PONE-D-23-22230Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in Alzheimer's disease ratPLOS ONE

Dear Dr. Xia,

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.

Please submit your revised manuscript by Dec 04 2023 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Tosin Abiola Olasehinde

Academic Editor

PLOS ONE

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Additional Editor Comments:

Authors should revise the manuscript appropriately and address all comments indicate by the reviewers

Abstract

The concentration of the ginkgo biloba extract 50 was not specified

Administration of GBE50 can reverse the activity of these three enzymes and reduce the level of H2O2 – this is not clear. The study has been done already, why did authors indicate it can reverse. The use of grammar in the abstract is not appropriate

Methods

Section 2.2 animals - Male SD rats (220 ± 10 g) – what kind of animals were used? SD is not defined.

Line 94 – what is concentration of Aβ25-35 used?

How was Aβ25-35 prepared and aggregated? For how long was it prepared before administration. Was it a once off administration or continuous?

How did the authors confirm that the rats had Alzheimer’s disease before administering the drug? Was a confirmatory test done on all the rats before GBK was administered?

Alzheimer’s disease is a progressive disease and may be developed overtime especially. Why did authors choose to administer GBK a day after Aβ25-35 injection?

What is the justification for the dose (n at dose of 75 or 150 mg/kg) and 15 days treatment

Line 103 – authors indicated Behaviour Tests but only one test (morris water maze) was done.Why did authors conduct only behavioural test. This cannot reveal a true picture behavioural function of the animal.

Results

Line 172 – 174 – the statistical analysis in figure 2b and footnote contradicts the arguments/explanation of the results in the result section (line 172-174(. Authors should check their statistical analysis to corroborate this explanation.

Similarly in Line 180 – 183 – MAO activity was weaker in CMC and VE, but the comparism cannot be seen in Figure 2D. The statistical analysis does not reveal this effect in Figure 2D

Authors should check the statistical analysis in all the tables and comparisms of the groups and revise appropriately

Line 185 – each them should be corrected

Line 183 – 186 and Figure 2c and e are confusing, diminishing of the enzyme but

Authors should revise the issues around the interpretation of the statistical analysis

Group comparism should be done

The report of the results is not specific,

Line 241 – authors should clarify the phrase “caused by aging Aβ.” The methods did not reveal anything related to aging being induced in the animals

Line 265 – 266 - It had been 266 confirmed that Aβ can change the activity of H2O2-related enzymes in cells in vitro – who confirmed this

Line 270 – 271 should be revised

Line 357 – 358 is confusing - include adjusting the ROS 358 metabolism enzyme activity to reduce H2O2 generation in the mitochondria

There are lots of grammatical errors in the manuscript. All sections should be checked for proper use of English

Reviewer's comments 1

I: ginkgo biloba capital letter for Ginkgo and italic

ad libitum italic

in vitro italic

in vivo italic

II: Reference for GBE, Aβ 25-35 , Vitamin E, and CMC doses.

III: Writing the references does not match the Plos one journal method.

Reviewer 2

It is necessary to investigate the proteins of the internal pathway of apoptosis.

The following proteins should be measured.

caspase 3

cleaved caspase 3

caspase 9

cleaved caspase 9

Measurement of amyloid beta peptide is necessary.

The quality of the images is low.

Reviewer 3

1. In the introduction section, the authors need to mention the impact of mitochondria oxidative stress in the pathogenesis and progression of Alzheimer’s disease

2. In the methodology section, the subheading “Determination of H2O2 and enzyme activities” should be changed to “determination of oxidative stress biomarkers and enzymes activities”

3. In the discussion section, authors need to thoroughly discuss the impact of their findings on the role of mitochondrial oxidative stress in Alzheimer’s disease. The discussion should provide a link of all the results for easy understanding on the therapeutic effect of Ginkgo biloba extract on Alzheimer’s disease.

4. What are the bioactive components of the extract? It is imperative that the authors identify the bioactive compounds of the extracts which may be responsible for its therapeutic effect.

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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: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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: Yes

Reviewer #3: Yes

**********

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

**********

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: Minor Revision

I:

ginkgo biloba capital letter for Ginkgo and italic

ad libitum italic

in vitro italic

in vivo italic

II: Reference for GBE, Aβ 25-35 , Vitamin E, and CMC doses.

III: Writing the references does not match the Plos one journal method.

Reviewer #2: It is necessary to investigate the proteins of the internal pathway of apoptosis.

The following proteins should be measured.

caspase 3

cleaved caspase 3

caspase 9

cleaved caspase 9

Measurement of amyloid beta peptide is necessary.

The quality of the images is low.

Reviewer #3: 1. In the introduction section, the authors need to mention the impact of mitochondria oxidative stress in the pathogenesis and progression of Alzheimer’s disease

2. In the methodology section, the subheading “Determination of H2O2 and enzyme activities” should be changed to “determination of oxidative stress biomarkers and enzymes activities”

3. In the discussion section, authors need to thoroughly discuss the impact of their findings on the role of mitochondrial oxidative stress in Alzheimer’s disease. The discussion should provide a link of all the results for easy understanding on the therapeutic effect of Ginkgo biloba extract on Alzheimer’s disease.

4. What are the bioactive components of the extract? It is imperative that the authors identify the bioactive compounds of the extracts which may be responsible for its therapeutic effect.

