PONE-D-23-14508Lobeglitazone inhibits LPS-induced NLRP3 inflammasome activation and inflammation in the liverPLOS ONE

Dear Dr. Jang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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The article is about the roles of Lobeglitazone on LPS-induced NLRP3 activation in Kupffer cells, hepatocytes, and Hepatic stellate cells. The evaluations among the reviewers are quite different but I think the manuscript can be reevaluated after major revisions. One reviewer gave some critical questions and please respond to them carefully.

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Kenji Fujiwara, PhD, MD

Academic Editor

PLOS ONE

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"This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF‐2021R1I1A3046593, NRF‐ 2021R1I1A3059150), and was supported by a NRF grant funded by the Korea government (MIST) (NRF‐2022R1A2C1006416). (BK Jang, MK Kim, HY Seo)"

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Additional Editor Comments:

Dear Dr. Jang.

The article is about the roles of Lobeglitazone on LPS-induced NLRP3 activation in Kupffer cells, hepatocytes, and Hepatic stellate cells. The evaluations among the reviewers are quite different but I think the manuscript can be reevaluated after major revisions. One reviewer gave some critical questions and please respond to them carefully.

I am looking forward to resubmission.

Best regards,

Kenji Fujiwara

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study investigated the roles of Lobeglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, on LPS-induced NLRP3 activation in primary Kupffer cells (KCs) and hepatocytes and fibrosis on stellate cells. The authors need to consider the following issues.

1. PPARgamma has been reported to be responsible for the M2/anti-inflammatory polarization of macrophages (PMID: 33627030). I suggest the authors investigate the status of KCs polarization.

2. The authors investigated the roles of Lobeglitazone on LPS-induced NLRP3 inflammasome activation in primary hepatocytes. However, NLRP3 inflammasome has been suggested to be mainly assembled in macrophages, and hepatocytes have been demonstrated to be resistant to pyroptosis due to the low expression of caspase 1/11.

3. Figure 5- the authors need to investigate the roles of Lobeglitazone on CM-treated HSCs.

4. Figure 6-the authors found that Lobeglitazone could downregulate LPS-induced up-regulation of TGF-β. Then they focused on the roles of TGF-β on IL1β and CTGF on hepatocytes. However, if they want to reveal the roles of Lobeglitazone on the activation of HSCs, they need to investigate the effects of Lobeglitazone on HSCs but not hepatocytes.

Reviewer #2: Seo et al., found lobegilitazone inhibit LPS induced NLRP3 inflammasome activation and inflammatin in the liver. But the resluts was worried. Activation of NLRP3 inflammasomes at the cellular level requires reagents, otherwise they cannot be activated, but this paper does not provide them. There are no positive drugs, and the dosage of the drugs should be at least two.

Reviewer #3: The manuscript was technically sound, the conclusions were supported by data, and appropriate statistical methods were used. The article is written in standard English, the language is clear, concise and to the point. Accept the article。

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Reviewer #1: Yes: TAO ZENG

Reviewer #2: No

Reviewer #3: No

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Lobeglitazone inhibits LPS-induced NLRP3 inflammasome activation and inflammation in the liver

PONE-D-23-14508R1

Dear Dr. Jang,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kenji Fujiwara, PhD, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Dr. Jang.

Thank you for revising your manuscript appropriately. The reviewer and I agreed to the acceptance.

Yours sincerely,

Kenji Fujiwara

Academic editor

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

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