Pharmacokinetic profiles of Moutan Cortex after single and repeated administration in a dinitrobenzene sulfonic acid-induced colitis model

Jin-Hwa Kim; Ji-Soo Jeong; Jeong-Won Kim; Eun-Hye Chung; Su-Ha Lee; Je-Won Ko; Youn-Hwan Hwang; Tae-Won Kim

doi:10.1371/journal.pone.0337713

Peer Review History

Original SubmissionSeptember 3, 2025
30 Sep 2025 Decision Letter - Zheng Yuan, Editor Dear Dr. Kim, 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. ============================== Note from the Academic Editor: Please note that I have acted as a reviewer for this manuscript, and you will find my comments below, under Reviewer 1. ============================== Please submit your revised manuscript by Nov 06 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Zheng Yuan Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following financial disclosure: “The authors declare that there are no conflicts of interest that could have appeared to influence the work reported in this paper.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. Thank you for stating the following in your Competing Interests section: “The authors declare that there are no conflicts of interest that could have appeared to influence the work reported in this paper.” Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. 4. PLOS ONE now requires that authors provide the original uncropped and unadjusted images underlying all blot or gel results reported in a submission’s figures or Supporting Information files. This policy and the journal’s other requirements for blot/gel reporting and figure preparation are described in detail at https://journals.plos.org/plosone/s/figures#loc-blot-and-gel-reporting-requirements and https://journals.plos.org/plosone/s/figures#loc-preparing-figures-from-image-files. When you submit your revised manuscript, please ensure that your figures adhere fully to these guidelines and provide the original underlying images for all blot or gel data reported in your submission. See the following link for instructions on providing the original image data: https://journals.plos.org/plosone/s/figures#loc-original-images-for-blots-and-gels. In your cover letter, please note whether your blot/gel image data are in Supporting Information or posted at a public data repository, provide the repository URL if relevant, and provide specific details as to which raw blot/gel images, if any, are not available. Email us at plosone@plos.org if you have any questions. 5. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: No ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: The authors of the manuscript focused on not only profiling the PKs of two chemicals from Moutan Cortex after single and repeated administration but also detailed the pharmacology process through molecular biological methods. It deserves stress that the authors adopted repeated administration and discovered the exposure differences of the two chemicals. The manuscript will help understand pharmacology and provide a good model for profiling the PKs of multiplex constitutes of herbal medicine. What is more, the manuscript was written well, and the workload is also enough. The manuscript is recommended to be accepted by the journal PloS One. Here are several minor concerns for the authors to improve the quality of the manuscript: 1) In the Abstract section, the authors provided some results with fold. If the authors can provide number comparisons such as “number vs. number”, will help readers understand the work of the manuscript more directedly. 2) In the Keywords section, the last keyword should be deleted. And the word “pharmacokinetic” should be moved as the last keywords. 3) In line 67 and ling 68, the abbreviation ADME should be added. 4) As the authors used animal experiments, ethical issues should be provided or exhibited. 5) When introducing the western blot analysis procedure, the version of the ImageJ software should be provided. Reviewer #2: Major concerns: 1. The manuscript inconsistently refers to “mice” in some sections (abstract/introduction) while the Methods clearly state that Sprague-Dawley rats were used. This is a fundamental error and must be corrected throughout the text for clarity and accuracy. 2. Each group contains only five animals, which is relatively small for pharmacokinetic and histological comparisons, especially given the large interindividual variability observed (e.g., paeonol Cmax at high dose). The authors should either increase the sample size, provide power calculations, or at minimum show individual concentration–time profiles to illustrate variability. 3. Please provide raw PK data (machine-readable) as mentioned. Reference them clearly in the main text. Minor concern: 1. Given the dramatic increase in paeonol systemic exposure at the high dose, safety/toxicity monitoring is important. The manuscript currently states that no euthanasia endpoints were met, but it does not report biochemical markers (e.g., liver/kidney function) or histopathological observations beyond the colon. These should be included or at least discussed as a limitation. ****** 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 Reviewer #2: Yes: Zixu Wang ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0337713.r001
Revision 1
31 Oct 2025 Author Response Reviewer 1. 1) In the Abstract section, the authors provided some results with fold. If the authors can provide number comparisons such as “number vs. number”, will help readers understand the work of the manuscript more directedly. We agree with this comment. To help readers understand the differences more intuitively, we revised the text to include the exact numerical values instead of fold changes (Line 34–35 and 37–39). 2) In the Keywords section, the last keyword should be deleted. And the word “pharmacokinetic” should be moved as the last keywords. We appreciate the thoughtful suggestion. We have removed the last key word and repositioned “pharmacokinetic” as the final keyword. 3) In line 67 and ling 68, the abbreviation ADME should be added. Thank you for the comment. We have added the abbreviation “ADME” to the text (Line 68-69). 4) As the authors used animal experiments, ethical issues should be provided or exhibited. Thank you for the valuable comment. We have provided detailed information on ethical approval and considerations with the laboratory animal care guidelines (Line 101-105). 5) When introducing the western blot analysis procedure, the version of the ImageJ software should be provided. Thank you for pointing that out. We have added the ImageJ software version used for densitometric analysis in the Methods part (Line 209). Reviewer 2. 1) The manuscript inconsistently refers to “mice” in some sections (abstract/introduction) while the Methods clearly state that Sprague-Dawley rats were used. This is a fundamental error and must be corrected throughout the text for clarity and accuracy. Thank you for pointing this out. We carefully reviewed the entire manuscript and corrected all to accurately refer to rats instead of mice (Line 31). 2) Each group contains only five animals, which is relatively small for pharmacokinetic and histological comparisons, especially given the large interindividual variability observed (e.g., paeonol Cmax at high dose). The authors should either increase the sample size, provide power calculations, or at minimum show individual concentration–time profiles to illustrate variability. We appreciate your concern. We agree that using five animals per group may limited in several PK endpoints. We have now included the individual concentration-time profiles for paeonol and paeoniflorin in the Supplementary figure (Fig. S2 and S3) and referred them in the text (Line 242 and 273-274). Additionally, we inserted a new paragraph in the manuscript (Line 426-432) to describe this inclusion. 3) Please provide raw PK data (machine-readable) as mentioned. Reference them clearly in the main text. We appreciate the reviewer’s comment. The raw plasma concentration-time data for all individual animals have been provided in a machine-readable format thought the Zenodo database (DOI: 10.5281/zenodo.17462573). This information has been clearly referenced in the main text (Line 163-164). Minor 1) Given the dramatic increase in paeonol systemic exposure at the high dose, safety/toxicity monitoring is important. The manuscript currently states that no euthanasia endpoints were met, but it does not report biochemical markers (e.g., liver/kidney function) or histopathological observations beyond the colon. These should be included or at least discussed as a limitation. We agree with your suggestion. We have expanded the discussion of limitations to acknowledge that safety biomarkers (ALT, AST, ALP,…) and multi-organ histopathology were not assessed in this study, which limits definitive conclusions on systemic toxicity (Line 433-436). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0337713.r002
13 Nov 2025 Decision Letter - Zheng Yuan, Editor Pharmacokinetic profiles of Moutan Cortex after single and repeated administration in a dinitrobenzene sulfonic acid-induced colitis model PONE-D-25-45138R1 Dear Dr. Kim, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Zheng Yuan Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0337713.r003
Formally Accepted
Acceptance Letter - Zheng Yuan, Editor PONE-D-25-45138R1 PLOS ONE Dear Dr. Kim, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Zheng Yuan Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0337713.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .