkins example and give Ibuprofen or Montelukast (Singular) for a few days before and after and remember to never give Paracetamol/Acetaminophen (Tylenol) in response to fever after a vaccine. Paracetamol/ Acetaminophen reduces the body’s key antioxidant GSH just when the baby/child may need its neuroprotection most.

Some conditions are associated with preterm births, a good example is Cerebral Palsy (CP), which is twice as common in babies born very early. CP is rarely genetic and is usually considered to be caused by a complication during pregnancy, birth or shortly thereafter. I think you would find a correlation between C-sections and CP, but in this case I doubt you would find it in elective C-sections.   In other words C-sections do not “cause” CP, but they may be associated with it. The ID/MR often found in CP might be elevated by C-section and, if so, would be treatable.


Conclusion

In order to halt the rise in incidence of the disabling kinds of autism there should be steps taken to reduce some of the very many factors that are driving the increase, albeit each one sometimes by a tiny amount.

This would be a good application of all those thousands of autism research papers, many of which have shown what factors contribute to increased risk, that now sit gathering dust.

We are not at the stage of wide scale gene editing, but many simple steps can be taken today to improve future health.  This does not mean do not vaccinate, or avoid medically necessary C-sections; vaccinations and C-sections have saved millions of lives. But, why would you not want to take a good thing and make it even better?  That is what we humans tend to be good at, like the Swedes and their Volvos.

Perhaps take your C-section with a generous smear of Mum's bacteria and a shot of synthetic oxytocin?  

There will be more on Cerebral Palsy in a later post on D-NAC (Dendrimer N-Acetyl Cysteine). 

                                                               



Wednesday, 14 December 2016

Refining Antioxidant (ROS & RNS) Therapy in Autism -  Selenium and Molybdenum




Today’s post is about further refining antioxidant therapy.

As we saw in a recent post, oxidative and nitrosative stress is a very common feature of autism and is treatable with OTC products.

The cheapest antioxidant, N-acetylcysteine (NAC), looks to be the best one, but there are numerous others with exotic names and equally exotic prices.

Today we just look at selenium and molybdenum.  Selenium was on my to-do list for a long time because it affects some key enzymes call GPX (glutathione peroxodases).
Molybdenum was enthusiastically recommended in a recent comment and this blog has previously touched on Molybdenum Cofactor Sulfurase (MOCOS).

Rather surprisingly, there is a commercial product that contains NAC, Selenium and Molybdenum. 


Selenium and GPX (glutathione peroxodases)

There are eight different glutathione peroxodases, but GPx1, GPx2, GPx3, and GPx4 are all made from selenium.

GPX speeds up the antioxidant reactions that involve glutathione (GSH).

In autism we know that both GSH and GPX are lacking.

We know how to make more GSH, just take some NAC.  But what about the catalyst GPX? 
There may be an equally easy way to increase that. 


Selenium and Thyroid  Enzymes

Selenium is also part of the three deiodinase enzymes D1, D2 and D3.

The active thyroid hormone is called T3, but most of what is circulating in your body is the inactive pro-hormone form called T4.

Deiodinase 1 (D1)  both activates T4 to produce T3 and inactivates T4. Besides its increased function in producing extrathyroid T3, its function is less well understood than D2 or D3.

Deiodinase 2 (D2), located in the ER membrane, converts T4 into T3 and is a major source of the cytoplasmic T3 pool.  It looks like some people with autism may lack D2 in their brain.

Deiodinase 3 (D3) prevents T4 activation and inactivates T3. It looks like some people with autism have too much D3 in their brain.

D2 and D3 are important in homeostatic regulation in maintaining T3 levels at the plasma and cellular levels.


·        In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T3

·        in hypothyroidism D2 is upregulated and D3 is downregulated to increase cytoplasmic T3 levels


Serum T3 levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T3 to maintain homeostasis since T3 and T4 levels may vary by organ.  

It appears that some people with autism may have central hyperthyroidism, meaning in their brain.

Regular readers may recall this post:-


The major source of the biologically active hormone T3 in the brain is the local intra-brain conversion of T4 to T3, while a small fraction comes from circulating T3. 

As evidence derived from in vitro studies suggests, in response to oxidative stress D3 increases while D2 decreases (Lamirand et al., 2008; Freitas et al., 2010).  As we know in the autistic brain we have a lot of oxidative stress.



Furthermore, in ASD, the lower intra-brain T3 levels occur in the

Absence of a systemic T3 deficiency (Davis et al., 2008), most likely due to the increased activity of D3.



So in some autistic brains we have too much D3 which is inactivating T3 and preventing T4 being converted to T3.

Reduced D2 is reducing the conversion of T4 to T3. 

We would therefore want to increase D2 in some autism.

This can be achieved by:-

·        Reducing oxidative stress, which we are already sold on. 

·        We can also potentially upregulate the gene that produces D2 using some food-based genetic therapy. Kaempferol (KPF) appears to work and may explain why broccoli sprout powder makes some people go hyper and some others cannot sleep  



The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF



·        Perhaps low levels of selenium differentially affect the synthesis of D1, D2 and D3?

  

Where does selenium come from? 

We know from Chauham/James that selenium levels are reduced in autism, but we also know that selenium levels vary widely by geography.  

You get selenium from your diet and the level of selenium in the soil varies widely.  It is widely held that most healthy people should have plenty selenium in their diet. 

In the following paper there is an analysis of Selenium status in Europe and the Middle East.
Since we have plenty of Polish readers I have included the chart with the Polish data (on the left).  It shows that Polish people may be a little deficient in selenium.
You can see the level of selenium in Poland is below that needed to optimise plasma GPx activity.
So if you already have reduced GPx activity, because of autism, and you really need to make the most of your limited glutathione (GSH) because you have oxidative/nitrosative stress, then a little extra selenium could be just what the doctor should have ordered.

  

Se is an essential non-metal trace element [3] that is required for selenocysteine synthesis and is essential for the production of selenoproteins [4]. Selenoproteins are primarily either structural or enzymatic [2], acting as catalysts for the activation of thyroid hormone and as antioxidants, such as glutathione peroxidases (GPxs) [5]. GPx activity is commonly used as a marker for Se sufficiency in the body [6], where serum or plasma Se concentrations are believed to achieve maximum GPx expression at 90–100 μg/L (90.01 μg/L as proposed by Duffield and colleagues [7] and 98.7 μg/L according to Alfthan et al. [8]). However, plasma selenoprotein P (SEPP1) concentration is a more suitable marker than plasma GPx activity [9]. Prospective studies provide some evidence that adequate Se status may reduce the risk of some cancers, while elevated risk of type 2 diabetes and some cancers occurs when the Se concentration exceeds 120 μg/L [10]. Higher Se status has been linked to enhanced immune competence with better outcomes for cancer, viral infections, including HIV progression to AIDS, male infertility, pregnancy, cardiovascular disease, mood disorders [2] and, possibly, bone health [11–14].





  




Selenium and NAC for Rats with TBI

Perhaps not surprisingly, selenium and NAC have been found beneficial for Rats unfortunate enough to have sufferred a traumatic brain injury (TBI).




It has been suggested that oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI). N-acetylcysteine (NAC) and selenium (Se) display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties although there is no report on oxidative stress, antioxidant vitamin, interleukin-1 beta (IL)-1β and IL-4 levels in brain and blood of TBI-induced rats. We investigated effects of NAC and Se administration on physical injury-induced brain toxicity in rats. Thirty-six male Sprague–Dawley rats were equally divided into four groups. First and second groups were used as control and TBI groups, respectively. NAC and Se were administrated to rats constituting third and forth groups at 1, 24, 48 and 72 h after TBI induction, respectively. At the end of 72 h, plasma, erythrocytes and brain cortex samples were taken. TBI resulted in significant increase in brain cortex, erythrocytes and plasma lipid peroxidation, total oxidant status (TOS) in brain cortex, and plasma IL-1β values although brain cortex vitamin A, β-carotene, vitamin C, vitamin E, reduced glutathione (GSH) and total antioxidant status (TAS) values, and plasma vitamin E concentrations, plasma IL-4 level and brain cortex and erythrocyte glutathione peroxidase (GSH-Px) activities decreased by TBI. The lipid peroxidation and IL-1β values were decreased by NAC and Se treatments. Plasma IL-4, brain cortex GSH, TAS, vitamin C and vitamin E values were increased by NAC and Se treatments although the brain cortex vitamin A and erythrocyte GSH-Px values were increased through NAC only. In conclusion, NAC and Se caused protective effects on the TBI-induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.

  


  

And now to Molybdenum 

Molybdenum (Mo) is a trace dietary element necessary for human survival.

Low soil concentration of molybdenum in a geographical band from northern China to Iran results in a general dietary molybdenum deficiency, and is associated with increased rates of esophageal cancer.  Compared to the United States, which has a greater supply of molybdenum in the soil, people living in those areas have about 16 times greater risk for esophageal cancer.
So you would not want to have molybdenum deficiency.

Four Molybdenum-dependent enzymes are known, all of them include molybdenum cofactor (Moco) in their active site: sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase, and mitochondrial amidoxime reductase.

Moco cannot be taken up as a nutrient, and thus it requires to made in your body from molybdenum.

If your body cannot make enough Moco you may develop what is called molybdenum cofactor deficiency, which would ultimately kill you. It is ultra rare.

Symptoms include early seizures, low blood levels of uric acid, and high levels of sulphite, xanthine, and uric acid in urine.


When caused by a mutation in the MOCS1 gene it is called the type A variant.

Molybdenum cofactor deficiency may indeed be extremely rare, but MOCS1 is a known autism gene.  Perhaps there exists partial molybdenum cofactor deficiency, which is not rare at all?





Source:-  Identification of candidate intergenic risk loci in autism spectrum disorder



MOCOS (Molybdenum cofactor sulfurase)


Molybdenum cofactor sulfurase is an enzyme that in humans is encoded by the MOCOS gene.

MOCOS sulfurates the molybdenum cofactor of xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1), which is required for their enzymatic activities.

MOCOS is downregulated in autism and is suggested to induce increased oxidative-stress sensitivity, which would not be good.

So it looks like we need a clever way to upregulate MOCOS.

You need adequate molybdenum cofactor (Moco), for which you do need adequate molybdenum.

You need the genes MOCS1 and MOCOS to be correctly expressed.

SIRT1 activation, which is a future therapy for Alzheimer’s, is suggested to increase MOCOS, as may NRF2.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are molecules able to prevent aging related diseases like Alzheimer's, diabetes, and obesity.  There is quite a long list that includes ranges from polyphenols such as resveratrol, the flavonols fisetin, and quercetin also butein, piceatannol, isoliquiritigenin,


Fisetin is found in strawberries, cucumbers and supplements.  In normal animals, fisetin can improve memory; it also can have an effect on animals prone to Alzheimer's.




Here is the excellent French paper on MOCOS:-



With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.  

Lately, a diminished seric expression of glutathione, glutathione peroxidase, methionine and cysteine has been highlighted in a meta-analysis from 29 studies on ASD subjects.45 Along this line, purines and purine-associated enzymes are recognized markers of oxidative stress. ROS are generated during the production of uric acid, catalyzed by xanthine oxidase and XDH.46 Conversely, uric acid is nowadays recognized as a protective factor acting as a ROS scavenger.47, 48 Interestingly, allopurinol, a xanthine oxidase inhibitor, was found efficient in reducing symptoms, especially epileptic seizures, in ASD patients displaying high levels of uric acid.49 However, in our cohort, only 3 out of 10 patients exhibited an abnormal uric acid secretion. It can therefore be postulated that still unknown other MOCOS-associated mechanisms may have a role in the unbalanced stress response observed in ASD OSCs.
Identifying and manipulating downstream effectors of MOCOS will be the next critical step to better understand its mechanisms of action. In parallel, we plan to ascertain some of its upstream regulators. For example, bioinformatic analyses revealed that the promoter region of MOCOS includes conserved binding sites for transcription factors such as GATA3 and NRF2. In addition, other putative interactors, such as the NAD-dependent deacetylase sirtuin-1 (SIRT1), may have a regulatory role on MOCOS expression. Interestingly, these three genes have been associated with ASD, fragile X syndrome, epilepsy and/or oxidative stress.54, 55, 56, 57 In conclusion, our study opens an unexplored new avenue for the study of MOCOS in ASD, and could set bases for the development of new diagnostic tools as well as the search of new therapeutics.

Conclusion

It looks like a little extra selenium may be in order to increase those GPx enzymes that are need to speed up aspects of the antioxidant activity of GSH.

