Epigenetics of Homocystinuria, Hydrogen Sulfide, and Circadian Clock Ablation in Cardiovascular–Renal Disease
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear authors,
I attach My comments
Comments for author File: 
Comments.pdf
I explain to the author my comments
Author Response
We thank the reviewer for the constructive critique of our manuscript. We have revised the manuscript according to the reviewer’s recommendation, as following:
Comments
Line 15: “mictochondrial” Correct please Line 45: “discussion”
Response: corrected.
The subtitle of the article is confusing. You should correct Line 126-131:
Response: corrected.
Please, the caption of the figure 3 must have a distance from the other text.
Response: corrected. Because there is subscript therefore it seems to be distant from the text.
Line 139: the same style in all words “transsulfuration” style?
Corrcted.
Line 201…: You give so many details in one paragraph.
Response: Thank you for the suggestion. The focus is homocystinuria and epigenetic in circadian and mitochondrial response. Therefore, it is best way to present.
It would be best if you prepared different paragraphs Line 291: Why did you choose “….to investigate circadian rhythms regulation by hyperhomocysteinemia, and its effects on cardiovascular disorder”?
Response: Thank you for the suggestion. The focus is homocystinuria and epigenetic in circadian and mitochondrial response. Therefore, it is best way to present.
Another parameter except for hyperhomocysteinemia?
As above.
Other diseases? Line 344: The title of the journal in reference 7 is in italic form and is different from the previous references.
Corrected.
Please follow the journal instructions to complete/correct your references. Please check all the references
Author Response File: Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors1.The introduction, while rich in detail, lacks sufficient clarity and conciseness.
2.The description of mechanisms is sometimes dense and assumes prior knowledge of specific pathways, which could alienate a broader readership.
3.The central hypothesis could be more clearly defined and consistently referenced throughout the manuscript, as the novel mechanisms are not tied together seamlessly.
4.The plagiarism % is high. Please decrease it to less than 10%..
5.Figure 3 is out of manuscript and needs to be modified.Some figures, such as the pathway linking homocysteine metabolism and circadian rhythms, are visually dense and difficult to interpret. Simplifying these images or adding stepwise breakdowns would improve clarity.
6.The manuscript discusses various experiments, including genetic models (DNMT1 knockout mice) and dietary interventions (high-fat diet) to study the effects of homocysteine metabolism and circadian disruption.While the experiments seem comprehensive, the manuscript could benefit from more explicit details on controls used to validate the findings, particularly around genetic models and diet-induced changes.
7.The manuscript lacks clear methodologies for validating key findings. The manuscript could improve by integrating validation techniques such as gene expression analysis and protein quantification to corroborate the effects of circadian disruption.
8.The manuscript could benefit from including more tables summarizing key experimental results or highlighting important data points (e.g., gene expression levels, methylation markers).
9.The manuscript concludes by proposing that homocysteine metabolism and circadian rhythms may serve as therapeutic targets for treating cardiovascular and renal diseases. The conclusion could benefit from a more cautious interpretation of the findings. While the proposed mechanisms are promising, more experimental evidence is needed before making definitive statements about therapeutic strategies.
Comments on the Quality of English Language
The quality of English language in the manuscript is generally acceptable, but it could benefit from further refinement to enhance readability and clarity. Here are some specific observations:
- Areas for Improvement:
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Complex Sentence Structures: Many sentences are overly long and complicated, making it difficult to follow the main points. Breaking these into shorter, more focused sentences would improve readability.
- Example: Sentences in the abstract and introduction, such as "Epigenetic gene writer (DNMT), gene eraser (TET/FTO), and editor (ADAR) regulate the rhythmic i.e., reversible methylation/demethylation of H3K4, H3K9, H4K20, m6A and m5C," could be split to simplify the presentation.
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Clarity and Flow: Some parts of the manuscript lack flow, and ideas are introduced abruptly without proper transitions.
- Suggestion: Improve transitions between sentences and paragraphs to create a more logical progression of ideas.
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Word Choice: The manuscript occasionally uses overly technical jargon without adequate explanation, which may not be accessible to all readers.
