Rhoa/ROCK, mTOR and Secretome-Based Treatments for Ischemic Stroke: New Perspectives

Round 1

Reviewer 1 Report

I appreciate the authors for presenting this review article focusing on targeting cellular signaling pathways for stroke treatment. This is a well-reviewed review article. The associated signaling pathway information for ischemic strokes, such as the RhoA/ROCK and mTOR signaling pathways, have been published in many articles. Therefore, a well-organized review article is necessary to provide clear, summarized information for the authors. My comments are as follows:

 1. Figure 1: The depiction of Neurovascular unit changes secondary to ischemia is well-presented and easy to understand.

2. Could you provide a summary graphic for the RhoA/ROCK pathway, mTOR signaling pathway, and secretome effects based on your paper review?

 3. It is noted that there are a total of 183 references. Approximately 36 of these references date back to more than 10 years ago (prior to 2014). If not deemed necessary, these older references could be omitted.

 4. There is a lack of conclusion in the manuscript

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

In the MS cimb-2946249, the authors propose a review of signaling pathway-related therapy of stroke. The MS title is very general, and extensive literature data are available for each mechanism; therefore, the author's purpose appears to be very comprehensive because there are a few types of stroke with numerous different molecular mechanisms.

1. The authors mention ischemic stroke in the abstract, but it is still unclear whether they refer to this one or, generally, to all stroke types. 

2. In the abstract and introduction, the authors mention "the article explores/delves" (lines 23-24, 52); the reviewer believes this is inappropriate once because the current MS is a review and second because this type of publication only critically reviews the other authors' research. 

3. After a very short and non-relevant background, the authors report that the work is focused especially on the RhoA/ROCK and mTOR pathways (lines 53-54). It is better to mention these aspects in the title and abstract.

4. The Introduction should contain general data about stroke types,  current treatment, and a synthesis of cellular and molecular mechanisms implied in ischemic stroke. Then, the authors could focus on the selected pathways, making a clear difference between cellular and molecular mechanisms developed in their review. All abbreviations should be explained at the first mention in the MS text. 

5. The 3 points developed in section 4 should be similar in their organization, following the same steps. The presentation of active compounds should be specially announced to maintain the reader's attention.  

6. The letters from Figure 1 could be augmented for better visualization.

7. Line 181 - plant species with italics

8. Table 4—The authors are encouraged to check and reorganize it to make more space in the columns. The reviewer suggests removing column 1 and placing each term in a separate row. Moreover, the reference can be placed in the extreme right part of the table as the final column. Most tables in MDPI reviews are performed in the same mode - the authors can check and see them. Moreover, the table footer should indicate the significance of the abbreviation used in column 2 (therapy).

9. After all rectifications, the Title, Abstract, Discussion, and potential Conclusions should be restructured for more clarity. 

10. The authors are encouraged to edit the references in MDPI style.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors suitably responded to previous comments. The reviewer highly appreciates their efforts; the current version is better organized and substantially improved. 

A few minor comments are available below:

Lines 24 and 70: "review article" or simple "review" is correct according to https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/pmc/articles/PMC4548566/.

Lines 69-70: The authors are encouraged to make a gradual transition from data regarding the treatment of ischemic stroke to optimize neurological recovery and the cellular signaling cascades implicated in ischemic stroke, with a particular focus on the RhoA/ROCK. 

The reviewer suggests briefly presenting the pathophysiological mechanisms involved in ischemic stroke and mentioning the main signaling pathways. 

Then, the authors can highlight the importance of selected pathways for the present review, motivating their choice.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf