PONE-D-20-03892

Quercetin treatment reduces the severity of renal dysplasia in a beta-catenin dependent manner

PLOS ONE

Dear Dr Bridgewater,

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The manuscript entitled “Quercetin treatment reduces the severity of renal dysplasia in a beta-catenin dependent manner” by Cunanan et al found that quercetin treatment reduced the nuclear localization of β- catenin in renal dysplasia. This study also identified that quercetin treatment increased the development of maturing neurons by improving the epithelial organization associated with higher E-cadherin levels. The manuscript provided very valuable observation and revealed the efficacy of quercetin in reducing renal dysplasia. However, some further studies are required to confirm the result provided, and need minor clarifications.

Major points

1. Figure 6 shows the expression levels of vimentin and E-cadherin in normal and dysplastic kidney tissue by immunostaining. Please include mRNA expression or protein expression levels of vimentin and E-cadherin in these samples for the conformation of immunostaining results.

2. Based on the data presented in the manuscript please discuss the effect of quercetin on β-catenin and E-cadherin complex formation, include relevant references also.

Minor points

1. Please indicate the method used for statistical analysis with a separate heading.

2. Here multiple samples were compared to control samples (Figure 2 G, H and I). The authors indicated that “data was analyzed using two-tailed Student’s t-test”. Usually, the t-test is used to compare two values and one-way Anova is useful to compare multiple values. Please confirm.

3. Please define the *, **, and *** in the figure legends (Figure 2)

Reviewer #2: In this work, the authors revealed that quercetin treatment attenuates the severity of renal dysplasia in a beta-catenin dependent manner. Several suggestions are made as follows to improve the quality of the manuscript.

1. Many references have been cited before 2010 especially references 29-39. β-catenin signaling pathway have been widely reported in the decade. The reviewer suggests the authors updated and cited the latest publications. I have searched the references for the different section of manuscript.

2. Please introduce more backgrounds about renal fibrosis treatment and explain why do you study quercetin? The bioactivities of quercetin have been widely reported many studies, such as Br J Pharmacol 2020,177(8):1841-1852; Redox Biol 2020,28:101337; Sci Rep 2019,9(1):19176; Free Radic Biol Med 2019,145:146-160; Free Radic Biol Med 2019,143:240-251; Phytomedicine 2019,57:65-71; Phytomedicine 2019,56:183-193; Sci Rep 2018,8(1):6194. Please summarize and cite them in the introduction section.

3. All abbreviations should be substantiated for the first time.

4. Natural products against renal injury via β-catenin signaling pathway have been widely reported by several recent reviews, such as Trends Pharmacol Sci 2018,39(11):937-952; Med Res Rev 2020,40(1):54-78; Biomed Pharmacother 2019,117:108990. Please summarize and cite them in the introduction section.

5. Chemicals, Reagents and antibodies should be provided. Please include both the manufacturer’s name and location (including city, state, and country) for specialized equipment and reagents throughout the manuscript.

6. β-catenin signaling pathway in Renal injury and fibrosis has been reported several articles such as Br J Pharmacol 2018,175(13):2689-2708; Phytomedicine 2018,42:207-218; Ther Adv Chronic Dis. 2019,10:2040622319869116; J Agric Food Chem 2018,66(8):1828-1842; Redox Biol 2017,12:505-521. Please discuss and cite them in the discussion section.

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Reviewer #1: No

Reviewer #2: No

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Quercetin treatment reduces the severity of renal dysplasia in a beta-catenin dependent manner

PONE-D-20-03892R1

Dear Dr. Bridgewater,

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

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With kind regards,

Mirjam M Zegers, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: