PONE-D-24-01162Nesfatin-1 regulates the phenotype transition of cavernous smooth muscle cells by activating PI3K/AKT/mTOR signaling pathway to improve diabetic erectile dysfunctionPLOS ONE

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Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Review Comments to the Author

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Reviewer #1: The authors examine the effect of a high-fat diet-induced type 2 diabetes on erectile function (T2DMED) through the PI3K/AKT/mTOR signaling pathway and explore the impact of Nesfatin-1 on T2DMED and its underlying mechanism in regulating the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs). They conclude that Nesfatin-1 enhances erectile function by activating the PI3K/AKT/mTOR signaling pathway to induce the conversion of CCSMCs to a contractile phenotype. The study is potentially interesting, but several concerns are listed in detail below.

Comments

1- Previous studies have shown that HFD results in erectile dysfunction through impaired endothelial function and the NO-cGMP pathways, which are the primary mechanisms for erection. Additionally, PI3-kinase/Akt activates eNOS and physiologically mediates erection. I am surprised the authors did not investigate the effect of Nesfatin-1 on the pAKT-NO-cGMP pathway in this study. Please discuss.

2- There was a significant decrease in body weight after Nesfatin-1 treatment in HFD mice. Did the authors measure how much food the HFD mice + treatment group consumed compared to the HFD group?

3- Did the authors consider using an additional control group that was given less HFD food without Nesfatin-1 treatment to see whether the effect of Nesfatin-1 is only related to treatment, not weight loss?

4- Please discuss why the authors did not use esculetin for in vivo experiments.

5- HFD can activate the mTOR signaling pathway as an upstream mediator of NADPH oxidase in the corpus cavernosum. Please discuss.

6- Lastly, the discussion needs a revision. The authors should summarize the key findings in the first paragraph and interpret the results in the following paragraphs, referencing previous conclusions in the literature.

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Reviewer #1: Yes: Serkan Karakus

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Nesfatin-1 regulates the phenotype transition of cavernous smooth muscle cells by activating PI3K/AKT/mTOR signaling pathway to improve diabetic erectile dysfunction

PONE-D-24-01162R1

Dear Dr. Guangyong,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Academic Editor

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