When it comes to molybdenum, things get much more complex. You certainly do not want to be deficient in molybdenum and you do not want Molybdenum cofactor deficiency; you also do not want molybdenum cofactor Sulfurase (MOCOS) mis-expression.

It is fair to say that quite likely there is a problem related to molybdenum that affects oxidative stress in autism; but it is not yet clear what to do about it.  I rather doubt the solution is as simple as just a little extra molybdenum, but it is easy to try.

On the plus side, we see that if you have autism, epilepsy and high uric acid you are likely to benefit from allopurinol, which also seems to help in COPD.

There is nothing new about allopurinol possibly be effective in some autism, as from this 25 year old book, Diagnosis and Treatment of Autism.



Again we see that activating NRF2 looks a good idea, that applies to both autism and COPD.
One thing to note is that NRF2 activators are good for cancer prevention, but if you have a cancer you want NRF2 inhibitors.

NRF2 activators include sulforaphane (SFN), R-alphalipoic acid (ALA), resveratrol and curcumin.  SFN is by far the most potent.  Resveratrol and curcumin have a problem with bioavailability.











Tuesday, 29 September 2015

Is Reductive Stress a common feature of Atypical Autism?







Lay summary:


·        Oxidative injury can be caused by both oxidative stress and the opposite, reductive stress. 

·        Both extremes of redox balance are known to cause cardiac injury

·        Both extremes of redox balance disrupt mitochondria

·        It appears that either extreme of redox balance may occur in autism.


Reductive stress is the opposite of oxidative stress and I am calling it “Atypical Autism” because all the research shows that the great majority of autism and indeed schizophrenia is associated with oxidative stress.


NAC and stereotypy/stimming

Most young children with classic autism exhibit stereotypy/stimming; this kind of obsessive, repetitive behavior can really get in the way of daily life.  You can use the principles of ABA to limit or redirect this behavior, but it turns out that there is a biological cause for it.

Taking NAC (N-acetylcysteine) increases the body’s production of GSH, its main antioxidant.  Once the intake in NAC is high enough to shift the balance between oxidants and antioxidants the stereotypy/stimming stops all by itself.  This does not mean that the child will still not enjoy repetition.

In some children it takes quite a lot of NAC before any effect is visible, one parent mentioned no effect until 1,800 mg a day.  In other people, the effect starts with the first 600mg and just keeps growing before plateauing around 3,000 mg a day.

This variation makes sense; it all depends just how out of balance the oxidants/antioxidants were at the outset.

If you have access to lab testing you would look at the ratio between GSH and GSSG. This would give you a good indication of your Redox balance.


NAC and Nrf-2 Activators making things worse

In a small number of cases NAC and Sulforaphane/broccoli (a Nrf-2 activator) actually makes things worse.  This does not mean more stereotypy/stimming; I think it quite likely that in those people, stereotypy/stimming are not a feature of their "autism",

Worsening autism can be an increase in anxiety.

Anxiety is often a feature of Asperger’s.

Anxiety is not an issue at all in many cases of classic autism.

NAC is itself an anti-oxidant as well as increasing GSH.  

Sulforaphane/broccoli activates Nrf-2 which in turn affects the genes that control the antioxidant response.  If this make things worse, it seems likely that there was no oxidative stress; either redox was in balance or they are already at the other extreme, reductive stress.


Some Science

The summary below is from the following paper




“Whenever a cell’s internal environment is perturbed by infections, disease, toxins or nutritional imbalance, mitochondria diverts electron flow away from itself, forming reactive oxygen species (ROS) and reactive nitrogen species (RNS), thus lowering oxygen consumption.

This “oxidative shielding” acts as a defense mechanism for either decreasing cellular uptake of toxic pathogens or chemicals from the environment, or to kill the cell by apoptosis and thus avoid the spreading to neighboring cells.

Therefore, ROS formation is a physiological response to stress.

The term “oxidative stress” has been used to define a state in which ROS and RNS reach excessive levels, either by excess production or insufficient removal. Being highly reactive molecules, the pathological consequence of ROS and RNS excess is damage to proteins, lipids and DNA. Consistent with the primary role of ROS and RNS formation, this oxidative stress damage may lead to physiological dysfunction, cell death, pathologies such as diabetes and cancer, and aging of the organism.”


