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REDOX, Disease & Evolution – Conclusion – Vitamin C in Sickness & in Health

REDOX, Disease & Evolution – Conclusion – Vitamin C in Sickness & in Health

Although it may seem surprising that humans in antiquity also suffered from the same diseases that are prevalent in today’s high tech world, if we take some time to examine some of the science available, we will understand that REDOX imbalance is behind the cause of disease, past and present.

Many would like to believe that technology, especially 5G could cause inestimable health consequences in the human race.  Is that assumption correct? How could technology like 5G cause cancer when it was not present 1.98 million years ago, when the first evidence of cancer was found in the remains of the hominin, Australopithecus sediba from Malapa. [1]  

I do not doubt technology, including 5G can cause disease, but we need to distinguish direct from indirect cause. A good way to understand this difference is to look at some recent discoveries in science. 

A paper released in August 2019, attracted quite a bit of attention because the authors showed that blue light at 410 nm inhibited the circadian clock PER1 in human skin cells. A brief exposure to 410 nm at 100 J/cm2 reduced PER1 levels. The gene expression of PER1 continued to decline for several hours after the exposure. The authors also observed increased ROS production, DNA damage and increased inflammatory mediators in cell cultures. The conclusion was, blue light caused circadian rhythm disruption in skin cells because it reduced PER1, a clock gene vital to circadian rhythm regulation. [2]

To understand the implications of this successful experiment, we need to understand  “Why” and “How”. Why does blue light inhibit PER1, what is the purpose, if any, for inhibiting PER1; and How is it able to accomplish that effect.  The answers to these questions will bring us one step closer to understanding the role of REDOX in disease and health.

Every reaction in our body has a history that can be traced in evolution. How PER1 reacts under light stimulation is no exception. 

An elegant study published in 2015 revealed that PER1 is cell-autonomous, and controls pigmentation in melanocytes.  The authors found that by knocking down PER1 resulted in the upregulation of melanogenesis, and a significant increase in melanin content.  Well, now that makes a lot of sense, doesn’t it? Exposure to light in the past is from the sun ONLY. And when we are in the sun, we need protection from melanin. That is the reason why we tan.  Light will inhibit PER1, which results in increased melanin synthesis. [3] 

To find the answer as to  HOW light is able to inhibit PER1, we need to look at the frequency used by the authors in the experiment. The researchers used the blue light frequency of 410 nm, which is at the beginning of the blue spectrum, close to the end of the UV-A range. 410 nm is a shorter frequency than the classic 480 nm blue light, and therefore has a higher level of energy.  Having a higher energy state also means that this frequency of light can create more reactive oxygen species in cells. This is the reason why the authors observed DNA damage and increased ROS in the skin cells. That also means, light, by creating ROS controls how circadian clocks like PER1 functions. 

When life first began at the dawn of the Great Oxygenation Event about 2.45 billion years ago, the earth’s atmosphere was changed from a reducing one to an oxidizing one.  The cyanobacteria is a photosynthetic organism that uses light from the sun to create energy, producing oxygen as a ‘by-product’.  During photosynthesis, cyanobacteria also produces hydrogen peroxide. Hydrogen peroxide is a free radical, and too much of it is harmful to any organism. In fact, excess hydrogen peroxide can inhibit electron transport in cyanobacteria. [4]  To adapt, cyanobacteria evolved mechanisms to neutralize hydrogen peroxide. These protective responses evolved into rhythmic cycles that helped it to anticipate light dark cycles and the accompanying hydrogen peroxides created. That is the beginning of the REDOX circadian system of peroxiredoxins.  

Hydrogen Peroxide, the Driver of REDOX signaling and Circadian Rhythm

How does hydrogen peroxide (H2O2) control the inhibition of PER1 in the experiment where researchers exposed skin cells to 410 nm blue light? 

Hydrogen peroxide (H2O2)  is the original signaling molecule in cyanobacteria.  The use of H2O2 as signaling molecule is still evident in prokaryotic bacteria, and all eukaryotes. Humans are no exception. [5]  In humans, hydrogen peroxide modulates the activity of several important transcription factors. One of those is Nrf2, nuclear factor erythroid 2–related factor 2. 

Nrf2 regulates how cells respond to oxidants. Nrf2 is able to sense oxidants like H2O2, and initiates appropriate antioxidant defenses by modulating the expression of antioxidant genes.  [6]  In Feb 2018, a paper was published on the ability of Nrf2 to modulate circadian clock genes, including PER1. NRF2 is activated by hydrogen peroxide. When Nrf2 is activated, Nrf2 modulates gene expression by interacting with specific DNA regions [7]. 

