Glucose as a Major Antioxidant: When, What for and Why It Fails?

aliml

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Abstract​

A human organism depends on stable glucose blood levels in order to maintain its metabolic needs. Glucose is considered to be the most important energy source, and glycolysis is postulated as a backbone pathway. However, when the glucose supply is limited, ketone bodies and amino acids can be used to produce enough ATP. In contrast, for the functioning of the pentose phosphate pathway (PPP) glucose is essential and cannot be substituted by other metabolites. The PPP generates and maintains the levels of nicotinamide adenine dinucleotide phosphate (NADPH) needed for the reduction in oxidized glutathione and protein thiols, the synthesis of lipids and DNA as well as for xenobiotic detoxification, regulatory redox signaling and counteracting infections. The flux of glucose into a PPP—particularly under extreme oxidative and toxic challenges—is critical for survival, whereas the glycolytic pathway is primarily activated when glucose is abundant, and there is lack of NADP+ that is required for the activation of glucose-6 phosphate dehydrogenase. An important role of glycogen stores in resistance to oxidative challenges is discussed. Current evidences explain the disruptive metabolic effects and detrimental health consequences of chronic nutritional carbohydrate overload, and provide new insights into the positive metabolic effects of intermittent fasting, caloric restriction, exercise, and ketogenic diet through modulation of redox homeostasis.
 
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aliml

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What is the strongest antioxidant?​

by Mo.Magnon

Free radicals are a fact of life since our body is constantly exposed to them. Most of those free radicals don't come from the foods we eat but are generated in the metabolic processes within our cells. When our cells are exposed to free radicals they lose electrons. This is known as oxidative stress. Our defense mechanism against oxidative stress is composed of antioxidants which are electron-donating substances such as vitamin C, vitamin E, lipoic acid, coenzyme Q10, and the strongest one of them all - glutathione. The antioxidants in our body don't just act on their own. They are intertwined and "help each other out."

Let's assume there is a fat-soluble free radical somewhere in the body.
  • The fat-soluble vitamin E will jump in to deactivate that free radical by donating an electron.
  • This process now turns vitamin E into a free radical, which will then be mitigated by vitamin C. Now vitamin E is regenerated but vitamin C has turned into the free radical called dehydroascorbate.
  • To get it back into its antioxidant state we need the strongest antioxidant in the body, glutathione. When glutathione donates an electron it will in turn become a free radical known as oxidized glutathione (GSSG).
So where does this antioxidant system come to an end? What is the final electron donor to help glutathione get back to its antioxidant antic state? The answer to that question is, believe it or not, good old glucose. There is a pathway in the cells known as pentose-phosphate-pathway where glucose doesn't get used for energy but instead acts as a building block for the electron donor NADPH. NADPH has many different uses such as steroid synthesis, lipid synthesis and breakdown, cholesterol synthesis, detox reactions, sphingolipid synthesis and to donate electrons glutathione.

This means that antioxidants alone won't help much as long as we don't get enough electrons from adequate amounts of glucose. One of the most important enzymes in the pentose-phosphate-pathway is G6PD (glucose-6-phosphate-dehydrogenase). Without G6PD our red blood cells deteriorate and glutathione can't work properly anymore. The pentose-phosphate-pathway is anabolic_pathway that requires optimal insulin sensitivity to work.

As you can see, glucose is much more than just a simple energy substrate. Everything is about context and balance. Too much glucose in the bloodstream can become very harmful and act as a destructive free radical. But a healthy body needs certain amounts of glucose to maintain its antioxidant pathway system to protect itself from oxidative stress.

The way to health is not to cut out all glucose from your food intake but to become insulin sensitive so that your body can properly handle the glucose and benefit from it instead of being harmed by it. Don't let people with a limited understanding of the body's biochemistry vilify a single substance and tell you that you have to completely cut out that substance.
 

ATP

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So the authors are saying that glucose is a good thing only when it is primarily utilised in the pentose phosphate pathway and not completing glycolysis. This would increase the amount of reducing equivalents and change the redox state of the cell.

They also said "Exercise, caloric restriction, intermittent fasting, a ketogenic diet and some drugs have something in common—in that they deplete organisms’ glycogen stores [44], reduce glucose availability for the cells, restore the physiological redox signaling suppressed by chronic excessive glucose consumption and lead to a dramatic improvement of life- and health-spans in model organisms and humans".

So many people argue that the most desirable state is as many reducing equivalents as possible and don't even entertain the possibility of reductive stress. @haidut What are your thoughts on this?
 

Korven

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So the authors are saying that glucose is a good thing only when it is primarily utilised in the pentose phosphate pathway and not completing glycolysis. This would increase the amount of reducing equivalents and change the redox state of the cell.

They also said "Exercise, caloric restriction, intermittent fasting, a ketogenic diet and some drugs have something in common—in that they deplete organisms’ glycogen stores [44], reduce glucose availability for the cells, restore the physiological redox signaling suppressed by chronic excessive glucose consumption and lead to a dramatic improvement of life- and health-spans in model organisms and humans".

So many people argue that the most desirable state is as many reducing equivalents as possible and don't even entertain the possibility of reductive stress. @haidut What are your thoughts on this?

Yeah cancer cells accumulate NADPH to protect themselves from getting destroyed by ROS:

"A growing body of evidence has shown that regeneration and maintenance of the cellular NADP(H) content is strongly implicated in a variety of pathological conditions, such as diabetes, cardiovascular disease, neurodegenerative diseases, aging,4,5 especially in tumorigenesis and cancer progression.10 Compared with non-tumor cells, tumor cells usually maintain high levels of NADPH, not only to power redox defense but also to use for biosynthetic reactions to sustain their rapid growth.5,11 This realization has prompted molecular studies of NADPH metabolism and its exploitation for the development of anticancer agents. Recent advances have revealed that therapeutic modulation based on NADPH metabolism has been widely viewed as a novel and effective anticancer strategy" NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications - Signal Transduction and Targeted Therapy

Interestingly aspirin blocks the G6PD enzyme, and lowers NADPH synthesis, which could be yet another anti-cancer mechanism of aspirin: Aspirin inhibits glucose‑6‑phosphate dehydrogenase activity in HCT 116 cells through acetylation: Identification of aspirin-acetylated sites - PubMed
 

Korven

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Also, fatty acid oxidation can contribute to NADPH synthesis, so it's not just glucose:

"In addition, FAO pathway is also key for providing NADPH indirectly, which is indispensable in many cancers especially under metabolic stress. FAO generates NADH, FADH2, and acetyl coenzyme A (CoA) in each round,163 and NADH and FADH2 enter the ETC while the acetyl CoA enters the TCA cycle to produce citrate, which is exported to the cytosol to engage in NADPH production through ME1 and IDH1.34 FAO and FAS are both essential for tumor progression and support each other. Acetyl CoA and NADPH accumulated from FAO metabolism in the cytosol are needed to initiate FAS.164 The carnitine palmitoyl transferases (CPT), the rate-limiting enzymes in the FAO pathway, transport long-chain acyl-CoA from the cytosol to mitochondria.165 CPT-mediated FAO activation is reported to play key roles in maintaining NADPH homeostasis and promoting cell metastasis and chemoresistance in gastrointestinal cancer166,167 and melanoma.168 Recent studies also show that knocking down PPAR coactivator 1α (PGC1α), an important transcriptional coactivator regulating CPT1A and CPT1B, obviously decreases the ratio of NADPH/NADP+ and ATP levels, impairing radiation resistance in nasopharyngeal carcinoma (NPC) cells.169 What’s more, AMP-activated protein kinase (AMPK) also regulates the function of FAO in maintaining NADPH homeostasis and promotes tumor cell survival under oxidative stress or metabolic stress.170,171,172,173"
 

ATP

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Yeah cancer cells accumulate NADPH to protect themselves from getting destroyed by ROS:

"A growing body of evidence has shown that regeneration and maintenance of the cellular NADP(H) content is strongly implicated in a variety of pathological conditions, such as diabetes, cardiovascular disease, neurodegenerative diseases, aging,4,5 especially in tumorigenesis and cancer progression.10 Compared with non-tumor cells, tumor cells usually maintain high levels of NADPH, not only to power redox defense but also to use for biosynthetic reactions to sustain their rapid growth.5,11 This realization has prompted molecular studies of NADPH metabolism and its exploitation for the development of anticancer agents. Recent advances have revealed that therapeutic modulation based on NADPH metabolism has been widely viewed as a novel and effective anticancer strategy" NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications - Signal Transduction and Targeted Therapy

Interestingly aspirin blocks the G6PD enzyme, and lowers NADPH synthesis, which could be yet another anti-cancer mechanism of aspirin: Aspirin inhibits glucose‑6‑phosphate dehydrogenase activity in HCT 116 cells through acetylation: Identification of aspirin-acetylated sites - PubMed
That article literally contradicts the other article which advocated for an abundance of NADPH.
 

ATP

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Also, fatty acid oxidation can contribute to NADPH synthesis, so it's not just glucose:

"In addition, FAO pathway is also key for providing NADPH indirectly, which is indispensable in many cancers especially under metabolic stress. FAO generates NADH, FADH2, and acetyl coenzyme A (CoA) in each round,163 and NADH and FADH2 enter the ETC while the acetyl CoA enters the TCA cycle to produce citrate, which is exported to the cytosol to engage in NADPH production through ME1 and IDH1.34 FAO and FAS are both essential for tumor progression and support each other. Acetyl CoA and NADPH accumulated from FAO metabolism in the cytosol are needed to initiate FAS.164 The carnitine palmitoyl transferases (CPT), the rate-limiting enzymes in the FAO pathway, transport long-chain acyl-CoA from the cytosol to mitochondria.165 CPT-mediated FAO activation is reported to play key roles in maintaining NADPH homeostasis and promoting cell metastasis and chemoresistance in gastrointestinal cancer166,167 and melanoma.168 Recent studies also show that knocking down PPAR coactivator 1α (PGC1α), an important transcriptional coactivator regulating CPT1A and CPT1B, obviously decreases the ratio of NADPH/NADP+ and ATP levels, impairing radiation resistance in nasopharyngeal carcinoma (NPC) cells.169 What’s more, AMP-activated protein kinase (AMPK) also regulates the function of FAO in maintaining NADPH homeostasis and promotes tumor cell survival under oxidative stress or metabolic stress.170,171,172,173"
Yeah fatty acid oxidation leads to fatty acid synthesis and slows down the metabolic rate.
 

Korven

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That article literally contradicts the other article which advocated for an abundance of NADPH.

I'm too dumb to make sense of all of this but it's true that NADPH is necessary to protect cells from stress. For instance, individuals with a G6PD deficiency have a higher risk of developing hemolytic anemia because red blood cells are more fragile due to low glutathione. I guess NADPH becomes a problem in the context of excessive reductive stress/hypothyroidism/cancer metabolism as the cancer cells use it as a defence against oxidative stress. Apparently NADPH is also supplied by FAO and is used by cancer cells for fatty acid synthesis.
 

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