But reductive stress also leads to ROS formation


Reductive Stress and Oxidants

Reductive stress can be just as bad as oxidative stress and, very surprisingly, can have exactly the same negative effect on mitochondria (see below)




Abstract

To investigate the effects of the predominant nonprotein thiol, glutathione (GSH), on redox homeostasis, we employed complementary pharmacological and genetic strategies to determine the consequences of both loss- and gain-of-function GSH content in vitro. We monitored the redox events in the cytosol and mitochondria using reduction-oxidation sensitive green fluorescent protein (roGFP) probes and the level of reduced/oxidized thioredoxins (Trxs). Either H2O2 or the Trx reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), in embryonic rat heart (H9c2) cells, evoked 8 or 50 mV more oxidizing glutathione redox potential, Ehc (GSSG/2GSH), respectively. In contrast, N-acetyl-l-cysteine (NAC) treatment in H9c2 cells, or overexpression of either the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) or GCL modifier subunit (GCLM) in human embryonic kidney 293 T (HEK293T) cells, led to 3- to 4-fold increase of GSH and caused 7 or 12 mV more reducing Ehc, respectively. This condition paradoxically increased the level of mitochondrial oxidation, as demonstrated by redox shifts in mitochondrial roGFP and Trx2. Lastly, either NAC treatment (EC50 4 mM) or either GCLC or GCLM overexpression exhibited increased cytotoxicity and the susceptibility to the more reducing milieu was achieved at decreased levels of ROS. Taken together, our findings reveal a novel mechanism by which GSH-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.—Zhang, H., Limphong, P., Pieper, J., Liu, Q., Rodesch, C. K., Christians, E., Benjamin, I. J. Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.


Reductive Stress in Disease





Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production.

However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADP/NADPH and GSH/GSSG. Here we have further explored, using isolated intact and permeabilized cardiac mitochondria and purified NADP-dependent enzymes, how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems.

We show that one of the latter components, thioredoxin reductase 2, is converted into a potent NADPH oxidase during reductive stress, due to limited availability of its natural electron acceptor, oxidized thioredoxin. This finding may explain in part how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury.



Reductive stress: A new concept in Alzheimer’s disease



Reactive oxygen species play a physiological role in cell signaling and also a pathological role in diseases, when antioxidant defenses are overwhelmed causing oxidative stress. However, in this review we will focus on reductive stress that may be defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. This may occur in hypoxia and also in several diseases in which a small but persistent generation of oxidants results in a hormetic overexpression of antioxidant enzymes that leads to a reduction in cell compartments. This is the case of Alzheimer’s disease. Individuals at high risk of Alzheimer’s (because they carry the ApoE4 allele) suffer reductive stress long before the onset of the disease and even before the occurrence of mild cognitive impairment. Reductive stress can also be found in animal models of Alzheimer’s disease (APP/PS1 transgenic mice), when their redox state is determined at a young age, i.e. before the onset of the disease. Later in their lives they develop oxidative stress. The importance of understanding the occurrence of reductive stress before any signs or symptoms of Alzheimer’s has theoretical and also practical importance as it may be a very early marker of the disease.








 Oxidative Shielding

I was surprised that one of the very few papers to mention Reductive Stress is by Robert Naviaux, a well-known autism researcher.  He is the one behind Antipurinergic Therapy and Suramin as a therapy.  I just promoted him to my Dean’s List.




Abstract
In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed “oxidative shielding” response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health

In his paper Naviaux is quite right, it is much better to treat the cause of the oxidative/reductive stress; right now I do not know how to do this.



Oxidants as a therapy?

Most people with autism should avoid oxidants.

They should avoid paracetamol/ acetaminophen/Tylenol, because it depletes the body’s main antioxidant, GSH.  This is the mechanism behind why, at very high doses, it can kill you.  If they put NAC inside Tylenol, people could not use it to kill themselves.

One surprising oxidant that some people use to “treat” autism is MMS a, toxic solution of 28% sodium chlorite.  Is this the reason why there is such a cult therapy for drinking “bleach” to “cure” autism?

The only reason I mention this is that one reader whose child responded negatively to NAC and Sulforaphane had responded very positively to three doses of MMS some years ago.

For people with autism, and apparent reductive stress, I certainly do not suggest drinking bleach, but a few days of paracetamol / acetaminophen, as if you had the flu, might tell you a lot.

For most people with autism, Ibuprofen is a much better choice of painkiller;  it does not deplete GSH.