In essence, light, by creating hydrogen peroxide, initiates a chain of REDOX reactions as a result of billions of years of adaptive evolution, to inhibit the expression of PER1.  The inhibition of PER1 causes melanin in skin cells to be increased as a natural protectant. Nature can be rather brilliant, but only when we understand her methods. 

Hydrogen Peroxide is a Double-Edged Sword

Everything in nature has the potential to be a double-edged sword. Hydrogen peroxide is perhaps one of the best examples. Hydrogen peroxide (H2O2) is one of the major mediators in redox signaling. H2O2 can diffuse through cells and tissues as a messenger molecule, initiating cellular effects that changes the shape of cells. H2O2 can induce the proliferation and recruitment of immune cells. [8] It can modify cysteine thiols on redox sensitive proteins including peroxiredoxins. [9]  When H2O2 are sensed by transcription factors in multiple complex pathways, H2O2 exerts its influence in the modulation of gene expressions through reactions with these transcription factors. [10]

That is how bluelight at 410nm was found to inhibit PER1.  By causing increased hydrogen peroxide, which started to function as a signaling messenger, activating Nrf2, the transcription factor, light produced the ultimate effect of increasing melanin content in skin cells through the inhibition of PER1, via the activation of Nrf2 by hydrogen peroxide.  But when hydrogen peroxide concentration exceeds physiological range that is usually under 100 nM in humans, H2O2 no longer functions as a signaling messenger. 

Hydrogen Peroxide and Cellular Damage

Increased levels of hydrogen peroxide is associated with biomolecule damage. When human endothelial cells are exposed to excess H2O2, they showed elevated intracellular calcium concentration and increased calcium release from endoplasmic reticulum. [11]  H2O2 is also capable of targeting DNA, causing single or double-stranded breaks, in addition to DNA cross links. Hydrogen peroxide has been observed to exert both nuclear as well as mitochondrial DNA damage in various types of cells in humans. [12,13] H2O2 is now recognized as cause for aging, inflammation and cancer metabolism and metastasis. [14] 

It is important to remember that hydrogen peroxide is as ancient as the cyanobacteria, which survived all extinction events, and is alive and well today.  Like cyanobacteria, humans evolved successful complex pathways that regulates the homeostasis of hydrogen peroxide. One of the most important systems that was first used by cyanobacteria to regulate hydrogen peroxide and is still conserved across ALL phyla is the REDOX circadian system of Peroxiredoxins. 

Peroxiredoxins in Health & Disease

Peroxiredoxins are now widely accepted to oscillate rhythmically, maintaining a 24-hour circadian rhythm that is temperature-entrainable, and temperature-compensated. [15]  That actually makes a lot of sense because peroxiredoxins first evolved in the cyanobacteria to regulate hydrogen peroxide. Hydrogen peroxide is produced as a result of photosynthesis, which takes place in the presence of light.  So how effective is peroxiredoxins against hydrogen peroxide?

When comparing the more well-known antioxidant systems like glutathione peroxidase and catalase to peroxiredoxins, newer scientific measuring metrics discovered that peroxiredoxins have the ability to reduce more than 90% of hydrogen peroxide in cells. [16]   Peroxiredoxins actually have specific high-affinity binding sites for H2O2, unlike catalase and glutathione peroxidase (GPx), which lack specific binding sites for hydrogen peroxide. [17] The binding reactions under different states of peroxiredoxins are in turn, responsible for the direct regulation of intracellular signal transduction pathways that involve H2O2.  So you can say that the state of the peroxiredoxins will affect how signals of hydrogen peroxide are interpreted by our body. For a review in the basic mechanisms for peroxiredoxin, please read Part 3 of this series, Hearts on Clocks. [18] 

Peroxiredoxins were first discovered in 1989. [19] Its enzymatic processes were definitively identified only in 2000 [20].  There has been a deluge of impressive research on the roles of peroxiredoxins in health and disease. Due to the complexity of the mechanisms involved in the functioning of the six isoforms discovered to date, science has perhaps, more questions than answers, especially in the role of peroxiredoxin in cancer development. 

Cancer & Peroxiredoxins

Since its discovery in 1989, peroxiredoxins are understood to have the ability to protect cells against oxidative DNA damage and reduce genomic instability; they also participate in the regulation of redox signaling generated by hydrogen peroxide and modulate cell differentiation and proliferation, immune response and apoptosis. [21]  

The ability of peroxiredoxins to maintain genomic stability is critical in the understanding of its role in cancer progression. Genomic instability is one of the major hallmarks of cancer. [22]  How do peroxiredoxins maintain genomic stability? As of the end of 2018, scientists believe that a combination of mechanisms employed by peroxiredoxins that can potentially lower mutation rates include oxidant defense, protein homeostasis, redox signaling and the intricate balancing of thioredoxin and thioredoxin substrates. [23]

Cancer cells exhibit an increased production of reactive oxygen species (ROS) like hydrogen peroxide. [24]  Of all the oxidant defense genes that maintain genomic stability, peroxiredoxin 1 has been found to exert the strongest influence in the suppression of mutations in yeast cells. Cells lacking peroxiredoxin 1 exhibit a 5 to 10-fold increase in mutation rates. [25]

However, scientists discovered that the involvement of peroxiredoxins in cancer is not straightforward. 

For example, decreased levels of peroxiredoxin 1 in papillary thyroid carcinomas is associated with a more aggressive clinical outcome. [26]  Whereas in pancreatic cancer, both downregulation and upregulation of peroxiredoxin 4 (PRDX4) have been reported. [27] In prostate cancer, overexpressed  PRDX3 and PRDX4 were found to enhance the rate of cell proliferation. [28] Overexpression of peroxiredoxins, especially PRDX4, has been correlated with metastatic potential in various types of epithelial cancers including breast, ovarian, and lung cancer. [29]  Whereas PRDX4 is significantly downregulated in acute promyelocytic leukemia. [30]

To understand why peroxiredoxins can exhibit such contrasting effects in cancer, we must understand how its functions changes according to its REDOX status.

REDOX & Peroxiredoxins

Scientists have observed both increased or decreased expression of peroxiredoxins in many cancers. Studies in both in vitro and in vivo models have shown that overexpression of peroxiredoxins can either inhibit or promote cancer growth, depending on the specific isoform and the type of cancer involved. [31]  How is that possible?

The six isoforms of peroxiredoxins exist in three states: reduced, oxidized or hyperoxidized. [32]  When peroxiredoxins reduce hydrogen peroxide to water, they become oxidized. These oxidized peroxiredoxins can be regenerated by the thioredoxin system, utilizing NADPH as the source of reducing power. [33]  Generally, the oxidation and reduction of peroxiredoxins are executed in a rhythmic circadian manner, and these distinct oscillation patterns have been observed in archaea, bacteria and eukaryotes. More interestingly, this redox driven rhythm persists in living organisms where the canonical circadian clock is either endogenously absent, or deleted pharmacologically. [34]

If peroxiredoxins are not regenerated back into their reduced state after the cysteine component is oxidized by H2O2, they can be reversibly, or irreversibly INACTIVATED when they are further oxidized by H2O2 into a hyperoxidized state. In the hyperoxidized but more stable state, peroxiredoxins no longer assume antioxidant functions but instead, take on the ability to operate as molecular chaperones, binding partners, enzyme activators and/or redox sensors. [35]

Scientists believe that the hyperoxidation of peroxiredoxins may serve specific functions in the cell, including lowering of cellular toxicity by recruiting chaperones to counteract the accumulation of ubiquitinated-protein aggregates as a result of increased protein misfolding during cellular stress. [36] 

Chaperones, Alzheimer’s & Cancer: The Peroxiredoxin Connection

Cells increase chaperones called  heat shock proteins (HSP) when they are under stress. Cancer cells are observed to significantly upregulate HSPs because these chaperones can promote cell proliferation and inhibit apoptosis pathways. [37]  The activation of HSPs as a response to environmental, physical and chemical stresses limit the consequence of damage, cell death (apoptosis) and assists in facilitating cellular recovery. [38] Excessive accumulation of hydrogen peroxide creates stress in the cells, and heat shock proteins have been observed to be induced by H2O2. [39]  

About six months ago, in February of 2019, a paper was published showing for the first time, that in addition to hyperoxidation, peroxiredoxins can be changed into chaperones to reduce cellular stress when they are exposed to a physiologically relevant amount heat shock proteins. [40] This new observation is critical to the understanding of why and how peroxiredoxins appear to have opposing effects in different cancer cell types. Even though the 2019 experiment was conducted on peroxiredoxins found in mitochondria of the parasite Leishmania infantum, the authors believed that because human mitochondria do not express a high level of HSPs, that peroxiredoxins actually have taken over the crucial function to protect mitochondria proteome during heat shock conditions. [40]  This theory is extremely plausible as both heat shock proteins and peroxiredoxins have similar structures and peroxiredoxins are known to convert to chaperones during oxidative, heat or low pH stresses. [40]

Even though increased chaperones like heat shock proteins and peroxiredoxins can enhance tumorigenesis [41], lack of chaperones is correlated to Alzheimer’s progression. 

The chaperone activity of human peroxiredoxin 2 (hPrxII) has been found to protect against α-synuclein aggregation. Alpha-synuclein have been observed to migrate from the nucleus where they perform critical DNA repair functions and aggregate into the dangerous Lewy bodies [42] when there is excess reactive oxygen species generated by superoxide and hydrogen peroxide. [43]  Yet when hPrxII is converted from their reduced antioxidant form into the hyperoxidized chaperone structures, peroxiredoxins are able to prevent oxygen free radical mediated denaturing and aggregation of alpha-synuclein. [44] 

The dual function of peroxiredoxins as a result of changes in REDOX balance is probably the reason why uric acid has been found in some cases, to be beneficial in Alzheimer’s.  In a first general population-based study involving over 298,000 subjects, gout was found to be inversely associated with the risk of developing Alzheimer’s disease, supporting the highly debated potential of uric acid in neuroprotection. [45]  Yet in my paper, “URIC ACID & VITAMIN C: DEVOLUTION OF EVOLUTION IN A 5G WORLD” [46] I talked in-depth about the extremely high correlation between uric acid and cancer [47], and the various potential mechanisms that could be linked to uric acid and cancer development.   Yet one of the most obvious mechanisms remain unexplored. 

Vitamin C, Uric Acid and Peroxiredoxins: A Tale of REDOX

In humans, uric acid assumes an antioxidant function in plasma. Neutrophils in plasma readily oxidizes uric acid into the reactive free radical urate hydroperoxide. [48] Urate hydroperoxide may be the reason behind uric acid’s association with endothelial and renal dysfunctions, hypertension, inflammation and cardiovascular diseases. [49]   

Peroxiredoxin 2 is the third most abundant protein in red blood cells, because it maintains redox homeostasis in erythrocytes. [50]  Urate hydroperoxide is able to oxidize glutathione and sulfur-containing amino acids. They are also extremely reactive towards thiols in peroxiredoxins.   Urate hydroperoxides have been found to hyperoxidize peroxiredoxin 2 at rates comparable to hydrogen peroxide in red blood cells.  [51] 

When urate hydroperoxides hyperoxidate peroxiredoxins, peroxiredoxins no longer can function as antioxidants.  Uric acid is incapable of reducing superoxide in plasma.  Without adequate reducing agents, superoxide will form even more hydrogen peroxide. Thus the vicious circle of free radical cascade is perpetuated by the inactivation of peroxiredoxins.  In addition, hyperoxidized peroxiredoxins convert into chaperones. We now understand that the presence of chaperones can be a double-edged sword, especially in the context of cancer development. [52,53]

The question to ask is, how does the body maintain redox homeostasis to ensure optimal functioning of peroxiredoxins?  The answer lies with how peroxiredoxins are regenerated or ‘reduced’ in the context of REDOX balance. 

Thiols, NADPH & Peroxiredoxins: The Ascorbic Acid Connection

Peroxiredoxins belong to either the one-Cys or two-Cys enzyme groups. The ‘cys’ components are the redox-active cysteine residues found in peroxiredoxins.  In mammals, there are five 2-Cys peroxiredoxins (PRDX1-5), and PRDX6 is the only 1-Cys peroxiredoxin discovered to date. The regeneration of one-Cys and two-Cys peroxiredoxins are slightly different. 

Until 2017, the understanding was that thiols and the thioredoxin system are used exclusively for the regeneration of peroxiredoxins. The discovery that ascorbate is actually a peroxiredoxin reducing agent for the 1-Cys PRDX6 overturned the existing thiol-specific paradigm. [54]  This discovery also has huge implications for mitochondrial REDOX homeostasis, because PRDX6, peroxiredoxin 6, is highly expressed in mitochondria under duress. Mice bred without PRDX6 were associated with increased mitochondrial generation of H2O2 and mitochondrial dysfunctions. [55].  PRDX6 is also associated with both tumor promotion and tumor suppression. [56] We all know of course, this dual effect is related to REDOX balance.

If you believe ascorbic acid is only critical for the regeneration of 1-Cys peroxiredoxins, I would like to remind you that the thioredoxin system depends on NADPH as the source of reducing equivalents.  In my article “VITAMIN C – SPECIAL EDITION – PRIMORDIAL OCTANE FUEL” [57], I explained how the oxidized form of ascorbic acid, DHA (dehydroascorbic acid) can stimulate the activity of G6PD, the rate-limiting enzyme for NADPH production in the pentose phosphate pathway. This stimulation of G6PD resulted in an impressive 3.3-fold increase in glutathione, due to increased production of NADPH.  [58] An adequate supply of NADPH will ensure that the thioredoxin system can effectively regenerate 2-Cys peroxiredoxins when necessary.

Perhaps with the understanding of how Vitamin C, ascorbic acid and uric acid affects peroxiredoxins, one can begin to appreciate how stressful conditions leading to excess oxidative stress and the accumulation of hydrogen peroxide could be the cause for the various evidences of diseases found in the mummies from antiquity as described in Parts 1, 2, and 3 of this mini-series. 

The Tyrolean Iceman named Ötzi who grew up and lived in different valleys in the southern region of the Alps 5,300 years had major calcifications in the carotid arteries, distal aorta and right iliac artery.  The Egyptian Princess Ahmose-Meryet-Amon also showed evidence of atherosclerosis some 3,500 years ago. The six cases of cancer from 1087 mummies buried between 3000 and 1500 BC at the Dakhleh Oasis in Egypt; and even the extinct hominin, Australopithecus sediba from Malapa, from 1.98 million years ago found with the earliest evidence of cancer, could all be the results of excess oxidative stress, being the true activator of diseases.  

Both the Iceman from the Alps, the Egyptian princess and mummies probably lived under high levels of UV exposure. What would happen if their bodies were depleted of ascorbic acid or other reducing agents like NADPH?  It is not a coincidence that the pentose phosphate pathway is acutely activated in human skin cells when exposed to high stress conditions like UV radiation. [59] Without adequate regeneration, peroxiredoxins may become hyperoxidized, losing their antioxidant functions. Increased uric acid as a result of genetic insulin resistance, or inappropriate diets exacerbated the problem, inactivating peroxiredoxins and increasing oxidative stress, triggering the perfect conditions for inflammation, disease and cancer formation. 

Peroxiredoxins in Disease

If peroxiredoxins under oxidative stress conditions caused disease in antiquity, is it reasonable to assume that the elevation of oxidative stress generated by our modern high tech environment would facilitate even higher levels of disease?  

Scientists seem to think so as the role of peroxiredoxin in different diseases is currently being explored at a feverish pace. Overexpression of PRX4 is found to protect against nonalcoholic fatty liver progression in mouse models. [60]  Peroxiredoxins 1 to 4 are now considered to be effective biomarkers of cardiovascular disease in type 2 diabetes. [61] Peroxiredoxin 6 knockout mice have been observed to develop a phenotype that is remarkably similar to early-stage type 2 diabetes, showing reduced insulin secretion, increased insulin resistance and impaired insulin signaling. [62]

Peroxiredoxin 2 deficiency was found to exacerbate atherosclerosis in mice bred without ApoE (Apolipoprotein E).  Prdx2 is is highly expressed in endothelial and immune cells. Prdx2 is also able to block the increase of H2O2 generated during atherogenic stimulation. Deficiency of Prdx2 led to the accelerated formation of plaque as well as increased expression of vascular adhesion molecules that often results in the development of atherosclerosis. [63]

At this point I would like to conclude this mini-series by emphasizing the importance of REDOX homeostasis as the central focus in anyone’s search for optimal health.  Past history and present understanding shows us that REDOX drives disease and health. It is not inconceivable that humans in the past have always been slightly deficient in ascorbic acid.  Our changing environment now demands even higher levels of ascorbic acid than ever to maintain REDOX homeostasis in the face of man made electromagnetic radiation that is the never-ending source of oxidative stress. 

So I will leave you with my favorite question:  Have you had your AA today?

 

REFERENCES

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Doris Loh

Doris Loh

Doris Loh is an independent researcher and writer specializing in the investigation of familiar and innovative health topics using unique perspectives in traditional and quantum biology. Her training as a classical pianist allows her the freedom to explore concepts and theories with a curiosity that often results in distinctive conclusions. Recent works by Doris are focused on how health and disease are greatly affected by electromagnetic radiation that surround us everywhere we go. Her works on EMF offer insight and solutions to the challenges humans and other living organisms face during this era of change. Major works by Doris include an in-depth series on deuterium, as well as a startling series on the birefringent quantum properties of the major REDOX balancer, Vitamin C (ascorbic acid).

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