- Suggestion: Define complex terms when first introduced or consider using more straightforward language where possible.
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Repetition: Some phrases and ideas are repeated unnecessarily, which can make the text feel redundant.
- Example: Terms like "epigenetic gene writer, eraser, and editor" are mentioned several times in close proximity. Consider reducing repetition to streamline the text.
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Typos and Minor Errors: There are occasional typographical errors, such as "circardial" instead of "circadian" and "combi-nation" instead of "combination."
- Suggestion: A thorough proofreading would help eliminate these small mistakes.
Author Response
We thank the reviewer for the constructive critique of our manuscript. We have revised the manuscript according to the reviewer’s recommendation, as following:
Reviewer #2:
1.The introduction, while rich in detail, lacks sufficient clarity and conciseness.
Response: We have revised the Introduction as follows:
“Combating soldiers, shift workers and anxiety/depression patients face with unformidable consequences of sleep deprivation and cardiovascular and renal diseases. The role of disruption in sleep and circadian clock in chronic diseases is suggested [1-10], however, the mechanism(s) are far from understanding. We discuss a paradigm shift mechanistic pathway that causes the circadian clock related diseases in which the activation of super cervical ganglion (SCG), excitatory neurotransmitter receptor NMDA-R1 by disruption in epigenetic folate 1-carbon metabolism (FOCM) and increasing homocysteine (Hcy, i.e., homocystinuria) [11-14]. Although the inhibition of ATP citrate lyase (ACLYi) attenuates hyperlipidemia [158, 159]. The ACLY acetylates the histones by epigenetic mechanisms [160]. However, its role in HFrEF and epigenetic control of homocystinuria is unknown. Here we suggest that ACYL inhibition will mitigate the HFrEF by attenuating the epigenetic homocystinuria.”. This reported on page 2.
2.The description of mechanisms is sometimes dense and assumes prior knowledge of specific pathways, which could alienate a broader readership.
Response: The description of the mechanisms is elaborated in the text and in the Figures and their legends.
3.The central hypothesis could be more clearly defined and consistently referenced throughout the manuscript, as the novel mechanisms are not tied together seamlessly.
Response: Although the hypothesizes are several due to the connection of epigenetic, methylation, homocysteine, clock genes and heart failure. We have tried significantly to be clarified.
4.The plagiarism % is high. Please decrease it to less than 10%..
Response: Most of the text is referenced to give proper credit.
5.Figure 3 is out of manuscript and needs to be modified. Some figures, such as the pathway linking homocysteine metabolism and circadian rhythms, are visually dense and difficult to interpret. Simplifying these images or adding stepwise breakdowns would improve clarity.
Response: Figure 3 legend is now elaborated to elicit the proposed contributions of mitochondria in epigenetics and bioenergetics.
6.The manuscript discusses various experiments, including genetic models (DNMT1 knockout mice) and dietary interventions (high-fat diet) to study the effects of homocysteine metabolism and circadian disruption. While the experiments seem comprehensive, the manuscript could benefit from more explicit details on controls used to validate the findings, particularly around genetic models and diet-induced changes.
Response: In these review article we suggested the possibility of the future experiments to substantiate these hypotheses.
7.The manuscript lacks clear methodologies for validating key findings. The manuscript could improve by integrating validation techniques such as gene expression analysis and protein quantification to corroborate the effects of circadian disruption.
Response: In this review article we suggest the possibility of the future experiments to substantiate these hypotheses.
8.The manuscript could benefit from including more tables summarizing key experimental results or highlighting important data points (e.g., gene expression levels, methylation markers).
Response: The experiments to support these prospective hypotheses are proposed for future direction.
9.The manuscript concludes by proposing that homocysteine metabolism and circadian rhythms may serve as therapeutic targets for treating cardiovascular and renal diseases. The conclusion could benefit from a more cautious interpretation of the findings. While the proposed mechanisms are promising, more experimental evidence is needed before making definitive statements about therapeutic strategies.
Response: This is a prospective review article and not an original research article. These studies will be proven in future studies.
Author Response File: Author Response.pdf
