A Case For High ROS, Antioxidants Are Useless And Potentially Harmful!

[Obi-wan]

Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism

Abstract
Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose-stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans.

Summary and conclusion
ROS are produced as a consequence of normal mitochondrial energy metabolism. When transiently and/or moderately increased, ROS can activate signaling pathways involved in cellular adaptation to various types of (metabolic) stress. One of these pathways is the stimulation of glucose uptake. When ROS levels are too high and/or remain increased during a prolonged period of time, a vicious circle of ROS-stimulated glucose uptake and glucose-stimulated ROS production can be triggered. This pathological cycle can be broken by restoring mitochondrial ROS production to normal levels. We presented three major mechanisms that, in principle, can lower mitochondrial ROS production: (1) reducing glucose uptake, (2) increasing lactate secretion and (3) depolarization of Δψ. Unfortunately, these mechanisms have also been associated with increases in ROS and/or appear to be not effective in all experimental models. Undesirable side effects include reduced NADPH production during reduced glucose uptake, a high rate of lactate secretion potentially inducing lactic acidosis and induction of mitochondrial dysfunction and apoptosis by (high-magnitude) and/or prolonged Δψ depolarization. We conclude that cellular glucose metabolism and mitochondrial ROS production are coupled by various signaling mechanisms, which need to be controlled by the cell to avoid oxidative stress. A more detailed understanding of how these pathways interact with mitochondrial ROS production, endogenous antioxidant systems and mitochondrial/cellular function is required to explain why oxidative stress induction still appears to contribute to pathology induction in humans (e.g., diabetes, cancer, mitochondrial dysfunction).

Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism

Great explanation @Mito on glucose generating ROS. Maybe even higher than beta oxidation. It also shows how complicated the process is. Also a higher metabolism will generate higher ROS (in my chart above) but then use a powerful antioxidant system to avoid oxidative stress The question is what came first, the pathology or the oxidative stress induction. Obvious answer is the pathology. The cells will use acute ROS to kill the pathology then temper the ROS with its antioxidant system. But why take external antioxidants to dampen the acute cycle then keep ROS steady state at a higher level as shown in the graph I posted above.

This was interesting " In general, if ROS levels exceed a certain threshold, they will impair OXPHOS complexes and further stimulate ROS production (Galloway and Yoon 2012). In the light of the above, it is not surprising that increased ROS levels, although not always oxidative stress, are observed during various pathological conditions. For example, primary fibroblasts derived either from CI deficient mice or patients show increased ROS levels, but no obvious signs of oxidative stress (Koopman et al. 2007; Valsecchi et al. 2013; Verkaart et al. 2007a, b). Increased ROS levels also have been observed in multiple types of cancer (e.g., prostate, colorectal, ovarian, pancreatic, breast, liver, bladder, melanoma, glioma), neurogenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease) and during insulin-resistance and diabetes"

 

[sunraiser]

I like blueberries as a more pragmatic example of this sort of process, although this is only a hypothesis as there could be unknown compounds in blueberries that act on things I / other humans don't understand.

They're foods that are rich in polyphenols (antioxidants), providing only a little fibre and almost no energy or other nutrients.

On a personal level I simply don't crave them all the time. Some days they're pleasant and other days they're completely unappealing. Just like everything else they're used on an as needed basis.

I don't think anything that occurs in the body is purely a negative and obi wan's post above would make logical sense to me.

Anecdotally again, I simply don't crave large amounts of vitamin C or vitamin E rich foods - maybe occasional pistachios or the odd avocado.
I own a vitamin E supplement but have never actually taken it as my cravings simply aren't often going in that direction; despite more pufa intake than most of you.

Reductionist thinking isn't often useful, but it seems to completely infest the world of health and nutrition (and especially medicine!).

 

[jb116]

Just wanted to add saturated fats increase ROS when coupled with sugar/carbs. They used to look at this as some kind of insulin resistance caused by SFA but turns out it's not only protective for that but also regulates glucose uptake. I believe somebody posted about this.

