Antioxidants and Atherosclerosis: Mechanistic Aspects
Round 1
Reviewer 1 Report
The manuscript by Malekmohammad et al describes the role of antioxidants in atherosclerosis, with specific emphasis in the mechanism of action. This is a comprehensive and well-written review, providing descriptions on numerous antioxidant activities. However, it would benefit from some rearrangements that would make it more focused and easier for the reader to follow.
1) A Figure depicting the main atherosclerotic events described in the text would be helpful to the reader
2) Is there any evidence regarding the stages of atherosclerosis that are targeted by the antioxidants described? If so, it would be helpful to also include in a figure
3) While it is important to include information on all antioxidants with different modes of action (enzymatic, non-enzymatic, natural, synthetic), the authors could consider including information for only a few examples per category, preferably selecting ones with more research evidence available. Key points on mode of action of all antioxidants could be provided in a table format. In this way, information provided to the reader will be more focused and easier to follow.
4) Regarding the medicinal plants, please include a brief description on their antioxidant properties. The table included provides their mechanism of action other than antioxidant activity. Which of these medicinal plants exert antioxidant activities? Is there any evidence on the underlying mechanism of this property?
5) A brief description of the main findings from the use of antioxidants in clinical studies would be useful. What were the clinical parameters examined, what drugs were used and how did these fail to protect from atherosclerosis?
6) Since antioxidants have so far failed to produce positive outcomes in atherosclerosis patients, how do the authors envision their future as therapeutic strategies? Would other strategies, (eg lipid lowering or apo-mimetics), that also exert some antioxidant properties hold promise as future therapies?
7) Among the different mechanisms of antioxidants action that are described in the conclusion section, which do the authors believe would be the most promising to target for future therapies?
Minor
1) Please ensure that font size is the same throughout the text
Author Response
Dear reviewer,
The manuscript was revised based on the respective your comments as follows. The changes were highlighted on the manuscript.
Reviewer 1
The manuscript by Malekmohammad et al describes the role of antioxidants in atherosclerosis, with specific emphasis in the mechanism of action. This is a comprehensive and well-written review, providing descriptions on numerous antioxidant activities. However, it would benefit from some rearrangements that would make it more focused and easier for the reader to follow.
Thanks a lot.
1) A Figure depicting the main atherosclerotic events described in the text would be helpful to the reader.
A figure was added in the manuscript.
2) Is there any evidence regarding the stages of atherosclerosis that are targeted by the antioxidants described? If so, it would be helpful to also include in a figure
A figure was added in the manuscript.
3) While it is important to include information on all antioxidants with different modes of action (enzymatic, non-enzymatic, natural, synthetic), the authors could consider including information for only a few examples per category, preferably selecting ones with more research evidence available. Key points on mode of action of all antioxidants could be provided in a table format. In this way, information provided to the reader will be more focused and easier to follow.
A table about information on all antioxidants with different modes of action was added in the manuscript (table 1).
4) Regarding the medicinal plants, please include a brief description on their antioxidant properties. The table included provides their mechanism of action other than antioxidant activity. Which of these medicinal plants exert antioxidant activities? Is there any evidence on the underlying mechanism of this property?
The provided plants all possess antioxidant activity which may contribute significantly to their overall effectiveness. Therefore, the title of the table was changed and corrected in the manuscript. (Title of the table 2. Non-antioxidant potential mechanisms in medicinal plants with antioxidant effects).
5) A brief description of the main findings from the use of antioxidants in clinical studies would be useful. What were the clinical parameters examined, what drugs were used and how did these fail to protect from atherosclerosis?
Clinical studies about the use of antioxidants were added in the manuscript.
6) Since antioxidants have so far failed to produce positive outcomes in atherosclerosis patients, how do the authors envision their future as therapeutic strategies? Would other strategies, (eg lipid lowering or apo-mimetics), that also exert some antioxidant properties hold promise as future therapies?
The use of antioxidants as a therapeutic strategy should be identified with large– scale studies, and if they were not effective, it should be focused on strategies such as lipid lowering or apo-mimetics.
7) Among the different mechanisms of antioxidants action that are described in the conclusion section, which do the authors believe would be the most promising to target for future therapies?
It is not clear which of these mechanisms of antioxidants actions are more effective, but it seems that the use of multiple antioxidants is more effective target for therapies. It was added in the conclusion section of manuscript.
Minor
1) Please ensure that font size is the same throughout the text
It was checked
Best Wishes,
Prof. Mahmoud Rafieian-Kopaei
Reviewer 2 Report
This paper omits many treatments that must be discussed. It then lists a lot of herbs without any discussion of their validity. It does not review surrogate endpoints or hard endpoints for CHD such as carotid IMT, plaque, CAC, MI, CHD etc. Here are only a few of the omissions
1. Diet/ and dietary nitrate : 0.1 mmol/kg of body weight /day. 10
servings of fruits (4)(berries) and vegetables (6) with dark green
leafy vegetables. DASH 2 and Mediterranean diets. Caloric
restriction (12.5/12.5 EE with overnight fast. 30 % protein, 30
% MUFA and omega 3 FA with limited SFA and no trans fat,
minimal refined CHO(50 grams), more complex CHO (40%).
Consume smaller meals more frequently with antioxidants/meal
Minimal caffeine depending on CYP 1A2 status.
2. Vitamin C sustained release : 250-500 mg bid.
3. Vitamin K 2 MK 7 200-1000 mcg per day
4. Polyphenols: 20 grams dark chocolate (>70%), EGCG 500 mg bid or green tea 32 oz/day ( decaffeinated), 6 ounces red wine.
5. Quercetin 500-1000 mg/day.
6. Curcumin 500 mg-1000 mg bid.
7. 2 gram sodium, 10 gram potassium, 1000 mg magnesium /day
8. 500 mg beetroot juice: 45 mmol/L or 2.79 g/L inorganic nitrate/day.
9. Pomegranate seeds: 1/2 cup per day or juice 6 ounces/day.
. BH4 2mg/kg/day with 5 methyl folate 1000 -5000ug
per day with B complex vitamins.
10. R-lipoic acid (RLA) 100 mg per day with biotin 5000
ug/day for GSH (glutathione) and acetyl –L-carnitine 1000 mg/d
(mitochondrial function)
11. NAC(n-acetyl cysteine) 500 mg bid for GSH (glutathione) etc.
12. Whey protein 30-40 grams per day for GSH (glutathione)
13. Niacinamide 500-1000 mg bid for GSH ( glutathione) etc.
14. MSM 500 mg bid
15. Branched chain amino acids ( leucine , valine, isoleucine 4:1:1 ratio)
5000 mg/d
16. D-Ribose 5 grams tid and nicotinomide riboside one per day
17. Phosphatidyl Serine 300-600 mg bid
17. Trans-resveratrol 250 mg per day with grape seed
extract 500 mg bid
18 . Balanced omega 3 FA (DHA, EPA, GLA with gamma delta
tocopherols: 2- 5 grams per day
Plant sterols 2.5 grams per day and sterolins.
Reishi and Shiitake mushrooms: one serving per day.
Vitamin D3 to level of 60 ng/ml.
AGED garlic (Kyolic) CV formulation: 600 mg bid.
Co enzyme Q 10 :100 mg per day to level of 3 ug/dl and PPQ 20 mg/d
Lycopene: 20 mg per day ( supplement, tomato, pink grapefruit, watermelon etc.).
Carnosine 500 mg bid
Berberine 500-1000 mg per day
High quality varied multivitamin and fruit and vegetable extracts
Probiotics: 50 billion CFU per day
This paper needs MAJOR revision before it can be accepted
Author Response
Dear reviewer,
The manuscript was revised based on the respective your comments as follows. The changes were highlighted on the manuscript.
Reviewer 2
Comments and Suggestions for Authors
This paper omits many treatments that must be discussed. It then lists a lot of herbs without any discussion of their validity. It does not review surrogate endpoints or hard endpoints for CHD such as carotid IMT, plaque, CAC, MI, CHD etc. Here are only a few of the omissions
1. Diet/ and dietary nitrate : 0.1 mmol/kg of body weight /day. 10
servings of fruits (4)(berries) and vegetables (6) with dark green
leafy vegetables. DASH 2 and Mediterranean diets. Caloric
restriction (12.5/12.5 EE with overnight fast. 30 % protein, 30
% MUFA and omega 3 FA with limited SFA and no trans fat,
minimal refined CHO(50 grams), more complex CHO (40%).
Consume smaller meals more frequently with antioxidants/meal
Minimal caffeine depending on CYP 1A2 status.
2. Vitamin C sustained release : 250-500 mg bid.
3. Vitamin K 2 MK 7 200-1000 mcg per day
4. Polyphenols: 20 grams dark chocolate (>70%), EGCG 500 mg bid or green tea 32 oz/day ( decaffeinated), 6 ounces red wine.
5. Quercetin 500-1000 mg/day.
6. Curcumin 500 mg-1000 mg bid.
7. 2 gram sodium, 10 gram potassium, 1000 mg magnesium /day
8. 500 mg beetroot juice: 45 mmol/L or 2.79 g/L inorganic nitrate/day.
9. Pomegranate seeds: 1/2 cup per day or juice 6 ounces/day.
. BH4 2mg/kg/day with 5 methyl folate 1000 -5000ug
per day with B complex vitamins.
10. R-lipoic acid (RLA) 100 mg per day with biotin 5000
ug/day for GSH (glutathione) and acetyl –L-carnitine 1000 mg/d
(mitochondrial function)
11. NAC(n-acetyl cysteine) 500 mg bid for GSH (glutathione) etc.
12. Whey protein 30-40 grams per day for GSH (glutathione)
13. Niacinamide 500-1000 mg bid for GSH ( glutathione) etc.
14. MSM 500 mg bid
15. Branched chain amino acids ( leucine , valine, isoleucine 4:1:1 ratio)
5000 mg/d
16. D-Ribose 5 grams tid and nicotinomide riboside one per day
17. Phosphatidyl Serine 300-600 mg bid
17. Trans-resveratrol 250 mg per day with grape seed
extract 500 mg bid
18 . Balanced omega 3 FA (DHA, EPA, GLA with gamma delta
tocopherols: 2- 5 grams per day
Plant sterols 2.5 grams per day and sterolins.
Reishi and Shiitake mushrooms: one serving per day.
Vitamin D3 to level of 60 ng/ml.
AGED garlic (Kyolic) CV formulation: 600 mg bid.
Co enzyme Q 10 :100 mg per day to level of 3 ug/dl and PPQ 20 mg/d
Lycopene: 20 mg per day ( supplement, tomato, pink grapefruit, watermelon etc.).
Carnosine 500 mg bid
Berberine 500-1000 mg per day
High quality varied multivitamin and fruit and vegetable extracts
Probiotics: 50 billion CFU per day
Diet, lifestyle recommendations and balance of nutrients were added in the manuscript.
Best Wishes,
Prof. Mahmoud Rafieian-Kopaei
Round 2
Reviewer 1 Report
