The Effect of Phytocannabinoids and Endocannabinoids on Nrf2 Activity in the Central Nervous System and Periphery
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have written a review that details the interaction of cannabinoids with the Nrf2 transcription factor which is heavily involved in ROS generation and oxidative stress. They conclude that the literature highlights these interactions and particularly the ability of CBs to be antioxidants. While the review’s scientific merit is clear, there are many issues that need to be resolved. There is also much room for improving the grammar and style of writing. Below are some of the points that can be addressed to improve the quality of the manuscript.
Line 30- 31: The opening line can be worded better. Beneficial-risk ratio sounds awkward.
Line 46-50: Run-on sentence that doesn’t convey the facts.
Line 53- 55: The distinction between phyto and synthetic cannabinoids should be made clear to the reader.
Line 99-113: Since this is a neurology journal, the chemistry described is not in sufficient detail to clarify to the reader how cannabinoids are exactly antioxidants. This section should be developed further, with the chemistry explained. Why does a reddish-purple hue form? What is this test indicating? Only one study is given for the antioxidant effects of cannabinoids, please provide at least two more studies so the reader can get a full picture especially that the paper hinges on this assumption.
Line 137-139: This is a strong statement, there are no references that support it in your text. “is widely recognized as one of the principal regulators of cellular redox homeostasis, antioxidant defense, and detoxification. “ Please provide references for it.
Line 121: What pathological conditions? There is insufficient context.
Line 140-152: What is the significance of these complexes? Where is it physiologically relevant? What systems is it active in?
The following is a recurrent issue in section 4 but is best exemplified in these lines:
Line 165-170: This paragraph (line 165- 170) be rewritten as follows:
CBD was found to reduce the severity of 5-fluorouracil-induced oral mucositis in mice and human oral keratinocytes by upregulating the expression level of antioxidant enzymes such as HO-1 and NQO1 along with an increase in the expression and nuclear translocation of Nrf2. In parallel, CBD decreased Keap1 activation— state the significance of decreasing Keap1 activation — cont’d The general protective effect of CBD was counteracted either by the Nrf2 inhibitor ML385 and by Nrf2-siRNA transfection (this is an important finding that supports your hypothesis, you should clearly state that the abrogation of the protective effects of CBD by an Nrf2 inhibitor further supports findings that link cannabinoids and Nrf2 activation.)
The way you had the paragraph written was very bad and this is a common theme in this section and elsewhere in the paper. There is alot of revision required in that regard. Please make sure to mention the significance of a research finding and not simply state the finding as that does not mean anything without the broader context.
Line 197-205: This might be my own misunderstanding but why is neuropathic pain in the section of CBs and Nrf2 outside the CNS? Isn’t neuropathic pain ultimately a neurological disorder?
Line 209-213: It is unclear what this means “an attenuated decrease in h202 induced cell viability” are more cells dying or surviving?
Line 302-303: What pathologies?
Line 322-328: You mention microglial polarization and then give an example of RAW macrophages, while these cell types have similar functions, they are very distinct cell types with different developmental origins. Please revise.
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsAuthors in their review manuscript discuss the relationship between Nrf2 pathway and phytocannabinoids/endocannabinoids.
1. Though the topic is interesting, it is suggested to focus this revew on the topic involving more information on Nrf2 pathway and its relation to biochemical background of cardiovascular diseases in a separate chapter. Different pathway mechanisms are mentioned in the text which could be summarized (antioxidant Nrf2/HO-1 pathway, AMPK-Nrf2-TFAM signalling, PI3K/Akt/Nrf-2 228 signal pathway, Keap1/Nrf2/HO-1 pathway). A suggested reference for example: Michelle Yi et al. Int. J. Mol. Sci. 2024, 25(2), 821; https://doi.org/10.3390/ijms25020821
2. It is also suggested to summarize clinical relevancies and therapeutic potential.
3. It is also suggested to extend the Table for more examples and to give a Summary Figure on the topic indicating the relationship between Nrf2 pathway and phytocannabinoids/endocannabinoids.
Specific comments:
Title: Please specify title involving more facts related to Nrf2 pathway (e.g antioxidant capacity)
Abstract: Please specify more fact related to Nrf2 pathway and introduce all abbreviations.
Lines 44-50, this sentence is too long, please separate it into 2.
From line 114, section 3: Please give separate chapters to „antioxidant mechanisms” and „Nrf2 pathway” and give more explanation to each.
Line 143, please reduce brackets and put numbers of refs together.
Line 344, please put this reference ((Jin et al., 2014) as numbered and rearrange reference numbers with this (from 79 to 82).
From 356, please extend table to more examples. Please number all refs in Table. (Juknat et al., 2012, 2013; Kozela et al., 2016)
From line 359, please focus more the Conclusion.
Line 361, please indicate „Nrf2 pathway”
Lines 380-388, please summarize and conclude the discussed facts here, do not introduce new facts (e.g. PUFA).
Please explain all abbreviations at first mention.
Please check all references in the text if they are correct.
Comments on the Quality of English LanguageMinor correction of English is necessary
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe manuscript "Phytocannabinoids and endocannabinoids involvement in central nervous system Nrf2 activity" is interesting and contributes to the trends in neuroscience, however there are a few suggestions to improve the work.
1. The title of the article does not exactly match the contents as a big paragraph 4. is focused on the effects not beyond the CNS. Maybe the title should be modified a bit?
2. In the introduction I miss at least short characterization of Nrf2 system in CNS and its role in CNS disorders.
3. Some information from the concusion part could be incorporated into paragraph 5. Some information should be additionally extended, e.g. the role in sirtuin1 activity, p62. I think that paragraph 5. is not comprehensive enough.
4. There are some inconsistencies within the text, e.g. HT-22 vs HT22, BV2 vs BV 2 etc. Furthermore, some abbreviations are explaines, some not. Maybe a list of abbreviations could be added?
5. Figure 1 is poor in quality. It should be improved.
6. Another figure could be added showing an interaction between CBs and Nrf2.
7. There are some language mistakes - please, read the manuscript again carefully or ask for help native speaker.
8. Some mistakes to be corrected: there is no paragraph 6, line 163 Muscaria - should be muscaria, line 285: Nfr2 instead of Nrf2, 233: NFr2, 188:" could favoring" instaed fo "could favour"
9. Please, explain the statement in line 324 that activation of microglia can be protective but also harmful.
10. The explanations for the table 1 should be added below.
Good luck!
Comments on the Quality of English Language
There are some language mistakes - please, read the manuscript again carefully or ask for help native speaker.
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThank you very much for your revisions!
Author Response
Once again, I want to thank the reviewer for their insightful recommendations.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe MS has improved a lot.
Author Response
Once again, I want to thank the reviewer for their insightful recommendations.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe paper has been significantly improved. Even though, the tables and figures are based on journal's layouts, they should be provided with the descriptions that enable the readers to understand them independently from the text. Furthermore, the figure 2 misses the title. There was only a description in the text saying what the figure contains.
Comments on the Quality of English Language
The paper has been improved but still minor mistakes can be found.
Author Response
Comment:
The paper has been significantly improved. Even though, the tables and figures are based on journal's layouts, they should be provided with the descriptions that enable the readers to understand them independently from the text. Furthermore, the figure 2 misses the title. There was only a description in the text saying what the figure contains.
Response:
The tables and figures (highlighted in red within the text) now have descriptions that allow readers to understand them without having to read the text. Figure 2 now has the title (text marked in red).
Once again, I want to thank the reviewer for their insightful recommendations.
