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Manuscript is significantly improved, and the authors have addressed all the raised concerns. Manuscript now can be accepted in its current presented form.
[# PeerJ Staff Note - this decision was reviewed and approved by Brenda Oppert, a PeerJ Section Editor covering this Section #]
Manuscript is significantly improved by the authors. However, there are some suggestions from the Section Editor below, which require further revision to improve the manuscript.
"The health benefit is inferred (extrapolated) to humans from this study in rats. While you see this when you read the methods (line 99), it's not in the title, abstract, or results. I find "rat" in line 346 in the discussion referencing another rat study. It's also not in any of the figure legends. So, you have to dig to find out that this was not done in human cardiomyocytes. But the relevance is to humans with heart disease, because they mention that people use it as a preventative and treatment for heart disease.
I think it is misleading, and the authors should qualify that the study was in rat cardiomyocytes in the title, in the abstract, in the results, and in the figure legends (as appropriate). And reinforced in the discussion. Please clearly mention "rats" everywhere in the manuscript, where relevant to present the right picture of the work.
The manuscript also needs some editing for English."
**Language Note:** The Academic Editor has identified that the English language must be improved. PeerJ can provide language editing services - please contact us at [email protected] for pricing (be sure to provide your manuscript number and title). Alternatively, you should make your own arrangements to improve the language quality and provide details in your response letter. – PeerJ Staff
Though the manuscript is significantly improved by the authors, reviewer 3 still has raised some suggestions to improve the manuscript. Please revise considering the comments and resubmit. Concerns raised by the reviewer are extremely important and reflect the intended quality, and it is necessary to undertake and address all comments.
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The reviewer is satisfied with the improvements made by the authors, and all previous concerns have been addressed effectively. The manuscript is now suitable for publication.
The revisions undertaken by the authors not only address the initial concerns but also add value to the scientific discourse. Therefore, I am in agreement with the decision to accept the manuscript, looking forward to its contribution to advancing knowledge and inspiring further research in this domain.
The authors have meticulously addressed and implemented changes in response to all the queries.
The authors have meticulously addressed and implemented changes in response to all the queries.
I appreciate the authors' revisions. Most of my issues are addressed; however, there are several other things that the authors must address.
1) Line 581: Figure legends section - This is not the formatting that PeerJ uses. Please add legends properly to your figures as per the guidelines of PeerJ.
2) Figure 1 is still way too crowded. This can be fixed by labeling the respective sections with the appropriate figure number. Label the individual components with the appropriate figures. For example, "Component-target networks", and "PPI Network analysis" should refer to Figure 2, "Molecular mechanisms" should refer to Figure 7, and so on.
3) Your conclusion section is inadequate. A five-line conclusion section will only undermine your work. Make sure that your conclusion section is well stated, answers the various research questions and hypotheses you have discussed, and wraps up your work nicely.
4) URL's are not cited correctly. For example: Line 372, 123, 119, 120, etc
5) "Statistical analysis" section (Line 182) is vague.
The authors say, "Statistical analysis was performed using SPSS statistic software 13.0" - How did they perform it? You must include the details of your analyses in such a way that others can reproduce your work exactly.
Please elaborate on the various details of this section.
6) In Figure 2 there is a typo - I think in Figure 2, B, the authors meant to say "Disease"
This same error is present in Figure 1 too, please correct. Please proofread your complete manuscript before resubmitting.
7) Lines 371, and 372: It would be good if the authors mention how they did this. What do they mean by "provided"? The link that they have given takes me to a website but I do not get any information from that, the website seems to have various tools. Authors must specify what they used and how they used it.
Refer to Section 1
Refer to Section 1
Refer to Section 1
All the reviewers' comments must be carefully addressed as recommended.
**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
Wei et al showed Gypenosides (GYPs) protect ADR-induced cardiomyocyte dysfunction. For the western blotting reported in this manuscript (Fig. 6&7), the authors only show one sample per group. Please provide all western blotting images they used for quantification in the supplement, or changes quantification panels (Fig. 6A-B, Fig. 7A-D) with individual data points shown in each group.
The authors used Adriamycin (ADR) as the positive control to induce cytotoxicity and to determine whether GYPs have protective effect against it. However, the authors failed to show the effect of GYPs on mitochondrial function under basal condition. In addition, for mitochondrial functional measurement in Figure 5, the authors need to perform Mito Stress Test using Agilent’s commercial kit.
For experiments reported in Figure 4&5, data were collected at different time-point post ADR treatment. For cell viability they used 24 hour, and in ATP measurement they used 16 hour. For mitochondrial membrane potential and ROS production, they collected samples 12h post ADR treatment. This inconsistency hugely impact the quality of this manuscript and it is highly recommended the authors used same time-point across the experiments. Also, please verify at which time-point they collect samples for Figure 6&7.
Previous literatures showed doxorubicin (ADR) impaired mitochondrial fission and fusion which the authors didn’t see in their experiments. (Here is a nice review about it: doi: 10.3390/pharmaceutics15041182). The authors need to discuss why they didn’t see such changes in their experiments.
Please correct the typo in Figure 1, should be failure not falure. Also, in line 136, please use full name ‘rhodamine 123’ before using abbreviates. It is also recommended to use 'Doxorubicin' instead of 'Adriamycin', as the former is commonly used in studies.
I have had the opportunity to review your manuscript comprehensively. First and foremost, I commend the authors for their detailed exploration of Gypenosides and their potential cardioprotective mechanisms. The network pharmacology approach is both innovative and thorough. The findings from the cell experiments also provide valuable insights into potential therapeutic benefits. However, to enhance the manuscript's clarity and depth, I offer the following suggestions.
1. The manuscript would greatly benefit from additional in vivo studies, enhancing the validity of the proposed cardioprotective mechanisms of GYPs.
2. A deeper exploration of the interactions of the PI3K/Akt/GSK-3β/Mcl-1 signaling pathway with other pathways is recommended to provide a more comprehensive understanding.
3. To ensure a clear narrative, it's important to distinguish between the insights derived from network pharmacology and direct experimental findings.
Comments on Results Section:
1. For clarity, please expand on the exclusion criteria for the 142 components based on the SwissTargetPrediction database.
2. The discussion around oral bioavailability (OB) and drug-like indexes (DL) could be enhanced by incorporating quantifiable metrics or comparative data.
3. It would be beneficial to delve deeper into the connection between identified targets and the role of GYPs in treating HF. A particular focus on key targets like MAPK and EGFR is suggested.
4. A visual aid, such as a flowchart depicting the process of identification and exclusion of components, can further improve the comprehensibility of this section.
On GO Enrichment, KEGG Pathway Analysis, and Cell Experiments:
1. A more detailed discussion on the implications of key enriched terms/pathways would be beneficial. References to the presented figures would further enrich this discussion.
2. Given the manuscript's emphasis on various signaling pathways, providing readers with a brief background or literature context on their significance would be insightful.
3. A rationale or prior research citation justifying the selected non-toxic concentrations of GYPs would further strengthen this section.
4. Offering more depth about ADR-induced cardiotoxicity mechanisms and GYPs' countering effect would be valuable.
Sections on Mitochondrial Homeostasis, Mitophagy, and PI3K/Akt/GSK-3³/Mcl-1 Transduction:
1. The manuscript's assertion about GYPs' lack of anti-oxidative potency is intriguing. Delving deeper into this, supported by relevant literature, would be beneficial.
2. While fluorescence images showcasing mitochondria co-localization are insightful, adding quantitative data, if available, would substantiate these findings. A discussion on the role of PINK-1 and parkin proteins in the context of mitophagy is recommended.
3. Lastly, it would be worthwhile to provide a brief rationale for the choice of proteins and pathways in the western blot analyses. An in-depth discussion or hypothesis around the connection between GYPs and the PI3K/Akt/GSK-3³/Mcl-1 signaling is also suggested.
After carefully reviewing your manuscript, I find the topic and methodology to be of considerable interest. However, given its current structure and content, I recommend a major revision to enhance the depth and clarity of this paper.
Even though the work by the authors on the cardioprotective effect of Gypenosides is interesting, I have concerns about the data provided. The main issue is the blurred gel electrophoresis images. Even the RAW image files of Figures 1, 6, and 7 are unclear. The SDS-PAGE gel electrophoresis setup is not mentioned properly anywhere.
This must be re-submitted with the correct RAW data of the Western blot analysis. Many micrographs are of low quality and do not have a scale. Fix that.
RAW data of the images must be in high resolution.
Figure 1, step 2/3 is illegible. Even the zoomed-in version of the RAW image file is not readable.
Please adjust and split images as necessary. Every image needs to be high-resolution and readable, especially those with data.
Without proper data, reviewing this in the present condition is impossible. Please resubmit.
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