 

[Obi-wan]

If there are oxygen species, it means that oxygen is present but it's not being used properly. Cancer cells produce more of those than a normal cell, and one of the reasons for the antioxidant upregulation is in response to such stress. So even though the glutathiod ratio reflects the tendecy towards reduction, it's a high-everything situation.

But the main focus should be on nourishing the body, not on stressing the tumor. I guess we can't deal with advanced cancer using flower petals, but what you're trying to accomplish by limiting those nutrients can in fact contribute to a more reducing environment of the cell because there can't be adequate function without them, oxygen likely being diverted.

They can indeed weaken the effect of chemotherapy, but most of the material available on reduced glutathione and resistance to such therapies seem so fixated on destroying the tumor that they appear to neglect that there might a taxed body harboring it.

Acetoacetate should be helpful, I assume because it oxidizes NADH and relieves such state of cells, and it will reflect on the ratio of reduced to oxidized glutathiod.

The podophile (not to be confused with pedophile, I already commented that I'm not into that anymore) here is confused by the usefulness of pyruvate because of the following:
- Considering the role of pyruvate in tumor cells during hypoxia
What am I missing?

Glucose and Beta Oxidation generate Pyruvate via PDH. Acetal CoA starts the Krebs cycle and citrate starts the ETC. By product of the ETC is ROS. ROS is not an "if" It is a normal part of the ETC and keep in check via the antioxidant system for cell signaling and to avoid oxidative stress. Cancer is a pathology with defective metabolism, DNA, RNA, etc. A primitive form of a cell that uses fermentation to survive (PDK and LDH to generate Lactate). It also uses OXPHOS for high ROS but tempers it with the antioxidant system to keep the oxidative stress from destroying itself.

It amazes me that we think of supplements as the holy grail. I have a great balanced diet and eat good food so getting all of the nutrients that my body needs. But I have a pathology called advanced prostate cancer that's smart and uses the redox system to advance its agenda. Pyrucet uses Ethyl Acetoacetate (@SB4) hopefully to create cell apoptosis by shifting the ratio of GSH/GSSG toward its oxidized state and hopefully create the oxidative stress to kill the cancer via its own generation of ROS and in my case Chemo also since I need to bring my PSA down.

 

[Obi-wan]

I like blueberries as a more pragmatic example of this sort of process, although this is only a hypothesis as there could be unknown compounds in blueberries that act on things I / other humans don't understand.

They're foods that are rich in polyphenols (antioxidants), providing only a little fibre and almost no energy or other nutrients.

On a personal level I simply don't crave them all the time. Some days they're pleasant and other days they're completely unappealing. Just like everything else they're used on an as needed basis.

I don't think anything that occurs in the body is purely a negative and obi wan's post above would make logical sense to me.

Anecdotally again, I simply don't crave large amounts of vitamin C or vitamin E rich foods - maybe occasional pistachios or the odd avocado.
I own a vitamin E supplement but have never actually taken it as my cravings simply aren't often going in that direction; despite more pufa intake than most of you.

Reductionist thinking isn't often useful, but it seems to completely infest the world of health and nutrition (and especially medicine!).

Per Wikipedia "The diverse structures and uncertain metabolic fate of phenolic compounds following digestion prevent understanding about their potential health effects. Specifically, because the presumed antioxidant role of polyphenols in vivo cannot be established, the US Food and Drug Administration (FDA) issued labeling guidance to manufacturers that polyphenols cannot be mentioned as antioxidant nutrients unless physiological evidence exists to verify such a qualification and a DRI value has been established.[54][56] Further, because purported health claims for specific polyphenol-enriched foods remain unproven,[57] health statements about polyphenols on product labels are prohibited by the FDA."

Are they really antioxidants? Or pro oxidants...

 

[Obi-wan]

I like blueberries as a more pragmatic example of this sort of process, although this is only a hypothesis as there could be unknown compounds in blueberries that act on things I / other humans don't understand.

They're foods that are rich in polyphenols (antioxidants), providing only a little fibre and almost no energy or other nutrients.

On a personal level I simply don't crave them all the time. Some days they're pleasant and other days they're completely unappealing. Just like everything else they're used on an as needed basis.

I don't think anything that occurs in the body is purely a negative and obi wan's post above would make logical sense to me.

Anecdotally again, I simply don't crave large amounts of vitamin C or vitamin E rich foods - maybe occasional pistachios or the odd avocado.
I own a vitamin E supplement but have never actually taken it as my cravings simply aren't often going in that direction; despite more pufa intake than most of you.

Reductionist thinking isn't often useful, but it seems to completely infest the world of health and nutrition (and especially medicine!).

Just read this read:How Glutathione Can Save Your Life

Talk about reductionist thinking!

 

[sunraiser]

Just read this read:How Glutathione Can Save Your Life

Talk about reductionist thinking!

I think a lot of it comes down to making either a product or idea marketable. If you create a distinct notion or entity for "good" it becomes far easier to sell.

Good guys vs bad guys is a very relatable and low level idea that won't require time or energy investment from the consumer to understand.

One of the great downfalls of unregulated capitalism is that it gives unimaginable power to branding, so much so that it no longer matters if a product is doing good. As long as it isn't doing noticeable short term bad and people BELIEVE it's helping then the social good of a product or business no longer matters - capital can still be generated.

As for the blueberries, whatever they're doing for me (pro or antioxidant) is not something my particular body needs on a daily basis. Therefore it's probably neither wholly good nor bad, merely situational.

There are big chunks of physiology research that identify trends in pathologies of sick people, and then use the correlation to presume compounds that reduce those factors common to sickness will cure the person. But often they're protective, and as always it's far more complex.

Complexity and nuance unfortunately don't increase the bottom line though, unless the bottom line is wisdom and human progress.

 

[Obi-wan]

I think a lot of it comes down to making either a product or idea marketable. If you create a distinct notion or entity for "good" it becomes far easier to sell.

Good guys vs bad guys is a very relatable and low level idea that won't require time or energy investment from the consumer to understand.

One of the great downfalls of unregulated capitalism is that it gives unimaginable power to branding, so much so that it no longer matters if a product is doing good. As long as it isn't doing noticeable short term bad and people BELIEVE it's helping then the social good of a product or business no longer matters - capital can still be generated.

As for the blueberries, whatever they're doing for me (pro or antioxidant) is not something my particular body needs on a daily basis. Therefore it's probably neither wholly good nor bad, merely situational.

There are big chunks of physiology research that identify trends in pathologies of sick people, and then use the correlation to presume compounds that reduce those factors common to sickness will cure the person. But often they're protective, and as always it's far more complex.

Complexity and nuance unfortunately don't increase the bottom line though, unless the bottom line is wisdom and human progress.

Promoting antioxidants has been a HUGH marketing success! Especially if done via reliable sources??? We are all aware of fake news, how about fake science...the more health conscious you are the more you gobble up fake science as I did in all of my years...

 

[Captain_Coconut]

Per Wikipedia "The diverse structures and uncertain metabolic fate of phenolic compounds following digestion prevent understanding about their potential health effects. Specifically, because the presumed antioxidant role of polyphenols in vivo cannot be established, the US Food and Drug Administration (FDA) issued labeling guidance to manufacturers that polyphenols cannot be mentioned as antioxidant nutrients unless physiological evidence exists to verify such a qualification and a DRI value has been established.[54][56] Further, because purported health claims for specific polyphenol-enriched foods remain unproven,[57] health statements about polyphenols on product labels are prohibited by the FDA."

Are they really antioxidants? Or pro oxidants...

Plant polyphenols mobilize endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: A putative mechanism for anticancer properties
https://febs.onlinelibrary.wiley.com/doi/full/10.1016/j.febslet.2005.12.059

 

[Amazoniac]

Hey amazoniac, how would you recomend getting acetoacetate, I assume you are not referring to ketosis, ethyl/methyl acetoacetate? Or something else?

I was referring to it because Zeus' product containing it was mentioned.

Glucose and Beta Oxidation generate Pyruvate via PDH. Acetal CoA starts the Krebs cycle and citrate starts the ETC. By product of the ETC is ROS. ROS is not an "if" It is a normal part of the ETC and keep in check via the antioxidant system for cell signaling and to avoid oxidative stress. Cancer is a pathology with defective metabolism, DNA, RNA, etc. A primitive form of a cell that uses fermentation to survive (PDK and LDH to generate Lactate). It also uses OXPHOS for high ROS but tempers it with the antioxidant system to keep the oxidative stress from destroying itself.

It amazes me that we think of supplements as the holy grail. I have a great balanced diet and eat good food so getting all of the nutrients that my body needs. But I have a pathology called advanced prostate cancer that's smart and uses the redox system to advance its agenda. Pyrucet uses Ethyl Acetoacetate (@SB4) hopefully to create cell apoptosis by shifting the ratio of GSH/GSSG toward its oxidized state and hopefully create the oxidative stress to kill the cancer via its own generation of ROS and in my case Chemo also since I need to bring my PSA down.

Obi, a reductionistic view is one that prioritizes the tumor to the detriment of the rest of the body. I know your dealing with a real threat, but I still doubt that the solution is to deplete the body of such nutrients because they're needed for proper function of all cells, and many are probably already depleted of them. This doesn't mean that it's desirable to shove them down.

Cruciferous vegetables have some anti-cancre properties. One of their classic effects is through oxidative stress and the benefits appearing when the body responds to it by increasing glutathione production.

Out of curiosity (not to be taken seriously):

- A Cancer Therapy By Max Gerson - Selected Parts

I think there are approaches that are more sophisticated (such as acetoacetate) because they don't add more stress to the story, they work by clearing the way for the affected tissue to revert to normal.

Reductionist thinking isn't often useful

Same for exclusively oxidationist thinking.

 

[Mito]

Glucose and Beta Oxidation generate Pyruvate via PDH.

Pyruvate only comes from glucose, but both glucose and beta oxidation (and amino acids) generate Acetyl CoA.

Acetal CoA starts the Krebs cycle and citrate starts the ETC.

The electron carriers that carry elections into the ECT are generated after citrate in the Krebs cycle.

 

[sunraiser]

Same for exclusively oxidationist thinking.

Yep, but whatever role, known or unknown, antioxidants and prooxidants are playing in our bodies we can include foods that have properties that don't go far beyond that particular thing (berries are the best example I have) and allow cravings to dictate what we do and don't need.

I think this thread provides good balance and lets people get out of any boxes they might potentially have been stuck in.

I only posted because it interested me and brought up an overarching point that's so consistently neglected on here, although probably not by you specifically.

I'm in no way well versed enough to give obi advice on which direction his specific situstion should take. Also I don't think a person should avoid antioxidant(?) rich foods if they're craving them. Supplements are another story, though.

 

[Amazoniac]

Obi! Is you restricting methionid? Because if not, it makes no sense to be so careful with those nutrients while providing plenty of substrate for glutathione synthesis:

- Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer?

 

[Obi-wan]

Obi! Is you restricting methionid? Because if not, it makes no sense to be so careful with those nutrients while providing plenty of substrate for glutathione synthesis:

- Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer?

Eggs have the highest methionine content

 

[Obi-wan]

And then we have Lapodin for higher ROS β-Lapachone-induced reactive oxygen species (ROS) generation mediates autophagic cell death in glioma U87 MG cells. - PubMed - NCBI

"Reactive oxygen species (ROS) were involved in β-lapachone-induced autophagic cell death of U87 MG glioma cells, because β-lapachone induced ROS production"

Also Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent. - PubMed - NCBI

"beta-lapachone-induced ROS formation and cancer cell killing"

And Induction of apoptosis by beta-lapachone in human prostate cancer cells. - PubMed - NCBI

"These results suggest that beta-lapachone is a potential compound to be added to cancer chemotherapy, particularly for prostate cancer."

I stopped taking Niacinamide as per @haidut "niacinamide protects from the excessive ROS" Amazing Medicinal Properties Of Beta-lapachone (β-lapachone)

 

[Obi-wan]

Pyruvate only comes from glucose, but both glucose and beta oxidation (and amino acids) generate Acetyl CoA.View attachment 12448

The electron carriers that carry elections into the ECT are generated after citrate in the Krebs cycle.View attachment 12449

Thanks for the correction

 

[Obi-wan]

Another case for Beta-lapachone https://onlinelibrary.wiley.com/doi...-0045(19970901)32:4<284::AID-PROS9>3.0.CO;2-J

"the angiogenesis inhibitor, linomide, and a plant extract, β‐lapachone, demonstrate very promising apoptosis‐inducing effects on prostate cancer cells in a proliferation‐independent manner"

 

[Obi-wan]

From @LeeLemonoil

10. Beta-lapachone, a compound found in the bark of the South American Lapacho tree, is a potent activator of the NQO1 protein and produces ROS in cancer cells, but reduces ROS in non-cancer cells. It also inhibits pathological retinal neovascularization, but does not inhibit physiological neovascularization.

The most exciting thing about NQO1 is that there is a natural, cheap, compound found in the tree bark of a South American tree. The compound is called beta-Lapachone and is a NQO1 activator. Specifically, NQO1 is a “two-electron transfer” enzyme that can extinguish free radicals in normal cells, but produces free radicals in cancer cells. It has been shown to be a very effective compound for treating lung cancer. Here is how it works:

• Beta-lapachone undergoes a redox cycle by NQO1, which reduces beta-lapachone to an unstable semiquinone. The semiquinone then rapidly undergoes a two-step oxidation back to the parent stable compound, beta-lapachone. This produces what is called a “perpetuating futile redox cycle”. This results in an unbalance of intracellular reactive oxygen species in cancer cells, resulting in the cell death of the cancer cells. This “perpetual futile redox cycle” is totally dependent on the concentration of NQO1 within cells. Here is a diagram of the reaction:

Illustration reference: 2014 The Chemotherapeutic Effects of Lapacho Tree Extract: β-Lapachone

The downstream effects of perpetual futile redox cycling include 4 apoptotic pathways and one necroptotic pathway:

1. Mitochondrial-induced apoptosis – The induction of ROS in mitochondria opens the MPTP pores and results in PARP activation and caspace activation. This induces apoptosis.
2. ER-induced apoptosis – The induction of ER stress induces sarcoplasmic release of calcium which induces high levels of cytoplasmic Ca++. This also induces apoptosis via the ER.
3. DNA-damage mediated apoptosis – beta-lapachone also induces Topoisomerase I and II. The activation of topoisomerases induces DNA breaks, which induces PARPs. This PARP hyper-activation induces apoptosis independently from mitochondrial ROS or ER stress.
4. Cell cycle arrest-induced apoptosis – The futile redox cycling of beta-lapachone also induces cycle cycle arrest via the activation of p21, p27, and the phosphorylation of JNK, PI3K, and Akt. This induces cancer cell apoptosis as well.
5. Calpain-induced cell necrosis – Unlike the 4 pathways above, futile redox cycling also induces calcium influx into the cells independently of ER stress. This calcium influx into the cell activates Calpain, which induces cell death by the necrosis pathway, not the apoptosis pathway.

Conclusion: beta-lapachone induces cancer cell death by five different pathways, all dependent on perpetual futile redox cycling which is dependent on NQO1 expression. Here is a diagram that illustrates these 5 pathways:

 

[Inaut]

Beta lapachone is probably the most abundant and/or studied quinone in Pau Darco but there is a total of 16 naptho and anthraquinones found in the bark. It may vary from batch to batch but id assume they all have some anti cancer properties as well. I think isolates are useful but the whole array found in nature is what is intended for us hu-mans. JMO of course

 

[Obi-wan]

Per Wikipedia-

Bioactivation of antitumor agents[edit]
Several anti-tumor agents such as mitosenes, indolequinones, aziridinylbenzoquinones and β-lapachone have been designed be bioactivated by NQO1 from various prodrugs. The high levels of NQO1 expression in many human solid tumors compared to normal tissue ensures their selective activation within tumor cells.[14][15]