**********

6. 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

Reviewer #2: Yes: Mohammad Amin Dehghani

Reviewer #3: No

**********

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Attachments

Attachment

Submitted filename: Minor Revision.pdf

PONE-D-23-22230R1Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in Alzheimer's disease ratPLOS ONE

Dear Dr. Xia,

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.

Authors needs to provide detailed information on the characterization and identification of bioactive principles in the GBE extract which contributed to the activity described by the authors. 

Please submit your revised manuscript by Mar 30 2024 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.

Please include the following items when submitting your revised manuscript:

• 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,

Tosin Abiola Olasehinde

Academic Editor

PLOS ONE

Additional Editor Comments:

The authors are yet to provide the information on the characterization and identification of the bioactive constituents of GBE. The journal policy requires that information be provided on identification and characterization of extracts.

Please note that this manuscript describes the use of traditional medicinal compounds or extracts that may not be sufficiently chemically characterized.

[Note: HTML markup is below. Please do not edit.]

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

Reviewer #2: (No Response)

**********

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

Reviewer #2: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

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

Reviewer #2: (No Response)

**********

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

Reviewer #2: (No Response)

**********

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)

Reviewer #2: (No Response)

**********

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

Reviewer #2: Yes: Mohammad Amin Dehghani

**********

[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.

PONE-D-23-22230R2Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in Alzheimer's disease ratPLOS ONE

Dear Dr. Xia,

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.

==============================

Authors should extensively revise the manuscript as indicated in the reviewer's comments. The manuscript requires extensive English editing. The result section should also be thoroughly revised appropriately==============================

Please submit your revised manuscript by Apr 26 2024 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.

Please include the following items when submitting your revised manuscript:

• 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,

Tosin Abiola Olasehinde

Academic Editor

PLOS ONE

Additional Editor Comments:

Authors did not carry out thorough revision of the manuscript

Abstract

- Line 22 and 23 – two concentrations should be removed

- Line 28 – Oxiditive stress should be oxidative stress

- Line 37 suggested should be suggest

Introduction

- Line 61 - EGb761, as a commercial product of GBE, - what is the difference between EGb761 and GBE. Does processing of the commercial product affect the levels of the bioactive constitutents.

- Line 64 – that similar should be that is similar.

- Line 64 and 65 – what does authors mean and its effect component contains……this is not appropriate and should be revised

- Line 65 – authors only mentioned the class of compounds – flavonoids and lactones present in GBE-50. What are the specific constituents present in GBE50 which has been published as indicated in reference [21]. This should be stated appropriately

- Line 70 – the phrase - A rat model of AD-like is not appropriate. Should be corrected

- Line 115 should be Vit E was administered at 100 mg/kg according to previous study

Results

- The result section should be completely revised. The level of significance should be indicated.

- The presentation of the results which was revised is very poor grammatically. Authors need to employ the service of an English editor to edit the entire manuscript

- Line 192 and 195, no statistical difference at what level?

- Line 199 – comparing should be compared

- No sequential order for the presentation of the results. Presentation of results from Figure 2D must come be after 2B and 2C

- Line 198-199 – MAO activity was increase in which group compared to Sham?

- Line 198 – 200 should be revised. It is confusing considering elevated in the CMC and, VE and G1 groups without statistical difference

- Line 203 – comparing should be compared

- Line 210 – there were on statistical difference – this grammatical expression is not correct

- Line 219 – authors should clarify (Fig 2 A) (3) – cyto C protein expression

- Line 231 – authors should clarify (Fig 2 A) as BcL

- Line 332 – suggested should be suggest

- Line 349 - Furthermore, the result has had indicated that EGb761 – this is not correct

- Line 394 – 395 – should be corrected - and the mechanisms include may be involve the adjusting the activity of H2O2 metabolism enzymes

- Grammatical error in line 396

- Authors should note that the constituents of GBE50 majorly contributed either individually or synergistically to the activities reported in this study. The role of the constituents in the biochemical mechanism of GBE is missing in the discussion. Furthermore, the antioxidant activity of GBE50 which has been reported may also play an important role in the observed activity reported, but all these arguments are missing.

- The manuscript requires extensive English editing

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[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.

PONE-D-23-22230R3Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in a rat model of Alzheimer's diseasePLOS ONE

Dear Dr. Xia,

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.

Comment from Editor

Authors have significantly improved the manuscript. However, authors still need to sufficiently present or justify that GBE50 has been sufficiently characterized as per journal requirement. Authors cited a review article (reference 50) to indicate the constituents of GBE50. Authors should rather use an original research article that has previously characterized GBE50

Please submit your revised manuscript by Aug 03 2024 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.

Please include the following items when submitting your revised manuscript:

• 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,

Tosin Abiola Olasehinde

Academic Editor

PLOS ONE

Journal Requirements:

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.

Additional Editor Comments:

Authors have significantly improved the manuscript. However, authors still need to sufficiently present or justify that GBE50 has been sufficiently characterized as per journal requirement. Authors cited a review article (reference 50) to indicate the constituents of GBE50. Authors should rather use an original research article that has previously characterized GBE50

[Note: HTML markup is below. Please do not edit.]

[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.

Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in a rat model of Alzheimer's disease

PONE-D-23-22230R4

Dear Dr. Xia

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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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,

Tosin Abiola Olasehinde

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: