Enhancing Bioavailability of Nutraceutically Used Resveratrol and Other Stilbenoids
Round 1
Reviewer 1 Report
Stilbenoids and resveratrol are both hot topics, and there are pretty many research results that can be accessed. This article focuses on the part of "enhancing the bioavailability of resveratrol and other stilbenoids". However, in section 6, which is the most important section to present this article's key issue, the authors summarized the effect of bioenhancers on the bioavailability of resveratrol and oxyresveratrol in both human and animal studies, the discussion about the different conclusions in them is lacking. In addition, for the new methods to improve the bioavailability of stilbenoids, the authors did not make an effort to summarize the results. Instead, the authors quoted a review paper as a reference, which is missing in the article.
The major problem is the English writing, which needs to be further improved to satisfy readers' comprehension. Other minor opinions are listing in the following.
Line 82-83, the description needs to be further confirmed. It is questionable that RES conjugates would appear in the gastrointestinal tract.
Overall, the expression of functions needs to be consistent, for example, antimicrobial or anti-microbial.
Line 194-195 "where resveratrol-4’-O-sulphate forms SULT1E1 and resveratrol-3-O-sulphate forms SULT1A2 and SULT1A3." The sentence does not make sense.
Line 240 wrong spelling: important
It is pretty confusing whether matrix effect exists when compare lines 244-245 and 142-144, 174
Line 251-252 The description "Piperine, which is a potent inhibitor of drug metabolism, is therefore a strong enhancer of absorption". It is not logical that drug metabolism inside the cell (after absorption) would affect the absorption outside.
Figure legend of figure 3 needs to be improved. The first line of the figure legend is suggested to change to "increasing intestinal permeability with (A) Res alone, (B) Quercetin, (C) piperin. As shown….
Author Response
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Author Response File: 
Author Response.docx
Reviewer 2 Report
RES has received considerable attention from both the research community and nutraceutical industry for many years. Many reviews have been published, many very recently. How does this review mirror that of others and stand out to contribute to the literature? This is where it falls short as mentioned It would be suggested to have someone with strong English grammar skills review a manuscript before submitting it for peer review. Examples of grammatical issues that appear frequently early on in the manuscript submission and continue throughout the submission are provided.
Line 30. Would suggest the authors say “the compound, resveratrol.” Otherwise, it reads like it is a botanical plant or product.
Line 31. Suggest “well known for its association in explaining the lower mortality in France compared to the American population”, rather than “starts to be famous due to…”
Line 33. “has” should be“ have”; “amount” should be “amounts”; next line “rate” should be “rate”.
Line 42. “many” not needed.
Line 41 to 53. Suggest removing this section. The manuscript submission is on a compound, not all of the compounds among stilbenoids. Do all of the plant-based foods the authors cite contain stilbenoids? Chocolate does. Is this an example of a food that is healthy given how much refined sugar it contains? The introduction is the author’s opportunity to help the read understand the focus of their review. Not until lines 60-61 is it clear that the manuscript is about resveratrol, not stilbenoids. Yet the compound is not mentioned in this sentence. It should be.
Line 64. Also, to inhibit bacterial growth.
Lines 63 to 67. Here again the question is what is this submission about? It starts discussing stilbenoids at lines 63-64. Why not just start with the resveratrol, a stilbenoid, at the beginning of this paragraph?
Line 66. “presented’ should be “present in foods like the skin…”
Line 67. Awkward grammar. Simply state that Takaoka isolated the compound from…” Do the authors know the scientist’s first name or affiliation? The discover deserves better recognition than just their last name.
Line 73. Suggest removing “great” as it is meaningless unless placed in the context of other molecules. How about “exceptional bioactivity”, but on what specific “biological properties”?
Line 76-77. Suggest removing “in the food industry”? Note the title of the manuscript.
Line 80. “type” should be “types of cells”; “teams” should be replaced by “research groups.”
Line 84. Remove “an” No comma needed after “evidence”
Lines 84-85. The authors should expand upon how it influences circadian rhythm, as well as the “type of meal”. A list of what foods effect its bioavailability graded by impact would be new information that adds to the literature.
Lines 86-87. What at the authors trying to say? Difficult to decipher.
Line 88. It is not clear whether the authors are saying the optimal dose to improve bioavailability, or health benefits, or exactly what, is a dose greater than 100 mg/day? Up to what amount? When does it risk adverse events? What might that be?
Line 89-90. Unless consumed with what? Are there any macro- or micro-nutrients in the diet that would effect solubility in the presence of RES? What can the authors teach the reader that they may not already know by reading the same literature? What discoveries will the reader learn about that is not apparent in reviewing the literature?
Lines 92-94. The authors excluded stilbenoid’s anti-inflammatory properties and in depigmentation. Do all these properties, including the ones mentioned share a common signaling pathway or pathways? If so, that would be helpful to know. If not, state that.
Line 94. No need to use the word “phytonutrient”. The authors established that in the introduction.
Line 95-96. Authors did not make clear that the list of cited activities are based on in vitro studies. It is important to make this distinction, as was done in the next sentence.
Lines 91-105. This is a poorly developed discussion on physiological and therapeutic effects. There is a lot of comingling of in vitro studies that have not demonstrated therapeutic benefits based on experimental evidence in humans, with in vivo studies that may have done so. However, the authors do not provide insights into the degree of evidence that support any such benefits in vivo.
The manuscript lacks evidence of having performed a literature search with the intention of performing a critical review. Otherwise, the authors are simply listing numerous papers that report results. How does this add to the literature?
This section should also offer information on what is known about the safety of this compound.
Line 100. What is “reprotoxicity”? Assume the authors mean reproductive toxicity. What reproductive toxicological studies were performed?
Line 107-111. Here is how another author describes RES’s mechanism of action: Some molecular mechanism of resveratrol action include inhibition of prohypertrophic signaling molecules, improvement of myocardial Ca2+ handling, phosphorylation of prosurvival (Akt-1, GSK-3β) and stress signaling (MKP-1) pathways, and the reduction of oxidative stress and inflammation (iNOS, COX-2 activity, and ROS).
What this reviewer was hoping for is a submission on this subject that teaches the reader information that is not found in other recent reviews, such as that of Bahare Salehi and colleagues in Biomedicines (2018), or that of Tiantian Meng (January 2021) in Molecules, or Wenzhe Dong and colleagues (2016) in Pharmacology & Pharmacy, as examples. It would be a good idea to review these author’s papers along with several other reviews on RES and ask oneself what information is conveyed in the authors manuscript that these authors have not covered or conveyed adequately? The aim is best served when it provides new information that cannot be obtained in reading other reviews on the subject.
A suggestion would be an in-depth manuscript on RES bioenhancers. This can include, as Jin-Ah Lee and colleagues reported in Nutrients (2015) showing how RES can enhance the anti-inflammatory activities of apigenin. Or a manuscript on what agents found in the diet or available as a nutraceutical ingredient enhance its potential health benefits by improving bioavailability, supported by new experimental evidence.
Author Response
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Round 2
Reviewer 1 Report
The manuscript has been largely improved in the second version. However, the expression in lines 97-98, 104, 141-142 is confusing. Please check and make sure the descriptions are correct.
Author Response
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Reviewer 2 Report
The revised manuscript is vastly better than the original submission. The English is significantly improved. The additions have added substantially to the information the authors conveyed. Well done.
Author Response
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